Electrochemically initiated intermolecular C-N formation/cyclization of ketones with 2-aminopyridines: An efficient method for the synthesis of imidazo[1,2-: A] pyridines

Article abstract of DOI:10.1039/c8gc03622e

Electrochemical intermolecular C-N formation/cyclization of ketones with 2-aminopyridines using catalytic hydriodic acid as the redox mediator was developed, providing imidazo[1,2-a]pyridines under more environmentally benign conditions. The reaction proceeds in a simple undivided cell, using low toxic ethanol as the solvent, without external oxidants, and exhibits high atom economy. A variety of ketones including acetophenones, unsatruated and alkyl ketones are amenable to this reaction, affording the corresponding products in moderate to excellent yields. A three-component tandem reaction realizing C-N, C-S/C-Se bond formation can also be achieved under standard conditions.

Full text of DOI:10.1039/c8gc03622e

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DOI: 10.1039/C8GC03622E
Green Chemistry
ARTICLE
Electrochemically Initiated Intermolecular C-N Formation
/Cyclization of Ketones with 2-Aminopyridines: an Efficient
Method for the Synthesis of Imidazo[1,2-a]pyridines
Received 00th January 20xx,
Accepted 00th January 20xx
Mei-Lin Feng, a Shu-Qi Li, a Hui-Zi He, a Long-Yi Xi, a Shan-Yong Chen, *a and Xiao-Qi Yu *a
DOI: 10.1039/x0xx00000x
www.rsc.org/
Electrochemical intermolecular C-N formation/cyclization of ketones with 2-aminopyridines using catalytic hydriodic acid
as the redox mediator was developed, providing imidazo[1,2-a]pyridines under more environmentally benign conditions.
The reaction proceeds in a simple undivided cell, using low toxic ethanol as the solvent, without external oxidants, and
exhibits high atom economy. A variety of ketones including acetophenones, unsatruated and alkyl ketones are amenable
to this reaction, affording the corresponding products in moderate to excellent yields. A three-component tandem
reaction realizing C-N, C-S/C-Se bond formation can also be achieved under standard conditions.
Introduction
Electrosynthesis, which employs electrons as reagents, has least, one for C-N formation, and another for cyclization. How
been recognized as a green technology since it does not
N
generate reagent waste1. It provides an alternative method to
Cl
O
S
N
N
achieve C–H functionalization by electron transfer between an
electrode (direct electrolysis) and a substrate or by using a
redox catalyst (indirect electrolysis)2. During the past decade,
the application of electrochemical anodic oxidation in
synthetic organic chemistry has received increasing attention3,
2c, and a series of elegant eletroorganic reactions for C-C4, C-N5,
C-O6, C-S7 bond formations have been developed
independently by several research groups.
N
O
N
Saripidem
Zolimidine
O
N
nPr
N
N
Cl
N
Cl
N-heterocycles are widely found in biologically active natural
products, pharmaceuticals, and functional materials8.
Accordingly, efficient, green and sustainable strategies for the
synthesis of important N-heterocycles are highly demanding.
The development of modern organic electrosynthesis provides
a new platform for the synthesis of N-heterocycles in a green
way9. Various intramolecular electrochemically oxidative
aminations of alkenes, alkynes, arenes and alkanes have been
developed for the construction of N-heterocylces10. Despite
the great progresses in electrosynthesis, only limited
intermolecular amination to access N-heterocycles was
reported11. To form N-heterocycles by intermolecular
amination, each component needs two functional groups at
O
O
Zolpidem
N
N
Aldiped
Fig.1 Commercial drugs containing imidazo[1,2-a]pyridine
to control electrochemical oxidative conditions to realize C-N
formation while not interfere with another functional group is
challenging.
Imidazo[1,2-a]pyridine is an important class of privileged
structural motif and is recognized as a “drug prejudice”
scaffold due to its wide range of applications in medicinal
chemistry12. Imidazopyridines show a variety of activities such
as antipyretic13, antiviral14, antibacterial15, anticancer16,
antiulcer17 and anti-inflammatory18 properties (Fig. 1).
