Palladium-catalyzed direct arylation of indoles with cyclohexanones

Article abstract of DOI:10.1021/ol500231c

A novel palladium catalyzed approach to 3-arylindoles was developed from indoles and cyclohexanones. Various cyclohexanones acted as aryl sources via an alkylation and dehydrogenation sequence using molecular oxygen as the hydrogen acceptor. This method showed good regioselectivity and afforded 3-arylindoles as the sole products.

Full text of DOI:10.1021/ol500231c

Letter
pubs.acs.org/OrgLett
Palladium-Catalyzed Direct Arylation of Indoles with
Cyclohexanones
Shanping Chen,† Yunfeng Liao,*,†,‡ Feng Zhao,† Hongrui Qi,† Saiwen Liu,† and Guo-Jun Deng*,†
†Key Laboratory of Environmentally Friendly Chemistry and Application of Ministry of Education, College of Chemistry, Xiangtan
University, Xiangtan 411105, China
‡School of Chemistry & Chemical Engineering, Hunan Institute of Engineering, Xiangtan 411104, China
S
* Supporting Information
ABSTRACT: A novel palladium catalyzed approach to 3-
arylindoles was developed from indoles and cyclohexanones.
Various cyclohexanones acted as aryl sources via an alkylation
and dehydrogenation sequence using molecular oxygen as the
hydrogen acceptor. This method showed good regioselectivity
and afforded 3-arylindoles as the sole products.
Scheme 1. Various Methods for C-Arylindoles
ndole and its derivatives are frequently found in natural
Iproducts, functional materials, agrochemicals, and pharma-
ceuticals.1 Among them, C-arylated indoles show great
potential in pharmaceuticals, especially as anticancer drugs.2
Since its discovery in 1869, great efforts have been made to
develop efficient synthetic methodologies for the preparation
and further functionalization of indole.3 Recently, much focus
has been devoted to the transition-metal-catalyzed direct
arylation of indoles with activated arenes. This strategy avoids
the prefunctionalization of indole derivatives and thus can
potentially provide an efficient synthetic route to rapidly
construct various biaryls containing an indole nucleus.4 Aryl
halides were the most commonly used coupling partners for
direct C-arylation of indole derivatives promoted by transition-
metal catalysts.5 Apart from aryl halides, various aromatic
coupling partners, including organoboranes,6 aromatic hyper-
valent iodine chemicals,7 arylsiloxanes,8 arylhydrazines,9 aryltri-
flates,10 aromatic carboxylic acids,11 and sodium sulfinates12
have been successfully employed as arylation agents (Scheme 1,
eq 1). More recently, nonactivated arenes were also used as
coupling partners for arylated indole preparation via a cross-
dehydrogenative-coupling (CDC) reaction under oxidative
reaction conditions (Scheme 1, eq 2).13,14 The CDC reaction
avoids the prefunctionalization of both coupling partners and
thus affords the most direct approach for the preparation of
arylindoles. However, this method is mainly suitable for
nonsubstituted or symmetrical substituted arenes.
these compounds could be dehydrogenated under palladium
catalyzed reaction conditions to afford the corresponding
phenols or cyclohexenones using molecular oxygen as a
hydrogen acceptor.17 We and others successfully used cyclo-
hexanones as aryl sources for C−C and C−heteroatom bond
formation.18 Similarly, phenothiazines could be prepared from
cyclohexanones and 2-aminobenzenethiols via condensation−
tautomerization reactions in the absence of transition metals.19
We and others also developed methods for 2-arylsulfanylphenol
formation from thiols and cyclohexanones using a catalytic
amount of iodine as the catalyst under metal-free conditions.20
In this transformation, cyclohexanones acted as phenol sources.
It would be attractive and challenging to use cyclohexanones as
aryl sources to prepare biaryls containing an indole moiety via
However, all of the above-mentioned approaches require two
aromatic coupling partners. The direct arylation of heteroarenes
with readily available and cheap nonaromatic coupling partners
is very rare. Cyclohexanone is cheap, readily available, and facile
to convert into other important organic materials such as
hexanedioic acid, which is an important precursor for the
production of nylon.15 Cyclohexanone also could be used as an
alkylation reagent for indoles in trichloroacetic acid using
triethylsilane as a reductant, selectively affording 3-cyclohexyl-
indole in good yield.16 Recently, the Stahl group found that
Received: January 22, 2014
Published: March 5, 2014
© 2014 American Chemical Society
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Organic Letters
Letter
direct arylation of free indole C(sp2)−H bonds. Herein, we
describe a palladium-catalyzed 3-arylindole formation from
cyclohexanones and free indoles using oxygen as the hydrogen
acceptor (Scheme 1, eq 3).
