Scalable Electrochemical Transition-Metal-Free Dehydrogenative Cross-Coupling Amination Enabled Alkaloid Clausines Synthesis

Article abstract of DOI:10.1002/adsc.202000228

Reported herein is an environmentally benign electrochemical C?H bond dehydrogenative amination protocol for the construction of privileged carbazole moiety with broad generality. Preliminary mechanistic investigations implied a radical reaction pathway.

Full text of DOI:10.1002/adsc.202000228

Title: Scalable Electrochemical Transition-Metal-Free Dehydrogenative
Cross-coupling Amination Enabled Alkaloid Clausines Synthesis
Authors: Pan Zhang, Baoying Li, Liwei Niu, Ling Wang, Guofeng
Zhang, Xiaofei Jia, Guoying Zhang, Siyuan Liu, Li Ma, Wei
Gao, Dawei Qin, and Jianbin Chen
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To be cited as: Adv. Synth. Catal. 10.1002/adsc.202000228
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10.1002/adsc.202000228
Advanced Synthesis & Catalysis
COMMUNICATION
DOI: 10.1002/adsc.201((will be filled in by the editorial staff))
Scalable Electrochemical Transition-Metal-Free
Dehydrogenative Cross-Coupling Amination Enabled Alkaloid
Clausines Synthesis
Pan Zhang,a Baoying Li,a Liwei Niu,a Ling Wang,a Guofeng Zhang,a Xiaofei Jia,b
Guoying Zhang,b Siyuan Liu,a* Li Ma,a* Wei Gao,a Dawei Qin,a and Jianbin Chena*
a
Shandong Provincial Key Laboratory of Molecular Engineering, School of Chemistry and Pharmaceutical Engineering,
Qilu University of Technology (Shandong Academy of Sciences), Jinan, 250353, PR China, E-mail: jchen@qlu.edu.cn
Shandong Key Laboratory of Biochemical Analysis, Key Laboratory of Optic-electric Sensing and Analytical
b
Chemistry for Life Science, MOE, College of Chemistry and Molecular Engineering, Qingdao University of Science
and Technology, Qingdao 266042, PR China
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))
o
500 C), affording carbazole scaffolds in moderate
Abstract. Reported herein is an environmentally benign
electrochemical C-H bond dehydrogenative amination yields (Eq. 1, Scheme 1).[5] From the point of green
protocol for the construction of privileged carbazole moiety
with broad generality. Preliminary mechanistic
investigations implied radical reaction pathway.
Compared with traditional ionic routes, the scalable
transition-metal and exogenous-oxidant free strategy
highlighted the green and sustainable nature of this method.
and sustainable chemistry, there are currently three
generations regarding to the C-H bond amination
strategy. Firstly, transition-metal-catalyzed (Rh,[6] Ir,
a
[7]
Pt,[8] Pd,[9] Cu[10]) C-H bond activation of N-
substituted 2-aminobiaryl enables carbazole synthesis
with the assistance of chemical oxidants (Eq. 2,
Scheme 1). Secondly, transition-metal-free strong
chemical oxidant mediated carbazole construction via
radical and/or nitrenium ion intermediates. For
example, Antonchick, Chang, and Mal’s group
disclosed the hypervalent iodine (III)-mediated
protocols towards carbazole scaffolds, respectively
(Eq. 3, Scheme 1).[11] Despite these meaningful
advances, the approaches described above have
disadvantages associated with the requirements of
costly transition-metal,[12] elevated reaction
Keywords: electrosynthesis; dehydrogenative cross-
coupling; amination; alkaloid clausines; C-H activation
Carbazole is a ubiquitous motif that constitutes the
core structure for a diverse array of natural and non-
natural products. Notably, a wide range of biological
and physiological properties, including antitumor,
antiplatelet
aggregative,
antibiotic,
antiviral,
antiplasmodial, anticonvulsant and sigma receptor
antagonist, have been demonstrated.[1] Moreover,
carbazole is commonly treated as electronic materials,
such as photoconducting polymers and organic
optoelectronic materials, owing to their excellent
photophysical characteristics.[2] Consequently, the
development of synthetic strategies for carbazole
scaffolds holds potential significance in biological
and material fields.
