External Oxidant-Free Regioselective Cross Dehydrogenative Coupling of 2-Arylimidazoheterocycles and Azoles with H2 Evolution via Photoredox Catalysis

Article abstract of DOI:10.1002/adsc.201800531

In this work, we achieved a site-selective amination of 2-arylimidazoheterocycles on the C3 position using photo-induced external oxidant-free strategy. The C?N bond formation with H₂ evolution was realized via the oxidative C?H/N?H coupling. This protocol may have significant implications in the late-modification of complicated drug molecules. In addition, we also used CV and DFT calculations to study the mechanism, which showed that the arene radical cation played an important role in accelerating the C?H amination process. (Figure presented.).

Full text of DOI:10.1002/adsc.201800531

Title: External-Oxidant-Free Cross Dehydrogenative Coupling of
2-Arylimidazoheterocycles and Azoles with H2 Evolution via
Photoredox Catalysis
Authors: Hong Chen, Hong Yi, Zilu Tang, Changliang Bian, Heng
Zhang, and Aiwen Lei
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.201800531
Link to VoR: http://dx.doi.org/10.1002/adsc.201800531

10.1002/adsc.201800531
Advanced Synthesis & Catalysis
FULL PAPER
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
External Oxidant Free Regioselective Cross Dehydrogenative
Coupling of 2-Arylimidazoheterocycles and Azoles with H2
Evolution via Photoredox Catalysis
This paper is dedicated to Professor Xiyan Lu on the occasion of his 90th birthday.
Hong Chen,a, Hong Yi,a, Zilu Tang, a Changliang Bian,a Heng Zhang,*,a and Aiwen
Lei*,a,b
a
College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan
430072, P. R. China
b
National Research Center for Carbohydrate Synthesis, Jiangxi Normal University, Nanchang 330022, P. R. China
e-mail: hengzhang@whu.edu.cn; aiwenlei@whu.edu.cn
Received: ((will be filled in by the editorial staff))
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201######.((Please
delete if not appropriate))
Abstract. In this work, we achieved a site-selective and DFT calculations to study the mechanism, which
amination of 2-arylimidazoheterocycles on the C3 position showed that the arene radical cation played an important
using photo induced oxidant free strategy. The C-N bond role in accelerating the C-H amination process.
formation with H2 evolution was realized via the oxidative C-
H/N-H coupling. This protocol may have significant
implications in the late-modification of complicated drug
molecules. In addition, we also used CV
Keywords: C−N bond formation; Hydrogen evolution; C-
H amination; Photoredox catalysis; Synergetic catalysis.
Imidazopyridines are important fused bicyclic 5-6
functionalization offers
a
straightforward and
membered heterocycles and recognized as
a
efficient route to form C-C and C-heteroatom bonds
in the past decades.[11] Consequently, the
incorporation of various functional groups on the C3
position via the selective C-H functionalization of
imidazoheterocycles have attracted extensive
research interests.[12] Up to now, there have been
several methods developed which realized the
construction of C-C and C-X bonds at C3 position.[13]
Adimurthy and co-workers recently described the C-
H amination of heterocycles, which was an important
privileged scaffold in drug discovery due to its wide
range of applications in medicinal chemistry.[1] In
addition, the imidazo[1,2-ɑ]pyridine derivatives have
been confirmed to have broad implications in the area
of antifungal, anti-inflammatory and antitumor etc.[2]
There have been several commercial available drugs
which contains the imidazo[1,2-ɑ]pyridine skeleton,
such as zolpidem (the treatment of insomnia),[3]
saripidem (work as an anxiolytic agent),[4] zolimidine
(the treatment of peptic ulcer)[5] and so on. In addition, work for the C-H amination via photoredox catalysis
2-hydroxyphenyl substituted imidazo[1,2-ɑ]pyridine
derivatives at the C2 position are important molecular
structures in the field of optoelectronics as they
exhibit excited state intramolecular proton transfer
(ESIPT).[6] Some abnormal N-heterocyclic carbenes
can also be prepared based on imidazo[1,2-
ɑ]pyridines.[7] It is reported that substituents on the
C3 position of imidazo[1,2-ɑ]pyridine has dramatic
effect on the pharmacological activity.[8] The
conventional approach for the construction of
imidazo[1,2-ɑ]pyridine moiety is based on the
[14] However, some limitations still exist, such as the
need of transition metals, harsh reaction conditions,
stoichimetric oxidant and the low atom economy
(Scheme 1A). Therefore, it is highly desirable to
explore a general and green method to functionalize
the imidazoheterocycle skeleton.
