FeCl3-catalyzed C-3 functionalization of imidazo[1,2-a]pyridines with diazoacetonitrile under oxidant- and ligand-free conditions

Article abstract of DOI:10.1016/j.tetlet.2020.151774

A facile synthesis of 2-(imidazo[1,2-a]pyridin-3-yl)acetonitriles via FeCl₃-catalyzed site-selective C(sp²)-H alkylation of imidazo[1,2-a]pyridines with diazoacetonitrile is presented. This new method features with an environmentally benign catalyst, easily obtainable substrates, and oxidant- and ligand-free reaction conditions. Moreover, the importance of the products thus obtained is showcased by their ready transformation into some synthetically and pharmaceutically interesting products with good efficiency.

Full text of DOI:10.1016/j.tetlet.2020.151774

Journal Pre-proofs
FeCl −catalyzed C−3 functionalization of imidazo[1,2-a]pyridines with diaz-
3
oacetonitrile under oxidant- and ligand-free conditions
Guang Chen, Bin Li, Bing Hu, Xinying Zhang, Xuesen Fan
PII:
S0040-4039(20)30206-9
DOI:
https://doi.org/10.1016/j.tetlet.2020.151774
TETL 151774
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Tetrahedron Letters
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21 February 2020
Please cite this article as: Chen, G., Li, B., Hu, B., Zhang, X., Fan, X., FeCl −catalyzed C−3 functionalization of
3
imidazo[1,2-a]pyridines with diazoacetonitrile under oxidant- and ligand-free conditions, Tetrahedron Letters
(
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Tetrahedron Letters
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FeCl −catalyzed C−3 functionalization of imidazo[1,2-a]pyridines with
3
diazoacetonitrile under oxidant- and ligand-free conditions
Guang Chen, Bin Li*, Bing Hu, Xinying Zhang, Xuesen Fan*
Henan Key Laboratory of Organic Functional Molecules and Drug Innovation, Key Laboratory of Green Chemical Media and Reactions, Ministry of Education,
Collaborative Innovation Center of Henan Province for Green Manufacturing of Fine Chemicals, School of Environment, School of Chemistry and Chemical
Engineering, Henan Normal University, Xinxiang, Henan 453007, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
A facile synthesis of 2-(imidazo[1,2-a]pyridin-3-yl)acetonitriles via FeCl
3
-catalyzed site-selective
2
C(sp )−H alkylation of imidazo[1,2-a]pyridines with diazoacetonitrile is presented. This new method
features with an environmentally benign catalyst, easily obtainable substrates, and oxidant- and ligand-
free reaction conditions. Moreover, the importance of the products thus obtained is showcased by their
ready transformation into some synthetically and pharmaceutically interesting products with good
efficiency.
Available online
2
019 Elsevier Ltd. All rights reserved.
Keywords:
Imidazo[1,2-a]pyridine
Diazoacetonitrile
FeCl
3
2
Site-selective C(sp )−H alkylation
Introduction
the cyano group enables them to be ready candidates for amides,
[6]
amines, ketones, acids, esters, etc.; 3) the acetonitrile moiety as
a whole could be used as a building block for the construction of
Imidazo[1,2-a]pyridine and its derivatives have attracted
c
onsiderable attention due to their wide applications in medicinal
[7]
various N-heterocycles. Given the importance of both C−3
functionalized imidazo[1,2-a]pyridines and (hetero)arylaceto-
nitriles, the development of efficient and practical methods for
the preparation of 2-(imidazo[1,2-a]pyridin-3-yl)acetonitriles
constitutes an important topic for the synthetic community.
In recent years, direct functionalization of inert C(sp2)−H
bonds is emerging as a highly valuable tool for organic
synthesis due to its excellent step-economy and atom-efficiency.
In this regard, extensive studies have been made on the efficient
introduction of diverse functional groups onto the C−3 site of the
chemistry and material sciences. For examples, numerous
functionalized imidazo[1,2-a]pyridines, especially the C−3
substituted ones, are found to possess pharmaceutical and
biological activities such as antitumor, antiviral, antiprotozoal,
[
1,2]
antiapoptotic, antipyretic, analgesic as well as antitubercular.