Although some valuable approaches for the
synthesis of carbazole skeletons have been reported,
such as Fischere-Borsche synthesis, Graebee-
Ullmann synthesis, and conversion of indole
derivatives to carbazoles,[3] developing a step-
economic procedure is still highly desired.[4] For
instance, direct cyclization of 2-aminobiaryl,
represented as one of the most straightforward ways,
has attracted tremendous attention. Specifically,
Horaguchi et al reported a pyrolysis cyclization
reaction over calcium oxide at high temperature (>
Scheme 1. Representative protocols for the C-H bond
amination towards carbazole.
1
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10.1002/adsc.202000228
Advanced Synthesis & Catalysis
temperature, and strong oxidants used in
stoichiometric amounts.[13] These raises concern
regarding to atom economy and environmental
issues.[14] Therefore, the development of a green and
sustainable approach for highly efficient preparation
of carbazole framework remains a desirable task.
Fortunately, organic electrochemistry offers a facile
and mild alternative to traditional chemical
approaches.[15] The easily scalable feature and
absence of exogenous chemical oxidants highlighted
the green nature. Interestingly, Francke and
Nishiyama’s group independently described the
electrochemically phenyl iodide-mediated carbazole
scaffolds synthesis, in which hypervalent iodine was
anodically generated.[16] However, the preparation of
the electrocatalyst was time- and energy-consuming.
Considering the forementioned synthetic challenge of
bioactive carbazoles, we[17] envisioned the third
detected (34%, entry 3). Compared with the original
choice of electrodes, alternative niether the anode
material, reticulated vitreous carbon (RVC), nor the
cathode material, nickel foam (with greater
overpotential for proton reduction), was effective in
promoting the product formation (entries 4 & 5).
Both replacing of the electrolyte (potassium
hexafluorophosphate, KPF6 instead of nBu4NPF6,
entry 6) and increasing the proportion of TFE in the
solvent (entry 7) resulted in decreasing product
yields. Besides, neither decreasing nor increasing the
current could improve the efficiency any further
(entries 8 & 9).
With the optimized reaction conditions in hand, we
next explored the substrate scope (Table 2). First, we
explored the 2-amidobiaryls bearing various
substituents on the benzene ring which was linked to
the aniline moiety. The outcome indicated that
generation, namely,
a
transition-metal and
exogenous-oxidant free protocol for the preparation
of carbazole derivatives via a dehydrogenative cross-
coupling strategy (Eq. 4, Scheme 1).[18]
Table
2.
Generality
of
the
electrochemical
dehydrogenative C-H bond amiation protocol.
We commenced the study by optimizing the
electrochemical conditions for the dehydrogenative
C-H bond amination of arylsulfonamide 1’ (Table 1).
The optimal reaction condition was obtained as
followed: 10 mol % of tetrabutylammonium iodide
(nBu4NI) as the catalyst,
tetrabutylammonium
2
equivalents of
hexafluorophosphate
(nBu4NPF6) as an electrolyte, a commercially
available graphite rod as the anode, a platinum plate
as the cathode, under constant current electrolysis of
1.7 mA at room temperature in the solvent mixture of
trifluoroethanol and dichloromethane (TFE/DCM, 1:1,
entry 1). And the target carbazole product 1 was
afforded in 81% yield. Interestingly, a good result
was still observed in the absence of nBu4NI catalyst
(69%, entry 2). However, when ferrocene (Cp2Fe)
was utilized as the catalyst, an inferior yield was
Table 1. Optimized condition.
