Regioselective Rh-catalyzed direct carbonylation of indoles to synthesize indole-3-carboxylates

Article abstract of DOI:10.1039/c1cc15143f

Rh-catalyzed C-H carbonylation of indoles under 1 atm of CO has been achieved. Various substituted indoles and indole with free N-H could be carboxylated with linear- and/or cyclic-alcohol to give the desired indole-3-carboxylates with up to 92% yield. A mechanism involving Rh ^III initiated C-H metallation is proposed.

Full text of DOI:10.1039/c1cc15143f

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COMMUNICATION
Regioselective Rh-catalyzed direct carbonylation of indoles to synthesize
indole-3-carboxylatesw
Rui Lang,ac Junliang Wu,a Lijun Shi,a Chungu Xia*a and Fuwei Li*ab
Received 18th August 2011, Accepted 3rd October 2011
DOI: 10.1039/c1cc15143f
Rh-catalyzed C–H carbonylation of indoles under 1 atm of CO
has been achieved. Various substituted indoles and indole with free
N–H could be carboxylated with linear- and/or cyclic-alcohol to
give the desired indole-3-carboxylates with up to 92% yield. A
mechanism involving RhIII initiated C–H metallation is proposed.
catalysts in the aromatic C–H functionalization to form C–C
and C–X bonds,3d,9 Rh-catalyzed6b,11a C–H carbonylative
functionalization of (hetero)arene has rarely been realized if
compared with Pd catalysts.5 We herein disclose a novel and
efficient Rh-catalyzed oxidative carbonylation of indoles to
regioselectively form indole-3-carboxylates without any basic
or acidic additives.
Since the pioneering work developed by Heck and co-workers
in 1974,1 transition metal catalyzed carbonylations of aryl
halides, triflates and tosylates with CO and alcohol have been
well developed and became one of the most straightforward
access to carboxylic esters,2 which are important structural
motifs in many valuable commodity chemicals and fine chemicals.
Recently, aromatic C–H functionalizations have found increasing
applications in the preparation of organic building blocks and
therapeutically important scaffolds due to the advantage of
avoiding the prefunctionalization of Ar–H and thereby the
usage of a stoichiometric amount of bases.3 In this context, the
first direct carbonylation of arenes was reported by Fujiwara
and co-workers in 1980, affording carboxylic acid with a
26–48% yield relative to the Pd(OAc)2 catalyst.4 Recently,
the ortho-selective carbonylation of chelating aromatic C–H
bonds to give the corresponding aryl carboxylic acids and
derivatives has also been intensively studied.5,6 However, efficient
and regioselective synthesis of carboxylic ester through direct
C–H bond oxidative carbonylation of nonchelating substance is
still a challenging area.7
Initially, optimization of reaction conditions was carried out
in the direct oxidative carbonylation of N-methyl indole (1a)
with n-butanol (2a) under 1 atm of CO as a benchmark
reaction. As shown in Table 1, 3a could be obtained as a main
product in 6% yield in toluene at 110 1C when Pd(OAc)2 and
K2S2O8 were used as a catalyst and an oxidant, respectively
(entry 1). PdCl2(COD) gave 8% yield of the desired product and
RuCl3 could not initiate the carbonylation (entries 2 and 3).
Under the same reaction conditions, we were pleased to find that
62% yield of 3a could be achieved using RhCl3 salt as a catalyst
(entry 4). Interestingly, 2 mol% [Rh(COD)Cl]2 demonstrated
excellent reactivity toward the regiocontrol alkoxycarbonylation
Table 1 Optimization of reaction conditions in the direct oxidative
carbonylation of N-methyl indole (1a)a
Indole derivatives such as indole-3-carboxylates are important
building blocks in the synthesis of many pharmaceuticals and
biologically active compounds. In 1982, Itahara reported a direct
C–H carbonylation of N-substituted indole catalyzed by 0.5 equiv.
of Pd(OAc)2 with Na2S2O8 as an oxidant under reflux in AcOH,
giving 54–75% yield of indole-3-carboxylic acid.8 On the other
hand, although Rh complexes have been proved to be effective
Entry
Catalyst
Oxidant
Solvent
Yieldb (%)
1
2
3
4
5
6
7
8
Pd(OAc)2
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
Oxone
Cu(OAc)2
Ag2CO3
TBHP
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
Toluene
DMAc
6
8
PdCl2(COD)
RuCl3
RhCl3
0
62
95 (86)
40
16
o5
o5
57
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
[Rh(COD)Cl]2
9
a State Key Laboratory for Oxo Synthesis and Selective Oxidation,
Lanzhou Institute of Chemical Physics, Chinese Academy of
Sciences, Lanzhou, 730000, China. E-mail: fuweili@licp.cas.cn;
Fax: +86-931-4968129
10
11
12
13
14
15c
BQ
K2S2O8
K2S2O8
K2S2O8
K2S2O8
K2S2O8
0
DMF
NMP
n-Butanol
Toluene
o5
o5
30
b Suzhou Institute of Nano-Tech and Nano-Bionics,
Chinese Academy of Sciences, Suzhou, 215123, China
c Graduate University of Chinese Academy of Sciences, Beijing,
100049, China
69
a
Reaction conditions: 1a (1 mmol), n-butanol (5 mmol), oxidant
(2 mmol), and catalyst (2 mol%) in solvent (1.0 mL) under CO
w Electronic supplementary information (ESI) available: Experimental
details and characterization data for new compounds. CCDC 838366.
For ESI and crystallographic data in CIF or other electronic format
see DOI: 10.1039/c1cc15143f
b
(1 atm) at 110 1C for 24 h. Yields determined by HPLC analysis
and based on 1a, isolated yield in parentheses. 90 1C.
c
c
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Chem. Commun., 2011, 47, 12553–12555 12553

