Visible-Light-Induced Regioselective Cyanomethylation of Imidazopyridines and Its Application in Drug Synthesis

Article abstract of DOI:10.1021/acs.joc.7b00750

3-Cyanomethylated imidazopyridines were synthesized via a visible light-promoted reaction of imidazopyridines with bromoacetonitrile or iodoacetonitrile catalyzed by fac-Ir(ppy)₃ under mild conditions. For the substrates with various substituents on benzene or pyridine ring, the reaction proceeded smoothly to give the corresponding products in moderate to good yields. The synthetic utility of this visible-light-induced reaction has been illustrated in the efficient synthesis of zolpidem and alpidem.

Full text of DOI:10.1021/acs.joc.7b00750

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Article
Visible-Light-Induced Regioselective Cyanomethylation
of Imidazopyridines and Its Application in Drug Synthesis
Qing Chang, Zhengyi Liu, Ping Liu, Lu Yu, and Peipei Sun
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 04 May 2017
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Visible-Light-Induced
Regioselective
Cyanomethylation
of
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Imidazopyridines and Its Application in Drug Synthesis
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Qing Chang, Zhengyi Liu, Ping Liu,* Lu Yu and Peipei Sun*
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College 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
sunpeipei@njnu.edu.cn; pingliu@njnu.edu.cn
ABSTRACT: 3ꢀCyanomethylated imidazopyridines were synthesized via a visible lightꢀpromoted
reaction of imidazopyridines with bromoacetonitrile or iodoacetonitrile catalyzed by facꢀIr(ppy)3
under mild conditions. For the substrates with various substituents on benzene or pyridine ring, the
reaction proceeded smoothly to give the corresponding products in moderate to good yields. The
synthetic utility of this visibleꢀlightꢀinduced reaction has been illustrated in the efficient synthesis
of zolpidem and alpidem.
■ INTRODUCTION
Imidazo[1,2ꢀa]pyridine is considered as “drug bias” skeleton in drug discovery and has
aroused great attention.1 Imidazo[1,2ꢀa]pyridines show an impressively wide range of biological
activities, such as antiꢀinflammatory,2 antiviral activity,3 antiprotozoal agents,4 inhibitors of
cyclinꢀdependent kinases,5 etc. Some marketed drugs containing imidazo[1,2ꢀa]pyridine cycle and
amide group are shown in Scheme 1ꢀa, which include anxiolytic drugs alpidem, saripidem and
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necopidem. The topꢀselling blockbuster drug zolpidem was used to treat insomnia in the
imidazopyridines family. The general procedures to synthesize zolpidem involved a Mannich
reaction to give N,Nꢀdimethyl amino imidazopyridine derivative, followed by the reaction with
methyl iodide to form a quaternary ammonium salt, and the nucleophilic substitution with the
toxic sodium cyanide. Zolpidem was finally obtained by the hydrolysis and amination of the
3ꢀcyanomethylated imidazo[1,2ꢀa]pyridine derivative (Scheme 1ꢀb).6 In 2010, Gevorgyan and
coꢀworkers explored an efficient one pot copperꢀcatalyzed threeꢀcomponent coupling reaction of
2ꢀaminoꢀ5ꢀmethylpyridine, pꢀtolualdehyde and N,Nꢀdimethylpropiolamide to access zolpidem in a
glovebox.7 N,NꢀDimethylꢀ4ꢀoxoꢀ4ꢀtolylbutanamide, MBH acetates of nitroalkenes and xanthates
were also used as the substrates for the assembly of zolpidem by several groups.8 Despite the
significant advances have been made in this field, establishing more straightforward methods as
well as developing environmentally friendly reaction conditions to prepare diverse
imidazo[1,2ꢀa]pyridine derivatives are still highly desirable.
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The majority of imidazo[1,2ꢀa]pyridineꢀbased drugs feature C3 substituents, and many
successful examples of the direct C3 functionalization of imidazo[1,2ꢀa]pyridine are reported in
recent years.9 In our previous works, the regioselective C3ꢀfluorination and ꢀalkoxycarbonylation
of imidazoheterocycles were successfully achieved using selectfluor and carbazates respectively.10
As an effective means of organic synthesis, visibleꢀlightꢀinduced organic reaction has aroused
much attention in recent years since these reactions can take place under very mild reaction
conditions with low photocatalystꢀloadings.11 In 2015, Hajra et al demonstrated the
C3ꢀthiocyanation of imidazoheterocycles via visible light photoredox catalysis using eosin Y as a
photocatalyst.12 Successively, in the report by Fu, Xu and coꢀworkers, the 2,2,2ꢀtrifluoroethyl
group
was
introduced
in
C3ꢀposition
of
imidazo[1,2ꢀa]pyridines
by
using
1,1,1ꢀtrifluoroꢀ2ꢀiodoethane based on a similar photoredox process in the presence of
facꢀIr(ppy)3.13 It is well known that cyano is a versatile group in organic synthesis, especially in
drug synthesis since it can be converted into a variety of useful functional groups,14 therefore the
cyanation of organic compounds is continuously the attractive research subject to organic chemists.
Cheap bromoacetonitrile was successfully used as a cyanomethyl radical source for the
preparation of nitriles.15 As the continuous study of our group on the synthesis of functionalized
heterocyclic compounds via C−H bond functionalization, we now wish to report the efficient
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visibleꢀlightꢀpromoted cyanomethylation of imidazopyridines using bromoacetonitrile as the
reaction partner. The products could be conveniently transformed into zolpidem, alpidem and
other related compounds (Scheme 1).
