Practical and scalable preparation of Minodronic acid and Zolpidem from 2-chloroimidazole[1,2-a]pyridines

Article abstract of DOI:10.1016/j.tet.2019.01.015

Practical and scalable procedures for Minodronic acid and Zolpidem are developed with short reaction sequences from 2-aminopyridines and maleic anhydride, respectively. The new procedures avoid column chromatography for the purification in all synthetic steps. Key aspects of this development involve reductive hydrodechlorination and Suzuki coupling reaction of 2-chloroimidazole[1,2-a]pyridines, and their application towards synthesis of the two drugs is also addressed.

Full text of DOI:10.1016/j.tet.2019.01.015

Accepted Manuscript
Practical and scalable preparation of Minodronic acid and Zolpidem from 2-
chloroimidazole[1,2-a]pyridines
Yuheng Wang, Bingbing Zhang, Yinying Zheng, Qiaoning Ma, Qiang Sui, Xinsheng
Lei
PII:
S0040-4020(19)30030-4
https://doi.org/10.1016/j.tet.2019.01.015
TET 30067
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 7 November 2018
Revised Date: 4 January 2019
Accepted Date: 7 January 2019
Please cite this article as: Wang Y, Zhang B, Zheng Y, Ma Q, Sui Q, Lei X, Practical and scalable
preparation of Minodronic acid and Zolpidem from 2-chloroimidazole[1,2-a]pyridines, Tetrahedron
(2019), doi: https://doi.org/10.1016/j.tet.2019.01.015.
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Graphical Abstract
Practical and scalable preparation of
Minodronic acid and Zolpidem from 2-
chloroimidazole[1,2-a]pyridines
Leave this area blank for abstract info.
a
a
a
a
b
a
Yuheng Wang , Bingbing Zhang , Yinying Zheng , Qiaoning Ma , Qiang Sui and Xinsheng Lei ∗ �
a
School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Pudong Zone, Shanghai 201203, China
China State Institute of Pharmaceutical Industry, No. 285 Gebaini Road, Pudong Zone, Shanghai 201203,
b
China

1
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Tetrahedron
journal homepage: www.elsevier.com
Practical and scalable preparation of Minodronic acid and Zolpidem from 2-
chloroimidazole[1,2-a]pyridines
a
a
a
a
b
a
Yuheng Wang , Bingbing Zhang , Yinying Zheng , Qiaoning Ma , Qiang Sui and Xinsheng Lei ∗
a
School of Pharmacy, Fudan University, No. 826 Zhangheng Road, Pudong Zone, Shanghai 201203, China
China State Institute of Pharmaceutical Industry, No. 285 Gebaini Road, Pudong Zone, Shanghai 201203, China
b
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Practical and scalable procedures for Minodronic acid and Zolpidem are developed with short
reaction sequences from 2-aminopyridines and maleic anhydride, respectively. The new
procedures avoid column chromatography for the purification in all synthetic steps. Key aspects
of this development involve reductive hydrodechlorination and Suzuki coupling reaction of 2-
Available online
chloroimidazole[1,2-a]pyridines, and their application towards synthesis of the two drugs is also
addressed.
Keywords:
2009 Elsevier Ltd. All rights reserved.
Imidazo[1,2-a]pyridine
Zolpidem
Minodronic acid
Hydrodechlorination
Coupling reaction
∗
Corresponding author. Tel.: +0-086-021-51980128; fax: +0-086-021-51980128; e-mail: leixs@fudan.edu.cn

2
Tetrahedron
1
. Introduction
hydrodechlorination of 2 in the presence of Et N under H
3 2
16a-b
ACCEPTED MANUSCRIPT
atmosphere.
difficult to reproduce (vide infra).
However, this procedure appears to be tricky and
With an aging population and budget restrictions on national
16c-d
Herein, we describe our
health insurers, those aging-related diseases increasingly impose
a large economic burden on the individual and society, and the
price of drugs has become a major challenge in today’s world.
There is still interest to develop innovative, simple and overall
more cost-effective industrial processes for the preparation of the
results on reductive dechlorination and coupling reaction of 2-
chloroimidazole[1,2-a]pyridines, as well as their application to
practical and scalable synthesis of both Minodronic acid and
Zolpidem in a simple and cost-efficient manner.
1
drugs , especially those related to the chronic and costly diseases.
Figure 1. The selected drugs containing imidazo[1,2-a]pyridine.
Figure 2. The diverse approach to reach both Zolpidem and
Imidazo[1,2-a]pyridine, as one important nitrogen-containing
heterocycle, is very prevalent in pharmaceuticals (Figure 1). Such
Minohydronic acid.
heterocycle derivatives show
activities , and several marketed drugs contain this privileged
scaffold. Among them, Minodronic acid and Zolpidem are
clinically used in treatment of osteoporosis and insomnia,
respectively, and have demonstrated great benefit to the patients.
a
wide range of biological
2. Results and discussion
2
3
4
2
.1. Hydrodechlorination of 2-chloroimidazole[1,2-
a]pyridines
Starting from 2-aminopyridines (2.0 equiv.) and maleic
anhydride, acylation was carried out in toluene （0.5-0.3 M）at
rt for 2-4 h, and the resulting white precipitate underwent
intramolecular Michael addition in refluxing MeOH for 0.5-1 h,
giving the white precipitated acid (1) without any further
Therefore, there is continuous interest in the development of
new synthetic methods for this scaffold, and so far differen5t
synthetic strategies and various approaches have been achieved.
Despite great achievements, the current processes for both
6
7
9
Minodronic acid and Zolpidem still require multi-step
preparation, with the condensation of ɑ-haloketone or its
equivalents with 2-amino-pyridines as the key step for the
preparation of the imidazo[1,2-a]pyridine scaffold. Meantime, in
order to install the side chain on the parent core, some uneasily
available staring materials or toxic reagents are required in
purification (Figure 2). Next, 1 was suspended in one kind of
suitable alcohols except t-BuOH (reaction concentration: 0.5-0.3
M), and upon treating with SOCl (2.0 equiv.) at rt for 4-5 h, the
crude ester was obtained as a hydrochloride salt from the reaction
solution after removing the solvent. After that, the crude salt was
2
refluxed in POCl
POCl under reduced pressure, the resulting black residue was
(8.0 equiv.) for 2-4 h, and upon removal of
3
8a
subsequent multi-step transformations. Although one atom-
economic approach was developed to reach both Zolpidem and
Minodronic acid by V. Gevorgyan and us , the procedures still
included the use of expensive reagents (such as proponynates),
chromatography purification and difficult scale-up to some extent.
