Direct Regioselective Oxidative Cross-Coupling of Indoles with Methyl Ketones: A Novel Route to C3-Dicarbonylation of Indoles

Article abstract of DOI:10.1021/ol503366r

The first C3-dicarbonylation of indoles was realized through direct oxidative cross-coupling of indoles with methyl ketones in the presence of molecular iodine and pyrrolidine. This reaction constructed a highly efficient indolyl diketones scaffold, which

Full text of DOI:10.1021/ol503366r

Letter
pubs.acs.org/OrgLett
Direct Regioselective Oxidative Cross-Coupling of Indoles with
Methyl Ketones: A Novel Route to C3-Dicarbonylation of Indoles
Qinghe Gao,† Jingjing Zhang,† Xia Wu,† Shan Liu,† and Anxin Wu*,†,‡
†Key Laboratory of Pesticide & Chemical Biology, Ministry of Education, College of Chemistry, Central China Normal University,
Wuhan 430079, P. R. China
‡State Key Laboratory of Applied Organic Chemistry, Department of Chemistry, Lanzhou University, Lanzhou 730000, P. R. China
S
* Supporting Information
ABSTRACT: The first C3-dicarbonylation of indoles was realized
through direct oxidative cross-coupling of indoles with methyl ketones
in the presence of molecular iodine and pyrrolidine. This reaction
constructed a highly efficient indolyl diketones scaffold, which might be
regarded as a useful biological and pharmacological tool in the
exploration of therapeutic A2BAR modulators. The use of inexpensive
molecular iodine and pyrrolidine and a broad substrate scope make this
protocol very practical. Preliminary mechanistic studies indicate that two paths are involved in this process.
he oxidative coupling of two different C−H bonds has
glyoxylation/Stephens−Castro coupling, in which the decarbon-
Temerged as a powerful tool for the selective construction of ylative elimination was avoided (Scheme 1a). Li12 developed a
C−C bonds and plays an integral part in organic synthesis.1
Transition metals play an important role in many oxidative C−
H/C−H coupling reactions;2 This is because they can partake in
a diverse range of electron transfer processes.3 As a nonmetallic
element, iodine also has diverse oxidation states and moderate
redox potential. Molecular iodine has the lowest homolytic
dissociation energy of the nonradioactive halogens, which makes
it amenable to the single-electron-transfer process.4 These
properties led researchers to explore the use of molecular iodine
in oxidative coupling reactions. In 2010, I2-mediated intra-
molecular cyclization of enamines, via iodide intermediates, was
realized by Li et al.5 Recently, molecular iodine has also proven
successful for the assembly of polycyclic spiroindoline scaffolds.
This involves an intramolecular oxidative coupling of dianions
derived from indole-embodied β-ketoamides6 and has been
applied to the total synthesis of an indole alkaloid.7 Most
recently, Itoh and Prabhu independently described a versatile
molecular iodine catalyzed oxidative C−C bond formation
reaction between tertiary amines and a carbon nucleophile.8
Despite these promising results, the use of molecular iodine in
oxidative coupling reactions is still a young and fascinating
theme. Herein, we report our progress in the I2-mediated
dicarbonylation of indoles with methyl ketones.
Scheme 1. Dicarbonylation of Indoles
Pd-catalyzed direct dicarbonylation of indoles for synthesis of
indole-3-α-ketoamides, which proceeded via an iodo-3-indole
intermediate, followed by the sequential incorporation of two
molecules of carbon monoxide (Scheme 1b). Li et al.13
demonstrated an interesting route for the selective synthesis of
2-(1H-indol-3-yl)-2-oxo-carbonyls, and arylamines were gen-
erated concurrently as byproducts (Scheme 1c). Obviously, the
direct utilization of methyl ketones as coupling partners with
indoles for the construction of indolyl diketones would be an
appealing approach (Scheme 1d).
The indole moiety is common in bioactive synthetic and
natural products and occupies a privileged position in drug
discovery.9 Consequently, much attention has been paid to the
synthesis of substituted indoles, through either construction or
modification of indole rings. The electron-rich nature of the
indole ring enables it to undergo direct C−H bond
functionalization with electrophiles to form C−C bonds.