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Scheme 1. Examples of Imidazo[1,2-a]pyridine-Based Drugs and Synthetic Routes of
Zolpidem
■ RESULTS AND DISCUSSION
Initially, we selected 2ꢀphenylimidazo[1,2ꢀa]pyridine (1a) and bromoacetonitrile (2) as
model substrates to test the feasibility of the cyanomethylation reaction (Table 1). Gratifyingly, the
reaction indeed occurred in the presence of 2 mol % facꢀIr(ppy)3 as the photocatalyst and 2 equiv
Et3N as a base under 5 W blue lightꢀemitting diode (LED) bulb irradiation in CH3CN at room
temperature, and gave the cyanomethylated imidazopyridine 3a in 70% yield (entry 1). When this
reaction was performed in the absence of base, only trace amount of product was observed and
most of the imidazopyridine 1a was recovered (entry 2). Several commonly used bases, such as
N,Nꢀdiisopropylethylamine (DIPEA), N,Nꢀdicyclohexylmethylamine (Cy2NMe), NaHCO3,
NaOAc were also successful for this transformation and the highest yield of 85% was obtained
through the use of NaHCO3 (entries 3–6). Solvent had evident influence on this cyanomethylation
reaction and DMSO outperformed other solvents such as CH3CN, DMF, H2O and toluene to give
the best result (entries 5, 7−10). A series of photocatalysts were then screened, and the results
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revealed that Ru(bpy)3Cl2·6H2O only gave the product in 11% yield, while organic photocatalyst
such as eosin Y and rhodamine B did not showed any catalytic activity to this reaction (entries
11ꢀ13). In addition, no desired product was observed with the control experiments lacking either
the photocatalyst or visible light irradiation (entries 14, 15). The formation of product 3a
drastically decreased when the reaction was performed under air instead of argon (entry 16). It
should be noted that the use of iodoacetonitrile instead of bromoacetonitrile delivered the product
in a comparable yield (entry 17). The highest yield was achieved when 4 equiv bromoacetonitrile
was used. Reduced it to 3 equiv led to a lower yield of 68% (entry 18).
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Table 1. Optimization of Reaction Conditionsa
N
N
photocatalyst
+
Br
CN
N
N
base, solvent
Blue LEDs
CN
1a
2
3a
entry
1
photocatalyst
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
fac-Ir(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
base
NEt3
–
solvent
MeCN
MeCN
MeCN
MeCN
MeCN
MeCN
DMSO
DMF
yield (%)
70
2
trace
65
3
DIPEA
4
Cy2NMe
NaHCO3
NaOAc
82
5
85
6
81
7
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
NaHCO3
87
8
65
9
H2O
54
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12
13
14
15b
16c
17d
18e
toluene
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
50
Ru(bpy)3Cl2·6H2O
eosin Y
11
trace
0
rhodamine B
–
0
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
facꢀIr(ppy)3
0
12
86
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aReaction conditions (unless otherwise specified): 1a (0.2 mmol), 2 (0.8 mmol), base (0.4 mmol),
4
5
photocatalyst (2 mol %) and solvent (2 mL) were carried out in a sealed tube under Ar atmosphere
6
7
b
c
d
upon irradiation of 5 W blue LEDs for 12 h. In the dark. Under air. Iodoacetonitrile was used
8
9
instead of bromoacetonitrile. eReduced the amount of 2 to 0.6 mmol (3 equiv).
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With the optimized conditions in hand, we next investigated the generality and scope of the
reaction with a series of imidazopyridines (Table 2). 2ꢀAryl substituted imidazopyridines were
firstly examined. Electronꢀdonating groups such as methyl, methoxyl and tertꢀbutyl on the
benzene ring were tolerated and the reactions selectively gave the desired products in excellent
yields (3b−3d). Substrates bearing electron withdrawing groups Cl or Br on the paraꢀ or
metaꢀposition of the benzene ring also gave high yields (3f, 3g and 3i), whereas orthoꢀCl seemed
not suitable to the reaction well and lower yields were obtained (3e and 3h). The presence of
strong electronꢀwithdrawing substituent CF3 lowered the yield to 65% (3j). The reaction of
imidazopyridine with biphenyl or thienyl on 2ꢀposition also proceeded smoothly and gave high
yields (3k and 3l). The substrates with various substituents on pyridine ring were then employed.
The methyl at different position on the pyridine ring of imidazopyridines had no evident effect on
the reaction and the corresponding cyanomethylated products were obtained in good yields (3m–
3o, 3s). The existence of Cl or Br group on the pyridine ring reduced the reactivity of the
substrates, and the reaction provided moderate yields (3p, 3q and 3t). Notablely, for 2ꢀαꢀnaphthyl
substituted reactant, a very low yield (less than 20%) was obtained probably due to steric
hindrance. To improve the yields for some substrates, iodoacetonitrile was used instead of
bromoacetonitrile. With αꢀ and βꢀnaphthyl substituted imidazopyridines, 60% and 86% yields
were obtained respectively (3u and 3v). In addition, the reaction of 2ꢀalkyl substituted
imidazopyridines could react with iodoacetonitrile to give the corresponding 3ꢀcyanomethylated
products in satisfactory yields (3w and 3x).