This could be well exemplified by a number of imidazo[1,2-
a]pyridine-containing commercial drugs such as zolpidem,
alpidem, saripidem, and necopidem, etc. (Figure 1). In addition,
many imidazo[1,2-a]pyridine derivatives have demonstrated
unique photo-physical properties, and have thus been developed
[
3]
as a new class of fluorescent probes and luminophores
.
On the
2
imidazo[1,2-a]pyridine scaffold through regioselective C(sp )−H
other hand, (hetero)arylacetonitrile is a privileged scaffold widely
found in clinical drugs or drug candidates.[4] More attractively,
the derivatives of (hetero)arylacetonitrile are versatile synthetic
[8]
bond functionalization reactions
.
Inspired by those elegant
pioneering studies and as a continuation of our own interests in
2
transition metal-catalyzed C(sp )−H functionalization of 2-
intermediates
owing to their distinctive structural characteristics:
[9]
arylimidazo[1,2-a]pyridines and in diazo compounds as a class
[
5]
1
) the acidic methylene unit makes them good nucleophiles; 2)
of efficient coupling partners for Rh(III)-catalyzed C–H bond
N
N
N
[10]
derivations,
we have explored the reaction of imidazo[1,2-
Me
Me
Cl
N
N
N
Me
Me
[11]
a]pyridines with diazoacetonitrile.
From this study, a facile
O
O
N
and convenient synthesis of 2-(imidazo[1,2-a]pyridin-3-yl)
acetonitriles was successfully established (Scheme 1 (3)). It is
worthwhile to note herein that although some excellent synthetic
protocols toward 2-(imidazo[1,2-a]pyridine-3-yl)acetonitriles via
N
N
Me
n-Pr
Saripidem
Me
O
Zolpidem
N
Alpidem
Cl
N
O
N
N
CO H
2
2
[12]
C(sp )−H functionalization have already been developed
Scheme 1 (1) and (2)), an alternative method to fulfill this task
SO2Me
N
N
N
Me
(
i-Bu
Zolimidine
Miroprofen
by using the cheap and sustainable FeCl as a catalyst under
3
Necopidem
oxidant- and ligand-free conditions has not been reported
Figure 1. Selected pharmaceuticals containing an imidazo[1,2-
a]pyridine scaffold.
previously. Herein, we wish to present our detailed results in this
regard.

2
Tetrahedron Letters
ref. 12a
fec-Ir(ppy)3, base
N
Table 1
N
N
N
R
R
R
R
+
+
+
NC
NC
NC
Br
H
N
(1)
Optimization studies for the formation of 3aa
DMSO, Ar, 12 h
W Blue LEDs
N
N
N
5
CN
N
N
conditions
+
N2
CN
ref.12b
FeCp2, DCP
00 oC, 20 h, Ar
N
N
N
N
R
N
N
(2)
(3)
1a
2
3a
CN
1
CN
o
Yield (%)b
Entry
Catalyst
[RhCp*Cl
[RhCp*Cl2]2
PdCl
Fe(ClO
Fe(acac)
FeCl
CuCl ·2H
Cu(OAc)2
Solvent
CH CN
CH CN
T ( C)
this work
FeCl3
CH3CN, 60 o
R
1c
2
3
4
5
6
7
8
9
]
40
40
40
40
40
40
40
40
50
60
70
60
60
60
60
60
60
60
60
60
60
21
22
20
25
26
47
17
18
57
66
58
53
61
39
26
46
67
68
61
53
ND
N2
2
2
3
C
CN
3
Scheme 1. Different approaches toward 2-(imidazo[1,2-a]pyridine-
-yl)acetonitriles.
2
CH
CH
CH
CH
CH
3
3
3
3
3
CN
CN
CN
CN
CN
3
4 2
)
3
Results and discussion
3
Our study was initiated by treating a mixture of 2-phenyl-
imidazo[1,2-a]pyridine (1a) and diazoacetonitrile (2) in CH
with [RhCp*Cl and AgSbF at 40 °C under air for 6 h. From
2
2
O
3
CN
3
CH CN
2
]
2
6
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
FeCl
CH
CH
CH
CN
CN
CN
3
3
3
3
3
3
3
3
3
3
3
3
3
3
3
this reaction, the desired 2-(2-phenylimidazo[1,2-a]pyridin-3-
yl)acetonitrile (3a) was obtained in 21% yield (Table 1, entry 1).
