Electrochemical Palladium-Catalyzed Intramolecular C—H Amination of 2-Amidobiaryls for Synthesis of Carbazoles

Article abstract of DOI:10.1002/cjoc.202000407

The synthesis of carbazoles based on the electrochemical Pd-catalyzed intramolecular C—H amination of 2-amidobiaryls through oxidative cross coupling has been achieved under mild reaction conditions. The reaction can be carried out in undivided cell without the addition of external chemical oxidant. Besides good functional group compatibility, the desired carbazoles can be scaled up and modified easily. Compared with previous methods, this protocol affords a simple and sustainable avenue for the construction of carbazoles.

Full text of DOI:10.1002/cjoc.202000407

Chinese Journal
of Chemistry
CJC
中 国 化 学 - An International Journal
Accepted Article
Title: Electrochemical Palladium-catalyzed Intramolecular C-H Amination of 2-
amidobiaryls for the Synthesis of Carbazoles
Authors: Qingqing Wang, Xiaojing Zhang, Pan Wang, Xinlong Gao, Heng Zhang,*
and Aiwen Lei,*
This manuscript has been accepted and appears as an Accepted Article online.
This work may now be cited as: Chin. J. Chem. 2020, 38, 10.1002/cjoc.202000407.
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published online in Early View: http://dx.doi.org/10.1002/cjoc.202000407.
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Chinese Journal
of Chemistry
electrochemistry, Amination, carbazole, oxidant-free, synthetic method
Report
CJC
中
国 化 学 - An International Journal
Electrochemical Palladium-catalyzed Intramolecular C-H Amination of 2-
amidobiaryls for the Synthesis of Carbazoles
Qingqing Wang,† Xiaojing Zhang,† Pan Wang,† Xinlong Gao,† Heng Zhang,*,† and Aiwen Lei,*,†,‡,∲
†College of Chemistry and Molecular Sciences, Institute for Advanced Studies (IAS), Wuhan University, Wuhan 430072, P. R. 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 330022, Jiangxi, P. R. China
Cite this paper: Chin. J. Chem. 2020, 38, XXX—XXX. DOI: 10.1002/cjoc.201900XXX
Summary of main observation and conclusion: The synthesis of carbazoles based on the electrochemical Pd-catalyzed intramolecular C-H amination of 2-
amidobiaryls through oxidative cross coupling have been achieved under mild reaction conditions. The reaction can be carried out in undivided cell without
the addition of external chemical oxidant. Besides good functional group compatibility, the desired carbazoles can be scaled up and modified easily.
Compared with the previous methods, this protocol affords a simple and sustainable avenue for the construction of carbazoles
the synthesis of carbazoles is the oxidative cross coupling between
C-H and N-H in essence. Generally speaking, the reactions can be
Background and Originality Content
Carbazoles are a kind of ubiquitous core structural motif which
run at room temperature when strong chemical oxidants such as
can be found in various bioactive molecules and pharmaceuticals.1
hypervalent iodine(III) or oxone were used. However, high tem-
(Figure 1). Moreover, carbazoles have also been widely involved in
perature or expensive photoredox catalyst must be involved when
the functional electronic materials, such as the photoconducting
environmental benign dioxygen was used as oxidant. Nowadays,
polymers.2 Consequently, the development of efficient synthetic
electrosynthesis has played more and more paramount role in de-
methods to deliver the structurally diverse carbazoles represents
veloping atom-economic and sustainable synthetic methodology
an important objective in organic synthesis. 3 It is unquestionable
that transition metal-catalyzed intramolecular C-H amination of 2-
