Palladium on Carbon-Catalyzed C?H Amination for Synthesis of Carbazoles and its Mechanistic Study

Article abstract of DOI:10.1002/adsc.201600299

10% Palladium on carbon (10% Pd/C) successfully catalyzed the intramolecular C?H amination of various N-mesylated 2-aminobiphenyls in the presence of a catalytic amount of pyridine N-oxide in heated dimethyl sulfoxide (DMSO) under an oxygen atmosphere to afford the corresponding N-mesylcarbazoles. The reaction would proceed via a single-electron transfer process based on its significant suppression by the addition of a single-electron scavenger, tetracyanoquinodimethane (TCNQ), and the substituents on the aromatic rings of the substrate have an insignificant effect on the reaction progress. (Figure presented.).

Full text of DOI:10.1002/adsc.201600299

UPDATES
DOI: 10.1002/adsc.201600299
À
Palladium on Carbon-Catalyzed C H Amination for Synthesis of
Carbazoles and its Mechanistic Study
a,
a
a
a
Yasunari Monguchi, * Hiroki Okami, Tomohiro Ichikawa, Kei Nozaki,
a
b
a
a,
Toshihide Maejima, Yasunori Oumi, Yoshinari Sawama, and Hironao Sajiki *
a
Laboratory of Organic Chemistry, Gifu Pharmaceutical University, 1-25-4 Daigaku-nishi, Gifu 501-1196, Japan
Fax : (+81)-58-230-8109; phone: (+81)-58-230-8109; e-mail: monguchi@gifu-pu.ac.jp or sajiki@gifu-pu.ac.jp
Instrumental Analysis, Life Science Research Center, Gifu University, 1-1 Yanagido, Gifu 501-1193, Japan
b
Received: March 17, 2016; Revised: June 30, 2016; Published online: && &&, 0000
Supporting information for this article can be found under: http://dx.doi.org/10.1002/adsc.201600299.
[
5c,d]
Abstract: 10% Palladium on carbon (10% Pd/C)
successfully catalyzed the intramolecular CÀH ami-
A
H
U
G
R
N
U
G
for their potential biological activities and
[4e]
nation of various N-mesylated 2-aminobiphenyls in
the presence of a catalytic amount of pyridine N-
oxide in heated dimethyl sulfoxide (DMSO) under
an oxygen atmosphere to afford the corresponding
N-mesylcarbazoles. The reaction would proceed via
a single-electron transfer process based on its signif-
icant suppression by the addition of a single-elec-
We have previously reported the Pd/C-catalyzed
oxidations of alkynes to the corresponding 1,2-dike-
tones using oxygen gas (O ) and dimethyl sulfoxide
2
[
8]
(DMSO) as the oxidants or pyridine N-oxide as an
[
9]
oxidant. For the general palladium-catalyzed CÀH
functionalization reactions, the Pd(0) species would
be generated after each catalytic reaction cycle, and
the oxidation step should be required to reproduce
tron
scavenger,
tetracyanoquinodimethane
[
6]
(
TCNQ), and the substituents on the aromatic rings
the active Pd(II) species from Pd(0). We anticipated
of the substrate have an insignificant effect on the
reaction progress.
that the combined use of these oxidants, O , DMSO,
2
and pyridine N-oxide, would be effective for the Pd/
C-catalyzed CÀH functionalization. Very recently,
Ying et al. reported an N-acetylcarbazole synthesis
via the intramolecular CÀH amination of N-acetyl-2-
Keywords: CÀH amination; heterogeneous cataly-
sis; nitrogen heterocycles; nitrogen oxides; palladi-
um
aminobiphenyl catalyzed by their homemade Pd/C,
the Pd species of which more largely exists as Pd(II)
species rather than Pd(0), in DMSO under O in the
2
presence of molecular sieves as an essential re-
[
5c]
agent. In this study, we demonstrate that the use of
the commercially available Pd/C, which consists of
almost entirely Pd(0) species, could effectively cata-
Introduction
Palladium on carbon (Pd/C) has long been used for lyze the cyclization for the N-sulfonylcarbazole syn-
the hydrogenation of various reducible functional thesis without molecular sieves, and the effect being
[1]
groups. Recently, the advantages of its properties, due to the difference in the surface area of the acti-
such as its stability in air, easy removal of palladium vated carbons of Pd/C and pyridine N-oxide as an ac-
metal from the reaction media by simple filtration, re- celerator. Furthermore, we proposed the involvement
coverability, reusability, and commercial availability of a possible single electron transfer process during
at a relatively low cost, have been reviewed from the the reaction instead of the CÀH activation or Heck-
[
5c,6j]
perspective of green sustainable chemistry directly type mechanism.
