Direct arylation of pyrroles via indirect electroreductive C-H functionalization using perylene bisimide as an electron-transfer mediator

Article abstract of DOI:10.1021/acs.orglett.5b03581

The indirect electroreductive coupling of aryl halides and pyrroles was successfully conducted using a catalytic amount of perylene bisimide as a mediator in 1-ethyl-3-methylimidazolium bis((trifluoromethyl)sulfonyl)imide ([EMIM]NTf₂)/DMSO.

Full text of DOI:10.1021/acs.orglett.5b03581

Letter
pubs.acs.org/OrgLett
Direct Arylation of Pyrroles via Indirect Electroreductive C−H
Functionalization Using Perylene Bisimide as an Electron-Transfer
Mediator
Guoquan Sun, Shuya Ren, Xinhai Zhu,* Manna Huang, and Yiqian Wan
School of Chemistry and Chemical Engineering, Sun Yat-Sen University, Guangzhou 510275, P. R. of China
*
S Supporting Information
ABSTRACT: The indirect electroreductive coupling of aryl
halides and pyrroles was successfully conducted using a catalytic
amount of perylene bisimide as a mediator in 1-ethyl-3-
methylimidazolium bis((trifluoromethyl)sulfonyl)imide
(
[EMIM]NTf )/DMSO.
2
lectroorganic synthesis has been recognized as an environ-
mentally friendly methodology for the oxidation and
challenging. For example, Gryko and co-workers pioneered the
15
E
base-mediated direct arylation of pyrroles. However, hash
conditions such as the use of strong bases or high reaction
temperatures were required as a prerequisite, making this method
less practicable.
reduction of organic compounds because the dangerous and
toxic redox reagents often used in classic reactions are replaced
1
with an electric current. The traditional electrochemical
methods in electroorganic syntheses were reviewed a few years
Perylene-3,4:9,10-tetracarboxylic acid diimide derivatives
(abbreviated in this paper as PDIs) are an outstanding class of
organic dye molecules and have more recently been used in the
2
ago. In recent years, novel strategies and applications of new
3
methods for effecting organic electrooxidative reactions and
4
1
6
electroreductive reactions have been developed. Compared with
field of organic electronics and fluorescence materials.
direct electrolysis, indirect electroorganic conversions that use
redox mediators to achieve indirect processes are attaining
Recently, Ghosh and co-workers reported the use of PDIs as
photocatalysts for the reduction of aryl halides to generate aryl
5
17
increased significance and exhibiting numerous advantages. For
radicals. Moreover, some catalysts that are frequently used as
photoredox catalysts are useful mediators for electrochemical
example, indirect electroorganic synthesis exhibits higher
reaction selectivity because the electrolysis is conducted at
lower potentials than the redox potentials of the starting
materials. Although the concept of indirect electrolysis was
5
applications, such as 2,3-dichloro-5,6-dicyano-1,4-benzoqui-
18
19
none (DDQ). The electrochemical properties of PDIs
suggest that they could be used as possible mediators for indirect
electroorganic syntheses because of their lower reversible redox
6
established many years ago, many new exciting and useful
developments continue to be reported, especially with respect to
5
potentials. However, to the best of our knowledge, PDIs have
5
indirect electrooxidation reactions. However, progress in
never been used in indirect electroorganic syntheses. Hence, we
report the direct C−H arylation of pyrroles using PDIs as
electron transfer mediators.
Initially, two types of PDIs with good solubility were
synthesized (Figure 1, left). The electrochemical properties of
these compounds were investigated using cyclic voltammetry
indirect electroreductive chemistry remains slow and appears to
7
be restricted to the use of nickel and cobalt complexes, diphenyl
8
9
10
diselenide, other transition-metal complexes, fullerenes, and
4
f
carboranes. Notably, reports on the use of aromatic hydro-
carbons as mediators for electroreductive reactions have only
11
been found in selected numbers in older literature. As far as we
know, the indirect electrochemical method for the aryl C−C
coupling reactions are rare, although a powerful and practical
indirect electrooxidation method for the cross-coupling of
phenols with arenes, reported by Waldvogel and co-workers,
impressed us.