1
1
0
1
In the absence of AgSbF
2
6
, 3a was formed in a similar yield of
2% (entry 2), indicating that the presence of an additive is not
12
THF
DCM
DMF
2 4 2 3 3 2 2
necessary. Next, PdCl , Fe(ClO ) , Fe(acac) , FeCl , CuCl ·2H O
1
1
1
3
4
5
or Cu(OAc)
Among them, the economically and environmentally sustainable
FeCl was found to be the most effective to afford 3a in 47%
2
was tried as catalyst for this reaction (entries 3-8).
toluene
3
16d
CH
CH
CH
CH
CH
CN
CN
CN
CN
CN
yield (entry 6). Further study on the effect of different
3
3
3
3
3
temperatures showed that the yield of 3a could be improved to
7e
1
5
°
7%, 66% or 58% when this transformation was carried out at 50
C, 60 °C or 70 °C, respectively (entries 9-11). Next, THF,
DCM, DMF and toluene were tried as the reaction media. Among
them, DCM gave similar result as that with CH CN while others
1
8f
9g
1
20h
3
were much less effective (entries 12-15). As another aspect,
varying the molar ratio of 1a to 2a from 1:3 to 1:2 or 1:4 gave 3a
in yields of 46% and 67%, respectively (entries 16 and 17). It
was also found that prolonging the reaction period from 6 h to 8
h did not improve the yield of 3a obviously (entry 18) while a
shortened reaction period resulted in decreased efficiency (entry
21
3
CH CN
aReaction conditions: 1a (0.5 mmol), 2 (1.5 mmol), catalyst (0.05
mmol), solvent (2 mL), air, 6 h.
Isolated yield.
AgSbF (0.5 mmol).
6
(1.0 mmol).
b
c
d
2
2
e
f
(2.0 mmol).
1
9). When the reaction was carried out under nitrogen instead of
8
h.
h.
air, the yield of 3a decreased to 53% (entry 20). Finally, a control
experiment showed that 3a could not be formed in the absence of
the iron catalyst (entry 21).
g
4
hUnder N
2
.
moiety were compatible with the reaction conditions to give 3l-
w in moderate to good yields. In comparison, para-substituted
substrates were more efficient than their ortho-substituted
counterparts. Besides 2-phenylimidazo[1,2-a]pyridines, reactions
of 2-([1,1'-biphenyl]-4-yl)imidazo[1,2-a]pyridine, 2-(naphthalen-
After having established the optimal reaction conditions, the
scope of substrates for this reaction was then explored. First, a
series of 2-phenylimidazo[1,2-a]pyridines (1) bearing various
substituents on different sites of the imidazo[1,2-a]pyridine
scaffold were tested. The results listed in Table 2 showed that 1
with a methyl, methoxy, chloro or trifluoromethyl group attached
on the 6-position were well suitable for this reaction to give
products 3b-3e. Meanwhile, the electronic nature of the
imidazo[1,2-a]pyridine unit rendered some effect on this reaction
as those bearing electron-donating groups (EDGs) generally
resulted in higher yields than those bearing electron-withdrawing
groups (EWGs) (3b, 3c vs 3d, 3e). Next, imidazo[1,2-a]pyridine
with a methyl, methoxy or bromo unit attached on the 7-position
or a methyl or fluoro group attached on the 8-position were let to
react with diazoacetonitrile under standard conditions. It turned
out that the corresponding reactions proceeded smoothly to give
products 3f-3j in yields ranging from 45% to 62%. In comparison,
3
2
-yl)imidazo[1,2-a]pyridine and 2-(thiophen-2-yl)imidazo[1,2-
a]pyridine proceeded equally well to give 3x, 3y and 3z.