linked to practical use. A wide range of Pd/C-cata-
lyzed reactions, including cross-coupling reactions, has
[
2,3]
been developed,
functionalization reactions have been reported com-
while few uses of Pd/C for CÀH Results and Discussion
[
4–7]
pared to the homogeneous palladium catalysts.
Re- The N-tosyl- and N-mesyl-2-aminobiphenyls (1b and
cently, the Pd/C-catalyzed CÀH functionalization was 1c) in heated DMSO were smoothly cyclized into the
applied to the synthesis of heterocyclic compounds, corresponding carbazole derivatives in the presence
[
5a]
[5b]
e.g., isoquinolines,
benzofurans,
and carb- of catalytic amounts of 10% Pd/C (10 mol%) and pyr-
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Table 1. Effect of N-substituent on the carbazole synthesis.
tion (entries 6 and 7), while 3-hydroxypyridine N-
oxide and 4-nitropyridine N-oxide as well as m-chlor-
operoxybenzoic acid (mCPBA) showed a negative
effect as oxidizing reagents (entries 4, 5, and 8). Inter-
estingly, pyridine dramatically impeded the reaction
progress (entry 9), suggesting that pyridine would not
be transformed into the active pyridine N-oxide
under the present oxidative conditions and it would
work as a catalyst poison based on the strong coordi-
[a]
Entry
R
Time [h]
Ratio (1:2)
[
10]
nation ability to the Pd metal.
1
2
3
4
5
6
H (1a)
24
6
3
24
24
24
2a was not obtained.
When the reaction was carried out without 10%
Ts (1b)
Ms (1c)
Ac (1d)
Bz (1e)
Piv (1f)
0:100
0:100 (98%)
[b]
Pd/C, the CÀH amination never proceeded (Table 3,
[c]
72:28
100:0
100:0
entry 1). The reaction proceeds Pd/C-dose-dependent-
ly, and 10 mol% of 10% Pd/C was found to be re-
quired to complete the reaction within 3 h (entries 1–
4). Increasing the amount of pyridine N-oxide up to
20 mol% accelerated the reaction progress (Table 3,
entries 4–6 vs. Table 2, entry 1), while the addition of
an excess amount produced no beneficial effects
[
[
[
a]
b]
c]
1
The ratio was determined by H NMR.
The isolated yield is indicated in parentheses.
A small amount of deacetylated carbazole was detected
in the H NMR spectrum (<5%).
1
(
Table 3, entry 7). Furthermore, the carbazole was
scarcely obtained without either DMSO (Eentries 8–
idine N-oxide (20 mol%) under an O atmosphere 12) or oxygen (Entry 13). The temperature was also
2
(
Table 1, entries 2 and 3), although the free 2-amino- found to be an important factor for the present reac-
biphenyl (1a) and N-acylated 2-aminobiphenyls (1d, tion; heating below 1208C resulted in a drastic de-
1
e, and 1f) produced ineffective reactions (entries 1, crease in the yield of 2c (entries 14 and 15). The reac-
4–6). Especially, the N-mesylated 2-aminobiphenyl tion progress was significantly suppressed by the addi-
(
1c) was a good substrate, and the reaction was com- tion of 10 mol% of tetracyanoquinodimethane
pleted within only 3 h (entry 2). (TCNQ) as a single electron scavenger, and the reac-
The addition of pyridine N-oxide was found to be tion was almost quenched (entry 16). The addition of
very effective for the present cyclization based on the radical scavengers, such as 2,2,6,6-tetramethylpiperi-
CÀH amination (Table 2, entries 1–3), since it was in- dine 1-oxyl (TEMPO), 1,1-diphenylethene, and 2,6-di-
complete even after 24 h without pyridine N-oxide tert-butyl-4-hydroxytoluene (BHT), also decelerated
(
entries 1 and 2). 4-Nitroquinoline N-oxide and N- the reaction (entries 17–19).