In recent years, visible light mediated photoredox
catalysis has gained much attention[15] and served as a
powerful and important tool to develop sustainable
synthetic processes. Especially, the cross-coupling
hydrogen evolution (CCHE) reactions using
photoredox catalytic strategy have emerged as a
mighty approach for the construction of C-C and C-X
bond from C-H/X-H bonds along with hydrogen
releasing.[16] This method can achieve the bond
formations under mild conditions without external
condensation
halo/tosyloxy
of
2-aminopyridine
Recently,
with
α-
ketone.[8a],[9]
several
alternative methods have been developed to
synthesize imidazo[1,2-ɑ]pyridine derivatives using
easily available starting materials.[10] The C-H bond
1
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10.1002/adsc.201800531
Advanced Synthesis & Catalysis
oxidants.[17] In such a reaction system, photocatalytic
cycle and hydrogen evolution cycle can be tuned and
worked synergistically, and the proton serves as the
terminal oxidant. Due to the relative strong
coordination of imidazoheterocycle compounds, the
direct C-H functionalization of imidazoheterocycles
by transition metal is either inefficient or run on harsh
conditions. Except for the coordinative property, the
electron rich property of imidazoheterocycle moiety
can also s be used in organic synthesis.[8a] In view of
such as DMSO or DMF was not suitable for our
reaction, and MeCN which was usually employed in
photoredox reactions was not a good choice either
(entries 7-10). In addition, control experiments
showed that photocatalyst, cobaloxime catalyst and
irradiation of Blue LEDs were all indispensable for
this transformation (Table 1, entries 11-13). In the
-
end, we employed
5
mol% Acr+-MesClO4
(photoredox catalyst), 5 mol% Co(dmgH)(dmgH2)Cl2
(hydrogen evolution catalyst) and 3 mL DCE
(solvent) as the standard reaction conditions for the
following reactions.
the
unique
electron-rich
property
of
imidazoheterocycles, we envision that the direct
activation via single electron transfer may have
distinctive advantages, such as the efficiency and
selectivity. Employing a dual catalytic system
Table 1. Investigation of the reaction conditions. a)
containing
cobaloxime catalyst, we herein report a direct and
regioselective functionalization of
acridinium
photosensitizer
and
imidazoheterocycles employing azoles as reaction
partner with H2 evolution through oxidative C-H/N-H
cross-coupling strategy (Scheme 1B). The
imidazoheterocycle radical cation is proposed to play
a vital role in this photocatalytic transformation.
Entry
Photocatalyst
X
Y
Solvent
Yield(%)b)
-
1
2
Acr+-MesClO4
Ru(bpy)3Cl2
Eosin Y
5
5
5
5
5
3
3
3
3
5
-
3
3
3
3
3
3
3
3
3
5
5
-
DCE
DCE
DCE
DCE
DCE
DCE
DMF
DMSO
MeCN
DCE
DCE
DCE
DCE
64
4
2
3
23
n.d.
78
4
Rodamine 6G
5
Methylene Blue
-
6
Acr+-MesClO4
-
Acr+-MesClO4
16
7
-
Acr+-MesClO4
3
8
-
Acr+-MesClO4
12
9
87c)
n.d.
trace
n.d.