Thus, developing a cost-efficient, scalable and diverse process
for the two drugs is highly in demand.
3
carefully poured into crushed ice, neutralized and extracted with
AcOEt, conveniently giving the crude 2-chloroimidazo[1,2-
a]pyridines (2). The purified product for analysis could be
obtained through simple recrystallization or column
chromatography.
8
With a series of 2-chloroimidazo[1,2-a]pyridines in hand, we
Inspired by the common parent core of the two drugs, our
novel, diverse and cost-efficient approach is proposed, as shown
in Figure 2. Obviously, the key step will be reductive
hydrodechlorination or coupling reaction of 2-chloroimidazo[1,2-
a]pyridines (2), which can be easily obtained from 2-
aminopyridines and9 cheap maleic anhydride, including
amidation/cyclization , routine esterification and subsequent
chlorinative aromatization of the resulting lactam upon treatment
initially investigated reductive hydrodechlorination according to
16a-b
Chai’s procedure , and the results were shown in Table 1. To
our surprise, Pd/C-catalyzed hydrodechlorination with H gas
2
gave the desired product 3a in poor yield, with reduction of
pyridine ring as the predominant side reaction. Tremendous
efforts to optimize this transformation failed to suppress this
overreduction, including solvent screening, pressure, additives,
temperature, and Pd or Pd(OH)
available from different commercial resources. The above results
/C (5%, 10%, or 99.5%)
2
10,12b,14a
with POCl3
.
16c-d
and some literatures
easy to reproduce.
implied this trick transformation was not
Although less reactive heteroaryl chlorides have been found to
be workable in some metal-mediated hydrodechlorination
reactions or cross-coupling reactions, they are still problematic
Considering both diversity and cost-efficiency, we then tested
air- and moisture-stable (NHC)Pd(allyl)Cl complexes according
to Nolan’s method, which was reported to work well for both
hydrodechlorination and cross-coupling reaction with aryl
11
substrates in some cases , and the reaction of heteroaryl
chlorides is strongly dependent on the specific catalysts or the
12-14
substrates.
Our initial literature survey showed very few
17
reports for the two transformations with imidazo[1,2-a]pyridine
chlorides . However, in the case of 2a, all these catalysts did not
give a promising performance in either hydrodechlorination or
coupling reaction. Although organozinc species from 2a might be
used for both hydrodechlorination and Negishi coupling reaction,
15
chlorides except the iodides and triflates. Recently, Chai and
co-workers provided the almost same synthetic strategy for
Minodronic acid, wherein the key step was Pd/C-catalyzed

3
1
8
the attempt to prepare this organozinc species was not fruitful.
When 10% Pd/C was used as the catalyst in the
ACCEPTED MANUSCRIPT
19
20
21
Furthermore, screening free redical -type and Ru -, Ni -, or
hydrodechlorination of 2a, HCO Na, as the hydride source, gave
the similar result of H (Entry 1,2). However, for the substrates
with different ester groups, the conversion could be improved,
a slightly increasing selectivity (Entry 3,4).
Comparing with Pd/C (10%) and Pd(OH) (10%), less active
2
12
Pd -catalyzed hydrodechlorination methods did not afford
acceptable results. As a consequence, we had to focus our
attention on the tricky Pd-catalyzed hydrodechlorination with
different hydride sources, and the results were shown in Table 2.
2
along with
2
Pd/CaCO (10%) afforded a promising selectivity albeit with a
very low conversion (Entry 7, 3c:13%; 6c: 0%). Optimization of
3
Table 1. Pd/C-catalyzed hydrodechlorination under H gas
2
the reaction temperature demonstrated the hydrodechlorination
o
should be carried out at 55 C with an improved result (Entry 8,
3
c: 23%; 6c: 4%).
Subsequently, a series of additives were screened to improve
Entry
Time
6 h
2a
3a
5a
6a
the conversion (Entry 9-15, 19), and K CO was found to offer a
significantly improved result (Entry 14, 3c: 84%, 6c: 0%). In
2 3
a,b
1
2
3
4
65%
37%
17%
8%
17%
29%
29%
15%
0%
5%
6%
5%
3%
0%
13%
28%
49%
74%
addition to HCO Na, other hydride sources, such as HCO NH ,
2
2
4
12 h
24 h
32 h
48 h
HCO H and HCO K, were also tested in the transformation
2
2
(
Entry 16-18), and HCO K performed better than HCO Na,
2
2
giving 3c in 89% yield without generating 6c (Entry 18). The
above results indicated that the catalyst, the suitable basic
medium, less hydrolyzable substrates and controllable hydride
source were very important to reach a good and selective
conversion.
5
0%
100%
a
The reaction was carried out with 1.0 mmol of purified 2a, and monitored by
1
1
H NMR. The yields were obtained by H NMR analysis of the crude reaction
b
mixture. The standard samples of 2a-6a were obtained by column
1
chromatography and determined by H NMR and ESI-MS.
Table 2. Optimization on the hydrodechlorination with 2-chloroimidazole[1,2-a]pyridines
a
entry
R
Catalyst
[H]
Additive
Solvent
Temp.
Yield (%)
o
(
C)
2
3
5
6
1
2
3
4
5
6
7
8
9
Me
Me
Et
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd/C
10% Pd(OH)
H
2
(balloon)
MeOH
MeOH
EtOH
rt
rt
rt
rt
rt
rt
rt
26
24
15
13
65
85
81
70
53
0
25
35
50
55
0
7
34
30
24
22
33
0
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
HCO
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
Na
NH
8
7
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-Pr
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
i-PrOH
5
2
0
10% Pd/BaSO
4
9
0
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
10% Pd/CaCO
3
3
3
3
3
3
3
3
3
3
3
3
3
13
23
37
82
59
38
66
84
35
33
64
89
29
0
0
55
rt
0
4
KF
KF
KF
0
8
1
1
1
1
1
1
1
1
1
1
0
1
2
3
4
5
6
7
8
9
55
65
55
55
55
55
55
55
55
55
3
11
15
46
0
0
11
10
0
Cs
Na
CO
2
CO
3
.