methylmorpholine N-oxide also promoted the reac-
When a mixture of equimolar amounts of non-deu-
terated substrate (1c) and deuterated 1c-d in DMA
5
Table 2. Effect of the additive on carbazole synthesis from was stirred at 1208C under the optimal conditions for
N-Ms-2-aminobiphenyl.
1.5 h, 39.5% deuterium incorporation into the pro-
duced N-mesylcarbazole (2c) was observed by
1
[11]
H NMR spectroscopy (Scheme 1). The kinetic iso-
tope effect (KIE, k /k ) is estimated to be 1.53, indi-
H
D
cating that the CÀH cleavage process would not be
the rate-determining step. These results suggest an in-
volvement of a single electron transfer process during
the CÀH amination, although the oxidative addition
[
a]
Entry
1
Additive
Ratio (1c:2c) of the ortho-CÀH bond of non-aminated phenyl ring
25:75
of 1c to Pd(0) as the rate-determining step could not
be thoroughly excluded.
The 10% Pd/C-catalyzed intramolecular ring clos-
ing reaction proceeded with little influence of the
electronic property and substitution pattern of the
substituents on each benzene ring of the N-mesyl-2-
aminobiphenyl derivatives as the starting materials
–
–
[
b]
2
3
4
5
6
7
8
9
7:93
[c]
pyridine N-oxide
3-hydroxypyridine N-oxide
4-nitropyridine N-oxide
4-nitroquinoline N-oxide
4-methylmorpholine N-oxide
mCPBA
0:100 (98%)
41:59
36:64
6:94
12:88
33:67
(
Table 4). Carbazole derivatives bearing electron-do-
nating methoxy and methyl substituents (2g, 2h, 2l,
m, 2p, and 2s) or electron-withdrawing nitro, trifluor-
pyridine
83:17
[
[
[
a]
1
2
The ratio was determined by H NMR.
The reaction was carried out for 24 h.
Isolated yield is indicated in parentheses.
b]
c]
omethyl, ethoxycarbonyl, and chloro substituents (2i,
2j, 2k, 2n, 2o, 2q, and 2r) could be synthesized in
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Table 3. Optimization of the reaction conditions for the CÀH amination.
[a]
Entry
X [mol%]
Y [mol%]
Solvent
T [8C]
t [h]
Ratio (1c:2c)
1
2
3
4
5
6
7
8
9
0
1
5
20
20
20
20
5
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
NMP
CPME
mesitylene
cyclohexane
–
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
120
120
120
120
120
120
120
120
120
120
120
120
120
100
80
24
3
3
3
3
100:0
88:12
56:44
0:100 (98%)
7:93
1:99
22:78
94:6
[b]
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
10
40
20
20
20
20
20
20
20
20
20
20
20
20
3
3
24
24
24
24
3
24
3
3
3
3
3
3
98:2
10
11
12
13
14
15
16
17
18
19
>99:trace
100:0
100:0
100:0
96:4
100:0
95:5
25:75
88:12
80:20
[
c]
[
[
[
[
d]
e]
f]
120
120
120
120
g]
[
[
[
[
[
[
[
a]
1
The ratio was determined by H NMR.
The isolated yield is indicated in parentheses.
The reaction was carried out under argon.
TCNQ (10 mol%) was added.
b]
c]
d]
e]
f]
TEMPO (10 mol%) was added.
,1-Diphenylethene (1 equiv.) was added.
,6-Di-tert-butyl-4-hydroxytoluene (BHT, 1 equiv.) was added.
