Palladium-Catalyzed Electro-oxidative C-H Amination toward the Synthesis of Pyrido[1,2- A[benzimidazoles with Hydrogen Evolution

Article abstract of DOI:10.1021/acscatal.0c00103

Transition-metal-catalyzed oxidative C-H/N-H coupling reaction is an important method to construct C-N bonds. However, stoichiometric oxidants were usually necessary. Here, we report a palladium-catalyzed electro-oxidative intramolecular C-H/N-H annulation reaction without an external oxidant or additive. A variety of pyrido[1,2-a]benzimidazoles were constructed by a simple, green, and mild path. Experimental results suggested that Pd(0) could be oxidized on the anode to be recycled.

Full text of DOI:10.1021/acscatal.0c00103

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Letter
Palladium-catalyzed Electrooxidative C–H Amination towards the
Synthesis of Pyrido[1,2-a]benzimidazoles with Hydrogen Evolution
Zhengli Duan, Lin Zhang, Wenxin Zhang, Lijun Lu, Li Zeng, Renyi Shi, and Aiwen Lei
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c00103 • Publication Date (Web): 27 Feb 2020
Downloaded from pubs.acs.org on February 27, 2020
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Palladium-catalyzed Electrooxidative C–H Amination towards
the Synthesis of Pyrido[1,2-a]benzimidazoles with Hydrogen
Evolution
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†
‡
†
†
†
†
† ∮ ‡
,
Zhengli Duan , Lin Zhang , Wenxin Zhang , Lijun Lu , Li Zeng , Renyi Shi ,and Aiwen Lei*, ,
†The Institute for Advanced Studies (IAS), College of Chemistry and Molecular Sciences, Wuhan University, Wu-
han, Hubei 430072, PR China
∮
State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of
Sciences, 345 Lingling Road, Shanghai 200032, PR China
‡
National Research Center for Carbohydrate Synthesis Jiangxi Normal University, Nanchang, Jiangxi 330022, PR
China
ABSTRACT: Transition-metal catalyzed oxidative C-H/N-H coupling reaction is an important method to construct C-N
bond. However, stoichiometric oxidants were usually necessary. Here reported is a palladium-catalyzed electrooxidative
intramolecular C-H/N-H annulation reaction without external oxidant or additive. A variety of pyrido[1,2-a]benzimidazoles
were constructed by a simple, green and mild path. Experimental results suggested that Pd(0) could be oxidized on the
anode to recycle.
KEYWORDS: C–H amination, electrooxidization, palladium catalysis, hydrogen evolution, cyclization
Pyrido[1,2-a]benzimidazole is a primary motif in
medicinal chemistry, especially in some bioactive
molecules, for examples, antimalarial1, anti-cancer agent 2,
antitumor3, 4 and antiviral agent5 (Figure 1). Consequently,
substantial methods have been developed to construct
pyrido[1,2-a]benzimidazole and its derivatives via the
annulation of N-phenylpyridin-2-amines, which is one of
the most straightforward paths6, 7. In 2010, a Cu-catalyzed
annulation of N-phenylpyridin-2-amine was firstly
achieved to produce pyrido[1,2-a]benzimidazoles from N-
(p-tolyl)pyridin-2-amines8 (Scheme 1A). After that, I2 and
Electrochemical anodic oxidation is recognized as an
organohypervalent iodine reagents were found to be
effective to induce this process as oxidants9-11 (Scheme 1B).
Despite the notable progress, it still ‘can not be ignored
that stoichiometric oxidants were usually necessary and
only copper was found to be effective for this
transformation among transition metal catalysts. Thus it is
attracting and promising to find a mild, effcient and
external oxidant free reaction to construct this valuable
chemical structure.
efficient and environmentally friendly synthetic strategy
because it avoids the use of external oxidant. In the last
decades, electrooxidation has been developed wildly in
organic synthetic chemistry12-16. In particular, transition-
metal-catalyzed electrooxidative C-H activation reactions
have been proven to be a promising and feasible alternative
to construct C-C bond. Recently, Ackermann17-20, Xu21,
Mei22-25 and Lei26-28 have developed varieties of
electrooxidative transition metal catalytic systems,
providing efficient paths to construct important chemical
bonds, such as C-C, C-O, C-P, etc. Among these researches,
several transition metals, including Rh, Ru, Co, Pd, etc.,
were found to be effective. Despsite of the achievements,
transition-metal-catalyzed electrooxidative C-H activation
reactions are still under developed. Here we report a Pd
catalyzed electrooxidative C-H cycloamination to
Figure
1.
Biologically
active
pyrido[1,2-
a]benzimidazole derivatives
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synthesize pyrido[1,2-a]benzimidazoles under mild
conditions without external oxidant or additive.
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no catalyst
n. d.