0
2
CO
3
.
27
8
K
2
3
.
0
0
Et
3
N.
36
15
18
3
0
18
35
15
0
4
K
2
CO
CO
CO
3
3
3
.
.
.
16
0
HCOOH
K
2
HCO
2
2
K
K
K
2
0
HCO
AcOK
40
0
24
a
1
The reaction was carried out with 1.0 mmol of the purified sample of 2. The yields were obtained by H NMR analysis of the crude reaction mixture with 1,3,5-
trimethoxybenzene as internal reference standard.
In order to better evaluate the substrate scope of this novel
method, a series of 2-chloroimidazole[1,2-a]pyridines were
subjected to the optimal conditions, and the results were shown
in Table 3. We found many functional groups, such as F, Me,

4
Tetrahedron
OMe, CONH , CONMe2 and CO R, we
A
re
C
t
C
ole
E
ra
P
te
T
d
E
a
D
nd MApu
NU
rit
y
S
of
C
9
R
7%. In summary, starting from 2-aminopyridine and
I
P
T
2
2
afforded the desired products in rational yields except CO H.
maleic anhydride, Minhydronic acid was prepared via one short
reaction sequence with the overall yield of about 20% in a simple
and cost-efficient manner.
2
Notably, in contrast to the i-propyl ester (2c), the methyl or ethyl
ester (2a-2b, 2g-2j) had to be carried out in a suitable reagent-
grade alcohol to avoid interference of ester exchange, affording
the desirable products in mediate yields. In these cases, we also
found the formation of non-reactive 2-chloro acids through ester
hydrolysis when the reagent grade methanol or ethanol was used.
Interestingly, in the case of 2k, the defluorinated product (3c)
could be isolated in 30% yield together with the dechlorinated
product 3k in 58% yield. To our best knowledge, this is one rare
example demonstrating the cleavage of C-F bond of fluoro
imidazole[1,2-a]pyridines through Pd-catalyzed hydrogenation.
Table 3. The Pd-catalyzed hydrodechlorination with 2-
chloroimidazole[1,2-a]pyridines
a,b
2
2
R
G
Solvent
MeOH
EtOH
Yield of 3
2
.2
Process optimization of Minodronic acid
c
a
OMe
OEt
H
44%
c
Having identified the optimal conditions for the key
hydrodechlorination, we pursued its practical application in our
designed process for Minodronic acid, as shown in Scheme 1.
2b
H
63%
i
2
2
c
OPr
H
i-PrOH
i-PrOH
i-PrOH
MeOH
MeOH
MeOH
MeOH
MeOH
i-PrOH
i-PrOH
85%
d
d
OH
H
ND
In the first step, 1a was conveniently prepared according to
9
2e
NH
2
H
63%
71%
49%
53%
the above mentioned procedure (more than 0.20 mmol-scale, 5
2
2
2
f
NMe
OMe
OMe
OMe
OMe
2
H
runs) with no need of further purification, and the average yield
was 62% with a purity of 97%. In the second step, the
esterification of 1a was also easy to conduct by treating the
g
h
5-Me
4-Me
5-F
5-OMe
5-F
5-OMe
suspension of 1a in i-PrOH (0.3 M) with SOCl (5.0 equiv.), and
2
c
upon the removal of the solvent under reduced pressure, the
crude ester from the reaction solution could be used in the
subsequent step without further purification. After the crude ester
2i
31%
2
2
j
42%
i
e
k
OPr
58%
was refluxed in POCl , the resulting black solution was carefully
3
i
poured into crushed ice, neutralized, extracted, dried, filtrated
and evaporated under reduced pressure, affording the crude
semisolid 2c in 72% yield with a purity of 92%.
2l
OPr
83%
a
The reaction was carried out with 1.0 mmol of the purified sample of 2.
b
c
The products were isolated through column chromatography. In case of 2a
d
or 2b, acid 2d was formed besides the desirable product. Not determined.
e
The further defluorinated side product (3c) was isolated in 30% yield as well.
2
.3. Coupling reaction of 2-chloroimidazole[1,2-a]pyridines
From the aspect of simple, environment-friendly and cost-
efficient process, Negishi or Suzuki coupling reaction might be
an attractive approach to Zolpidem from 2-choroimidazo[1,2-
a]pyridines 2. However, the organozinc species of 2-
choroimidazo[1,2-a]pyridines as one of Negishi coupling
partners could not be obtained as above mentioned. In addition,
the initial effort failed to couple 2c with PhZnCl under the
routine Negishi coupling conditions. As a result, we focused on
Suzuki coupling reaction of 2c and 4-methylphenylboronic acid
(8a). After screening different Pd- or Ni-based complexes
Scheme 1. Synthesis of Minodronic acid. Reagents and conditions: a) i.
maleic anhydride (2.0 eq.), toluene, rt, 2 h; ii. MeOH, reflux, 0.5 h; yield:
6
2 3
2%, purity: 97% (5 runs); b) i. i-PrOH, SOCl (5.0 eq.), reflux, 5 h; ii. POCl
(
8.0 eq.), reflux, 5 h; yield: 72%, purity: 92%; c) i. Pd/CaCO
3
(10 mol%),
o
HCOOK (1.5 eq.), K
2
CO
3
(1.2 eq.), i-PrOH, 55 C, 20 h; ii. 36% HCl (conc.);
1
4,15
yield: 69%, purity: 97%; d) i. H
3
PO
3
(2.2 eq), PCl
3
(3.3 eq.), chlorobenzene,
reported to work well for aryl chloride substrates , only
o
14c
9
0 C, overnight; 36% HCl (conc.), reflux, 4 h; yield: 66%, purity: 97%.
NiCl (dppe) showed promising performance. Therefore, we
2
sought to optimize the Ni-catalyzed coupling condition with 2c
and 8a, and the results were depicted in Table 4.