Furthermore, substrates 1 with substituent attached on both the
imidazo[1,2-a]pyridine scaffold and the 2-phenyl unit took part
in this reaction smoothly to afford 3aa-3dd in moderate yields.
When 2-methylimidazo[1,2-a]pyridine was subjected to the
standard conditions for 6 h, it remained almost intact and the
desired product 3ee was not obtained.
As for possible mechanism accounting for the formation of 3a,
we noticed that Koenigs et al. have proposed that FeTPPCl-
catalyzed alkylation of indoles with diazoacetonitrile should
proceed via a radical pathway since the alkylation was
completely inhibited by 2,2,6,6-tetramethyl-1-piperidinyloxyl
5
-methyl-2-phenylimidazo[1,2-a]pyridine (1k) exhibited lower
[
11i]
reactivity toward 2, most likely due to higher steric hindrance.
Next, a number of 2-phenylimidazo[1,2-a]pyridines (1)
bearing various substituents on different positions of the 2-phenyl
unit were tried. It turned out that 1 with either EDGs such as
methyl and methoxy or EWGs such as halides and trifluoro-
methyl on the ortho-, meta- or para-position of the 2-phenyl
(TEMPO) as a radical scavenger.
3
To explore if this FeCl -
catalyzed alkylation of imidazo[1,2-a]pyridines with diazoaceto-
nitrile is also a radical process, the reaction of 1a with 2 was
conducted in the presence of 1 equiv., 2 equiv., or 3 equiv. of
TEMPO. Under these circumstances, 3a was obtained in 42%,
18% or 16% yield, respectively. The fact that the alkylation of

N
Table 2
N
standard conditions
TEMPO
Ph
Ph
+
N2
CN
N
Substrate scope for the synthesis of 3 (I) a,b
N
1a
2
3a
CN
N
FeCl3
CH3CN, 60 o
N
1 eq., 42%; 2 eq., 18%; 3 eq., 16%
R1
Ph
N2
R1
+
CN
Ph
N
C
N
Scheme 2. Control experiments in the presence of TEMPO.
1
2
3
CN
3
a
2
N
N
N
FeCl3
N
Ph
CN
Ph
CN
Ph
CN
Ph
H+
N2
N
N
N
N
Me
MeO
Cl
CN
N
NC
Ph
3
a, 66%
3b, 60%
3c, 58%
3d, 48%
Ph
FeCl3
N
Me
N
N
MeO
N
N
Br
N
I
N
N
Ph
Ph
CN
Ph
CN
Ph
III
FeCl3
N
F3C
NC
N
CN
CN
1a
H+
N
3
e, 30%
3f, 62%
3g, 56%
3h, 55%
H
II
FeCl3
Me
F
N
N
NC
N
N
Ph
CN
Ph
CN
Ph
CN
N
N
Scheme 3. Plausible mechanism accounting for the formation of 3a
Me
3
i, 62%
3j, 45%
3k, 38%
To illustrate the usefulness of the products thus obtained, the
following transformations were conducted. First, 3a was treated
with H SO in ethanol to afford ethyl 2-(2-phenylimidazo[1,2-a]
aReaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), FeCl
3
(0.05 mmol),
3
CH CN (2 mL), 60 °C, 6 h.
bIsolated yield.
2
4
[12a]
pyridin-3-yl)acetate (4) in high efficiency (Scheme 4 (1)).
Second, 3a was treated with H and K CO in DMSO to afford
-(2-phenylimidazo[1,2-a]pyridin-3-yl)acetamide (5) in 72%
2
O
2
2
3
Table 3
2
Substrate scope for the synthesis of 3 (II) a,b
[14]
yield (Scheme 4 (2)).
Third, a tetrazole derivative (6) was
N
FeCl3
CH3CN, 60 o
N
obtained through the reaction of 3a with NaN under the
R1
R2
3
R1
R2
CN
+
N2
N
C
N
promotion of ZnCl (Scheme 4 (3)).
[15]
2
1
2
3
CN
Given the importance of naphtho[1',2':4,5]imidazo[1,2-a]
[9]
pyridine derivatives, 4 was then treated with polyphosphoric
acid (PPA) with the aim to get naphtho[1',2':4,5]imidazo[1,2-a]
pyridin-5-ol (7) via an envisioned intramolecular Friedel-Crafts
acylation (IFCA) followed by a ketone-enol tautomerization. To
our surprise, 7 was not isolated from the resulting mixture.