Traditional methods starting from 2-aminopyridines and
ketones usually involve stoichiometric amount of chemical
oxidants or other toxic reagents and high temperature,
optionally the use of metal reagents19. We aim to explore an
efficient environmentally-friendly electrochemical method to
a. Key Laboratory of Green Chemistry and Technology, Ministry of Education,
Department College of Chemistry, Sichuan University
Chengdu 610064, P. R. China
E-mail: xqyu@scu.edu.cn
chensy@scu.edu.cn
Electronic Supplementary Information (ESI) available: [details of any
supplementary information available should be included here]. See
DOI: 10.1039/x0xx00000x
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J. Name., 2018, 00, 1-3 | 1
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ARTICLE
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construct this important N-heterocyclic moiety. The challenge of imidazopyridines from 2-aminopyridines and ketones. This
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DOI: 10.1039/C8GC03622E
lies in controlling reaction conditions to realize selective reaction proceeds in a simple undivided cell in low toxic
oxidative amination of ketones with pyridines, while the labile ethanol20 in the presence of catalytic amount of hydriodic acid
amino not being oxidized or undergoing other side-reaction. (HI), providing an environmentally benign access to prepare
Herein, we developed the first metal-free intermolecular important N-heterocycles.
electrochemical C-N formation cyclization for the construction
Results and discussion
Table 1. Optimization of reaction conditions a
when the amount of HI was reduced to 12 mol%, which
furnished the product in 95% yield (Entry 7 vs entries 3 and 6).
After carefully screening the amount of HI and the ratio of
substrates as well as other conditions, the optimized reaction
conditions (Entry 10) were established, affording the product
in 99% yield. Furthermore, the reaction also works using a
mixture of water and ethanol as the solvent (water/ethanol:
20/3) (Entry 14).
O
N
Catalyst
N
C-Pt
Undivided cell
N
NH2
3aa
1a
2a
Entry Equiv.
Catalyst
I or Ecell
Yieldb
T(℃)
of 2a
1
2
3
1.5
1.5
2
-
2.0 V
2.0V
2.0V
50
50
50
N.D
7%
39%
NaI 25%
TBAI 20%,
With the optimized reaction conditions in hand, we
examined the substrate scope of this transformation (Table 2).
Both the electron-deficient and electron-rich acetophenones
are found to be suitable substrates to provide the desired
products in moderate to excellent yields (3ba-3ia, 3ja and
3ka). This reaction tolerates a variety of functional groups
including nitro (3ba), trifluoromethyl (3ca), nitrile (3da),
sulfonyl (3ea), ester (3fa and 3ka), halides (3ga-3ia) and ether
(3ja). Notably, this reaction is a highly efficient method
towards Zolimidine (3ea), a gastroprotective drug used for
peptic ulcer and gastroesophageal reflux disease. Interestingly,
2-hydroxy acetophenones, which are usually labile in an
oxidation system, underwent this transformation smoothly,
affording 2-hydroxyl aryl imidazopyridines in good yields (3la,
3na, 3oa). These compounds exhibit efficient ESIPT
luminescence in the solid state21. This reaction was amenable
to unsaturated ketones, affording monosubstituted alkenyl
imidazopyridines exclusively (3ta, 3ua). To the best of our
knowledge, metal-free synthesis of alkenyl imidazopyridines
has not been reported22. Alkyl ketones, which usually have
lower boiling points and are less active than aromatic ketones,
underwent this transformation efficiently under modified
conditions (3va-3ya). The scope of 2-aminopyridines was also
studied. When alkyl or phenyl substituted 2-aminopyrides
were subjected to this reaction, the corresponding products
were isolated in good yields (3ab-3ae). 2-Aminoquinolin
afforded the corresponding product in 20% isolated yield (3af).
Electron-deficient halogenated 2-aminopyridines did not
undergo such transformation, keeping intact during
BF3·Et2O 20%
HI 1eq.
HI 1eq.
HI 1eq.
HI 50%
HI 12%
HI 12%
HI 12%
HI 25%
HI 25%
HI 35%
HI 50%
HI 25%
3
4c
5
6
7
8
9
10
11
12
13
14d
2
2
2
2
2
1.5
1.5
1.5
1.2
1.2
1.2
1.5
2.0V
2.0V
5 mA
2.0V
2.0V
2.0V
2.0V
2.0V
2.0V
2.0V
2.0V
2.0V
50
50
50
50
50
50
35
50
50
50
50
50
62%
33%
33%
90%
95%
65%
57%
99%
60%
64%
41%
30%
a
Reaction conditions: 1a (0.8 mmol), 2a, nBu4NBF4 (0.1 M) as
supporting electrolyte in EtOH (3 mL), undivided cell, carbon fell
anode (1.5 cm2), platinum cathode (1.5 cm2). Isolated yield.
b
c
d
under argon atmosphere.
solvent.