In the key third step, 2c was subjected to the optimal
conditions for hydrodechlorination in the reagent grade i-PrOH
with no trouble of ester hydrolysis. As expected, the scale-up was
smooth albeit with a little sacrifice of conversion (83-85%) due
to poor stirring efficiency. In order to avoid the interference from
the residual 2c, the amount of Pd supported on CaCO3 was
increased to 15 mol% for full conversion of this reaction. After
filtration and removal of solvent, the crude 3c was obtained as
syrup solid. Due to the solidity of the corresponding acid (3d),
We found NiCl (dppf) could efficiently catalyze the coupling
2
reaction, and its usage could be reduced to 5 mmol% of 2c
without a loss of yield (4ca: 93%, Table 4, Entry 4). An excellent
yield required using 2.5 equivalents of 8a due to production of
homo-coupling compound 9a, otherwise, 2c could not be
completely consumed and thus led to lower yield for
hydrodechlorinated product (3c). The optimal usage of K PO
3
4
further ester hydrolysis was carried out in
a
refluxing
was 2.0 equivalents, and meanwhile, toluene was the best solvent.
However, decreasing the temperature resulted in a lower yield.
concentrated HCl aqueous solution (36%), and after complete
hydrolysis, filtration and simple recrystallization in acetone could
provide a white solid (7c, ), as hydrogen chloride salt of 3d, in 69%
yield with a purity of 97%.
In order to evaluate the substrate scope of this novel method, a
variety of 2-chloroimidazole[1,2-a]pyridines (2) and arylboronic
acids (8) were subjected to the optimal conditions, and the results
were shown in Table 5. Many functional groups, such as F, Me,
OMe, SMe and CONMe2 were tolerated and the reaction
6
In the final step, according to the standard procedure , 7c
could be transformed into Minhydronic acid in 66% yield with a

5
afforded the desired products in satisfying yields, especially with
eq.), reflux, 5 h; yield: 87%, purity: 96%; c) i. NiCl
2
(dppf) (5 mol%), 4-Me-
ACCEPTED MANUSCRIPT
6 4 2 3 4
C H B(OH) (2.5 eq.), K PO (2.0 eq.), toluene, reflux, 4 h; ii. 36% HCl
2
g and 8a (Table 5, Entry 5, 84% isolated yield). However, for
those arylboronic acids bearing the strong electron-withdrawing
group such as CF and NO , the catalytic system did not work
(conc.); yield: 71%, purity: 99%; d) PCl
5 2 2 2
, CH Cl , Me NH (gas), rt; yield:
92%, purity: 98%.
3
2
well (see Entry 17-18).
Next, further ester hydrolysis of 4ga was carried out in a
concentrated HCl aqueous solution. After filtration and
concentration, simple recrystallization in acetone could provide
Table 4. Optimization on Ni-catalyzed Suzuki coupling
reaction with 2-chloroimidazole[1,2-a]pyridines
1
0 as a white solid in an average yield of 71% with a purity of
9
9%.
Table 5. The Ni-catalyzed coupling reaction with 2-
chloroimidazole[1,2-a]pyridines and arylboronic acids
a,b
Entry
[Ni]
Base
Solvent
toluene
Yield
43%
33%
1
2
3
4
5
6
7
8
9
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
NiCl
2
2
2
2
2
2
2
2
2
2
2
2
2
2
(dppe)
(dppp)
(dppf)
K
3
PO
PO
PO
PO
PO
PO
PO
4
4
4
4
4
4
4
K
3
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
dioxane
i-PrOH
c
K
3
93%
1
2
a,b
Entry
G
R
R
Yield of 4
(PCy
3
)
2
K
3
38%
22%
15%
11%
0%
c
1
2
3
4
5
6
7
8
9
H
OMe
OEt
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
4-Me
H
87%
(PPh
3
)
2
K
3
H
86%
90%
81%
84%
81%
78%
88%
81%
81%
84%
85%
71%
80%
66%
77%
(DavePhos)
(XantPhos)
(dppf)
K
3
i
H
OPr
K
3
H
NMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
2
5-Me
6-Me
5-OMe
5-F
H
(dppf)
t-BuOK
CO
Cs CO
CsF
0%
1
1
1
1
5
0
1
2
3
(dppf)
K
2
3
40%
10%
60%
16%
21%
(dppf)
2
3
(dppf)
(dppf)
K
3
PO
4
4
1
1
1
0
1
2
H
4-OMe
3-OMe
4-Et
(dppf)
K
3
PO
H
a
b
The reaction was carried out with 1.0 mmol of purified 2c. The yields were
H
1
obtained by H NMR analysis of the crude reaction mixture with 1,3,5-
c
13
H
4-Ph
trimethoxybenzene as internal reference standard. The yield was obtained
with 2.5 equivalents of 8a, compared with the yield of 83% with 2.0
equivalents of 8a.
1
1
1
4
5
6
H
4-F
H
2-Me
4-SMe
2
.4. Process optimization of Zolpidem
H
c
Having obtained the optimal conditions for the key Suzuki
coupling reaction of 2-chloroimidazole[1,2-a]pyridines, we
pursued its practical application in our designed process for
Zolpidem, as shown in Scheme 2.
17
H
3-NO
2
Trace
c
1
8
H
4-CF
3
Trace
a
b
The reaction was carried out with 1.0 mmol of the purified sample of 2. The
c
products were isolated through column chromatography. The desired product
was not isolated.
In the novel process, 2g was conveniently prepared via 2 steps
using the above mentioned procedure, and the average yield (5
runs) was 48% with a purity of 96%. In the key third step, 2g was
subjected to the optimal conditions for the coupling reaction. As
expected, the scale-up was smooth, and after routine work-up
7
Finally, according to the standard procedure , Zolpidem was
prepared from 10 by treating the corresponding acid chloride
with Me NH in an average yield of 92% with a purity of 98%. In
2
(
including quenched with a saturated aqueous NaHCO solution,
summary, Zolpidem could be prepared via one short reaction
sequence with the overall yield of about 28% in a simple and
cost-efficient manner.
3
extracted with AcOEt, washed with water, dried by Na SO ,
filtration and evaporation under reduced pressure), the crude 4ga
2
4
was obtained as a sticky solid.