Functionalized pyrroles are abundant in natural products and
(
CV). As illustrated in Figure 1 (right), the cyclic voltammograms
of PDI-1 and PDI-2 both showed two reversible one-electron
reduction waves, which indicates that the molecules could be
controllably reduced to stable radical mono- and dianionic
species with distinctive optical properties.
To explore the production of stable radical mono- and
dianionic species in more detail, the absorption spectra of the
radical mono- and dianionic species of PDI-1 were measured by
implementing a potentiostatic electrochemical experiment with
1
2
1
3
medicinal agents. The direct arylation of pyrroles through C−H
bond activation has been demonstrated to be a very powerful
method for the synthesis of various functionalized pyrroles.
However, most of the reported methods involve the utilization of
transition metals such as palladium, rhodium, copper, and cobalt
Received: December 17, 2015
1
4
as catalysts. In contrast, metal-free methodologies are rare and
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b03581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
17
formation of PDI dianions. Notably, the intensity and profile of
the spectrum collected immediately after the power was turned
off was unchanged after electrolysis for 20 min at −2.5 V.
However, slight shaking of the reaction mixture resulted in the
regeneration of the radical monoanion, whereas vigorous shaking
induced the regeneration of the neutral PDI-1 (Figure 2, below).
These results suggest that the neutral, monoanionic, and
dianionic species of PDI-1 were interchangeable and were
favorable for mediatory use in an electrocatalytic reaction.
To determine whether redox catalysis of the PDIs was possible,
we also recorded the cyclic voltammograms of PDI-1 and PDI-2
in the presence of 4-bromoacetophenone (1a). As illustrated in
Figure 3, the reductive current for PDI-1 increased and the
Figure 1. Left: Chemical structures of the synthesized PDIs. Right:
Cyclic voltammograms of PDI-1 and PDI-2. Conditions: 5 mM PDI in
0
.15 M [EMIM]NTf /DMSO (υ = 100 mV/s) using a glassy carbon
2
working electrode; potentials vs Ag/AgNO in CH CN.
3
3
an in situ spectroelectrochemistry measuring technique (Figure
2
0
2).
Figure 3. Electrocatalysis and reversibility. Experimental conditions:
PDI-1 (5 mM), substrate 1a (20 mM), mixture (5 mM PDI + 20 mM
1
a); measured in 0.15 M [EMIM]NTf /DMSO (υ = 100 mV/s) using a
2
glassy carbon working electrode; potentials vs Ag/AgNO in CH CN.
3
3
reoxidation peak disappeared, thereby indicating the presence of
a typical catalytic current. These results indicate that the transfer
of electrons from the electrode to PDI-1 occurred initially, with
subsequent electron transfer from the mono- or dianionic species
of PDI-1 to 1a. This result confirms that PDI-1 could mediate
electron transfer between the electrode and substrate. Compared
with the cyclic voltammogram of PDI-1 in the presence of
substrate 1a, that of PDI-2 showed no obvious catalytic current
(
Figure S3), likely as a consequence of the lower peak current of
PDI-2 at the same concentration. Hence, PDI-1 was
demonstrated to be a better candidate than PDI-2 and was
used for further research on indirect electroreductive C−H
functionalization reactions.
Figure 2. Spectroelectrochemistry of PDI-1. Conditions: PDI-1 (2 ×
In studies of indirect cathodic reduction, a divided cell is
usually used for the mediator system to prevent anodic oxidation
of the reductive species after they have been generated at the
cathode. Initially, the model reactions of 1-methyl-1H-pyrrole
−
5
1
0
M) in 0.15 M [EMIM]NTf /DMSO using a platinum minigrid
2
working electrode, a platinum wire counter electrode and a Ag/AgCl
reference electrode, without the protection of N . Potentiostatic
2
electrolysis at marked potentials vs Ag/AgCl.