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Table 2 Rh-catalyzed regioselective carbonylation of indolesa
of indole in the presence of 2 equiv. of K2S2O8 under low CO
pressure, giving 86% isolated yield of the expected indole-3-
carboxylate (entry 5). Following this optimized Rh(I) precatalyst,
other inorganic oxidants such as Oxone (2KHSO5KHSO4K2SO4),
Cu(OAc)2 and Ag2CO3 were screened, but showing less
effective reactivities (entries 6–8), and oxidative compatibilities
of representative organic oxidants with the current Rh(I)
catalytic system were also tested with BQ (benzoquinone)
affording moderate yield of 3a (entries 9 and 10). Similar to
the oxidant, the solvent also played an important role in the
C–H activation catalysis, very low yields were obtained when
carbonylation was carried out in polar solvents, such as
DMAc, DMF or NMP, and pure n-butanol also slowed down
the reaction although it is one of the reactants (entries 11–14).
Additionally, it was revealed that current Rh-catalyzed oxidative
carbonylation was also sensitive to temperature, a lower yield
(69%) was observed when temperature was reduced from 110 1C
to 90 1C (entry 15).
With the optimized conditions in hand, we then turned to
examine the scope of indole and alcohol in the Rh-catalyzed
direct carbonylation. As shown in Table 2, the carbonylative
functionalizations occurred smoothly at the C-3 position of
N-methyl indole with both primary and secondary alcohols to
give the corresponding indole-3-carboxylates in good to
excellent yields (3a–3d). Significant electronic effects of the
substituents on the benzene ring of N-methyl indole toward
reactivity were observed. Electron-deficient indoles, in general,
gave better yields (65–86%) and the bromo- or chloro-substitution
can be well tolerated under the reaction conditions without any
product of C–X (X = Br, Cl) bond carbonylation, which allows
further functionalization of the resultant indole carboxylic
esters (3e, 3f, 3g) at the halogenated positions. A representative
structure of the ester product (3e) was confirmed unambiguously
by single-crystal X-ray analysis (CCDC number: 838366).
Interestingly, substituents at the N-position of indole also signifi-
cantly influenced the efficiency of the direct C–H carbonylation.
The N-benzyl indole and its derivatives further substituted by
electron-donating methyl groups at the 5- or 6-position worked
efficiently, resulting in the desired indole-3-carboxylates (3i–3m) in
77–92% yields, however, N-benzyl-5-bromoindole showed quite
low carbonylative reactivity. N-Allyl indole derivatives with both
electron-donating and electron-withdrawing substituents can be
carboxylated selectively to the expected esters (3n–3q) in good to
excellent yield (52–86%), which are similar to the catalytic results
of N-methyl indoles.
a
A mixture of indole (0.5 mmol), alcohol (2.5 mmol), [Rh(COD)Cl]2
(0.02 mmol), and K2S2O8 (2.0 mmol) in toluene (1.0 mL) was stirred
under CO (1.0 atm) at 110 1C for 24 h, isolated yields based on 1 after
silica gel chromatography and all results are average from two runs.
b
Reaction was performed at 90 1C for 48 h.
Direct C–H carbonylation of N-phenyl indole also occurred