3
. Conclusion
Inspired by the common parent core of Minodronic acid and
Zolpidem, one novel, diverse and cost-efficient approach has
been developed, and the key aspects of this development involve
careful control of reductive hydrodechlorination or Suzuki
coupling reaction of 2-chloroimidazole[1,2-a]pyridines.
As for the reductive hydrodechlorination, the catalyst (10%
Pd/CaCO ), suitable basic medium (K CO in toluene) and
3
2
3
controllable hydride source (HCO K) proved to be very
important factors to achieve good and selective conversion of 2-
chloroimidazole[1,2-a]pyridines. Additionally, in the Suzuki
2
Scheme 2. Synthesis of Zolpidem. Reagents and conditions: a) i. maleic
anhydride (2.0 eq.), toluene, rt, 2 h; ii. MeOH, reflux, 0.5 h; yield: 48%,
2 3
purity: 97% (5 runs); b) i. MeOH, SOCl (5.0 eq.), reflux, 4 h; ii. POCl (8.0

6
Tetrahedron
o 1
coupling reaction, the catalyst (NiCl (dppf
A
)),
C
s
C
uit
E
ab
P
le
T
b
E
a
D
sic MA
C
NU
.
H
S
N
C
M
R
R
I
(4
P
00 MHz, CDCl ) δ 8.04 (d, J = 6.9 Hz, 1H), 7.63
3
T
2
medium (K PO in toluene) and aryl boric acids without electron-
withdrawing substituents (ArB(OH) ) were key factors for this
(d, J = 9.1 Hz, 1H), 7.55 (s, 1H), 7.20 (m, 1H), 6.85 (m, 1H),
3
4
13
3.95 (s, 2H), 3.71 (s, 3H). C NMR (150 MHz, CDCl ) δ 169.5,
2
3
good transformation.
145.9, 133.2, 123.9, 123.5, 117.9, 116.5, 112.3, 52.4, 30.2.
+
HRMS-ESI (m/z): [M + H] Calcd. For C H N O : 191.0815,
10
11
2
2
Based on the above results, efficient and scalable procedures
for Minodronic acid and Zolpidem have been developed from the
corresponding 2-aminopyridines and maleic anhydride,
respectively. Our new methods involve using cheap reagents,
simple operations and short synthetic routes, thus they are cost-
efficient and easy to reproduce in large scales, which may be
attractive to the industry.
found: 191.0816.
In the case of Pd/C-catalyzed dechlorinative hydrogenation,
two side products (5a and 6a) could be isolated. For compound
1
5a, faint yellow liquid, R = 0.45 (EtOAc/MeOH = 6/1). H NMR
f
(400 MHz, CDCl ) δ 3.80 (t, J = 5.3 Hz, 2H), 3.71 (s, 3H), 3.59
3
13
(s, 2H), 2.81 (t, J = 6.0 Hz, 2H), 1.97 (m, 2H), 1.89 (m, 2H).
C
NMR (150 MHz, CDCl ) δ169.8, 143.7, 127.5, 117.2, 52.4, 43.3,
3
4
. Experimental
.1. Chemistry
General. All chemicals were purchased from Adamas, SCRC,
+
2
8.7, 24.5, 22.5, 20.3. HRMS-ESI (m/z): [M + H] Calcd. For
C H ClN O : 229.0738, found: 229.0740. For compound 6a,
1
0
14
2
2
4
1
faint yellow liquid, R = 0.21 (EtOAc/MeOH = 6/1). H NMR
f
(400 MHz, CDCl
(s, 3H), 3.58 (s, 2H), 2.86 (t, J = 5.8 Hz, 2H), 1.99-1.97 (m, 2H),
) δ 6.85 (s, 1H), 3.82 (t, J = 5.6 Hz, 2H), 3.71
3
Alfa, Aesar, and used without further purification. Deuterated
solvents were purchased from Cambridge Isotope Laboratories.
All non-aqueous reactions were carried out using oven-dried (110
13
1.90-1.88 (m, 2H). C NMR (150 MHz, CDCl
) δ170.3, 145.4,
3
126.5, 122.4, 52.1, 42.6, 29.7, 24.7, 22.7, 20.3. HRMS-ESI (m/z):
o
+
C) or heat gun dried glassware under a positive pressure of
[M + H] Calcd. For C10
.1.2. General procedure for the synthesis of compounds (4)
An anhydrous toluene (10 mL) solution of compound 2 (1.00
H N O : 195.1128, found: 195.1130.
15 2 2
anhydrous argon unless otherwise noted. THF and
dichloromethane were purified by distillation and dried by
passage over activated 4 Å molecular sieves under an argon
atmosphere. H, C and F NMR data were recorded on a
Varian Model Mercury 400 MHz or Bruker 600 MHz
spectrometers using solvent signals (CDCl : δ 7.26/δC 77.0;
CFCl : δ 0) as references. H NMR chemical shifts (δ) are given
in ppm (s = singlet, d = doublet, t = triplet, q = quartet, m =
multiplet) downfield from Me Si. LC-MS data were recorded on
an Agilent 1260/6120 quadrupole LC/MS spectrometer, and high
4
1
13
19
mmol, 1.0 equiv), K PO (2.00 mmol, 2.0 equiv), NiCl (dppf)
3
4
2
(0.05 mmol, 0.05 equiv) and arylboronic acid (2.50 mmol, 2.5
equiv) was transferred into a reaction bottle. The reaction mixture
was then refluxed for 4–6 h under Ar. After the mixture was
cooled to 20 °C, the reaction was quenched with a saturated
sodium bicarbonate solution (20 mL). The organic and aqueous
layers were separated, and the latter was extracted with ethyl
acetate (20 × 3 mL). The combined organic layers were washed
with brine (10 mL) and dried (Na SO ), and then the filtrate was
3
H
1
3
F
4
TM
resolution mass spectra obtained on an AB SCIEX Triple TOF
5
600+ mass spectrometer, IR spectra data were recorded on an
2
4
Nicolet AVATAR 360 FT-IR spectrophotometer, Optical
rotations were recorded on a Rudolf Autopol IV automatic
polarimeter. HPLC Method for Minodronic acid: Agilent 1260
infinity series Chemostation; Agilent 5 ꢀm C18, 250 × 4.6 mm
column; mobile phase A (70%), sodium pyrophosphate aqueous
concentrated in vacuo. The residue was purified by flash column
chromatography with PE and EtOAc as eluent to give compound
4.