However, up to now, only rare examples have been reported to
realize the dicarbonylation of indoles.10 The Muller group11
Received: November 19, 2014
̈
reported a three-component approach to indolyl ynediones by a
© XXXX American Chemical Society
A
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Inspired by previous reports of oxidative coupling α to
nitrogen in tertiary amines,14 we tried the direct coupling of
indoles with iminium ions generated in situ from methyl ketones
and secondary amines to form a cross-dyhydrogenative-coupling
product (Scheme 2). These products can further undergo
entry 3). However, further increases in the amount of I2 did not
result in further increases in yield. The reaction was unable to
occur in the absence of I2 (Table 1, entry 5), indicating that
molecular iodine is essential for the reaction. Under these
conditions, various amines, such as piperidine, morpholine, and
L-proline, were used to obtain the desired products in acceptable
yields (Table 1, entries 6−8). However, N-methylaniline
afforded 3aa in only 25% yield (Table 1, entry 9), which
indicated that the ability of the N-aryl subunit in stabilizing the
charged iminium intermediate was unable to effectively promote
the reaction. Interestingly, the reaction also resulted in the
carbonylation of indole in the absence of amines (Table 1, entry
10), although less effectively, which can be attributed to the rapid
oxidation of I2.17 The reaction could also proceed successfully
when conducted at 90 °C (Table 1, entry 12).
Scheme 2. Design Strategy: Direct and Selective Oxidative
Cross-Coupling of Indoles with Methyl Ketones
With the optimized conditions in hand, the generality and
scope of the molecular iodine-pyrrolidine dicarbonylation of
indoles was explored. The reaction demonstrated wide substrate
scope in terms of the aromatic ketone unit (Scheme 3). Aryl
a
,b
Scheme 3. Scope of Methyl Ketones
oxidation to the second iminium ion, followed by hydrolysis, to
realize the dicarbonylation of indoles, which may be conveniently
transformed into highly conjugated polyheterocyclic com-
pounds.15 To the best of our knowledge, no examples of direct
and selective oxidative cross-coupling of indoles with methyl
ketones to construct indolyl diketone scaffolds have been
reported.
To test this, acetophenone (1a) and N-methylindole (2a)
were selected as model substrates. The reaction was successful in
25 mol % pyrrolidine over 12 h using 1.0 equiv of I2 at 100 °C in
DMSO. The products were a mixture of the desired 1-(1-methyl-
1H-indol-3-yl)-2-phenylethane-1,2-dione (3aa, 15%) and the
2,2-bis(1-methyl-1H-indol-3-yl)-1-phenylethanone (4a, 43%).16
Having obtained an initial and promising result, we next focused
on the optimization of the reaction conditions. Increasing the
amount of I2 to 1.5 equiv, the yield increased to 80% (Table 1,
a
a
Reaction conditions: 1 (0.5 mmol), 2a (0.5 mmol), and I2 (0.75
Table 1. Optimization of the Reaction Conditions
b
mmol) with pyrrolidine (25 mol %) in DMSO (2 mL) at 90 °C.
Isolated yield.
methyl ketones bearing electron-neutral (e.g., 4-Me), electron-
rich (e.g., 4-OMe, 4-OEt, 3,4-OMe2, 3,4-OCH2O), and electron-
deficient (e.g., 4-NO2, 3-NO2) phenyl rings were converted to
the corresponding products in moderate to good yields (74−
86%; 3ba−ha). The electronic and steric properties of the
aromatic ketones had little influence on the efficiency of this
reaction. Much to our satisfaction, the optimized conditions were
mild enough to allow a broad range of halogenated (e.g., 4-Br, 4-
Cl, 3,4-Cl2) substrates (69−75%; 3ia−ka) to be reacted, which
allowed for easy further functionalization. 2-Naphthyl methyl
ketone also provided the expected product (3la) in 73% yield.
Meanwhile, the optimized conditions could be applied to various
heteroaryl ketones, including furanyl, thienyl, and benzofuryl
methyl ketones, which gave the corresponding products in
moderate to good yields (57−79%; 3ma−pa). Moreover, the
desired dicarbonylation could also be obtained in moderate yield
from α,β-unsaturated methyl ketone (48%; 3qa). Furthermore,
the structure of 3ga was unambiguously confirmed by X-ray
crystallography. In addition, aliphatic methyl ketones, such as
acetone, cyclohexanone, and methylethylketone, were also
b
entry I2 (equiv)
cat.
temp (°C) yield 3aa/4a (%)
1
1.0
1.2
1.5
2.0
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
piperidine
100
100
100
100
100
100
100
100
100
100
110
90
15/43
73
2
3
80
4
78
5
0
6
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
1.5
74
7
morpholine
L-proline
70
8
77
9
N-methylaniline
25
10
11
12
13
14
38
pyrrolidine
pyrrolidine
pyrrolidine
pyrrolidine
80
80
80
43/5
12/38
50
a
Reaction conditions: 1a (0.5 mmol), 2a (0.5 mmol), catalyst (25 mol
b
%), solvent (2 mL). Isolated yields.
B
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investigated. However, none of the desired products were
observed under the standard conditions.