amidobiaryls is a high-performance strategy for the synthesis of
carbazoles.4,5 Since the pioneering work in this area contributed by
Buchwald and coworkers in 2005 which using Pd(OAc)2 as catalyst
in the presence of Cu(OAc)2 and dioxygen, this protocol has been
developed extensively. 4a Later, it was found that Cu(OAc)2 could
be replaced by DMSO as the co-oxidant by the same group.4b Gaunt
and coworkers made this transformation run under room
temperature when the combination of N-Bn biphenyl as substrate
and PhI(OAc)2 as oxidant was employed, which a Pd(II)/Pd(IV)
catalytic cycle was proposed in the mechanism.4c Using
hypervalent iodine(III) as oxidant, Chang group accomplished this
reaction in the absence of palladium under either Cu-catalyzed or
metal-free conditions.4d Youn and coworkers realized Pd-catalyzed
conversion at room temperature using oxone as an inexpensive
oxidant in the presence of p-TsOH as additive and PivOH/DMF as
cosolvent.4e Recently, visible light photoredox and palladium
catalysis were integrated for the synthesis of carbazoles using
dioxygen as oxidant by Cho, You and coworkers.4f Obviously,
stoichiometric amount of oxidant is indispensable for these
transformations because the aforementioned C-H amination for
due to the merits of using electrons as traceless reagents.6 By
employing the tactics of electrochemical anodic oxidation,
oxidative coupling can be accessed under external oxidant-free
conditions with the liberation of dihydrogen concomitantly.7 In
addition, the combination of electrosynthesis and transition metal
catalysis has supplied more powerful avenues for the constructing
of C-C and C-X bonds.9-12 Recently, multiple electrochemical
transition metal (Pd, Co, Ru, Ag, etc.) catalytic systems have been
disclosed by Ackermann13,14, Mei15, Xu16 and our group17. During
the preparing of this manuscript, Powers and coworkers reported
the electrosynthesis of N-acetylcarbazole based on the anodically
generated hypervalent iodine, Chen group published their
electrochemical protocol for the synthesis of N-sulfonylcarbazole
under transition metal free conditions.18-19 Herein, we reported a
Pd-catalyzed electro-oxidative intramolecular C-H amination under
external oxidant-free conditions for the synthesis of carbazoles
(Scheme 1).
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differences between this version and the Version of Record. Please cite this article as doi:
10.1002/cjoc.202000407
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First author et al.
Report
CO2Me
CO2Me
Entry
1
Variation from the standard conditions
Yield (%)b
80
MeO
N
H
N
H
N
OH
H
OH
none
clausine C
clausine E
Clausenol
2
no Pd(OAc)2
9
HN
3
PdCl2 instead of Pd(OAc)2
PPh3
39
OH
MeO
O
N
N
4
79
H
2C C
H
N
N
5
1,10-Phen instead of PPh3
bpy instead of PPh3
no p-TsOH
65
H
H
OMe
Carazolol
Murrastifoline B
photoconducting polymer
6
52
7
78
Figure1. Bioloactive molecules containing the carbazole structural motif.
Scheme 1 Reaction Design
8
nBu4NPF6 instead of LiClO4
nBu4NBF4 instead of LiClO4
4 mA
trace
32
9
10
11
12
13
57
work:
Previous
transition metal catalysis / metal free /
catalysis
photoredox
8 mA
72
R2
TFA
80
R2
R1
[Oxidant]
60
under air
R1
N
R3
NHR3
14
no electricity
n.d.
aThe standard reaction conditions were as follows: graphite rod anode (ф 6
mm), Pt plate cathode (15 mm×15 mm×0.3 mm), 1a (0.2 mmol), Pd(OAc)2
(5 mol%), p-TsOH (0.4 mmol), TFA (0.2 mmol), LiClO4 (0.1 mmol) as the
supporting electrolyte, MeCN (6 mL), rt, 3 h, constant current = 6.0 mA
(janode = 2.6 mA/cm2), undivided cell, nitrogen. bIsolated yields.
work:
This
electrochemical
amination
Pd-Catalyzed C-H
Ph
N
cat.