For a representative example, the spectra data of 4ca was
followed: white solid, R = 0.26 (PE/EtOAc = 3/2), Mp 158~159
f
(0.03 mol/L) including tetrabutylammonium bromide (adjusted
o
1
C. H NMR (400 MHz, CDCl ) δ 8.13 (d, J = 6.9 Hz, 1H), 7.67-
3
pH to 7.5 with H PO ); mobile phase B (30%), MeOH; flow rate
3
4
7
–
3
.74 (m, 3H), 7.28 (d, J = 7.8 Hz, 2H), 7.25 – 7.19 (m, 1H), 6.89
6.84 (m, 1H), 5.07 (h, J = 6.2 Hz, 1H), 3.98 (s, 2H), 2.41 (s,
H), 1.24 (d, J = 6.4 Hz, 6H) C NMR (150 MHz, CDCl3)
=
2
ꢀ
1 mL/min; column temperature: 30 °C; detector temperature:
5 °C; detection wavelength =280 nm; injection volume = 10.0
L. HPLC Method for Zolpidem: Agilent 1260 infinity series
13
δ168.9, 144.7, 137.8, 130.8, 129.3, 128.5, 128.4, 124.6, 123.7,
17.3, 113.0, 112.4, 69.3, 31.0, 21.7, 21.2. HRMS-ESI (m/z): [M
Chemostation; Agilent 5 ꢀm C18, 250 × 4.6 mm column; mobile
phase (18/23/59): acetonitrile, MeOH and 0.05 mol/L aqueous
H PO , (adjusted pH to 7.5 with Et N); flow rate = 1 mL/min;
1
+
+
H] Calcd. For C H N O : 309.1598, found: 309.1609.
19 21 2 2
3
4
3
column temperature: 30 °C; detector temperature: 25 °C;
detection wavelength =254 nm; injection volume = 10.0 ꢀL.
Besides, we also isolated side product. For compound 9a,
o
1
yellow solid, R = 0.34 (PE/EtOAc = 5/1), Mp 118~121 C. H
f
NMR (400 MHz, CDCl ) δ 7.47 (d, J = 7.2 Hz, 4H), 7.23 (d, J =
3
4
.1.1. General procedure for the synthesis of compounds (3)
+
7
.3 Hz, 4H), 2.38 (s, 6H). ESI-MS (m/z): [M+H] 183.1. The
22
spectrum was consisted with literature .
To a solution of compound 2 (2.00 mmol, 1.0 equiv) and 10%
Pd/CaCO catalyst (0.10 mmol, 0.05 equiv.) in anhydrous ROH,
such as methanol, ethanol and iso-propanol (5 mL), was added
3
4
.1.3. A scalable process for the synthesis of Minodronic acid
K CO3 (2.40 mmol, 1.2 equiv) and HCO K (3.00 mmol, 1.5
To a solution of 2-aminopyridine (94.1 g, 1.00 mol, 2.0 equiv)
2
2
equiv) under Ar, both of which should be pre-dried in vacuo for
.5 h. The reaction vessel was then heated at 55 °C in oil for 24
in toluene (1000 mL) was slowly added a solution of maleic
anhydride (49.3 g, 0.50 mol, 1.0 equiv) in toluene (500 mL) at 0
°C over 0.5 h. The mixture continued to stir for 2 h at rt. The
white precipitated salt was filtered and washed with ether (300
mL). The salt was dissolved in methanol (1500 mL) and refluxed
for 30 min. After cooled to rt, the resulting white solid was
filtered, dried to give 1a (59.5 g, yield: 62%, purity by HPLC:
97%). For the spectra data of the analytic sample of 1a: a white
0
h. After the reaction was completed, the solvent was removed the
under reduced pressure, then added with water (20 mL), and
extracted with ethyl acetate (20 mL × 3). The combined organic
phase was washed with brine (10 mL), dried (Na SO ), filtrated
2
4
and concentrated. Purification by flash chromatography with a
micture of Petroleum Ether (PE) and EtOAc as eluent could give
the compound 3.
o
1
solid, Mp 221~223 C. H NMR (400 MHz, D
.5 Hz, 1H), 8.30 (d, J = 8.8 Hz, 1H), 7.60 – 7.41 (m, 2H), 3.31
O) δ 8.53 (d, J =
2
6
For a representative example, the spectra data of 3a was
13
(s, 2H). C NMR (150 MHz, D O) δ 176.9, 176.2, 155.5, 149.0,
2
followed: white solid, R = 0.21 (PE/EtOAc = 1/3), Mp 110~113
f

7
The precipitated salt was filtered and washed with ether (300
mL). The salt was dissolved in methanol (1000 mL) and refluxed
for 30 min to produce a white solid. After filtration and drying,
the solid was recrystallized from 70 % ethanol (500 mL) to give
1
38.9, 121.5, 113.4, 64.9 (t, J = 22.5 Hz), 38.6. HRMS-ESI (m/z):
+
ACCEPTED MANUSCRIPT
[
M + H] Calcd. For C H N O : 193.0608, found: 193.0606.
9 9 2 3
To a stirring suspension of 1a (59.5 g, 0.30 mol, 1.0 equiv) in
iso-propanol (1200 mL) was slowly added SOCl (150 mL, 1.50
2
1
g (49.5 g, yield: 48%, purity by HPLC: 97%). For the spectra
mol, 5.0 equiv) at 0 °C over 0.5 h. The mixture continued to stir
until the solid disappeared and the solution became transparent.
Removal of the solvent under vacuum gave a white solid, and
then the crude product was refluxed in POCl (228 mL, 2.40 mol,
8
removal of POCl under reduced pressure, and the residue was
carefully poured into the crashed ice, neutralized with a saturated
Na CO solution, and extracted with CH Cl (600 mL × 3). The
organic phase was washed with H O (600 mL), brine (300 mL),
dried (Na SO ), filtrated and concentrated to obtain 2c (57.9 g,
o
data of the analytic sample of 1g: a white solid, Mp 228~231 C.