Using water/ethanol (20:3) as the
2-aminopyridine (1a) and acetophenone (2a) were chosen
to study reaction conditions for the oxidative
amination/cyclization reaction. Initially, the reaction was
carried out by the direct electrolysis of the mixture of 1a and
2a in ethanol. Various reaction conditions were tested, but no
obvious product formation was observed (Table 1, entry 1).
Then we turned our attention to indirect electrolysis. Using NaI
as the redox catalyst, the reaction underwent, albeit in low
efficiency (Entry 2). The addition of Lewis acid prompted the
reaction as we expected (Entry 3). We were pleased to find
that the addition of HI provided better results, affording the
product in 62% yield. Further improvements were observed
Table 2. Substrate scope of various ketones and 2-aminopyridines a
electrolysis
(data
not
shown).
O
HI 25 mol%
N
C-Pt 2.0 V
R2
R1
R2
R1
EtOH
N
N
NH2
Undivided cell
50 oC 24h
3
1
2
2 | J. Name., 2018, 00, 1-3
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ARTICLE
N
N
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N
N
NO2
DOI: 10.1039/C8GC03622E
CF3
CN
N
N
N
N
3da
94%
3aa
3ca 99%
99%
3ba
65%
92%
O
S
O
O
N
N
N
N
F
Cl
N
N
N
N
O
3ha
3ga
85%
HO
64%
3fa
3ea
94%
89%
O
N
N
N
N
Br
OMe
N
N
O
N
N
3ia
3ja
75%
HO
3la
70%
3ka
90%
HO
N
N
N
N
N
S
N
N
N
3pa
22%(65%)b
O
3ma
20%
HN
O
3oa
Cl
45%
57%
3na
60%
N
N
N
N
N
N
S
N
N
3ra
36%
3sa
3ta
3qa
64%
80%
N
N
N
OH
N
N
N
N
N
c
c
c
3va
69%
3wa
3ua
53%
60%
3xa
62%
52%
N
N
N
N
N
N
N
N
c
3ad
3ab
73%
3ya
75%
20%
40%
N
3ac
N
N
N
3af
3ae
48%
a Reaction conditions: ketone 1 (0.8 mmol), 2-aminopyridine 2 (1.5 equiv.), HI (25 mol%), nBu4NBF4 (0.1 M) in EtOH (3 mL), undivided cell,
carbon fell anode (1.5 cm2), platinum cathode (1.5 cm2), 50 oC. b Yield based on conversion. c Using ketone/ethanol (1:2) as the solvent.
N
O
O
R2
N
N
R1
X
Standard condition
Standard condition
X
R1
X
R2
N
NH2
N
N
NH2
4
5
1
2
R2
3aa
70%
1a
1.20 g
2a
1.5 eq.
HO
N
N
N
N
S
CF3
Scheme 1 Gram-scale synthesis of 3aa. Reaction conditions: 1a
(10 mmol), 2a (15 mmol), HI (25 mol%), carbon felt anode (6.0
cm2), platinum cathode (1.5 cm2), constant potential (Ecell=1.5
V), undivided cell, air, 50 oC, 48 h. Isolated yield.
N
N
N
N
S
S
S
5d
69%
5c
65%
5a
5b
48%
70%
N
A gram-scale reaction using 10 mmol of 1a (1.20 g) was
conducted to assess the scalability of this electrochemical
tandem cyclization under the standard condition (Scheme 1).
This transformation proceeded smoothly and imidazo[1,2-
a]pyridine 3aa was obtained in 70% isolated yield with 26%
recovery of 1a.
N
N
N
N
N
N
N
S
S
Se
SCH2CH2OH
46%
5h
32%
5g
58%
5f
60%
5e
MeO
Scheme 2 Three-component reaction of 2-aminopyridine,
acetophenones and sulfide/selenide derivatives under
standard conditions.
