Pd(II)-catalyzed intramolecular C-H activation/C-C cross coupling for the synthesis of carbazoles from diaryl acetamides

Article abstract of DOI:10.1016/j.tetlet.2011.11.082

Pd(II)-catalyzed intramolecular C-H activation/C-C cross coupling within N,N-diphenyl-acetamides allows the efficient formation of differently substituted carbazoles. In this cross-dehydrogenative coupling, many different functional groups are tolerated and the starting material N,N-diphenyl- acetamides can be easily prepared in one step from commercially available acetanilides and iodobenzenes.

Full text of DOI:10.1016/j.tetlet.2011.11.082

Tetrahedron Letters 53 (2012) 505–508
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Tetrahedron Letters
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Pd(II)-catalyzed intramolecular C–H activation/C–C cross coupling
for the synthesis of carbazoles from diaryl acetamides
⇑
Sichang Wang, Hui Mao, Zhangqin Ni, Yuanjiang Pan
Department of Chemistry, Zhejiang University, Hangzhou 310027, China
a r t i c l e i n f o
a b s t r a c t
Article history:
Pd(II)-catalyzed intramolecular C–H activation/C–C cross coupling within N,N-diphenyl-acetamides
allows the efficient formation of differently substituted carbazoles. In this cross-dehydrogenative cou-
pling, many different functional groups are tolerated and the starting material N,N-diphenyl-acetamides
can be easily prepared in one step from commercially available acetanilides and iodobenzenes.
Ó 2011 Elsevier Ltd. All rights reserved.
Received 27 August 2011
Revised 8 November 2011
Accepted 15 November 2011
Available online 22 November 2011
Keywords:
Palladium
C–H activation
C–C coupling
Carbazoles
Transition metal-catalyzed C–H activation reactions are among
the most popular processes in modern organic synthesis.1 Catalyt-
ically efficient activation of aromatic C–H bonds leading to useful
organic reactions such as new C–C bond formation is of consider-
able interest for the chemical and pharmaceutical industries and
remains a long-term challenge to chemists.2–5 C–H functionaliza-
tion is the most sustainable and straightforward method to con-
struct complicated structures and has received significant
attention in the past several decades.6 Chemists continue to devel-
op increasingly efficient methods for the construction of biaryl
molecules by C–H activation.
Carbazole alkaloids are attractive synthetic targets for they dis-
play a variety of biological activities.7–9 The indigenous application
of the stem bark of the curry-leaf tree as folk medicine led to the dis-
covery of antibacterial, antifungal, and antiviral properties of this
class of natural products.10,11 Carbazole derivatives have also been
extensively applied as organic materials and have been investigated
for the development of optoelectronic applications such as poly-
meric light-emitting diodes (PLED) and organic light-emitting
devices (OLED).12,13 In view of these important applications, we
set out to develop a metal-catalyzed synthesis of carbazoles. The
use of pivalic acid as solvent results in improved reproducibility,
higher yields, and broader scope for the intramolecular aryl–aryl
coupling.14 The development of better conditions for the transfor-
mation of diarylacetamides into carbazoles is greatly appealing. In-
stead of expensive pivalic acid, herein, acetic acid is used as the
reaction solvent together with Ag2O as oxidant, which also leads
to higher yields.
The requisite biaryl amines 3 were synthesized from acetani-
lides 1 and iodobenzenes 2 as model substrates by an Ullmann
C–N cross-coupling reaction (Scheme 1).15
A combination of a palladium catalyst and a reoxidant was used
to investigate the conversion of N,N-diphenyl-acetamide 3a to
N-acetyl carbazole 4a (Table 1). Preliminary results suggested that
the use of a combination of 5% Pd(OAc)2 and a stoichiometric
amount of Cu(OAc)2/Ag2O or CsCO3/Ag2O at 120 °C under an atmo-
sphere of air after 14 h provided a near quantitative yield of 4a in
acetic acid (Table 1, entries 9 and 10). No product was observed in
the absence of Pd(OAc)2 (Table 1, entry 14), suggesting that Ag2O
mediated the reoxidation of the reduced palladium species. Other
commercially available palladium precatalysts (Table 1, entries
1–4) were less efficient than Pd(OAc)2 in affecting the transforma-
tion. Other reoxidants (Table 1, entries 7–12) were also evaluated
in various palladium-catalyzed oxidative coupling reactions.14 Re-
sults show that a stoichiometric amount of Ag2O (Table 1, entry 13)
was sufficient to mediate the reoxidation process and deliver 4a in
comparable yields.
Next, the scope and limitations of this cascade reaction were
examined. The proposed method was tested on substrates causing
electronic variations on each ring of the diarylacetamides. Various
biarylacetamides bearing electron-donating (OMe) or -withdrawing
groups (Cl, F, CF3 and NO2) on the aromatic ring were treated with
palladium acetate to produce corresponding carbazoles in moderate
to good yields (Table 2, entries 2–15). For example, when mono-
substituted electron-rich diphenylacetamides were treated with
palladium acetate and silver oxide in acetic acid, good yields (up to
⇑
Corresponding author.
E-mail address: cheyjpan@zju.edu.cn (Y. Pan).
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.11.082