1
H NMR (400 MHz, D O) δ 8.37 (s, 1H), 8.16 (d, J = 13.4 Hz,
2
13
1
H), 7.42 (d, J = 7.8 Hz, 1H), 3.28 (s, 2H), 2.36 (s, 3H).
C
3
NMR (150 MHz, D O) δ 176.4, 153.0, 150.4, 137.4, 133.0, 112.6,
2
.0 equiv) for 4 h. The black sticky liquid was afforded after
+
6
4.9 (t, J = 22.4 Hz), 38.6, 18.7. HRMS-ESI (m/z): [M + H]
3
Calcd. For C H N O : 207.0764, found: 207.0765.
10
11
2
3
2
3
2
2
1
g (49.5 g, 240 mmol, 1.0 equiv) was suspended in methanol
2
(
480 mL), and then SOCl (50 mL, 0.50 mol, 2.0 equiv) was
2
2
4
slowly added into the stirring solution at 0 °C over 0.5 hours. The
mixture continued to stir until the solid disappeared and the
solution became transparent. Removal of the solvent under
vacuum gave a white solid, and then the crude product was
yield: 72%, purity by HPLC: 92%). For the spectra data of the
o
1
analytic sample of 2c: a white solid, Mp 112~114 C. H NMR
400 MHz, CDCl ) δ 7.99 (d, J = 6.9 Hz, 1H), 7.55 (d, J = 9.0 Hz,
(
1
3
3
H), 7.26 – 7.21 (m, 1H), 6.89 (m, 1H), 5.02 (h, J = 6.4 Hz, 1H),
13
refluxed in POCl (190 mL, 2.00 mol, 8.0 equiv) for 4 h. The
3
.92 (s, 2H), 1.22 (d, J = 6.4 Hz, 6H). C NMR (150 MHz,
black sticky liquid was afforded after removal of POCl under
3
CDCl ) δ 168.0, 143.5, 135.1, 124.9, 123.6, 117.2, 112.8, 112.3,
6
C H ClN O : 253.0738, found: 253.0750.
3
+
reduced pressure, and the residue was carefully poured into the
crashed ice, neutralized with a saturated Na CO solution, and
9.4, 29.7, 21.7. HRMS-ESI (m/z): [M + H] Calcd. For
2
3
12
14
2
2
extracted with CH Cl (500 mL × 3). The organic phase was
2
2
To a solution of compound 2c (57.9 g, 0.20 mol, 1.0 equiv)
washed with H O (500 mL), brine (250 mL), dried (Na SO ),
2 2 4
and 10% Pd/CaCO catalyst (31.8 g, 30.0 mmol, 0.15 equiv) in
filtrated and concentrated to obtain 2g (53.2 g, yield: 87%, purity
by HPLC: 96%). For the spectra data of the analytic sample of 2g:
3
iso-propanol (500 mL) was added pre-dried K CO (33.2 g, 0.24
2
3
o
1
mol, 1.2 equiv) and HCO K (25.2 g, 0.30 mol, 1.5 equiv). The
a white solid, Mp 112~115 C. H NMR (400 MHz, CDCl
3
) δ
2
reaction was purged with argon and heated at 55°C for 20 h.
After the reaction was completed, the solvent was removed under
vacuum, added with water (500 mL), and extracted with ethyl
acetate (500 mL × 3). The organic phase was washed with brine
7.86 (d, J = 7.2 Hz, 1H), 7.29 (s, 1H), 6.73 (d, J = 6.9 Hz, 1H),
13
3.94 (s, 2H), 3.72 (s, 3H), 2.40 (s, 3H). C NMR (150 MHz,
CDCl ) δ 169.0, 143.8, 136.0, 134.6, 122.8, 115.5, 111.1, 52.4,
3
+
29.0, 21.2. HRMS-ESI (m/z): [M + H] Calcd. For C11H12ClN O :
2 2
(
500 mL), dried (Na SO ), filtrated and concentrated. The residue
239.0582, found: 239.0591.
2
4
was diluted with 36% HCl (500 ml) and heated at 45°C for 5 h.
After removal of the solvent under vacuum, the residue was
mixed with acetone (300 mL) for 5 h at rt to give a white solid 7c
An anhydrous toluene (800 mL) solution of K
0.40 mol, 2.0 equiv), NiCl (dppf) (5.70 g, 8.40 mmol, 0.05
equiv), 2g (53.2 g, 209 mmol, 1.0 equiv) and an arylboronic acid
(68.0 g, 0.50 mol, 2.5 equiv) was transferred into a reaction bottle.
The reaction mixture was then refluxed for 4–6 h under Ar. After
the mixture was cooled to 20 °C, the reaction was quenched with
a saturated sodium bicarbonate solution (500 mL) was added.
The organic and aqueous layers were separated, and the latter
was extracted with ethyl acetate (500 × 3 mL). The combined
organic layers were washed with brine (300 mL) and dried
PO (84.8 g,
3
4
2
(
29.3 g, yield: 69%, purity by HPLC: 97%). For the spectra data
o 1
of the analytic sample of 7c: a white solid, Mp 253~255 C. H
NMR (400 MHz, D O) δ 8.38 (d, J = 6.8 Hz, 1H), 7.91 – 7.77 (m,
2
2
H), 7.69 (s, 1H), 7.40 (d, J = 3.9 Hz, 1H), 3.93 (s, 2H). The
6a
spectrum was consisted with literature . HRMS-ESI (m/z): [M +
H] Calcd. For C H N O : 177.0659, found: 177.0662.
+
9
9
2
2
After addition of 7c (29.3 g, 138 mmol, 1.0 equiv), H PO
3
3
(24.6 g, 304 mmol, 2.2 equiv) and chlorobenzene (300 mL) into
(
Na SO ), and then the filtrate was concentrated in vacuo. The
2 4
reaction bottle, the mixture was heated to 100 °C for 0.5 h, then
residue was mixed with 36% HCl (500 ml) and heated at 45°C
for 5 h. Removal of the solvent under reduced pressure, the
residue was stirred in acetone (300 mL) for 5 h to produce a
white precipitate. After filtration, the precipitate was mixed with
cooled to 80 °C, added dropwise with PCl (39.7 mL, 0.50 mol,
3
3
.3 equiv) in a slow speed and continued to stir at 90 °C for
overnight. After removal of chlorobenzene under vacuum, 6 M
HCl (600 mL) was added into the residue and refluxed for 4 h.