-
10
11
12
13d)
Acr+-MesClO4
-
Acr+-MesClO4
5
5
-
Acr+-MesClO4
5
-
Scheme 1. (A) Traditional oxidative coupling using
stoichiometric oxidant; (B) Oxidant-free oxidative cross-
coupling with the radical cation species as the key
intermediate (PC= Photo catalyst; Co =cobaloxime
catalyst).
Results and Discussion
The installation of the azole functionality into the
imidazopyridine
moiety may render these
compounds more valuable in the subject of drug
discovery and material applications.[18] Employing
zolimidine and 3,5-dimethylpyrazole 2a as model
reaction partners, the reaction conditions such as
photocatalyst, solvent and the ratio between
photocatalyst and cobaloxime catalyst were screened.
The screening of photocatalyst showed that Acr+-
a)
Conditions:
zolimidine
(0.25
mmol),
3,5-
dimethylpyrazole 2a (0.5 mmol), photocatalyst (X mol%)
and Co(dmgH)(dmgH2)Cl2 (Y mol%) was stirred in 3 mL
solvent for 24 h under irradiation at room temperature in
N2 atmosphere. b) The yields were determined by GC using
biphenyl as the internal standard. c) isolated yields. d) under
dark conditions.
-
MesClO4 was the best candidate which could result
in the highest yield compared with other common
organic dyes and the widely used Ru(bpy)3Cl2 (Table
1, entries 1-5). In addition, the ratio between
photocatalyst and cobaloxime catalyst was
investigated, the results implied that the 1:1 mixture
of these two catalysts gave the best performance. The
screening of solvent indicated that high polar solvent
With the optimized reaction conditions established,
we explored the scope of imidazo[1,2-ɑ]pyridines
using 3,5-dimethylpyrazole 2a as co-partner (Scheme
2). Firstly, the effect of substituents on the arene part
2
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10.1002/adsc.201800531
Advanced Synthesis & Catalysis
(Ar) to this transformation was investigated. A
variety of substituents on the aromatic ring were
compatible under the standard conditions. Halo
substituents including fluorine, chlorine and bromine
which were useful for further functionalization were
well tolerated and the target molecules could be
produced in nearly quantitative yields (3ba-3da).
Both electron-rich (3ea, 3fa) and electron-poor (3ga-
3ja) substituents were excellent reaction partners
under standard conditions, affording the desired
products with high isolated yields. In addition, as a
commercial available anxiolytic agent, zolimidine
was employed as reaction partner successfully (3ia).
Besides, OTf substituent which was a common good
leaving group was well tolerated in our conditions
(3ja). Notably, thiophene ring was tolerated as well,
leading to coupling product in 93% yield (3ka). We
then examined the effect of the substituents on the
pyridine ring. The pyrimidine group was proved to be
good candidate for this transformation (3la), which
was an important skeleton in many bioactive
molecules. Moderate yields could be obtained for the
ester and methyl substituted substrates (3ma, 3na). In
comparison, excellent yield could be achieved for the
substrate bearing a fluorine (3oa) on the pyridine ring.
because they are important structural moieties in
many kinds of pharmacologically active compounds
and usually act as directing groups in the transition
metal catalyzed reactions. Next we turned our
attention to investigate the tolerance of azoles 2 by
employing 1a as reaction co-partner (Scheme 3). As
shown in Scheme 4, substituted pyrazoles were all
excellent reaction partners, leading to the target
products in excellent yields (3ab-3ae). It was worth
mentioning that halogen groups which provided a
further functionalization site were tolerated well
under our conditions (3ad, 3ae). Besides pyrazoles,
imidazole
was
tolerated
well
by
using
hexafluoroisopropanol (HFIP) as co-solvent (3af). In
addition to pyrazoles, imidazole and triazoles
including 1,2,3-triazole and 1,2,4-triazole were
employed successfully, affording the corresponding
products in moderate yields (3ag, 3ah).