Table 2. Visible-Light-Induced Synthesis of Cyanomethylated Imidazopyridinesa
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N
Ph
N
CN
3k, 90%
aReaction conditions: 1 (0.2 mmol), 2 (0.8 mmol), facꢀIr(ppy)3 (2 mol %), NaHCO3 (0.4 mmol),
DMSO (2 mL), irradiation under Ar atmosphere at room temperature using 5 W blue LEDs for
12 h. All yields are isolated ones. bIodoacetonitrile was used instead of bromoacetonitrile.
It was interesting that for a 3ꢀposition substituted reactant 3ꢀphenylimidazo[1,2ꢀa]pyridine
(1y), no 2ꢀcyanomethylated product was generated under the standard conditions. This result
illustrated that the reaction regioselectively took place at 3ꢀposition (Scheme 2).
Scheme 2. Regioselectivity of Cyanomethylation Reaction
Furthermore, the visibleꢀlightꢀinduced cyanomethylation reaction could also regioselectively
occur on imidazo ring for other
imidazoheterocycles substrates such as
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2ꢀphenylbenzo[d]imidazo[2,1ꢀb]thiazole (4a) and 6ꢀphenylimidazo[2,1ꢀb]thiazole (4b), which
provided the cyanomethylated products in 88% and 84% yields (5a and 5b) respectively under the
same reaction conditions (Scheme 3).
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Scheme 3. Regioselective Cyanomethylation of Imidazoheterocycles
We then decided to use this convenient cyanomethylation in the synthesis of some drugs. The
3ꢀcyanomethylated derivative 3s or 3t was treated with concentrated sulfuric acid in EtOH to give
the corresponding ester (6). Zolpidem (7a) and alpidem (7b) were then obtained by the hydrolysis
of imidazopyridine esters and subsequent amidation (Scheme 4).8c
Scheme 4. Synthesis of Zolpidem and Alpidem
The control experiments were performed to study the mechanism of this visible
lightꢀpromoted cyanomethylation of imidazopyridines (Scheme 5). The results showed that this
visibleꢀlightꢀpromoted cyanomethylation reaction was obviously suppressed upon addition of a
radical scavenge 2,2,6,6ꢀtetramethylꢀ1ꢀpiperidinyloxy (TEMPO) and the substrate 1a was
recovered, which suggested that the reaction probably proceeded via a radical pathway. To further
verify the presence of the radical in this transformation, another radical scavenge
1,1ꢀdiphenylethene (4c) was used to trap the cyanomethyl radical. As that was expected, the
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formation of product 3a was suppressed, and the coupling product 4,4ꢀdiphenylbutꢀ3ꢀenenitrile
(5c) was obtained.
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Scheme 5. Control Experiments
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Based on the above results and related reports,13 a possible mechanism for the visibleꢀlight
photoredox cyanomethylation reaction is proposed in Scheme 6. Initially, the facꢀIr(III)(ppy)3 was
converted to the excited state upon the irradiation of visible light (blue LEDs). The formation of
cyanomethyl radical A and [facꢀIr(IV)(ppy)3]+ was established by the single electron transfer (SET)
from the excited IrIIIꢀphotocatalyst to bromoacetonitrile.15 The regioselective addition of the
electronꢀdeficient radical A to the electronꢀrich position of imidazopyridine 1a furnished the
radical B, which was oxidized by the [facꢀIr(IV)(ppy)3]+ to generate the carbocation C via another
SET process and regenerate the IrIIIꢀphotocatalyst. Finally, the deprotonation of C with the aid of a
base produced the desired product 3a.
Scheme 6. Proposed Reaction Mechanism
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■ CONCLUSIONS
In summary, we have successfully explored a regioselective cyanomethylation reaction of
imidazopyridines using available bromoacetonitrile or iodoacetonitrile as the cyanomethyl source
under visible light photoredox catalysis. Both electronꢀdonating and electronꢀwithdrawing groups
on the imidazopyridines are tolerated in the reaction and the corresponding products were
obtained in moderate to excellent yields. This new protocol features short synthetic route, low cost
and mild reaction conditions, which makes it attractive for the synthesis of the drug zolpidem and
alpidem, as well as other related compounds.
■ EXPERIMENTAL SECTION
General. Chemicals were commercially available and were used without purification.
Imidazo[1,2ꢀa]pyridines were prepared according to the literature procedures.16 The NMR spectra
were recorded at 400 MHz (1H), 100 MHz (13C NMR) and 376 MHz (19F) in CDCl3 or d6ꢀDMSO
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, dt = doublet of triplet, td
= triplet of doublet, q = quartet, m = multiplet. QꢀTOF was used for the HRMS measurements.
Melting points are uncorrected.
General Experimental Procedure for Cyanomethylation Reaction.
An ovenꢀdried Schlenk tube (25 mL) was equipped with a magnetic stir bar and charged with
2ꢀphenylimidazo[1,2ꢀa]pyridine (1a, 38.8 mg, 0.2 mmol), bromoacetonitrile (96.0 mg, 55.7 ꢁL,
0.8 mmol), facꢀIr(ppy)3 (2 mol %, 2.6 mg) and NaHCO3 (33.6 mg, 0.4 mmol). The flask was
evacuated and backfilled with argon for 3 times, DMSO (2 mL) was then added. The mixture was
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stirred under 5 W blue LEDs strip irradiation for 12 h. When the reaction was completed, the
mixture was diluted with water (10 mL) and extracted with DCM (15 mL × 3). The combined
organic phases were washed with brine (15 mL), dried over anhydrous Na2SO4, filtered and
concentrated in vacuo. The residue was purified by silica gel chromatography using petroleum
ether/EtOAc (2:1, v/v) as eluent to afford the pure product 3a.