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7
8
no electric current
trace
Scheme 1. Reaction design
aStandard reaction conditions: carbon cloth plate (10 mm×5
mm×0.36 mm) anode, Fe plate (10 mm×5 mm×1 mm) cathode,
constant current=2 mA, 1a (0.20 mmol), Pd(PPh3)2(OAc)2 (0.01
mmol), LiClO4 (0.40 mmol), CH3CN (2.5 mL), HCOOH (2.5 mL),
N2, room temperature, 6.5 hours, undivided cell. bYields were de-
tected by GC. n. d.=not detected. cIsolated yield.
9
With the optimized reaction conditions, we turned to
evaluate the substrate scope of palladium-catalyzed C-H
amination reactions (Table 2). For the substrates with
substitutes on the benzene ring, stronger electron
donating groups can lead to 99% yields (2b and 2c).
However, substrates with some weaker electron donating
groups only give moderate yields (2d-2e). And different
two substituent groups in the ortho-, meta- and para-posi-
tions could also be tolerated well (2f-2h). The 2i was iso-
lated as a mixture of two isomers of which the quantities
were close. However, this phenomenon was not found for
2g. That may be because of the little electron property dif-
ference between the two functional groups in the meta-
and para-positions of 2i. And eletron-withdrawing groups
resulted in the less reactivity of substrates to produce pyr-
ido[1,2-a] benzimidazoles (2j-2m). And substrate with phe-
nyl substituent in the para-position only gave moderate
yield (2n). The scope with respect to the pyridine ring was
also investigated. Electron donating groups in the pyridine
ring could be tolerated well (2o-2s) while trifluoromethyl
group resulted in poor yield. The studies of substrate scope
showed that generally electron rich substrates reacted bet-
ter than the electron poor ones, which may indicate the
palladium catalyzed electrophilic metalation-deprotona-
tion process is involved in the mechanism.
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N-(p-tolyl)pyridin-2-amine was applied as model
substrate to optimize the reaction conditions (Table 1).
When the 5 mol% Pd(PPh3)2(OAc)2 was used as catalyst
and 2 equivalent LiClO4 was used as electrolyte, 92%
isolated yield of 2a could be obtained under 2 mA constant
current and room temperature in an undivided cell (Entry
1). Lower yields were obtained when 5 mol% Pd(OAc)2 with
10 mol% PPh3 or 5 mol% Pd(PPh3)4 were used (Entry 2 and
n
3). The replacing of LiClO4 by Bu4NPF6 and NH4OAc led
to the significant decrease of the yield, that meant the
electrolyte was also critical for the reaction (Entry 4 and 5).
CH3CN and HCOOH were tried as solvent and the mixture
of them was found to be the most suitable solvent (Entry 6
and 7). And electrode material played vital role in the
reaction. 1a stayed unreacted when Pt plate was applied as
anode instead of carbon cloth (Entry 8). And Ni cathode
led to 50% yield (Entry 9). It was found that changing
constant current to a higher or lower current both led to
lower yields (Entry 10 and 11). Control experiments proved
that catalyst and electricity were all indispensable (Entry 12
and 13).
Table 2. Substrate scopea
Table 1. Optimization of reaction conditionsa
Entry 1
Variation from standard conditions Yieldb
none
92c
5 mol% Pd(OAc)2 and 10 mol% PPh3 78
1
2
3
5 mol% Pd(PPh3)4
64
38
61
4
5
2 equiv. nBu4NPF6
2 equiv. NH4OAc
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5 mL CH3CN as solvent
5 mL HCOOH as solvent
Pt anode instead of C cloth anode
Ni cathode instead of Fe cathode
1 mA, 13 h
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22
n. d.
50
72
3 mA, 3.25 h
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aStandard reaction conditions: carbon cloth plate (10 mm×5
mm×0.36 mm) anode, Fe plate (10 mm×5 mm×0.1 mm) cathode,
constant current=2 mA, 1a (0.20 mmol), Pd(PPh3)2(OAc)2 (0.01
mmol), LiClO4 (0.40 mmol), CH3CN (2.5 mL), HCOOH (2.5 mL),
N2, room temperature, 6.5 h, undivided cell. b1 mA, 13 h. c1 mA, 22
h. d2 mA, 22 h.
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0.05
0.04
0.03
0.02
0.01
0.00
-0.01
1a
Pd(PPh3)4
1a+Pd(PPh3)4
Scheme 2. Gram-scale synthesis
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0.0
0.5
1.0
1.5
2.0
Potencial (V)
Scheme 3. Competition experiment
Scheme 4. Proposed mechanism
To our delight, this electrooxidative Pd catalyzed C-H
amination protocol can be scaled up to give good yield.
After reacting for 48 hours at room temperature, 10.0 mmol
of 1a can be converted to 2a in 46% yield and 0.85 gram
desired products were isolated (Scheme 2). A competition
experiment was conducted to find that the animation
reaction favored electron-rich aryl substrate over electron-
deficient one (Scheme 3). This result indicated that a
electrophilic metaliation process may involved in the
reaction.