Scheme 3. Substrate scope of azoles. Reaction Conditions:
-
0.25 mmol 1a, 0.5 mmol 2, 5 mol% Acr+-Mes ClO4 , and 5
mol% Co(dmgH)(dmgH2)Cl2 was dissolved in 3 mL DCE.
The reaction solution was irradiated using 3W blue LEDs
for 24 h at room temperature under nitrogen atmosphere.
The yields were isolated yields. b Reaction time was 48 h. c
1.5 mL DCE and 1.5 mL HFIP (hexafluoroisopropanol)
was used as component solvent.
To expand the potential utility of this reaction for
medicinal chemistry, other imidazoheterocycles, such
as benzo[d]-imidazo[2,1-b]thiazole derivatives which
are important building blocks in synthetic organic
chemistry,[19] were also subjected to this reaction
protocol
(Scheme
4).
Unbiased
benzo[d]-
imidazo[2,1-b]thiazoles were well tolerated to afford
the desired products (5aa-5ca) in moderate yields.
Electron-rich substrate was successfully converted
into product in 75% yield under our conditions (5da).
Notably, substrate with nitro group which was
usually reduced in CCHE reactions was also
compatible although in relatively low yield (5ea).
Scheme 2. Substrate scope of imidazo[1,2-ɑ]pyridines.
Reaction Conditions: 0.25 mmol 1, 0.5 mmol 2a, 5 mol%
-
Acr+-MesClO4 , and 5 mol% Co(dmgH)(dmgH2)Cl2 were
dissolved in 3 mL DCE. The reaction solution was
irradiated using 3W blue LEDs for 24 h at room
temperature under nitrogen atmosphere. The yields were
isolated yields.
It is of great significance to develop efficient
methods for the synthesis of functionalized azoles
3
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10.1002/adsc.201800531
Advanced Synthesis & Catalysis
Scheme 6. Gram-scale experiment
80
60
40
20
0
Scheme 4. Further application of our strategy to benzo[d]-
imidazo[2,1-b]thiazole derivatives. Reaction conditions:
0
1
2
3
4
5
6
-
0.25 mmol 4, 0.5 mmol 2a, 5 mol% Acr+-MesClO4 , and 5
mol% Co(dmgH)(dmgH2)Cl2 were dissolved in 5 mL DCE.
The reaction solution was irradiated using 3W blue LEDs
for 48 h at room temperature under nitrogen atmosphere.
The yields were isolated yields.
Figure 1. Profile of the reaction with the light on/off over
time.
As we proposed, the single electron oxidation of
arene is the initial and key step in this process. Cyclic
voltammetry (CV) experiments were conducted in
order to obtain some insights into this oxidant free
Several
arylimidazopyridines were tested. As shown in Figure
2A, obvious oxidation peaks of 2-
arylimidazopyridines 1 were detected. The oxidation
potentials of 2-arylimidazopyridines substituted with
electron-donating groups were relatively low (1n 1.24
V and 1e 1.26 V vs. saturated calomel electrode
(SCE)). The oxidation peaks of substrates with
electron-withdrawing groups, such as 1h (CF3) and 1j
(OTf) were all observed at 1.39 V vs. SCE. Moreover,
the oxidation potential of caffeine was 1.64 V vs.
SCE (Figure 2B), which implied that it might be
more difficult to be oxidized than 2-
arylimidazopyridines. An oxidation peak of 3,5-
dimethylpyrazole was observed 1.89 V vs. SCE.
We also tested other representative heterocycles to
investigate the applicability and limitation of our
method (Scheme 5). When testing the heterocycles
process.[20]
representative
2-
such
as
benzothiophene,
indole
and
6-
methoxyquinoline, no desired products could be
detected under the standard conditions. However, to
our delight, our method could be used to the direct
modification of caffeine and the site-selective C-H
amination of 2,6-dimethoxypyridine.
The CV experiments provide a direct route to
obtain the detail redox potential of 2-
arylimidazopyridine, while the shortage is the
necessity to synthesize various imidazoheterocycles.