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2ꢀ(2ꢀPhenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3a).17 Colorless solid (40.6 mg, 87% yield);
1
mp 100–101 °C; H NMR (400 MHz, CDCl3): δ (ppm) 8.06 (dt, J = 6.9, 1.1 Hz, 1H), 7.75–7.68
(m, 3H), 7.55–7.49 (m, 2H), 7.47–7.41 (m, 1H), 7.33 (ddd, J = 9.1, 6.8, 1.2 Hz, 1H), 7.00 (td, J =
6.8, 1.1 Hz, 1H), 4.16 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.4, 145.1, 133.1, 129.0,
128.6, 128.6, 125.4, 122.9, 118.0, 115.0, 113.4, 107.8, 13.9.
2ꢀ(2ꢀ(pꢀTolyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3b).17 Colorless solid (47.5 mg, 96% yield);
mp 123–124 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.05 (d, J = 6.8 Hz, 1H), 7.72 (d, J = 9.1
Hz, 1H), 7.60 (d, J = 8.1 Hz, 2H), 7.37–7.30 (m, 3H), 7.00 (td, J = 6.8, 1.0 Hz, 1H), 4.16 (s, 2H),
2.44 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.3, 145.2, 138.5, 130.2, 129.7, 128.4,
125.3, 122.9, 117.9, 115.1, 113.3, 107.5, 21.4, 14.0.
2ꢀ(2ꢀ(4ꢀMethoxyphenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3c).17 Colorless solid (50.0 mg,
95% yield); mp 120–121 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.06 (d, J = 6.8 Hz, 1H), 7.73
(d, J = 9.1 Hz, 1H), 7.65 (d, J = 8.6 Hz, 2H), 7.37–7.32 (m, 1H), 7.07–6.99 (m, 3H), 4.16 (s, 2H),
3.89 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 160.0, 145.3, 145.0, 129.8, 125.5, 125.3,
122.8, 117.8, 115.0, 114.5, 113.3, 107.2, 55.4, 14.0.
2ꢀ(2ꢀ(4ꢀ(tertꢀButyl)phenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3d). Colorless solid (52.1 mg,
90% yield); mp 158–160 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.06 (d, J = 6.8 Hz, 1H), 7.72
(d, J = 9.1 Hz, 1H), 7.67–7.64 (m, 2H), 7.56–7.54 (m, 2H), 7.33–7.29 (m, 1H), 6.98 (td, J = 6.8,
1.1 Hz, 1H), 4.17 (s, 2H), 1.39 (s, 9H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 151.7, 145.4, 145.2,
130.2, 128.2, 126.0, 125.2, 122.9, 117.9, 115.1, 113.3, 107.6, 34.7, 31.3, 14.0; HRMS (ESI) m/z:
calcd for C19H20N3 [M + H]+ 290.1652, found 290.1650.
2ꢀ(2ꢀ(2ꢀChlorophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3e). Yellow solid (6.4 mg, 12%
yield); mp 136−137 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.12 (d, J = 6.9 Hz, 1H), 7.73 (d, J
= 9.1 Hz, 1H), 7.63–7.57 (m, 1H), 7.55–7.49 (m, 1H), 7.44–7.32 (m, 3H), 7.03 (td, J = 6.8, 1.0 Hz,
1H), 4.00 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.4, 142.5, 133.2, 132.7, 132.1, 130.3,
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129.9, 127.2, 125.4, 123.1, 118.2, 114.7, 113.6, 109.6, 14.3; HRMS (ESI) m/z: calcd for
C15H11ClN3 [M + H]+ 268.0636 and 270.0607, found 268.0637 and 270.0606.
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2ꢀ(2ꢀ(3ꢀChlorophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3f). Colorless solid (45.5 mg, 85%
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yield); mp 129–130 °C; H NMR (400 MHz, CDCl3): δ (ppm) 8.05 (dd, J = 6.8, 1.0 Hz, 1H),
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7.71–7.68 (m, 2H), 7.53 (dd, J = 7.3, 1.5 Hz, 1H), 7.44–7.31 (m, 3H), 7.02–6.98 (m, 1H), 4.16 (s,
2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.4, 143.6, 135.0, 134.9, 130.2, 128.6, 128.6, 126.5,
125.8, 123.0, 118.0, 114.8, 113.7, 108.2, 13.9; HRMS (ESI) m/z: calcd for C15H11ClN3 [M + H]+
268.0636 and 270.0607, found 268.0636 and 270.0606.
2ꢀ(2ꢀ(4ꢀChlorophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3g).17 Yellow solid (46.6 mg, 87%
yield); mp 119−121 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.07 (d, J = 6.9 Hz, 1H), 7.72 (d, J
= 9.1 Hz, 1H), 7.64 (d, J = 8.4 Hz, 2H), 7.49 (d, J = 8.4 Hz, 2H), 7.40–7.33 (m, 1H), 7.03 (td, J =
6.8, 0.6 Hz, 1H), 4.15 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.4, 144.0, 134.7, 131.6,
129.7, 129.2, 125.7, 122.9, 118.0, 114.8, 113.7, 107.9, 13.9.