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Polyfunctional S- and Se-containing N-heterocyclic derivatives may proceed by the electrochemical formation of PhSI or
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DOI: 10.1039/C8GC03622E
are widely found in molecules with biochemical and PhSeI electrophilic species and subsequent electrophilic attack
pharmacological properties23. Yet, highly efficient and selective to the generated imdazo[1,2-a]pyridines 3.
formation of C–N and C–S/C-Se bonds simultaneously in one-
pot through C–H bond functionalization is still an interesting C-H functionalization for the synthesis of imidazo[1,2-
challenge24,19f,19h-19i On the basis of the oxidant-free a]pyridines19a. However, no obvious imine formation was
Imine formation was usually the first step in metal-catalyzed
.
electrochemical amination reaction that we have developed, a observed by running this reaction under standard reaction
three-component approach towards 3-sulfenylimidazo[1,2- conditions without electrifying. Therefore, we speculated that
a]pyridines was performed under standard conditions in the C-N formation between a pyridine and a ketone should occur
presence of diphenyl disulfides. The aim products were before the imine formation. Liquid chromatograph-mass
obtained in moderate to good yields (Scheme 2, 5a-5g). spectrometer analysis was used to monitor the reaction (See
Interestingly, 5b exhibits solid-state fluorescence and AIE the supporting information). Other than the reactants and the
properties (see the Supporting Information). Diphenyl product, which were assigned by comparison with authentic
diselenium can be applied to the same procedure to afford 3- samples, new specie appeared (0.343 min) during the
selanylimidazopyridine in 32% yield (Scheme 2, 5h). Based on electrolysis, giving two signals m/z 213 and m/z 195. The two
the results of control experiments (see the Supporting signals correspond to intermediates 6b and 6c respectively.
information) and literature25, this sulfenylation or selenation
I-
H2
O
A n o d e
O
O
I2
-I-
N
N
- H2O
I
-H+
N+
NH2
6a
6c
6b
N
NH2
N
N
3aa
Scheme. 3 The proposed reaction mechanism
iodo ketone 6a. The nucleophilic substitution between 2-
On the basis of the observations described above and aminopyridine and intermediate 6a gives intermediate 6b,
literature26, a possible mechanism is outlined in Scheme 3. The which subsequently undergoes an intramolecular cyclization to
reaction begins with the anodic oxidation of iodide to generate afford intermediate 6c. The deprotonation of 6c provides the
molecular iodine27, which reacts with the ketone to form α- desired product 3aa.
Conflicts of interest
Conclusions
The authors declare no conflict of interest.
In conclusion, we have developed an environmentally-friendly
electrochemical intermolecular C-N
formation/cyclization
reaction for the synthesis of imidazo[1,2-a]pyridines. The
electrolysis was performed under constant voltage in a simple
undivided cell using catalytic amount of hydriodic acid as the
redox mediator and low-toxic ethanol as the solvent. A variety
of ketones including acetophenones, unsaturated ketones and
alkyl ketones are amenable to the reaction, affording the
corresponding products in moderate to excellent yields. This
reaction was found to tolerate a variety of functional groups,
including hydroxyl, nitro, cyanogen, ether, ester, halides and
sulfonyl. We have also reported an electrochemical three-
component tandem reaction for the synthesis of 3-
sulfenylimidazopyridines. No external oxidants, lower
temperature and lower equivalence of pyridine substrates are
beneficial to actual industrial production.
Acknowledgements
This work was supported financially by the National Natural
Science Foundation of China (Nos. 21877082 and 21202107).
We also thank the Comprehensive Training Platform of
Specialized Laboratory, College of Chemistry, Sichuan
University for sample analysis.
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Green Chemistry
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6 | J. Name., 2018, 00, 1-3
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Green Chemistry
View Article Online
DOI: 10.1039/C8GC03622E
Electrochemically Initiated
Intermolecular C-N
O
N
R2
R1
Formation/Cyclization of
Ketones with
R1
EtOH
Undivided cell
N
N
NH2
R2
Electrochemical intermolecular C-N formation for the construction of
N-heterocycles: A metal- and oxidant-free, electrochemical intermolecular
C-N formation cyclization of ketones with 2-aminopyridines was developed,
providing a series of imidazo[1,2-a]pyridines under more environmentally
benign conditions. The reaction exhibits high atom economy and good
2-Aminopyridines: an Efficient
Method for the Synthesis of
Imidazo[1,2-a]pyridines
Mei-Lin Feng, a Shu-Qi Li, a Hui-Zi He, a Long-Yi
Xi, Shan-Yong Chen, *a and Xiao-Qi Yu *
functional-group tolerance.
A
three-component reaction towards
3-sulfenylimidazo[1,2-a]pyridines can also be achieved under standard
conditions.
Key words: Electrochemistry, electrochemical oxidation, C-N formation,
N-heterocycles, imidazo[1,2-a]pyridine