To further go deep into the mechanism, cyclic
voltammetry experiments of N-(p-tolyl)pyridin-2-amine
were conducted. As shown in figure 2, two obvious
oxidation peak of Pd(PPh3)4 were observed at 1.36 V and
1.75 V, of which the the peak of 1.36 V may result from Pd(0).
And the two oxidation peaks of N-(p-tolyl)pyridin-2-amine
were found at 1.53 V and 1.83 V. The lower oxidation peak
of Pd(PPh3)4 than N-(p-tolyl)pyridin-2-amine indicated
that the Pd(0) may be oxidized before 1a. However, the two
oxidation peaks of N-(p-tolyl)pyridin-2-amine stayed
unchanged. Considering the reported proposed Pd
catalytic mechanism 29, and combining the results of entry
3, entry 12 in Table 1 and cyclic voltammetry experiments,
a possible mechanism was proposed as follows (Scheme 4).
Firstly, Pd(II) coordinated with substrate 1, followed by a
two-step electrophilic deprotonation process with the
assist of X- (X=OAc or HCOO) to form Pd arylation
complex 3. Then palladium complex 3 underwent a
reductive elimination process to give desired product 4 and
Pd(0). Pd(0) would be oxidized by anode to be recovered
to Pd(II).
In summary, we developed a electrooxidative palladium
catalyzed C-H cycloamination to produce the important
chemical structure pyrido[1,2-a]benzimidazoles under
green, simple and mild conditions. This reaction avoided
the use of external oxidant and additive, and H2 was the
only byproduct. Different substituted substrates could give
moderate to good yields. And scale up experiment showed
the application potential of the reaction in industrial.
Preliminary mechanistic investigations indicated that
Pd(II) may induce the conversion of substrate to produce
Pd(0) which could be oxidized on anode. What is more,
this electrooxidative palladium catalyzed C-H/X-H (X= N,
O, P, S, etc.) activation is a promising strategy that might
be applied to develop traditional palladium catalyzed ther-
mal reactions to milder, greener and sustainable ones.
ASSOCIATED CONTENT
This material is available free of charge via the Internet at
http://pubs.acs.org.
Figure 2. Cyclic voltammetry experiments
AUTHOR INFORMATION
Corresponding Author
* E-mail: aiwenlei@whu.edu.cn.
ORCID
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Cleavage and Its Application in Aromatic C−H Bond
Functionalization. Angew. Chem. Int. Ed. 2017, 56, 587-590.
13. Huang, C.; Qian, X. Y.; Xu, H. C., Continuous-Flow
Aiwen Lei: 0000-0001-8417-3061.
Notes
The authors declare no competing financial interest.
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Electrosynthesis
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Dehydrogenative C-S Cross-Coupling. Angew. Chem. Int. Ed. 2019,
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SUPPORTING INFORMATION
Experimental details, NMR spectra of products.
14. Lips, S.; Franke, R.; Waldvogel, S. R., Electrochemical
Synthesis of 2-Hydroxy-para-terphenyls by Dehydrogenative
Anodic C–C Cross-Coupling Reaction. Synlett. 2019, 30, 1174-
1177.15. Waldvogel, S. R.; Rockl, J.; Schollmeyer, D.; Franke, R.,
Dehydrogenative Anodic C-C Coupling of Phenols Bearing
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16. Xu, F.; Long, H.; Song, J.; Xu, H. C., De Novo Synthesis of
Highly Functionalized Benzimidazolones and Benzoxazolones
through an Electrochemical Dehydrogenative Cyclization
Cascade. Angew. Chem. Int. Ed. 2019, 58, 9017-9021.
17. Qiu, Y.; Kong, W. J.; Struwe, J.; Sauermann, N.; Rogge, T.;
Scheremetjew, A.; Ackermann, L., Electrooxidative Rhodium-
Catalyzed C-H/C-H Activation: Electricity as Oxidant for Cross-
Dehydrogenative Alkenylation. Angew. Chem. Int. Ed. 2018, 57,
5828-5832.
18. Qiu, Y.; Stangier, M.; Meyer, T. H.; Oliveira, J. C. A.;
Ackermann, L., Iridium-Catalyzed Electrooxidative C-H
Activation by Chemoselective Redox-Catalyst Cooperation.
Angew. Chem. Int. Ed. 2018, 57, 14179-14183.
19. Qiu, Y.; Tian, C.; Massignan, L.; Rogge, T.; Ackermann, L.,
Electrooxidative Ruthenium-Catalyzed C-H/O-H Annulation by
Weak O-Coordination. Angew. Chem. Int. Ed. 2018, 57, 5818-5822.
20. Sauermann, N.; Mei, R.; Ackermann, L., Electrochemical C-H
Amination by Cobalt Catalysis in a Renewable Solvent. Angew.
Chem. Int. Ed. 2018, 57, 5090-5094.
21. Xu, F.; Li, Y.-J.; Huang, C.; Xu, H.-C., Ruthenium-Catalyzed
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ACKNOWLEDGMENT
This work was supported by the National Natural Science
Foundation of China (21520102003, 21702152) and the Hubei
Province Natural Science Foundation of China (2017CFA010).
The Program of Introducing Talents of Discipline to
Universities
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of China (111 Program) is also appreciated.
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