2ꢀ(2ꢀ(2,4ꢀDichlorophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3h). Brown solid (18.1 mg, 30%
yield); mp 217−218 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.14 (d, J = 6.9 Hz, 1H), 7.76 (d, J
= 9.1 Hz, 1H), 7.57–7.56 (m, 2H), 7.43–7.37 (m, 2H), 7.08 (td, J = 6.8, 0.8 Hz, 1H), 3.99 (s, 2H);
13C NMR (CDCl3, 100 MHz): δ (ppm) 145.4, 141.4, 135.7, 133.9, 133.5, 130.6, 129.7, 127.6,
125.7, 123.0, 118.3, 114.4, 113.8, 109.7, 14.3; HRMS (ESI) m/z: calcd for C15H10Cl2N3 [M + H]+
302.0246 and 304.0217, found 302.0246 and 304.0222.
2ꢀ(2ꢀ(4ꢀBromophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3i). Colorless solid (54.9 mg, 88%
yield); mp 128–130 °C; 1H NMR (400 MHz, d6ꢀDMSO): δ (ppm) 8.58 (d, J = 6.9 Hz, 1H), 7.78–
7.75 (m, 2H), 7.74–7.68 (m, 3H), 7.43–7.38 (m, 1H), 7.12 (td, J = 6.8, 1.2 Hz, 1H), 4.65 (s, 2H);
13C NMR (d6ꢀDMSO, 100 MHz): δ (ppm) 144.9, 142.2, 133.1, 132.2, 130.4, 126.2, 125.1, 121.9,
117.5, 117.2, 113.5, 110.3, 13.6; HRMS (ESI) m/z: calcd for C15H11BrN3 [M + H]+ 312.0131 and
314.0110, found 312.0131 and 314.0109.
2ꢀ(2ꢀ(4ꢀ(Trifluoromethyl)phenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3j). Yellow solid (39.2
mg, 65% yield); mp 104−106 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.09 (d, J = 6.9 Hz, 1H),
7.84–7.73 (m, 5H), 7.38 (ddd, J = 9.0, 6.8, 1.0 Hz, 1H), 7.04 (td, J = 6.8, 1.0 Hz, 1H), 4.18 (s, 2H);
13C NMR (CDCl3, 100 MHz): δ (ppm) 145.6, 143.6, 136.7, 130.4 (q,2JCꢀF = 32.5), 128.8, 126.0
(q,3JCꢀF = 3.7), 125.9, 124.0 (q,1JCꢀF = 270.5), 123.0, 118.2, 114.7, 113.9, 108.6, 13.9; 19F NMR
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(376 MHz, CDCl3): δ (ppm) ꢀ62.5; HRMS (ESI) m/z: calcd for C16H11F3N3 [M + H]+ 302.0900,
found 302.0899.
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2ꢀ(2ꢀ([1,1'ꢀBiphenyl]ꢀ4ꢀyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3k). Yellow solid (55.7 mg, 90%
yield); mp 150−151 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.06 (d, J = 6.8 Hz, 1H), 7.77 (ddd,
J = 11.3, 8.8, 3.5 Hz, 5H), 7.71–7.64 (m, 2H), 7.49 (t, J = 7.5 Hz, 2H), 7.44–7.31 (m, 2H), 7.00 (td,
J = 6.8, 0.9 Hz, 1H), 4.20 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.5, 144.7, 141.3,
140.3, 132.0, 128.9, 128.9, 127.7, 127.1, 125.5, 122.9, 118.0, 115.1, 113.5, 107.8, 14.0; HRMS
(ESI) m/z: calcd for C21H16N3 [M + H]+ 310.1339, found 310.1338.
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2ꢀ(2ꢀ(Thiophenꢀ2ꢀyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3l). Yellow solid (43.6 mg, 91%
yield); mp 125−127 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.05 (d, J = 7.2 Hz, 1H), 7.72 (d, J
= 8.8 Hz, 1H), 7.48–7.42 (m, 2H), 7.36–7.31 (m, 1H), 7.20 (dd, J = 5.2, 3.6 Hz, 1H), 7.01 (td, J =
6.8, 0.8 Hz, 1H), 4.27 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.4, 139.3, 135.7, 128.0,
126.8, 125.8, 125.7, 122.8, 117.9, 114.6, 113.6, 107.1, 13.8; HRMS (ESI) m/z: calcd for
C13H10N3S [M + H]+ 240.0590, found 240.0590.
2ꢀ(8ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3m). Colorless solid (46.0 mg, 93%
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yield); mp 90–91 °C; H NMR (400 MHz, CDCl3): δ (ppm) 7.93 (d, J = 6.8 Hz, 1H), 7.72–7.70
(m, 2H), 7.54–7.50 (m, 2H), 7.45–7.42 (m, 1H), 7.13 (d, J = 6.9 Hz, 1H), 6.92 (t, J = 6.8 Hz, 1H),
4.14 (s, 2H), 2.70 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.9, 144.7, 133.4, 129.0, 128.7,
128.4, 128.2, 124.1, 120.7, 115.2, 113.4, 108.1, 17.1, 14.0; HRMS (ESI) m/z: calcd for C16H14N3
[M + H]+ 248.1182, found 248.1182.