Therefore, we hope to determine the oxidation
potentials of various 2-arylimidazopyridines using
computational methods.[21] As shown in Figure 3, the
Scheme 5. The direct C-H amination of other heterocycles.
In addition, we conducted the photocatalytic
reaction
on
a
gram-scale
using
2-(4-
bromophenyl)imidazo[1,2-a]pyridine 1d as the
substrate (Scheme 6). The corresponding C-N
coupling product was smoothly formed under the
standard conditions, which showed the potential
value in industrial process. According to the profile
of the reaction with the light on/off over time (Figure
1), the continuous irradiation of visible light was
essential to this photocatalytic transformation and the
reaction should proceed through a photoredox
catalytic pathway.
oxidation
potentials
and
of
selected
2-
arylimidazopyridine
benzo[d]-imidazo[2,1-
b]thiazole derivatives were calculated to be between
1.41 and 1.67 V (vs. SCE). The density functional
theory (DFT) calculations were consistent with the
trend of the above CV results. Considering the
-
reduction potential of [Acr+-MesClO4 ]* (E1/2
=
red
+2.06 V vs. SCE), the single-electron oxidation of
4
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10.1002/adsc.201800531
Advanced Synthesis & Catalysis
we also probed the properties of other formed 2-
arylimidazopyridines and benzo[d]-imidazo[2,1-
b]thiazole radical cations (1l’, 1i’, 4a’). The results
showed that these arene radical cations all have
unique electron density at C3 position. Both results of
ASD and FMO analysis suggested that the radical
cation had higher reactivity at C3 position and
nucleophiles would preferentially react at this
position. To further study the arene radical cation in
this system, we then performed the trapping
experiment using 1,1-diphenylethylene as the
trapping reagent (Scheme 7). The C-C coupling
product 8 was detected and evidenced by GC-MS and
NMR spectra, which highly proved the existence of
2-arylimidazopyridine radical cation that might be
initially formed via the oxidation by excited
photoredox catalyst.
Figure 2. CV experiments in CH3CN with nBu4NBF4
(0.060 M) using Ag/AgCl electrode as the reference. (A)
CV results (vs. SCE) of 2-arylimidazo[1,2-a]pyridines. (B)
CV results (vs. SCE) of 2-arylimidazopyridine 1n, caffeine
and 3.5-dimethylpyrazole 2a.
various 2-arylimidazopyridines and benzo[d]-
-
imidazo[2,1-b]thiazoles by the [Acr+-MesClO4 ]* are
favorable, which can generate arene radical cation
intermediate to initiate this transformation.
Figure 4. Calculated Mulliken atomic spin densities
(ASD) and lowest unoccupied molecular orbital of the
corresponding radical cations.
Figure 3. The calculated oxidation potential (vs. SCE) of
selected arenes by DFT calculations.
Scheme 7. The trapping experiment using 1,1-
diphenylethylene.
To
probe
the
unique
selectivity
of
In previously reports, Nicewicz and co-workers
have researched the reaction between alkene radical
cation and nucleophiles via experimental and DFT
studies in detail.[23] We also used DFT calculations to
get some insights into the reaction between arene
radical cation and azole nucleophile. As shown in
Scheme 8, the pyrazole firstly reacts easily with 2-
arylimidazopyridine radical cation I with a free
energy barrier of only 11.4 kcal/mol to generate the
intermediate II, and the reaction free energy is 5.6
imidazoheterocycles in our system, density functional
theory (DFT) calculations were employed to study
the reactivity of the formed radical cation species.[22]
As shown in the following Figure 4, the calculated
results of Mulliken atomic spin densities (ASD) of
radical cation 1a’ suggested that the spin density on
C3 position was 0.58. Frontier molecular orbital
(FMO) analysis also revealed that the β-LUMO of
1a’ was mainly located on C3 position. In addition,
5
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10.1002/adsc.201800531
Advanced Synthesis & Catalysis
Conclusion
kcal/mol. The following step is the deprotonation of
radical
cation
intermediate
II.