Scheme 5. Control Experiments
The scope of this reaction was subsequently extended to
indole derivatives (Scheme 4). The oxidative coupling between
a
Scheme 4. Scope of Indoles and Methyl Ketones
surprise, 5a was converted to the carbonylation product in
excellent yield in the presence of I2 (Scheme 6). This reaction
Scheme 6. Control Experiment
a
Isolated yield.
methyl ketones and indoles with different N-protective groups
proceeded smoothly, giving good yields (70−88%; 3ab−ac).
Noteworthily, the dicarbonylation products of N-benzyl indoles
have been proven to be useful biological and pharmacological
tools in understanding the therapeutic potential of A2BAR
modulators, and their 3-diketoindole scaffold might be useful in
the design of new analogs.18 Electron-withdrawing moieties (N-
acetyl) prevented the reaction from proceeding due to decreased
electron density in the indolyl ring. Unfortunately, N-H indole
(R2 = H) did not give the desired carbonylation product, likely
due to the easy overoxidation of the N-H indole to the isatin.19
Furthermore, different indole derivative were investigated. The
electronic properties of the phenyl rings (2g−i) have a strong
influence on the yield.
showed that 5a could be the intermediate in the absence of
pyrrolidine. Furthermore, the intermediate 5a can reasonably
account for the reactions (Table 1, entry 10 and Scheme 5b)
which did not require the catalyst.
On the basis of the results in the current study and previous
reports,22 a possible mechanism has been proposed using
acetophenone (1a) and N-methylindole (2a) as examples
(Scheme 7). The initial reaction of I2 with 1a results in the
Scheme 7. Possible Mechanism
With the scope of the method established, the reaction
mechanism was investigated. Acetophenone (1a) was reacted
with I2 in DMSO at 90 °C to give phenylglyoxal (1ab) and the
corresponding hydrated species (1ac) in quantitative yield
(Scheme 5a). The hydrated species (1ac) was subjected to the
optimized reaction conditions and gave 3aa in good yields, both
with pyrrolidine (25 mol %) and without (Scheme 5b). This
result demonstrates that 1ac is an intermediate in the current
reaction and also suggests there might be an alternative path in
the absence of pyrrolidine. However, only trace amounts of 3aa
were detected when 1ac and 2a were reacted in the absence of I2
(Scheme 5c). This suggested that molecular iodine plays an
important role in this oxidative coupling process. In the absence
of indole, substrate 1ac was converted to 1-phenyl-2-(pyrrolidin-
1-yl)ethane-1,2-dione 6a in 67% yield (Scheme 5d), indicating
that an iminium ion intermediate (A) might be reacting with
indole to give the target product under the optimized
conditions.20 When the acetophenone substrate was replaced
with α-iodo acetophenone (1aa), which was identified as a
possible precursor of α-ketoaldehyde (1ab), the desired diketone
product was also obtained in 71% yield (Scheme 5e).
formation of an α-iodo ketone (1aa), which is converted to
phenyl glyoxal by a subsequent Kornblum oxidation. In the
presence of pyrrolidine (path a), pyrrolidine with the aldehyde
group of 1ab would generate an iminium ion intermediate A in
situ, which then reacts with the nucleophilic indole to produce
the intermediate B via a Friedel−Crafts-type reaction. Inter-
mediate B is quickly converted into intermediate C in the
presence of oxidants. Hydrolysis of intermediate C gives the
To further develop an understanding of the reaction
mechanism, 2-hydroxy-2-(1-methyl-1H-indol-3-yl)-1-phenyle-
thanone 5a21 was tested in the absence of pyrrolidine. To our
C
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(4) (a) Kupper, F. C.; Feiters, M. C.; Olofsson, B.; Kaiho, T.; Yanagida,
̈
desired product 3aa, and the released pyrrolidine can start a new
catalytic cycle. Without pyrrolidine as a catalyst (path b), the
aldehyde group of 1ab is activated by an excess of regenerated
Lewis acid I2.17 The activated aldehyde group of phenylglyoxal
would react with 2a to give the intermediate 5a directly, followed
by further rapid oxidation by I2 to afford 3aa.17
In summary, we have developed a convenient and general
method for the dicarbonylation of indoles via direct
regioselective oxidative cross-coupling of indoles with methyl
ketones in the presence of molecular iodine and pyrrolidine.
These reactions proceed under mild conditions with high
regioselectivity and show good functional group compatibility.
Preliminary mechanistic studies indicate two paths are involved
in this process. Further studies to elucidate a detailed mechanism
and identify synthetic applications for this protocol are currently
underway in our laboratory.
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Corresponding Author
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*E-mail: chwuax@mail.ccnu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the National Natural Science
Foundation of China (Grants 21032001, 21272085).
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