2ꢀ(7ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3n). Gray solid (45.0 mg, 91%
yield); mp 121–122 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.94 (d, J = 6.9 Hz, 1H), 7.69 (d, J
= 7.3 Hz, 2H), 7.52–7.40 (m, 4H), 6.82 (dd, J = 6.8, 1.2 Hz, 1H), 4.13 (s, 2H), 2.46 (s, 3H); 13C
NMR (CDCl3, 100 MHz): δ (ppm) 145.9, 144.8, 136.5, 133.3, 128.9, 128.5, 128.4, 122.1, 116.4,
116.0, 115.2, 107.1, 21.4, 13.9; HRMS (ESI) m/z: calcd for C16H14N3 [M + H]+ 248.1182, found
248.1182.
2ꢀ(6ꢀMethylꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3o).17 Colorless solid (42.5 mg, 86%
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yield); mp 125–126 °C; H NMR (400 MHz, CDCl3): δ (ppm) 7.83 (s, 1H), 7.68–7.59 (m, 3H),
7.50–7.42 (m, 3H), 7.17 (d, J = 8.0 Hz, 1H), 4.13 (s, 2H), 2.41 (s, 3H); 13C NMR (CDCl3, 100
MHz): δ (ppm) 144.7, 144.4, 134.4, 133.1, 129.0, 128.7, 128.5, 123.4, 120.6, 117.2, 115.2, 107.5,
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18.4, 14.0.
2ꢀ(6ꢀChloroꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3p).17 Colorless solid (40.2 mg, 75%
yield); mp 117–118 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.12 (d, J = 1.1 Hz, 1H), 7.71–7.67
(m, 3H), 7.56–7.51 (m, 2H), 7.49–7.44 (m, 1H), 7.31 (dd, J = 9.5, 1.9 Hz, 1H), 4.16 (s, 2H); 13C
NMR (CDCl3, 100 MHz): δ (ppm) 146.0, 143.7, 132.6, 129.1, 128.9, 128.8, 128.5, 126.9, 121.8,
120.8, 118.4, 114.6, 108.4, 13.9.
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2ꢀ(6ꢀBromoꢀ2ꢀphenylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3q). Colorless solid (32.5 mg, 52%
yield); mp 185–187 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.22 (d, J = 0.8 Hz, 1H), 7.70 (d, J
= 7.2 Hz, 2H), 7.64 (d, J = 9.2 Hz, 1H), 7.54 (t, J = 7.4 Hz, 2H), 7.46 (t, J = 7.4 Hz, 1H), 7.41 (dd,
J = 9.6, 1.6 Hz, 1H), 4.16 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.9, 143.9, 132.6,
129.1, 129.0, 128.9, 128.5, 123.0, 118.7, 114.6, 108.3, 108.2, 13.9; HRMS (ESI) m/z: calcd for
C15H11BrN3 [M + H]+ 312.0131 and 314.0110, found 312.0131 and 314.0108.
2ꢀ(6ꢀMethylꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3r). Colorless
solid (44.1 mg, 70% yield); mp 135–137 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.85–7.82 (m,
3H), 7.77 (d, J = 8.4 Hz, 2H), 7.65 (d, J = 9.2 Hz, 1H), 7.23 (dd, J = 9.2, 1.2 Hz, 1H), 4.15 (s, 2H),
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2.45 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 144.6, 143.3, 136.9, 130.3 (q, JCꢀF = 32.4),
129.1, 128.7, 125.9 (q, 3JCꢀF = 3.7), 124.1 (q, 1JCꢀF = 270.5), 123.8, 120.6, 117.5, 114.8, 108.1, 18.5,
13.9; 19F NMR (376 MHz, CDCl3): δ (ppm) ꢀ62.5; HRMS (ESI) m/z: calcd for C17H13F3N3 [M +
H]+ 316.1056, found 316.1057.
2ꢀ(6ꢀMethylꢀ2ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3s).17 Colorless solid (44.4 mg, 85%
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yield); mp 160–162 °C; H NMR (400 MHz, CDCl3): δ (ppm) 7.85 (s, 1H), 7.62 (d, J = 9.6 Hz,
1H), 7.59 (d, J = 8.0 Hz, 2H), 7.33 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 9.2 Hz, 1H), 4.15 (s, 2H), 2.44
(s, 6H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 144.5, 144.2, 138.5, 129.9, 129.7, 128.8, 128.4,
123.5, 120.6, 117.0, 115.1, 107.3, 21.3, 18.5, 14.0.
2ꢀ(6ꢀChloroꢀ2ꢀ(4ꢀchlorophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3t).17 Colorless solid
(25.4 mg, 42% yield); mp 172–173 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.13 (s, 1H), 7.70 (d,
J = 9.6 Hz, 1H), 7.65 (d, J = 8.4 Hz, 2H), 7.52 (d, J = 8.4 Hz, 2H), 7.35 (dd, J = 9.6, 1.6 Hz, 1H),
4.15 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.0, 143.9, 135.0, 131.1, 129.7, 129.4,
127.2, 122.1, 120.8, 118.5, 114.4, 108.5, 13.9.