Deviation from standard
conditions
Yield
(%)
Entry
1
2
3
4
5
6
7
8
9
none
81
69
34
0
No nBu4NI
Cp2Fe as catalyst
RVC as anode
Ni foam as cathode
KPF6 as electrolyte
TFE-DCM (9:1) as solvent
1.5 mA instead of 1.7 mA
2.0 mA instead of 1.7 mA
64
36
50
75
77
Reaction condition: Substrate (0.2 mmol), nBu4NI (10
mol %), nBu4NPF6 (2 equiv.), graphite rod (ϕ 10 mm) as
anode and platinum (10 mm  10 mm), 1.7 mA, TFE/DCM
(5/5 mL), 25 oC, N2, 12 h (3.8 F/mol).
2
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10.1002/adsc.202000228
Advanced Synthesis & Catalysis
several 2-amidobiaryls were compatible with this
reaction, affording the carbazole products 2-9 in
moderate to good yields (20-85%), regardless of the
presence of electron-donating substituents (methyl, t-
butyl, methoxy, methylenedioxy) or electron-
withdrawing substituents (chloro, fluoro). However,
the morpholine-substituted compound 6 was achieved
in relatively low yield presumably because of the
oxidation labile feature.[19] In addtion, a phenyl group
was introduced to the para-position of the benzene
ring and the target product 10 was smoothly formed
in 75% yield.
Remarkably, other aromatic ring, such as
naphthalene and phenanthrene could also be cyclized
and the related 2-amidobiaryls could be converted
into carbazole products 11-13 in 35-86% yields.
Significantly, heteroaromatic ring, such as
dibenzofuran and thiophene could be annulated and
the desired products 14 and 15 were obtained in 40%
and 69% yield, respectively. Similarly, several 2-
amidobiaryls bearing different substituents on the
aniline ring were tested too. The related substrates
bearing methyl, halo, ester, and trifluoromethyl at the
ortho, meta or para position to the nitrogen atom
were employed, and the desired products 16-22 were
smoothly formed in moderate to high yields (39-87%).
To broaden the generality of this methodology,
substrates bearing funtional groups on both benzene
rings were subjected to this protocol. And the
corresponding di-substituted carbazole products 23-
27 (30-82% yields) were formed as expected. Then,
variation of the protecting group displayed that
sulfonamide was better than amide (28-31). These
results were presumably due to the varied acidity of
the N-H bond in the presence of different protecting
groups.[20]
To demonstrate the practical utility of this protocol,
we tried to synthesize several natural alkaloids
(Clausine C, Clausine H, Clausine L, and
Glycozoline, Scheme 1). To our delight, N-
substituted alkaloids 32-35 were provided from
readily available substrates. After simple deprotection,
the corresponding natural alkaloids, Clausine series,
were obtained in good to excellent yields (73-93%,
Table 3). Furthermore, the scalability was illustrated
by the gram-scale synthesis with moderate efficiency
Figure 1. Control experiments.
without physically changing the electrode employed
(Eq. 1, Figure 1). To obtain insights into the
mechanism, a series of control experiments and
cyclic voltammetry were conducted. First, the
addition of radical scavengers, such as 2,2,6,6-
tetramethylpiperidine-1-oxyl (TEMPO), butylated
hydroxytoluene (BHT), and 1,1-diphenylethylene
into the standard conditions completely shut down the
reaction (Eq. 2, Figure 1). These phenomena
indicated a radical nature of the process. Second, the
intermolecular kinetic isotope effect was observed
with a KIE value of 0.98, implying an inverse
secondary kinetic isotope effect (Eq. 3, Figure 1).
The scenario was in line with the configuration
change of carbon center from sp2 to sp3 and
demonstrated that C-H bond cleavage might be not
involved in the amination step. Then, cyclic
voltammetry analysis of each compound of interest
was performed (Figure 2). The oxidative peak
potentials for substrate 1’ and iodide anion were 2.2
V vs SCE and 0.95 V vs SCE in TFE/DCM,
respectively. Notably, the peak potential for I- was
significantly shifted to 0.75 V vs SCE when the
above two species were mixed, inferring a hydrogen
0.6
Table 3. Alkaloid Clausines synthesis.
blank expriment
nBu NI
4
1，
0.4
1， +nBu NI
4
1， +nBu NOH
4
0.2
0.0
0.0
0.7
1.4
E/V vs SCE
Figure 2. Cyclic voltammetry.