[Pd]
NHTs
Ts
With the optimized conditions in hand, the substrate scope of
this method was evaluated as shown in Table 2. The methyl
substituted substrates such as 1b and 1c could afford the desired
products 2b and 2c in the yields of 71% and 61%, respectively. For
the C3'-substituted substrates such as 1d and 1e, there are two
potential reactive sites (C2' and C6'), therefore, a total yield of 60%
for 2e plus 2e' was obtained. However, 2d was formed in 50% with
high regioselectivity. For the C4-substituted substrates with methyl
and halide substituents (1f-1i), moderate to good yields were
achieved. C4'-substituted substrates with electron-donating
groups (1j-1m) performed better than those with electron-
withdrawing groups (1n, 1o). The halogenated carbazoles (2g-2i,
2n, 2o) could be used as potential candidates for the further
functionalization. Remarkably, except for the phenyl substituted N-
sulfonylanilines, other arenes such as naphthyl, thienyl etc. (1p-1s)
also performed well in the reaction, delivering the products in
moderate to good yields. At the same time, the substrates with
electron-withdrawing groups (e. g. CF3) could not be compatible
with this method and only trace amount of product could be
monitored.
room
cell
undivided
external oxidant
free,
temperature,
Results and Discussion
The reaction was carried out in an undivided cell under
constant current electrolysis (CCE) with Pd(OAc)2 (5 mol%) as the
catalyst and LiClO4 as the supporting electrolyte. After
considerable efforts, 80% yield of the product 2a could be obtained
at 6 mA for 4 h (entry 1). Notably, only 9% yields were obtained for
this transformation in the absence of Pd(OAc)2 (entry 2). When
triphenylphosphine was used as the ligand, the yield was
79%( entry 4). Changing the ligands was not successful to improve
the yield of 2a (entries 5-6). Then, the yield was only 29% in the
absence of the 4-methylbenzenesulfonic acid (entry 7). Further
experiments suggested that supporting electrolyte played a pivotal
role in this transformation (entries 8-9). Thereafter, the current
effect was also explored and the results indicated that slightly
lower yields were obtained by either decreasing or increasing the
operating current (entries 10-11). The reaction yield was decreased
dramatically when the reaction was exposed to air (entry 12). No
reaction took place without electric current (entry 14).
The effects of N-substituents on the scope of this
transformation were also explored. As shown in Table 3, various N-
sulfonylanilines 1t-1w could be transformed well under the stand-
ard reaction conditions, giving the desired carbazoles 2t-2w in 43-
76% yields. In addition, benzoyl and acetyl protected [1,1'-
biphenyl]-2-amine could also be compatible with this protocol,
which released the corresponding carbazoles (2x, 2y) in moderate
yields.
Table 1 Optimization of reaction conditionsa
C(+)/ Pt(-)
Ph
mol%
Pd(OAc)2 (5
)
N
NHTs
p-TsOH TFA
,
Ts
2a
LiClO4 MeCN
,
Moreover, as illustrated in Scheme 2, the removal of the Ts pro-
1a
cell
undivided
tecting group of 2a could be proceeded smoothly to give 3a in
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Running title
Chin. J. Chem.
nearly quantitative yield on 8.0 mmol scale. Specifically, halogen
containing carbazoles are useful for the introduction of additional
functionalization. Under the improved Suzuki cross-coupling
conditions,18 the deprotected carbazole 3b could be coupled with
aryl boronic acids to give the functionalized carbazoles (4a, 4b) in
high yields.