506
S. Wang et al. / Tetrahedron Letters 53 (2012) 505–508
2
R
0.1 equiv CuI, 2 equiv K PO
3
4
1
1
2
R
R
R
°
Dioxane, 110 C
N
I
NHAc
N,N'-dimethyl-ethylenediamine
( 0.2equiv)
Ac
2
1
3
Scheme 1. Synthesis of biaryl acetamides by Ullmann C–N cross-coupling.
Table 1
Screening of reaction conditions for synthesis carbazolea
Ag O, Pd(OAc)
2
2
°
AcOH, 120 C, N2
N
N
Ac
Ac
4a
3a
Entry
Pd(mol %)
Oxidant(equiv)
Solvent
Temperature (°C)
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
Pd(OAc)2(5)
PdCl2(5)
Pd(OAc)2(5)
PdCl2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Pd(OAc)2(5)
Cu(OAc)2(2), CsCO3(2)
Cu(OAc)2(2), CsCO3(2)
Cu(OAc)2(2), Ag2O(2)
Cu(OAc)2(2), CsCO3(2)
Cu(OAc)2(2), CsCO3(2)
Cu(OAc)2(2),CsCO3(2)
Cu(OAc)2(2), CsCO3(2)
Cu(OAc)2(2)
Cu(OAc)2(2), Ag2O(2)
CsCO3(2), Ag2O(2)
CsCO3(2)
Na2CO3(2)
Ag2O(1)
Toluene
Toluene
TFA
TFA
DMF
Dioxane
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
120
110
120
110
120
100
120
120
120
120
120
120
120
120
14
12
14
12
14
14
14
14
14
14
14
14
14
14
0
0
0
0
0
0
40
13
60
68
43
40
70
0
Ag2O(1)
a
All reactions were performed with N,N-diphenyl-acetamides (0.3 mmol), oxidant (0.3 mmol) and catalyst (5–8 mol %) in 2 mL of solvent under nitrogen atmosphere.
Isolated yield after silica gel chromatography.
b
Table 2
Scope and limitations of palladium(II)-catalyzed carbazole formation from diarylacetamidesa
R1
R2
R1
R2
Ag2O, Pd(OAc)2
AcOH, 120 °C, N2
N
N
Ac
Ac
4
3
Entry
1
Diarylamine
Product
Yieldb (%)
70
N
N
Ac
Ac
4a
OCH
OCH
3
2
68
N
N
Ac
Ac
4b
4e
F
F
3
4
5
55
60
43
N
N
Ac
Ac
4c
Cl
Cl
N
N
Ac
4d
Ac
CF3
CF3
N
N
Ac
Ac
NO
NO2
2
6
60
N
Ac
N
Ac
4f

S. Wang et al. / Tetrahedron Letters 53 (2012) 505–508
507
Table 2 (continued)
Entry
Diarylamine
Product
Yieldb (%)
H3CO
OCH3
H3CO
OCH3
7
76
N
Ac
N
Ac
4g
F
OCH3
F
OCH
3
8
9
53
66
48
68
58
40
58
53
N
N
4h
OCH3
Ac
Ac
Cl
OCH3
OCH3
OCH3
Cl
Cl
N
Ac
N
Ac
4i
OCH
F3C
O2N
F C
3
3
10
11
12
13
14
N
N
Ac
4j
Ac
O2N
O2N
OCH3
Cl
N
Ac
N
Ac
4k
O N
2
N
N
Ac
4l
Ac
F3C
Cl
Cl
F C
3
Cl
N
N
Ac
4m
Ac
Cl
Cl
F
Cl
N
Ac
N
Ac
4n
F
Cl
Cl
15
N
Ac
N
Ac
4o
a
All reactions were performed with N,N-diphenyl-acetamides (0.3 mmol), Ag2O (0.3 mmol) and Pd(OAc)2 (5–8 mol %) in 2 mL of solvent under nitrogen atmosphere.
Isolated yield after silica gel chromatography.
b
2
1
R
R
N
Ac
3
AcO
Pd
2
1
R
R
Ag O
2
0
Pd
Pd(OAc)
1
2
2
R
R
N
Ac
AcOH
5
N
Ac
reductive
elimination
4
AcO
Pd
2
1
H
R
1
2
R
R
R
Pd
N
Ac
N
Ac
AcOH
6
7
Scheme 2. Proposed pathway for carbazole synthesis.
68%) were obtained for the preparation of carbazole products (Table
2, entry 2). However, diarylacetamides with electron-withdrawing
groups afforded the product with reduced yields (Table 2, entries
3–6). In addition, carbazoles with good yields were obtained when
a series of disubstituted diphenylamines were employed (Table 2,
entries 7–15).

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S. Wang et al. / Tetrahedron Letters 53 (2012) 505–508
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2).14 First, substrate 3 and palladium(II) acetate could form a Pd(II)
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7 produces the carbazole product 4 and a Pd(0) species, which is
reoxidized to Pd(II) acetate in the presence of Ag2O to complete
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Acknowledgment
Financial support from Natural Science Foundation of China
(Nos. 21025207 and 20975092) is greatly acknowledged.
Supplementary data
Supplementary data associated with this article can be found, in
the online version, at doi:10.1016/j.tetlet.2011.11.082.
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