Both
2-
In conclusion, we have developed a photoredox
oxidant free oxidative C-H/N-H cross-coupling,
which can realize the site-selective functionalization
on the C3 position of imidazoheterocycles. With the
evolution of H2, a series of imidazoheterocycle
skeletons were successfully converted to the
corresponding structures in high yields by employing
azoles as co-partner. Other imidazoheterocycles such
as benzo[d]-imidazo[2,1-b]thiazole derivatives were
compatible well under our conditions, which shed
light on the potential application of this methodology.
Experimental and DFT calculation results
demonstrated that the arene radical cation played an
important role in this C-H amination process. Our
protocol can also be applied in the direct C-H
amination of electron-rich pyridine and caffeine.
However, the direct transformation of simple
heterocycles was failed under the standard conditions.
It is highly demand to develop new photocatalytic
system for the direct C-H functionalization of simple
heterocycles in further research.
arylimidazopyridine and Co(I) species could be acted
as base to trap the proton in this case. The reaction
free energy of the deprotonation process for these two
conditions are -11.5 kcal/mol and -28.7 kcal/mol,
respectively. The results illustrate that the reaction
between 2-arylimidazopyridine radical cation I and
pyrazole could be pulled by the following
deprotonation step.
Scheme 8. The DFT calculations of the reaction between
arene radical cation and pyrazole.
Experimental Section
Based on experiment results and our understanding
of the transformation, a plausible mechanism is
outlined in Scheme 9. Initially, the photocatalyst is
A mixture of imidazoheterocycle (0.25 mmol),
pyrazole (0.5 mmol), Acr+-MesClO4 (5 mol%), and
-
-
converted into its excited state [Acr+-MesClO4 ]*
through the irradiation of blue LEDs,[24] which
undergoes single-electron transfer (SET) process with
Co(dmgH)(dmgH2)Cl2 (5 mol%) was stirred in DCE
(3 mL) under nitrogen atmosphere in a 10 mL
Schlenk tube and irradiated by 3W blue LEDs for 24
h. After completion of the reaction, H2 was detected
by GC-TCD. Then the reaction system was quenched
by ethyl acetate. After evaporation of solvent the
imidazoheterocycles to form the
corresponding
radical cation species 9.[9],[18b],[22b] Subsequently,
azoles 2 as nucleophile attacks the radical cation 9,
then affording radical species 10 with losing one
proton. On the other hand, Co(III) catalyst oxidizes
the reduced photocatalyst to recycle the photocatalyst
and generate the Co(II) species at the same time.[25]
Then, the radical adduct 10 is likely to undergo a SET
process with Co(II) species, affording cation
intermediate 11, which can lose one proton and yield
the target product. Co(I) captures the proton to yield
Co(III)-H species.[26] H2 can be released through the
interaction between proton and Co(III)-H species 12,
which revives Co(III) and completes the catalytic
cycle.
crude
product
was
purified
by
column
chromatography on silica gel using petroleum
ether/ethyl acetate as eluent.
Acknowledgements
This work was supported by the National Natural Science
Foundation of China (21390402, 21520102003, 21272180) and the
Natural Science Foundation of Hubei Province (2016CFB571).. The
Program of Introducing Talents of Discipline to Universities of
China (111 Program) is also appreciated. The numerical
calculations in this paper have been carried out on the
supercomputing system in the Supercomputing Center of Wuhan
University.
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Advanced Synthesis & Catalysis
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Advanced Synthesis & Catalysis
FULL PAPER
TOC Graphic
Title Text: External Oxidant Free Regioselective
Cross
Dehydrogenative
Coupling
of
2-
Arylimidazoheterocycles and Azoles with H2
Evolution via Photoredox Catalysis
Adv. Synth. Catal. Year, Volume, Page – Page
Hong Chen,a, Hong Yi,a, Zilu Tang,a Changliang
Bian,a Heng Zhang,*,aand Aiwen Lei*,a,b
9
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