Me
MeO
Cl
Br
N
N
N
N
N
N
N
N
CN
CN
CN
CN
3
l, 55%
3m, 58%
3n, 46%
Cl
N
3o, 52%
Me
OMe
N
N
N
Instead,
naphtho[1',2':4,5]imidazo[1,2-a]pyridine-5,6-dione
Me
N
N
N
N
(NPDO, 8) was obtained in moderate yield (Scheme 5). It was
CN
CN
CN
CN
soon realized that the formation of 8 is both synthetically and
mechanistically attractive since it not only reveals an interesting
cascade reaction combining an IFCA and an in situ oxidation of
the methylene unit, but also provides a simple and direct
alternative synthetic method toward NPDOs, which have been
identified as highly reactive substrates of NADPH-dependent
3
N
p, 58%
3q, 63%
N
3r, 45%
N
3s, 76%
N
OMe
F
Cl
CF3
N
N
N
N
CN
CN
CN
CN
3
t, 66%
3u, 58%
3v, 46%
3w, 65%
Br
N
N
N
N
S
Ph
N
N
N
Me
N
Me
[16]
single- and two-electron transferring flavoenzymes.
CN
CN
CN
CN
Finally, to see whether this method is suitable for enlarged
synthetic missions, the synthesis of 3a was carried out on 5 mmol
scale. It turned out that the corresponding reaction proceeded
smoothly to afford 3a in 52% yield (Scheme 6).
3
x, 46%
3y, 62%
3z, 40%
3aa, 48%
Br
N
N
N
N
N
N
Me
Cl
Me
Et
N
N
Me
Me
Me
CN
CN
CN
CN
3
bb, 40%
3cc, 50%
3dd, 54%
3ee, not obtained
aReaction conditions: 1 (0.5 mmol), 2 (1.5 mmol), FeCl
N
N
3
(0.05 mmol),
H2SO4
EtOH, 90 o
Ph
Ph
CH
3
CN (2 mL), 60 °C, 6 h.
N
N
(1)
C
bIsolated yield.
CN
CO2Et
3a
4, 85%
N
N
1
a with 2 in the presence of TEMPO is much less efficient than
2 2 2 3
H O , K CO
Ph
Ph
O
N
DMSO, 0 oC to rt
N
(2)
that carried out in the absence of TEMPO suggests that it might
also involve the formation of radical intermediate(s) somewhere
in the cascade process. Meanwhile, the fact that 3a could still be
obtained in 16% yield even in the presence of 3 equiv. of
TEMPO indicates that another pathway involving the formation
of a carbene intermediate might also exist as proposed by
Zhou
diazophenylacetates or 4-diazo-4H-imidazoles with various
substrates. o be specific, 2 firstly reacts with FeC o form an
iron carbene species I. Reaction of I with 1a generates a
zwitterionic intermediate II. Next, a -elimination occurs with
II to give intermediate III. Finally, protonation of III affords
product 3a and releases the catalyst for the next catalytic cycle
CN
3a
5
, 72%
NH2
N
N
ZnCl , NaN3
2
Ph
Ph
N
N
(3)
n-BuOH, 120 o
C
N
N
CN
3a
6
, 67%
HN
N
[13a]
[13b]
and Moody
in their studies on the reactions of -
Scheme 4. Structural elaboration of 3a.
T
3
l t
N
N
N
N
PPA
N
Ph
N
N
140 o
N
C
CO2Et
O
O
OH
O
4
8, 42%
7, not obtained
(
Scheme 3). Admittedly, more efforts are still needed to clarify
Scheme 5. A novel synthesis of NPDO (8).
the exact reaction pathway for the formation of 3a.

4
Tetrahedron Letters
N
N
FeCl3
CH3CN, 60 o
(d) T. Mutai, T. Muramatsu, I. Yoshikawa, H. Houjou, M.