Initially, we examined the reaction of indole (1a) and
cyclohexanone (2a) in toluene under an oxygen atmosphere.
No arylated indole product was observed when the reaction
was carried out at 140 °C using 5 mol % PdCl2 as the catalyst as
determined by GC analysis (Table 1, entry 1). Under these
hydrogen acceptor, and replacement of it with inert argon
significantly decreased the reaction yield to 5% (entry 19).
Based on the optimized conditions, various indoles with
substituents were screened to explore the scope and generality
of this reaction (Table 2). The reaction was found to be
a
Table 2. Reaction of Various Indoles with 2a
a
Table 1. Optimization of the Reaction Conditions
b
temp
(°C)
yield
(%)
entry
catalyst
PdCl2
ligand
solvent
1
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
p-xylene
mesitylene
NMP
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
130
140
140
trace
trace
trace
3
2
PdBr2
3
Pd(COD)Cl2
Pd(acac)2
Pd(OAc)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
Pd(TFA)2
4
5
5
6
32
11
15
38
28
45
23
12
0
7
1,10-phen
DMAP
8
9
PPh3
10
11
12
13
14
15
X-phos
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
DPEphos
toluene
toluene
toluene
toluene
toluene
56
66
58
85
5
c
16
c
17
cd
,
18
19
ce
,
a
Conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (5 mol %),
ligand (5 mol %) solvent (2.0 mL), 24 h, under oxygen unless
b
otherwise noted. For entries 15−19, 0.75 mmol of 2a was used. GC
c
a
yield based on 2a using dodecane as internal standard. 10 mol %
Conditions: 1 (0.75 mmol), 2a (0.5 mmol), Pd(TFA)2 (0.05 mmol),
DPEphos (0.1 mmol), toluene (2.0 mL), 140 °C, 30 h, under oxygen.
Isolated yield based on 2a.
d
e
catalyst and 20 mol % ligand were used. 30 h. Under argon.
b
conditions, several other palladium salts were screened in the
absence of any ligand and proved to be ineffective for this type
of arylation reaction (entries 2−5). Fortunately, the expected
product 3-phenylindole (3a) was detected in 32% yield when
Pd(TFA)2 was used as the catalyst (entry 6). Various ligands
were then screened in the presence of Pd(TFA)2 (entries 7−
11). Nitrogen-containing ligands such as 1,10-phenanthroline
and DMAP (4-dimethylaminopyridine) were ineffective, and
their use resulted in lower yields (entries 7 and 8). Among the
phosphine ligands investigated, DPEphos ((bis{2-diphenyl-
phosphino}phenyl)ether) exhibited the best reactivity, and 3a
could be formed in 45% yield (entry 11). The choice of solvent
was pivotal, and the use of other solvents such as p-xylene,
mesitylene and NMP all resulted in lower yields (entries 12−
14). Increasing the catalyst and ligand loading increased the
reaction yield while decreasing the reaction temperature
decreased the reaction yield (entries 16 and 17). The reaction
yield could be further improved to 85% when the reaction time
was prolonged to 30 h (entry 18). Oxygen acted as an efficient
general, giving the desired 3-phenylindoles (3) in reasonable
yields and excellent selectivity. Common functional substitu-
ents were compatible with the optimized conditions. The
substituent position significantly affected the reaction yield, and
the reaction yield decreased from 81% to 64% when the methyl
substituent shifted from C-4 to C-7 (entries 2 and 3). Similar
phenomena were observed when a fluoro substituent was
located at a different position of indole (entries 5 and 6). No
desired product could be obtained when a bromo substituent
was presented in the indole moiety due to the cleavage of the
carbon−bromo bond (entry 9). Active functional groups such
as cyano and ester were well tolerated, and the C-arylation
products 3j and 3k were obtained in 70% and 72% yields,
respectively (entries 10 and 11). The reaction did not show
much difference when a hindered methyl substituent was
located at the C-2 position of indole, and the C-3 arylated
product 3l was isolated in 68% yield (entry 12). In all cases, the
reaction showed very good selectivity and no 2-phenylindole or
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Organic Letters
Letter
N-arylated byproducts were observed. When the C-3 position
was occupied by a methyl group, no coupled product could be
observed (entry 13). Protected 1-methylindole (1n) also could
be employed for this reaction and gave 1-methyl-3-phenyl-
indole (3n) in 74% yield (entry 14).