Table 3. Scope of N-substituentsa
C(+) | Pt(-)
mmol)
Pd(OAc)
2
(5%
TFA
mmol),
p-TsOH
eq.),
(2.0
LiClO4 MeCN(6 mL)
(0.2
NH
R3
N
R3
2
N2 rt, 6 mA, 3 h
undivided
,
cell
mmol)
1
(0.2
Table 2 Substrate Scopea
R2
C(+) | Pt(-)
mol%)
(0.2
Pd(OAc)2 (5
N
N
mmol),
R2
p-TsOH
TFA
R1
N
eq.),
(2.0
4
Ar
LiClO / MeCN mL)
(6
Ar
O
O
S
R1
O
S
O
O
O
S
N
NHTs
N2 rt, mA,
h
6
3
,
Me
Ts
cell
undivided
mmol)
1
2
(0.2
NO2
43%
Me
Me
2t
2u
2v
61%
N
76%
,
,
,
N
N
N
Ts
Ts
Me
Ts
2a,
80%
2b,
71%
2c, 61%
Cl
Me
N
N
O
O
S
COPh
Ac
nBu
68%
N
,
N
N
2w
2x
,
2y
Me
56%
53%
,
Ts
Ts
Ts
+
2d, 50%
2e 2e', 60%
R2 OMe, 75%
=
=
2j,
2k,
2f, R1
a Reaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol%), p-TsOH (0.4
mmol), TFA (0.2 mmol) in undivided cell with graphite rod anode (15
mm×15 mm×0.36 mm) and Pt plate cathode (15 mm×15 mm×0.3 mm),
LiClO4 (0.1 mmol) as the supporting electrolyte, MeCN (6 mL), rt, 3 h,
constant current = 6.0 mA (janode = 2.6 mA/cm2), nitrogen. Isolated yields are
shown.
2
tBu 66%
=
Me, 80%
R
,
R1 Br, 61%
R1
=
2l, R2 Me, 62%
R2
=
2g,
2h,
1
2
=
N
R
1
Cl, 52%
43%
=
N
2m,
R
Ph, 67%
2
=
2i,
R
Ts
=
Br,
F,
2n,
Ts
R
46%
39%
2o, R2
=
F,
O
S
O
N
N
N
N
Ts
Ts
Ts
Ts
67%
2p,
To further demonstrate the utility of this protocol, the scale-up
reaction was carried out in 7.0 mmol scale (Scheme 3). Considering
the high cost of platinum electrode, graphite rod was employed as
cathode. The target carbazole (2a) could be obtained in 56% yield.
2r,
2s,
50%
65%
81%
2q,
aReaction conditions: 1 (0.2 mmol), Pd(OAc)2 (5 mol%), p-TsOH (0.4 mmol),
TFA (0.2 mmol) in undivided cell with graphite rod anode (15 mm×15
mm×0.36 mm) and Pt plate cathode (15 mm×15 mm×0.3 mm), LiClO4 (0.1
mmol) as the supporting electrolyte, MeCN (6 mL), rt, 3 h, constant current
= 6.0 mA (janode = 2.6 mA/cm2), nitrogen. Isolated yields are shown.
Scheme2 Removal of N-protecting Group and Further Functionalization
MeOH/THF
Mg,
N
H
N
70 o
h
C,16
Ts
mmol)
2a
3a
8.0
%
(
(96 (1.28 g))
H
N
B(OH)2
Cl
Cl
R
MeOH/THF
Mg,
70 o
C,16
h
Pd(PPh3)
Na2CO3
4
N
N
H
3b
Ts
R
THF: H2O
2d
mmol
120 o 12 h
=
=
4a
;
:
4b
R
R
4-Ph, 85%
3-OH, 89%
C,
8
95%, 1.85 g
Chin. J. Chem. 2020, 38, XXX－XXX
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First author et al.
Report
for the reactions under different experimental conditions.4 In
addition, radical mechanism was also put forward for the copper
involved or metal free conditions when hypervalent iodine(III) was
used as oxidant.4c For the Pd catalyzed reactions,4d high tempera-
ture is obligate in order to facilitate the reduction elimination of
Pd(II) to the formation of carbazoles when dioxygen was used as
oxidant. Strong oxidants (PhI(OAc)2, oxone, etc.) or photoredox
catalyst which can oxidize Pd(II) to Pd(III) or Pd(IV) can make the
transformation run at room temperature. Considering our reaction
can proceed smoothly at room temperature, Pd(III) or Pd(IV) spe-
cies which can be formed through anodic oxidation from Pd(II)
intermediates may be involved in this protocol. Moreover, the con-
tribution of radical species to this reaction cannot be precluded as
no desired product was observed when radical scavenger such as
TEMPO, 1,1-diphenylethene or BHT was added to the reaction.