1
2
g]
good to excellent yields. Furthermore, the intramolec-
Removal of the N-mesyl group from the synthe-
ular CÀH amination of N-mesyl-3’-methoxy-2-amino- sized carbazole rings (2c, 2g, and 2i) was readily ach-
biphenyl (1l) could proceed in a regioselective ieved by the reported method for the detosylation of
manner to give the corresponding 3-substituted carba- N-tosylated indoles using Cs CO in the THF-MeOH
2
3
zoles (2l).
combined solvent that produced the corresponding
deprotected carbazoles (3c, 3g, and 3i) in excellent
[
12]
yields (Table 5).
The leaching behavior of palladium species into the
filtrate after the removal of the 10% Pd/C from the
reaction mixture was measured by inductively cou-
pled plasma-atomic emission spectrometry (ICP-
AES) using 1c as a substrate. Unfortunately, a decent
amount of palladium species was detected, and 43%
of the Pd from the 10% Pd/C was found to be leach-
[
13,14]
ed.
Next, we examined the so-called hot-filtration
experiment to clarify if the leached Pd can catalyze
[
15]
the reaction (Scheme 2).
A time-course study re-
vealed that the 10% Pd/C time-dependently catalyzed
the CÀH amination and N-Ms-carbazole (2c) was gen-
erated in 20% yield after 1 h. The reaction was simi-
larly conducted, and the mixture was filtered after 1 h
without cooling to remove the 10% Pd/C. The filtrate
Scheme 1. Competitive reactions of 1c and 1c-d5.
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Table 4. Substrate scope.
[
[
a]
b]
2
1
0 mol% of 10% Pd/C were used.
5 mol% of 10% Pd/C were used.
Table 5. Removal of N-Ms group from N-Ms-carbazoles.
[a]
Entry
R
Yield [%]
1
2
3
H (2c)
MeO (2g)
100 (3c)
99 (3g)
89 (3i)
[
b]
NO (2i)
2
[
[
a]
Isolated yield.
b]
The reaction was carried out in THF-MeOH (2:1) at
room temperature for 5 h.
without 10% Pd/C was then heated again at 1208C
under an O atmosphere and the time course was fol-
2
lowed. As a result, the CÀH amination also proceed-
ed after the removal of the 10% Pd/C, although the
reaction rate was significantly lower. These results in-
dicated that the palladium species were leached from
the Pd/C into the reaction media and they could func-
tion as the real catalyst species.
Scheme 2. Time-course study of the reaction in the filtrate
after the removal of 10% Pd/C. Standard run (^): The reac-
tion of N-Ms-2-aminobiphenyl (1c) was carried out without
The progress of the present CÀH amination was
also found to be dependent on the surface area of the
activated carbon used as the catalyst support
filtration. Hot-filtration ( ): 10% Pd/C was removed by fil-
&
(
Table 6). When the surface area of the activated tration without cooling after a 1-h reaction at 1208C and the
carbon support of 10% Pd/C is greater than filtrate was heated again at 1208C.
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Table 6. Effect of activated carbon of 10% Pd/C on the car-
bazole synthesis from N-Ms-2-aminobiphenyl.
[
a]
Entry Surface area of activated carbon of 10% Ratio
2
Pd/C (m /g)
(1c:2c)
1
2
3
1000
1150
1550
0:100
0:100
19:81
[
a]
1
Ratio was determined by H NMR.
2
À1
1
000 m g , the reaction was effectively catalyzed (en-
Scheme 3. Proposed reaction mechanism.
tries 1 and 2), while a part of N-mesyl-aminobiphenyl
1c) remained unreacted using the 10% Pd/C possess-
ing an excessively high surface area of the activated H O . H O can be readily decomposed to water and
(
2
2
2
2
2
À1
[14]
carbon (>1500 m g ) (entry 3). The large surface O in the presence of 10% Pd/C.
2
area of the catalyst support is generally considered to
be a crucial factor for the smooth reaction progress
because of the facilitation of the easy contact of the Conclusions
substrate with palladium metal on the catalyst surface.