(
2a) and 1a with or without a catalytic amount (10 mol %) of
mediator PDI-1 in 0.15 M [EMIM]NTf /DMSO were carried
2
out at room temperature in an H-type divided cell equipped with
a glassy carbon (GC) cathode and a graphite rod anode (Scheme
According to the CV results (with Ag/AgCl as a reference
electrode), reduction potentials of −0.4, −1.2, −1.8, −2.0, and
2.5 V were applied separately to compound PDI-1 for 100 s
before the absorption spectra were collected. As shown in Figure
(above), the absorption spectrum of PDI-1 remained
unchanged when the potential was increased from −0.4 to
1.8 V, which was probably because of the low current density.
1
). After 5 F/mol of electricity were consumed, the product, 3a,
−
was not detected in the absence of PDI-1; only the byproduct,
acetophenone generated from the dehalogenation reaction, was
obtained in 10% yield, as determined by gas chromatography
2
(
GC) (Table S1, entry 1). In contrast, when PDI-1 was used as a
−
Interestingly, when the potential was increased to −2.0 V, new
bands located at 704 and 798 nm emerged and increased in
intensity with increasing duration of electrolysis time; these
bands composed the diagnostic absorption spectrum of the
electrochemically generated PDI-1 radical monoanions. When
the potential was increased from −2.0 to −2.5 V, the intensities of
the bands at 704 and 798 nm decreased, whereas those of the
bands at 653 and 576 nm increased, which indicated the
Scheme 1. Indirect Electrocatalyzed Arylation of 1-Methyl-
H-pyrrole 2a with 1a
1
17
B
DOI: 10.1021/acs.orglett.5b03581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
mediator, the coupling product of 3a was obtained in 70% GC
yield (Table S1, entry 2). These results revealed the efficiency of
PDI-1.
Scheme 2. Indirect Electrocatalyzed C−H Arylation Reactions
a
of Aryl Halides with Substituted Pyrroles
The reaction parameters were further optimized under
constant-current electrolysis conditions (Table S1). Among the
solvents we had examined to this point, all except CH Cl were
2
2
effective in promoting the conversion of 1a. However, the major
product of the reaction was the unexpected byproduct that
resulted from the dehalogenation of 1a in DMF and DMAc
(Table S1, entries 6, 7). Fortunately, target 3a was generated in
higher yield in DMSO (70%) than when the reaction was
conducted in CH CN (59%) (Table S1, entries 2, 4). In addition,
3
the type of electrolyte used in the reactions substantially affected
the outcome of the model reaction (Table S1, entries 2, 8−12).
We determined that only imidazolium-based ionic liquids were
effective and that 1-ethyl-3-methylimidazolium bis((trifluoro-
methyl)sulfonyl)imide ([EMIM]NTf ) was more suitable as the
2
electrolyte in accelerating the reaction. Control experiments
confirmed that light was not necessary for the electroreduction
reaction (Table S1, entry 16); however, the extent of conversion
decreased substantially when the same amount of electricity was
used if the reaction was carried out with bubbling air (Table S1,
entry 17). We also investigated the stability of the PDI-1
mediator under constant-current electrolysis conditions (4 mA).
Up to 90% of the PDI-1 mediator was recovered even after 5 F/
mol of electricity were consumed. However, the relatively low
isolated yields of 3a (38%) prompted us to examine our reaction
conditions further.
When we analyzed the current (i.e., by collecting potential
curves of the reaction under constant-current electrolysis
conditions (4 mA)), we observed that the potential was very
high (as high as −7 V) because of the high electric resistance of
the H-type divided cell in the absence of electrodes with large
specific surface areas. And the selectivity of the target compound
a
Reactions were electrolyzed with 0.2 mmol of 1 and 25 or 50 equiv of
2 and PDI-1 (10 mol %) in 0.15 M [EMIM]NTf /DMSO (10 mL) at
room temperature under N protection; isolated yield.
2
2
5
regarded to be less reactive for the addition reaction of radicals,
did not carry out the C-arylation under the experimental
conditions. As a result, use of almost the same substrate scope
as that for our indirect electroreductive arylation of pyrroles
together with a shorter time and without Et N, in comparison to
the previously reported PDI-mediating photocatalyzed proto-
3
17
col, encouraged us to explore the mechanism further.