Scheme 2. Control Experiments and Possible Pathway
The scope of the reaction with cyclohexanones is outlined in
Table 3. Cyclohexanones bearing alkyl substituents at the para
a
Table 3. Reaction of 1a with Various Cyclohexanones
could be smoothly transferred into stable 3-cyclohexylindole
(4a) using the hydrogen generated from the cyclohexanone
dehydrogenation step (Scheme 2b). Further treatment of 5a or
4a with the standard conditions afforded the corresponding
product 3a in 85% and 82% yields, respectively (Scheme 2c and
d). However, treatment of 5a and 4a in the absence of
DPEphos only gave the target product 3a in 36% and 32%
yields, respectively (Scheme 2e and f). Both Pd(TFA)2 and
DPEphos were necessary to give the final biaryl product in a
satisfactory yield. Although we could not trap more important
intermediates between the starting material and the final
product to elucidate the exact reaction mechanism, the first step
should be the direct alkylation of indole under neutral
conditions. The second step should be the dehydrogenation
of alkylated intermediates (4a or 5a) using oxygen as the
hydrogen acceptor (Scheme 2g). It is very interesting that
DPEphos could significantly improve the direct alkylation of
indole with cyclohexanone under neutral conditions (Scheme
2a), which is usually carried out under acidic conditions.16,21,22
In summary, we have developed a novel approach for the
synthesis of 3-arylindoles using cyclohexanones as the aryl
source. The palladium-catalyzed coupling reaction of cyclo-
hexanones with an indole C(sp2)−H bond and subsequent
dehydrogenation−tautomerization reactions were realized in
one pot. Molecular oxygen was used as an efficient hydrogen
acceptor in this transformation. The reaction showed good
selectivity, and no 2-arylindole byproduct was observed. Since
cyclohexanones are readily available starting materials, this
method can afford an efficient and environmentally benign
approach for the preparation of biaryls and other arylated
heteroarenes. The generality, exact reaction mechanism, and
synthetic applications of this methodology are under
investigation.
a
Conditions: 1a (0.75 mmol), 2 (0.5 mmol), Pd(TFA)2 (0.05 mmol),
DPEphos (0.1 mmol), toluene (2.0 mL), 140 °C, 30 h, under oxygen.
b
Isolated yield based on 2.
position were able to smoothly couple with 1a to give the
corresponding biaryls in good yields (entries 2−4). When 4-
phenylcyclohexanone (2f) was employed to react with 1a,
product 3s was obtained in 63% yield (entry 5). To our delight,
the ester functional group was well tolerated in this reaction,
and the corresponding arylated product was obtained in 77%
yield (entry 6). The substituent position in cyclohexanone
significantly affected the reaction yield. When 3-methylcyclo-
hexanone (2h) was used, 3-(m-tolyl)-1H-indole (3u) was
obtained in 72% yield (entry 9). However, no desired product
3v could be isolated when 2-methylcyclohexanone (2i) was
used as a coupling partner (entry 8).
To gather more information about the reaction mechanism,
some control experiments were carried out under different
conditions (Scheme 2). An intermediate 5a (determined by
GC-MS, not isolable) was observed in 89% GC yield when the
reaction of indole (1a) and cyclohexanone (2a) was carried out
in the absence of Pd(TFA)2 (Scheme 2a). DPEphos played an
important role in this transformation, and only a trace amount
of 5a was observed in the absence of it. When the reaction was
stopped after 8 h using Pd(TFA)2/DPEphos as the catalyst, 5a
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Organic Letters
Letter
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ASSOCIATED CONTENT
* Supporting Information
General experimental procedure and characterization data of
the products. This material is available free of charge via the
Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Authors
■
*E-mail: liaoyunfeng900@126.com.
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Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (21172185, 21372187), the Hunan
Provincial Natural Science Foundation of China (11JJ1003,
12JJ7002), the Hunan Provincial Innovative Foundation for
Postgraduate (CX2013B269), the Research Fund for the
Education Department of Hunan Province of China
(13C192), and the Research Fund for the Doctoral Program
of Higher Education of China, Ministry of Education of China
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