Scheme3 Reaction Scale-Up
C(+) | C(-)
mol% p-TsOH
eq.)
Pd(OAc)2(5
),
(2.0
N
mA
N
rt, 6
,
2
TFA
(1.0 eq),
LiClO4 MeCN
NHTs
mmol)
Ts
,
2a
56%)
g,
(1.56
1a 7.0
(
The kinetic isotope effect (KIE) experiments had been performed.
Intermolecular competition reaction of 1a and [D5]-1a gave KIE
value of 1.06 (Figure 2a). The parallel reactions of 1a and [D5]-1a
which were carried out for 40 min separately, giving a KIE value of
1.23 (Figure 2b). These results indicated that the cleavage of the C-
H bond might not be involved in the rate-limiting step.
Based on the literature reports,4 a plausible mechanism is
outlined in Scheme 4. In the initial step of the route, coordination
of the amido group of 1 to Pd(OAc)2 facilitates cyclopalladation,
leading to the six-membered palladacycle 2. The palladacycle 2
may be oxidized to a PdIII or PdIV (complex 3). Then palladium
complex 3 undergo reductive elimination process to give desired
product 2b and Pd(I) or Pd(II). Pd(I) could be oxidized at anode to
give Pd(II) to finish the catalytic cycle. Proton reduction may be the
concomitant cathodic reduction reaction since a large amount of
hydrogen gas can be detected by GC in the reaction system after
the reaction is stopped (as seen the supporting information Figure
S1).
D
D
D
D
D
D
standard conditions
+
+
2b
1a
D
(a)
(b)
70mim,
2b
competitive
N
D
D
NH
Ts
:
2b
27%
+[D4]-
Ts
b
[D4]-2
mmol
mmol)
0.2
[D5]-1a, (0.2
=
H/ KD 1.06
K
standard conditions
40
1a
2b
min,Parallel
mmol
0.2
16%
standard conditions
b
[D5]-1a
mmol
[D4]-2
13%
40
min,Parallel
=
K
H/ KD 1.23
0.2
Conclusions
Figure2. The kinetic isotope effect (KIE) experiments
In summary, we have developed an effective electrochemical
Pd-catalyzed intramolecular oxidative C-H amination of 2-
amidobiaryls for the synthesis of carbazoles. This reaction can be
realized in undivided cell at room temperature under external
oxidant-free conditions, which provides a simple and atom-
economic way to synthesize carbazoles. A wide range of functional
groups are proved to be compatible under the optimized condi-
tions. The scale up experiments demonstrate the potential
application of this method, which will flourish the means of
production of carbazole and its derivatives.
Scheme4 Proposed Mechanism
anode
-e-
oxidation
PdI
or
PdII
Pd II
NHTs
C - H
H
Experimental
Ts
N
a c t i v a t i o n
1
An undivided cell was equipped with graphite rod anode (ф 6
mm), Pt plate cathode (15 mm×15 mm×0.3 mm) and connected to
a DC regulated power supply. To the cell was added 1a (1 mmol),
Pd(OAc)2 (5% mmol), p-TSOH (0.4 mol) and 6 mL of 0.1 M
LiClO4/CH3CN. The mixture was electrolyzed using constant
current conditions (6.0 mA) at room temperature under magnetic
stirring. When TLC analysis indicated that the electrolysis was
complete (witnessed by the disappearance of the 1a), the solvent
was removed under reduced pressure. The residue was then
extracted with DCM (3×20 mL), dried over Na2SO4, and
concentrated in vacuo. The residue was purified by column
chromatography on silica gel using a mixture of petroleum
ether/EtOAc (v: v = 10 : 1) as eluent to afford the desired pure
product.