A plausible mechanism for the electrocatalytic coupling
reactions of arylhalides 1 with pyrroles 2 using the PDI-1
mediator is shown in Scheme 3. PDI-1 is reduced at the cathode
3
a was directly related to the electrode potential. However, when
the electrode potential was reduced to below −2 V, the current
was too low to promote the reaction to occur. Thus, the model
reaction was conducted in an undivided cell. As expected, when a
graphite rod was used as an anode, conversion of the substrate
was only 30% even after 7.5 F/mol of electricity were consumed
Scheme 3. Plausible Catalytic Cycle for the Indirect
Electroreductive Arylation of Pyrroles Using PDI-1 as a
Mediator
(Table S2, entry 1). This low yield presumably resulted from the
reoxidation of PDI-1 radical anions to neutral PDI-1 moieties,
which inhibited the redox reaction between PDI-1 radical anions
and substrate 1a, leading to a significant decrease of the faradaic
efficiency of the reaction. To avoid such undesired anodic
reactions, we investigated the use of sacrificial anodes such as zinc,
iron, and brass (Table S2). Encouragingly, the conversion of 1a
and the yield of 3a were satisfactory when the reaction was run
with a zinc anode (Table S2, entry 2).
Then, electroreductive C−C bond-forming arylation reactions
using the PDI-1 mediator were successively applied to aryl
halides with substituted pyrroles (Scheme 2). Aryl bromides, aryl
iodides, and even aryl chlorides bearing electron-withdrawing
groups reacted with 1H-pyrrole, N-methylpyrrole, and N-
phenylpyrrole, affording the corresponding arylated products in
moderate-to-good isolated yields. Even the ortho-substituted aryl
halides generated the desired products in good yields. Although
there are many palladium-catalyzed methods that now can use
to generate PDI-1 radical anions by constant-current electrolysis.
The electron transfer between PDI-1 radical anions and 1 occurs
•
−
rapidly, yielding ArX and regenerating neutral PDI-1. The
•
−
ArX is unstable and undergoes a cleavage reaction yielding the
•
aryl radical, Ar , which then reacts with pyrroles, yielding C−C
−
coupling products 3, or is further reduced to generate Ar and
eventually the hydrocarbon, ArH (4). The neutral PDI-1
generated is then further reduced at the cathode to complete
the catalytic cycle. However, possibly because of that the aryl
14c−e
cheap aryl chlorides for pyrrole arylation,
it should be noted
that this method should be an alternative to the arylation of
pyrroles to be suitable for the C-arylation of NH pyrroles with
activated aryl chlorides as starting materials. However, the
analogs to pyrrole, such as furan, thiophene, or indole, which were
•
radical, Ar , is much easier to reduce than the ArX in the
21
electrochemical conditions, the expected TEMPO (2,2,6,6-
tetramethylpiperidinoxyl) adduct was unfortunately not detected
C
DOI: 10.1021/acs.orglett.5b03581
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
upon electroreduction. The reversible redox behavior of PDI-1
suggested that it was reduced to stable radical mono- and
dianionic species. To confirm the generation of these species, we
collected absorption spectra of the reaction mixture via a
constant-current electrochemical experiment involving an in situ
spectroelectrochemistry measuring technique. As shown in
Figure S4, both PDI-1 radical anions and PDI-1 dianion species
were detected under these reaction conditions. However, the
intensity of the absorption of PDI-1 radical anions at a low
potential was higher than that at a high potential. In addition, the
formation of PDI-1 dianions was more rapid at a high potential.
Notably, electroreduction afforded the coupling products at
either high or low potentials after consumption of the same
amount of electricity. However, the higher potential condition
resulted in higher reaction rates, and the lower potential
condition resulted in better target product selectivity according
to GC-MS analyses (Table S3). These results suggest that PDI-1
radical anions were the effective mediator for the coupling
reactions, which was also confirmed through the higher yield of
the coupling product when the reaction was conducted in an
undivided cell with a lower electric potential (less than −2.0 V).
In conclusion, novel methodology for indirect electroreductive
direct coupling of aryl halides and pyrroles was developed using a
catalytic amount of perylene bisimide as a mediator in
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ASSOCIATED CONTENT
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(
AUTHOR INFORMATION
Corresponding Author
E-mail: zhuxinh@mail.sysu.edu.cn.
■
*
1
(
7
Notes
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The authors declare no competing financial interest.
(
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ACKNOWLEDGMENTS
We thank the National Natural Science Foundation of China
Grant No. 21272282) for supporting this work.
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