+
N2
CN
C
N
Ogura, Org. Lett. 21 (2019) 2143−2146;
(e) Y. Li, S. Qi, C. Xia, Y. Xu, G. Duan, Y. Ge, Anal. Chim.
Acta. 1077 (2019) 243−248;
N
1a
2
CN
05.8 mg, 52%
3
a
5
mmol
15 mmol
6
(
f) C. Wang, S. Lei, H. Cao, S. Qiu, J. Liu, H. Deng, C. Yuan,
J. Org. Chem. 80 (2015) 12725−12732;
g) H. Cao, H. Zhan, Y. Lin, X. Lin, Z. Du, H. Jiang, Org.
Scheme 6. Enlarged-scale synthesis of 3a.
(
Conclusion
Lett. 14 (2012) 1688−1691 and references cited therein.
4] (a) M. J. Meyers, J. Sun, K. E. Carlson, G. A. Marriner, B. S.
Katzenellenbogen, J. A. Katzenellenbogen, J. Med. Chem. 44
[
In summary, we have developed a novel C−3 alkylation of
imidazo[1,2-a]pyridines with diazoacetonitrile, from which an
efficient and convenient method for the synthesis of the
synthetically and pharmaceutically valuable 2-(imidazo[1,2-a]-
pyridine-3-yl)acetonitriles was established. Compared with
literature methods, the protocol developed herein has advantages
such as simple substrates, sustainable catalyst, oxidant- and
ligand-free reaction conditions. Further studies to clarify the
reaction mechanism and find more applications of diazoaceto-
nitrile in C−H bond functionalization are currently underway in
our laboratory.
(
(
2001) 4230−4251;
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Shook, J. Med. Chem. 53 (2010) 7902−7917;
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(
Samje, F. Cho-Ngwa, S. Lustigman, K. D. Janda, J. Med.
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(
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(
1
Acknowledgments
[5] (a) H.-M. Xia, F.-L. Zhang, T. Ye, Y.-F. Wang, Angew.
Chem. Int. Ed. 57 (2018) 11770−11775;
We are grateful to the National Natural Science Foundation of
China (NSFC) (21572047), Plan for Scientific Innovation Talents
of Henan Province (184200510012), Program for Innovative
Research Team in Science and Technology in Universities of
Henan Province (20IRTSTHN005), Key Project of Science and
Technology of Henan Province (192102310412) and 111 Project
(
9
(
b) X. Zhang, S. Wang, C. Xi, J. Org. Chem. 84 (2019)
744−9749 and references cited therein;
c) Z.-H. Zhu, Y. Li, Y.-B. Wang, Z.-G. Lan, X. Zhu, X.-Q.
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Lett. 17 (2015) 50−53;
[
(D17007) for financial support.
(b) W. Kong, B. Li, X. Xu, Q. Song, J. Org. Chem. 81 (2016)
8
436−8443.
Supplementary data
[
7] (a) F. Xu, J. A. Murry, B. Simmons, E. Corley, K. Fitch, S.
Karady, D. Tschaen, Org. Lett. 8 (2006) 3885−3888;
Supplementary data associated with this article can be found in
the online version at doi:
(
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Declaration of interests
Highlights

The authors declare that they have no known
FeCl -catalyzed C−3 functionalization of
Leave this area blank for abstract info.
3
imidazo[1,2-a]pyridines with diazoacetonitrile
under oxidant- and ligand-free conditions
Guang Chen, Bin Li*, Bing Hu, Xinying Zhang, Xuesen Fan*
N
FeCl3
CH3CN, 60 o
N
R1
R2
R1
R2
+
N2
CN
N
C
N
Environmentally benign catalyst
Halide-free substrates and valuable products
Mild conditions in the absence of oxidant or additive
CN
N
N
N
N
Ph
Ph
Ph
N
N
N
N
N
CO2Et
CONH2
N
N
O
O
HN
competing financial interests or personal
relationships that could have appeared to influence
the work reported in this paper.
» Simple substrates without prefunctionalization
» Sustainable catalyst
» Oxidant- and ligand-free conditions
»
Site-selective transformations
☐
The authors declare the following financial
interests/personal relationships which may be
considered as potential competing interests:
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