The mixture was cooled to 80 °C and mixed with 3.0 g active
carbon for 0.5 h. After filtration to remove active carbon,
concentration, the residue was recrystallized in methanol (300
mL) to obtain a white solid of Minodronic acid (29.4 g, yield:
3
00 mL water until most solid disappeared. Then the aqueous pH
was adjusted to 5.0 to 6.0 with acetic acid. The precipitate was
filtered, washed, dried and recrystallized from methanol to obtain
1
0 (41.5 g, yield: 71%, purity by HPLC: 99%). For the spectra
o
data of the analytic sample of 10: a white solid, Mp 253~255 C.
6
6%, purity by HPLC: 97%). For the spectra data of the analytic
1
H NMR (400 MHz, D O) δ 8.38 (d, J = 6.8 Hz, 1H), 7.91 – 7.77
o
1
2
sample of Minodronic acid: a white solid, Mp 223~225 C. H
(
m, 2H), 7.69 (s, 1H), 7.40 (d, J = 3.9 Hz, 1H), 3.93 (s, 2H). The
NMR (400 MHz, D O) δ 8.59 (d, J = 6.6 Hz, 1H), 7.45 (s, 1H),
7a
2
spectrum was consisted with literature . HRMS-ESI (m/z): [M +
H] Calcd. For C H N O : 177.0659, found: 177.0662.
7
.38 (d, J = 9.0 Hz, 1H), 7.18 (t, J = 7.9 Hz, 1H), 6.82 (t, J = 6.7
+
9
9
2
2
Hz, 1H), 3.53 (t, J = 11.7 Hz, 2H). The spectrum was consisted
6a
+
with literature . HRMS-ESI (m/z): [M + H] Calcd. For
A mixture of 10 (41.5 g, 148 mmol), CH
Cl (500 mL) and
2 2
C H N O P : 323.0193, found: 323.0188.
PCl (33.9 g, 163 mmol, 1.1 equiv) was refluxed for reaction
5
9
13
2
7 2
completion. The reaction mass was cooled to 0 °C, and the
dimethyl amine gas was purged into it till the reaction completion.
Most of the solvent was removed under vacuum, and water (300
mL) was added to the residue. The mixture was heated to 90 °C
to remove traces of dichloromethane. The reaction mass was
cooled to room temperature, pH was adjusted to 9.0-10.0 using
4
.1.4. A scalable process for the synthesis of Zolpidem
To a solution of 5-methyl-2-aminopyridine (108 g, 1.00 mol,
.0 equiv) in toluene (1000 mL) was slowly added a solution of
2
maleic anhydride (49.3 g, 0.50 mol, 1.0 equiv) in toluene (500
mL) at 0 °C over 0.5 h. The mixture was stirred for 2.5 h at rt.

8
Tetrahedron
F. J. Heterocyclic Chem. 2012, 49, 183; b) Viciu, M. S.; Gabriela
A. Grasa, G. A.; Nolan, S. P. Organometallics 2001, 20, 3607; c)
Bhattacharjya, A.; Klumphu, P.; Lipshutz, B. H. Org. Lett. 2015,
caustic lye and stirred for solid isolation. The
A
so
C
lid
C
w
E
as
P
f
TED
d, MANUSCRIPT
ilt
ere
washed with water (300 mL) and dried. Finally, recrystallization
in acetone yielded a white solid of Zolpidem (41.9 g, yield: 92%,
purity by HPLC: 98%). For the spectra data of the analytic
1
7, 1122; d) Chelucci, G.; Figus,S. J. Mol. Catal. A 2014, 393, 191;
e) Chelucci, G.; Baldino, S.; Ruiu, A. J. Org. Chem. 2012, 77,
9921.
o
1
sample of Zolpidem: a white solid, Mp 194~196 C. H NMR
400 MHz, CDCl ) δ 8.16 (d, J = 7.0 Hz, 1H), 7.55 (d, J = 7.5 Hz,
(
13. For Pd-catalyzed Suzuki coupling reaction: a) Tang, Y.-Q.; Lu, J.-
M.; Shao, L.-X. J. Organomet. Chem. 2011, 696, 3741; b) Karimi,
B.; Akhavan, P. F. Chem. Commun. 2011, 47, 7686; c); d) Zhang,
Z.-M.; Gao, Y.-J.; Lu, J.-M. Tetrahedron 2017, 73, 7308; e)
Ghosh, R.; Adarsh, N. N.; Sarkar, A. J. Org. Chem. 2010, 75,
5320; f) Molander, G. A.; Trice, S. L. J.; Kennedy, S. M. J. Org.
Chem. 2012, 77, 8678; g) Gary, A.; Molander, G. A.; Ludivine
Jean-Gerard, L. J. Org. Chem. 2009, 74, 5446; h) Yang, W.; Liu,
C.; Qiu, J. Chem. Commun. 2010, 46, 2659.
3
2
4
H), 7.40 (s, 1H), 7.27 (d, J = 4.0 Hz, 2H), 6.73 – 6.59 (m, 1H),
.11 (s, 2H), 2.92 (s, 3H), 2.84 (s, 3H), 2.40 (s, 6H). The
7a
spectrum was consisted with literature . HRMS-ESI (m/z): [M +
H] Calcd. For C H N O: 308.1757, found: 308.1759.
+
19
22
3
Acknowledgments
1
4. For Ni-catalyzed Suzuki coupling reaction: a) Kalvet, I.; Guo, Q.;
Tizzard, G. J.; Schoenebeck, F. ACS Catal. 2017, 17, 2126; b)
Isley, N. A.; Wang, Y.; Gallou, F.; Handa, S.; Aue, D. H.;
Lipshutz, B. H. ACS Catal. 2017, 17, 8331; c) Hassan, Z.; Al-
Harrasi, A.; Rizvi, T.; Hussain, J.; Peter Langer, P. Synthesis,
We gratefully acknowledge National Natural Science
Foundation of China (No. 21472024) for the research financial
support.
2
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Supplementary Material
8
Supplementary data associated with this article, such as
compound 2, 3 and 4, can be found in Supporting Information.
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