2ꢀ(2ꢀ(Naphthalenꢀ1ꢀyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3u). Brown solid (34.0 mg, 60%
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yield); mp 75–77 °C; 1H NMR (400 MHz, d6ꢀDMSO): δ (ppm) 8.64 (d, J = 6.8 Hz, 1H), 8.05 (t, J
= 9.2 Hz, 3H), 7.78 (d, J = 8.8 Hz, 1H), 7.66 (t, J = 7.6 Hz, 1H), 7.60–7.57 (m, 2H), 7.54–7.46 (m,
2H), 7.20 (td, J = 6.8, 1.2 Hz, 1H), 4.39 (s, 2H); 13C NMR (d6ꢀDMSO, 100 MHz): δ (ppm) 144.6,
143.0, 133.9, 132.1, 130.7, 129.3, 128.7, 128.7, 126.9, 126.6, 126.4, 126.3, 125.9, 125.3, 117.4,
117.0, 113.6, 112.1, 13.5; HRMS (ESI) m/z: calcd for C19H14N3 [M + H]+ 284.1182, found
284.1182.
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2ꢀ(2ꢀ(Naphthalenꢀ2ꢀyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3v). Colorless solid (48.7 mg, 86%
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yield); mp 104–106 °C; H NMR (400 MHz, CDCl3): δ (ppm) 8.14 (s, 1H), 8.06 (d, J = 6.8 Hz,
1H), 8.00–7.94 (m, 2H), 7.91–7.84 (m, 2H), 7.76 (d, J = 9.2 Hz, 1H), 7.57–7.53 (m, 2H), 7.36–
7.32 (m, 1H), 7.00 (td, J = 6.8, 1.2 Hz, 1H), 4.21 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ (ppm)
145.5, 145.1, 133.4, 133.1, 130.5, 128.8, 128.3, 127.8, 127.7, 126.6, 126.6, 126.1, 125.5, 122.9,
118.0, 115.1, 113.5, 108.1, 14.0; HRMS (ESI) m/z: calcd for C19H14N3 [M + H]+ 284.1182, found
284.1186.
2ꢀ(2ꢀMethylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3w).18 Brown solid (24.0 mg, 70% yield); mp
144−145 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.98 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 9.2 Hz,
1H), 7.30–7.26 (m, 1H), 6.95 (td, J = 6.8, 0.8 Hz, 1H), 4.00 (s, 2H), 2.50 (s, 3H); 13C NMR
(CDCl3, 100 MHz): δ (ppm) 145.0, 141.8, 124.8, 122.5, 117.2, 114.7, 112.9, 107.7, 13.3, 12.9.
2ꢀ(2ꢀIsobutylimidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3x). Yellow liquid (27.7 mg, 65% yield); 1H
NMR (400 MHz, CDCl3): δ (ppm) 7.98 (d, J = 6.8 Hz, 1H), 7.61 (d, J = 9.2 Hz, 1H), 7.28–7.23
(m, 1H), 6.93 (t, J = 6.8 Hz, 1H), 3.99 (s, 2H), 2.62 (d, J = 7.2 Hz, 2H), 2.20–2.10 (m, 1H), 0.96
(d, J = 6.4 Hz, 6H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 145.3, 145.1, 124.8, 122.6, 117.3,
114.8, 112.9, 108.2, 36.7, 29.3, 22.5, 13.0; HRMS (ESI) m/z: calcd for C13H16N3 [M + H]+
214.1339, found 214.1335.
2ꢀ(2ꢀPhenylbenzo[d]imidazo[2,1ꢀb]thiazolꢀ3ꢀyl)acetonitrile (5a).19 Colorless solid (50.9 mg, 88%
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yield); mp 189–190 °C; H NMR (400 MHz, d6ꢀDMSO): δ (ppm) 8.15 (d, J = 8.0 Hz, 1H), 8.09
(dd, J = 8.0, 0.8 Hz, 1H), 7.70–7.68 (m, 2H), 7.64–7.60 (m, 1H), 7.54–7.46 (m, 3H), 7.44–7.39 (m,
1H), 4.74 (s, 2H); 13C NMR (d6ꢀDMSO, 100 MHz): δ (ppm) 147.9, 145.1, 133.4, 132.5, 129.8,
129.3, 128.3, 128.1, 127.2, 125.7, 125.6, 117.7, 114.2, 114.1, 15.2.
2ꢀ(6ꢀPhenylimidazo[2,1ꢀb]thiazolꢀ5ꢀyl)acetonitrile (5b).20 Yellow solid (40.2 mg, 84% yield); mp
144–145 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.60 (d, J = 7.4 Hz, 2H), 7.54–7.45 (m, 3H),
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7.39 (t, J = 7.3 Hz, 1H), 6.97 (d, J = 4.5 Hz, 1H), 4.09 (s, 2H); 13C NMR (CDCl3, 100 MHz): δ
(ppm) 150.0, 146.0, 133.2, 129.0, 128.2, 127.8, 116.8, 115.4, 113.8, 109.5, 14.7.
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4,4ꢀDiphenylbutꢀ3ꢀenenitrile (5c).21 (1,1ꢀDiphenylethene (4c) was added to the reaction mixture)
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7.38 (m, 3H), 7.36–7.30 (m, 3H), 7.28–7.18 (m, 4H), 6.06 (t, J = 7.4 Hz, 1H), 3.18 (d, J = 7.4 Hz,
2H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 147.5, 140.7, 138.0, 129.4, 128.8, 128.4, 128.2, 128.2,
127.5, 118.2, 115.5, 18.4.