The decrease in the catalyst efficiency for the present We have developed an efficient method for the syn-
reaction would be caused by the delayed elimination thesis of a wide variety of carbazole derivatives via
of the substrate or/and product from the reactive sites the Pd/C-catalyzed intramolecular cyclization by the
on the catalyst surface based on the increased interac- combined use of commercially available 10% Pd/C,
tion or intermolecular force between the carbon sup- DMSO, oxygen, and pyridine N-oxide. The pyridine
port and substrate/product. The palladium leaching N-oxide was revealed to significantly enhance the car-
would also be hampered by the coverage of the sub- bazole generation. The reaction progress was com-
strate and/or product on the carbon support based on pletely suppressed by the addition of a catalytic
the interaction.
amount of TCNQ, which acts as a single-electron
Scheme 3 shows our proposed reaction mechanism. scavenger. The kinetic study using the deuterated sub-
Some of the Pd(0) species would be oxidized to strate 2c-d suggested that the CÀD cleavage is not
5
[16]
Pd(II) oxide (A)
by the oxidative cooperation of a rate-determining step of this reaction. Therefore, we
O , DMSO, and pyridine N-oxide, and leached from newly proposed the reaction mechanism, which in-
2
10% Pd/C. Although the function of DMSO as volved a single electron transfer process as a key step.
a ligand might not be omitted, it should work as an Furthermore, the surface area of the activated carbon
oxidizing reagent, since the present reaction gives off of 10% Pd/C was found to be an important factor for
the strong odor of dimethyl sulfide. The nucleophilic the catalyst activity, and the absorption and desorp-
attack of the sulfonamide moiety of N-Ms-2-aminobi- tion of the substrate and/or product onto/from the
phenyl to the palladium would afford a Pd(II) amide catalyst support affected the reaction progress.
complex (B), where Pd(II) would be on the aromatic
ring to form a charge-transfer complex. A single elec-
tron could be transferred from the aromatic ring to Experimental Section
Pd(II) to generate a short-lived Pd(I)-OOH (C) and
radical cation bearing an amide anion within the mol- Typical Procedure for the Synthesis of N-Ms-
ecule (D), the latter of which would be converted to Carbazole Derivatives (Table 4)
the benzyl radical (E) via intramolecular cyclization.
A
mixture of the N-Ms-2-aminobiphenyl derivative
The radical (E) and Pd(I)-OOH (C) would be quickly
coupled to afford the Pd(II)-OOH species (F), and
the b-hydrogen elimination would afford the desired
(
250 mmol), pyridine N-oxide (4.8 mg, 50.0 mmol), and 10%
Pd/C (26.6 mg, 25.0 mmol) in DMSO (1 mL) was stirred at
208C under an O atmosphere. After a specific time, the
1
2
carbazole and H-Pd(II)-OOH. The subsequent reduc- mixture was cooled to room temperature and passed
tive elimination would give the Pd(0) species and through a celite pad. The pad was washed with EtOAc
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(
10 mL) and H O (10 mL), and the layers were separated.
trate, was heated again at 1208C for 1 h or 2 h. EtOAc
2
The aqueous layer was extracted with EtOAc (10 mL ꢁ 2),
and the combined organic layers were washed with brine
(10 mL) and H O (10 mL) were then added to each test
2
tube, and the layers were separated. The aqueous layer was
extracted with EtOAc (10 mL ꢁ 2), and the combined or-
ganic layers were washed with brine (20 mL), dried over
(
20 mL), dried over MgSO , filtered, and concentrated
4
under vacuum. The residue was purified by silica gel column
chromatography (hexane-EtOAc or CH Cl -MeOH).
MgSO , filtered, and concentrated under vacuum. The yields
2
2
4
of 2c after reheating for 0 h, 1 h, and 2 h were determined
using the same procedure for the standard run (18%, 34%,
and 43%, respectively).
Demesylation of N-Ms-Carbazoles (Table 5)
A mixture of the N-Ms-carbazole derivative (250 mmol) and
Cs CO (244 mg, 750 mmol) in THF-MeOH [1 mL (1:1 or
2
3
2
:1)] was stirred at room temperature or refluxed. After
a specific time, the mixture was cooled to room tempera-
ture, and partitioned between CH Cl (20 mL) and H O
Acknowledgements
2
2
2
(
10 mL). The organic layer was washed with brine (10 mL),
We thank the N.E. Chemcat Corporation for the kind gift of
the Pd/Cs and the ICP-AES measurements.
dried over MgSO , filtered, and concentrated in vacuo. The
residue was purified by silica gel column chromatography
4
(
hexane-EtOAc).