2.1
2.8
Condition 1 for products 32, 33, 34 with nBu4NF (5 equiv.)
in THF reflux and Condition 2 for product 35 with KOH (3
equiv.) in EtOH reflux.
3
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10.1002/adsc.202000228
Advanced Synthesis & Catalysis
immersion depth in solution) as the anode and platinum
plate (10 mm × 10 mm) as the cathode. Then the flask was
charged with nitrogen, followed by the sequential addition
of TFE (5.0 mL) and DCM (5.0 mL). The reaction mixture
was stirred and electrolyzed at a constant current of 1.7
mA at 25 °C for 12 h. When the reaction was completed,
as indicated by TLC, the solvent was removed with a
rotary evaporator and the residue was purified by column
chromatography on silica gel (ethyl acetate/petroleum
ether = 1:20 as eluent) to give the pure carbazoles 1-35.
bond existed. Remarkably, the initial oxidative
potential for the nitrogen anion (E = 0.65 V vs SCE)
was tremendously lower than that of the
corresponding N-H starting material. Importantly, the
hydrogen gas was detected from the headspace of the
reactor by the gas chromatography (GC) after the
completion of the model reaction (see Figure S2).
Based on the above information, a putative
mechanism was proposed in Scheme 3. Cathodically
reduction of the proton solvent initiated the
Acknowledgements
transformation, giving
a
strong base A.
Deprotonation of the substrate 1’ (see Figure S4)
took place to generate the nitrogen anion B.
Nucleophilic substitution to anodic generated iodine
afforded intermediate C, followed by homolytic
cleavage of the N-I bond delivering nitrogen-centered
radical D. Then intramolecular nitrogen radical
attacking to the aryl ring supplied species E.
Eventually, anodic heterogeneous oxidation in a
combination of the ensuing deprotonation furnished
the desired carbazole scaffold 1. Considering the
comparatively low initial potential for the nitrogen
anion which was similar to that of iodide, direct
anodic oxidation of species B was also feasible and
that was confirmed by entry 2 in Table 1.
We greatly appreciate the financial support from the National
Natural Science Foundation of China (No. 21801144), the Youth
Innovative Talents Recruitment and Cultivation Program of
Shandong Higher Education, the Natural Science Foundation of
Shandong Province (No. ZR2018BB017), Qilu University of
Technology (Shandong Academy of Sciences, No. 0412048811),
the Foundation (No. ZZ20190312) of State Key Laboratory of
Biobased Material and Green Papermaking, the QUSTHX202010,
and the Program for Scientific Research Innovation Team in
Colleges and Universities of Shandong Province.
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10.1002/adsc.202000228
Advanced Synthesis & Catalysis
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10.1002/adsc.202000228
Advanced Synthesis & Catalysis
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[19] Generally speaking, tertiary amine has relatively
low oxidative potential.
[20] A strong electron-withdrawing group was benefit to
stabilize the nitrogen-radical species.
[18] In the indirect electrolysis of ref 16, the
corresponding mediator was phenyl iodide which was
electrochemically oxidized to hypervalent iodine. In
contrast, our procedure was directly electrolysed of
the starting material and/or the simple iodide anion.
6
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10.1002/adsc.202000228
Advanced Synthesis & Catalysis
COMMUNICATION
Scalable Electrochemical Transition-Metal-Free
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Adv. Synth. Catal. Year, Volume, Page – Page
Pan Zhang, Baoying Li, Liwei Niu, Ling Wang,
Guofeng Zhang, Xiaofei Jia, Guoying Zhang,
Siyuan Liu,* Li Ma,* Wei Gao, Dawei Qin, Jianbin
Chen*
7
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