Procedure for the Hydrolysis of 3s or 3t.
To a 25 mL flask were sequentially added EtOH (4 mL), conc. H2SO4 (1.5 mL), 4 drops of
H2O and 2ꢀ(6ꢀmethylꢀ2ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetonitrile (3s, 130.7 mg, 0.5 mmol).
o
The reaction mixture was refluxed at 90 C for 12h. After cooling to room temperature, the
reaction mixture was quenched with sat. NaHCO3 aq. to wipe off excessive acid and extracted
with DCM (15 mL × 3). The combined organic phases were washed with brine (15 mL), dried
over anhydrous Na2SO4, filtered and concentrated in vacuo. The residue was purified by silica gel
chromatography using hexane/EtOAc (2:1, v/v) as eluent to afford the product 6a.
Ethyl 2ꢀ(6ꢀmethylꢀ2ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetate (6a).8c Colorless solid (146.3 mg,
95% yield); mp 96–97 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.93 (s, 1H), 7.74 (d, J = 8.0 Hz,
2H), 7.68 (d, J = 8.8 Hz, 1H), 7.31 (d, J = 8.0 Hz, 2H), 7.16 (d, J = 9.2 Hz, 1H), 4.25 (q, J = 7.2
Hz, 2H), 4.04 (s, 2H), 2.43 (s, 3H), 2.40 (s, 3H), 1.31 (t, J = 7.2 Hz, 3H); 13C NMR (CDCl3, 100
MHz): δ (ppm) 169.6, 144.4, 144.0, 137.6, 131.3, 129.3, 128.4, 127.6, 122.0, 121.3, 116.8, 112.4,
61.6, 30.9, 21.3, 18.5, 14.2.
Ethyl 2ꢀ(6ꢀchloroꢀ2ꢀ(4ꢀchlorophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetate (6b).8c Colorless solid
(142.7 mg, 82% yield); mp 121–123 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 8.26 (s, 1H), 7.80
(d, J = 8.2 Hz, 2H), 7.74 (d, J = 9.3 Hz, 1H), 7.50 (d, J = 8.1 Hz, 2H), 7.32 (d, J = 9.2 Hz, 1H),
4.28 (q, J = 7.1 Hz, 2H), 4.03 (s, 2H), 1.34 (t, J = 7.1 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ
(ppm) 168.7, 143.3, 142.8, 134.8, 129.9, 129.2, 127.2, 122.0, 121.6, 117.6, 113.9, 62.1, 30.7, 14.2.
Zolpidem and alpidem were synthesized according to the procedure of Namboothiri and
coꢀworkers.8c
8c
N,NꢀDimethylꢀ2ꢀ(6ꢀmethylꢀ2ꢀ(pꢀtolyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)acetamide (7a, zolpidem).7,
Colorless solid (43.0 mg, 70% yield); mp 193–195 °C; 1H NMR (400 MHz, CDCl3): δ (ppm) 7.96
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(s, 1H), 7.53 (dd, J = 8.6, 4.0 Hz, 3H), 7.25 (d, J = 7.9 Hz, 2H), 7.05 (dd, J = 9.1, 0.8 Hz, 1H), 4.06
(s, 2H), 2.94 (s, 3H), 2.90 (s, 3H), 2.38 (s, 3H), 2.33 (s, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm)
168.2, 143.7, 143.2, 137.6, 131.2, 129.3, 128.3, 127.9, 122.2, 122.0, 116.2, 113.8, 37.5, 35.8, 30.1,
21.3, 18.4.
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2ꢀ(6ꢀChloroꢀ2ꢀ(4ꢀchlorophenyl)imidazo[1,2ꢀa]pyridinꢀ3ꢀyl)ꢀN,Nꢀdipropylacetamide
(7b,
alpidem).8c Colorless solid (52.6 mg, 65% yield); mp 132–134 °C; 1H NMR (400 MHz, CDCl3): δ
(ppm) 8.27 (d, J = 1.2 Hz, 1H), 7.63–7.57 (m, 3H), 7.48–7.43 (m, 2H), 7.20 (dd, J = 9.5, 1.9 Hz,
1H), 4.07 (s, 2H), 3.35–3.29 (m, 2H), 3.19–3.13 (m, 2H), 1.62–1.47 (m, 4H), 0.88 (t, J = 7.4 Hz,
3H), 0.79 (t, J = 7.4 Hz, 3H); 13C NMR (CDCl3, 100 MHz): δ (ppm) 167.2, 143.5, 143.4, 134.2,
132.4, 129.8, 129.0, 126.2, 122.6, 120.7, 117.6, 115.6, 49.9, 48.0, 30.0, 22.2, 20.9, 11.3, 11.0.
■ ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI:
Copies of 1H NMR, 13C NMR and 19F NMR spectra for all products (PDF).
■ AUTHOR INFORMATION
Corresponding Authors
*Eꢀmail: sunpeipei@njnu.edu.cn; pingliu@njnu.edu.cn
Notes
The authors declare no competing financial interest.
■ ACKNOWLEDGMENTS
This work was supported by the National Natural Science Foundation of China (Project 21672104,
21502097), the Natural Science Foundation of the Education Department of Jiangsu province
(15KJB150015), and the Priority Academic Program Development of Jiangsu Higher Education
Institutions. The authors also thank Mr. Hailong Liu for the determination of HRMS.
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