2a
Ts
N
PdII
Ts
N
or
PdIII
IV
-e-
2
3
oxidation
anode
As to the mechanism of this transformation, Pd(0)/Pd(II),
Pd(II)/Pd(IV) and Pd(I)/Pd(III) catalytic cycles have been proposed
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Chin. J. Chem. 2020, 38, XXX－XXX
This article is protected by copyright. All rights reserved.

Running title
Chin. J. Chem.
Supporting Information
The supporting information for this article is available on the
WWW under https://doi.org/10.1002/cjoc.2020xxxxx.
P.; Zheng, N.; Buchwald, S. L. J. Am. Chem. Soc. 2005, 127, 14560 − 14561;
(b) Jordan-Hore, J. A.; Johansson, C. C. C.; Gulias, M.; Beck, E. M.; Gaunt, M.
J.; Oxidative Pd(II)-Catalyzed C−H Bond Amination to Carbazole at Ambient
Temperature. J. Am. Chem. Soc. 2008, 130, 16184 −16186; (c) Cho, S. H.;
Yoon, J.; Chang, S.; Intramolecular Oxidative C−N Bond Formation for the
Synthesis of Carbazoles: Comparison of Reactivity between the Copper-
Catalyzed and Metal-Free Conditions. J. Am. Chem. Soc. 2011, 133, 5996 −
6005; (d) Youn, S. W.; Bihn, J. H.; Kim, B. S.; Pd-Catalyzed Intramolecular
Oxidative C–H Amination: Synthesis of Carbazoles. Org. Lett. 2011, 13, 3738
− 3741; (e) Takamatsu, K.; Hirano, K.; Satoh, T.; Miura, M.; Synthesis of
Carbazoles by Copper-Catalyzed Intramolecular C–H/N–H Coupling. Org.
Lett. 2014, 16, 2892 − 2895; (f) Chng, L. L.; Yang, J.; Wei, Y.; Ying, J. Y.;
Palladium nanomaterials in catalytic intramolecular C–H amination
reactions Chem. Commun. 2014, 50, 9049 − 9052; (g) Suzuki, C.; Hirano, K.;
Satoh, T.; Miura, M.; Direct Synthesis of N-H Carbazoles via Iridium(III)-
Catalyzed Intramolecular C–H Amination. Org. Lett. 2015, 17, 1597 − 1600;
(h) Antonchick, A. P.; Samanta, R.; Kulikov, K.; Lategahn, J.; Organocatalytic,
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Acknowledgement
This work was supported by the National Natural Science
Foundation of China (21520102003) and the Hubei Province
Natural Science Foundation of China (2017CFA010). The Program
of Introducing Talents of Discipline to Universities of China (111
Program) is also appreciated. The numerical calculations in this
paper have been done on the supercomputing system in the
Supercomputing Center of Wuhan University.
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(The following will be filled in by the editorial staff)
Manuscript received: XXXX, 2020
Manuscript revised: XXXX, 2020
Manuscript accepted: XXXX, 2020
Accepted manuscript online: XXXX, 2020
Version of record online: XXXX, 2020
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Entry for the Table of Contents
Page No.
Electrochemical
Palladium-catalyzed
Intramolecular C-H Amination of 2-amidobiaryls
for the Synthesis of Carbazoles
Ph
+
H2
N
Ts
cat.
[Pd]
NHTs
room
cell
external
oxidant free,
undivided
temperature,
In this protocol, the reaction can be carried out in undivided cell without the addition of external
chemical oxidant. Besides good functional group compatibility, the desired carbazoles can be scaled
up and modified easily.
Qingqing Wang,† Xiaojing Zhang,† Pan Wang,†
Xinlong Gao,† Heng Zhang,*,† and Aiwen
Lei,*,†,‡,∲
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Chin. J. Chem. 2020, 38, XXX－XXX
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