References
Assay of Leached Palladium in the Reaction Media
A
2
mixture of N-mesyl-2-aminobiphenyl (1c) (618 mg,
.50 mmol), pyridine N-oxide (47.5 mg, 500 mmol), and 10%
Pd/C (266 mg, 250 mmol) in DMSO (10 mL) was stirred at
208C under an O atmosphere. After 3 h, the mixture was
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Standard run: Five test tubes were prepared, and the intra-
molecular cyclization of N-mesyl-2-aminobiphenyl (1c)
(
61.8 mg, 250 mmol) under an O2 atmosphere was carried
out using pyridine N-oxide (4.8 mg, 50.0 mmol) and 10% Pd/
C (26.6 mg, 25.0 mmol) in DMSO (1 mL) at 1208C in each
test tube. The reaction was treated after 15 min, 0.5 h, 1 h,
2
h, and 3 h according to the typical procedure for the syn-
thesis of the N-Ms-carbazole derivatives. The EtOAc ex-
tracts of each reaction mixture were concentrated under
1
vacuum. The residue was weighed, and the H NMR spectra
were measured. The yield of N-mesyl-carbazole (2c) was de-
1
termined by the H NMR ratio and weight of the residue,
which contained only 1c and 2c (0.3%, 5%, 20%, 71%, and
100% after 15 min, 0.5 h, 1 h, 2 h, and 3 h, respectively).
Hot filtration: Three test tubes were prepared, and the in-
tramolecular cyclization of N-mesyl-2-aminobiphenyl (1c)
124 mg, 500 mmol) under an O atmosphere was carried out
(
2
using pyridine N-oxide (9.5 mg, 100 mmol) and 10% Pd/C
53.2 mg, 50.0 mmol) in DMSO (2 mL) at 1208C in each test
(
tube. After 1 h, 1 mL from each reaction mixture in the
three test tubes was filtered using a 0.45-mm Millipore mem-
brane filter without cooling. Each filtrate, except for one fil-
Adv. Synth. Catal. 0000, 000, 0 – 0
6
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UPDATES
asc.wiley-vch.de
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[
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2
1
11] The H NMR experiments for the quantitative analysis
were conducted by setting the pulse delay at 15 second.
The methyl signal (for three proton atoms) of the
mesyl group of 2c was used as the internal standard,
see the Supporting Information.
2
[
5] For the Pd/C-catalyzed synthesis of heterocycles via CÀ
H functionalization, see: a) Z. Shu, W. Li, B. Wang,
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cantly decreased. When the recovered Pd/C was used
for the cyclization of 1c, 2c was obtained in only 50%
yield.
14] The X-ray diffraction (XRD) spectrum of the 10% Pd/
C recovered after a reaction using 2c as a substrate
shows that all peaks were slightly shifted to lower dif-
fraction angles, and the (220) and (311) peaks became
quite sharp in comparison with fresh 10% Pd/C. This
suggests that the crystalline structure of palladium par-
ticles of 10% Pd/C may change after the reaction. The
palladium particle sizes are estimated to be 5.6 nm and
[
1
72–173.
[
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.3–10.0 nm before and after the reaction, respectively,
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Adv. Synth. Catal. 0000, 000, 0 – 0
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These are not the final page numbers!

UPDATES
8
Palladium on Carbon-Catalyzed CÀH Amination for
Synthesis of Carbazoles and its Mechanistic Study
Adv. Synth. Catal. 2016, 358, 1 – 8
Yasunari Monguchi,* Hiroki Okami, Tomohiro Ichikawa,
Kei Nozaki, Toshihide Maejima, Yasunori Oumi,
Yoshinari Sawama, Hironao Sajiki*
Adv. Synth. Catal. 0000, 000, 0 – 0
8
ꢀ 2016 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ÞÞ
These are not the final page numbers!