smoothly, giving the desired indole-3-carboxylate (3r) in 61%
isolated yield. Unfortunately, only a trace amount of products
(3s and 3t) was observed when indole was N-substituted by
strong electronic-withdrawing groups such as Ts and Boc,
suggesting that the presence of Boc or Ts renders the indole
ring highly electron-deficient and retards electrophilic metallation.
To our delight, the current protocol can also be successfully
extended from linear alcohol to cyclic alcohol, and 76% isolated
yield of indole-3-carboxylic menthyl ester (3u) was obtained by
the direct carbonylation of N-methyl indole with menthol at
110 1C for 24 h. Replacing indole with N-substituted pyrrole also
proceeds smoothly, giving the expected pyrrole-3-carboxylic ester
(3v). Surprisingly, NH-free indole with (or without) a functional
group on the benzyl ring can also be regioselectively carboxylated
at the C-3 position instead of the N–H position, yielding the
desired ester (3w–3y) under oxidative carbonylation conditions,
which usually leads to the formation of carbamate or urea
product from an amine substrate in the presence of a Pd catalyst
system.5j
In the past decade, two kinds of reaction mechanisms were
discussed about the Rh-catalyzed C–H activation reactions,
and the main difference lies in which one initiates the C–H
activation, Rh(I)10 or Rh(III).11 To explore the mechanism of
current Rh-catalyzed carbonylation, some control experiments
were carried out (for experimental details, see ESIw). No reaction
c
12554 Chem. Commun., 2011, 47, 12553–12555
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Notes and references
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M. Beller, Angew. Chem., Int. Ed., 2009, 48, 4114.
3 For reviews on C–H functionalization, see: (a) D. Alberico,
M. E. Scott and M. Lautens, Chem. Rev., 2007, 107, 174;
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Scheme 1 Proposed mechanism for Rh-catalyzed direct carbonylation.
occurred from the carbonylation of 1a with n-butanol in the
presence of a stoichiometric amount of [Rh(COD)Cl]2 without
any oxidant under optimized reaction conditions. However, 3a
was clearly observed by HPLC analysis when replacing
[Rh(COD)Cl]2 with RhCl3 in the model reaction, suggesting
that the carbonylation process was possibly initiated by a
Rh(III) species. Pre-oxidation of [Rh(COD)Cl]2 with 100 equiv.
of K2S2O8 at 110 1C for 2 hours, followed by the addition of
indole and alcohol, gave a 99% yield of carbonylated product.
4 Y. Fujiwara, T. Kawauchi and H. Taniguchi, J. Chem. Soc., Chem.
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5 For Pd-catalyzed C–H carbonylation, see: (a) K. Orito,
A. Horibata, T. Nakamura, H. Ushito, H. Nagasaki, M. Yuguchi,
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Based on these observations and other related reports,11
a
plausible mechanism for the current catalytic process was
proposed as shown in Scheme 1. Pre-catalyst [Rh(COD)Cl]2 is
initially oxidized to a Rh(III) carbonyl species (A), which under-
goes an electrophilic metallation with indole at the C-3 position to
form the C–Rh bond and give intermediate B. Subsequent
insertion of CO to C–Rh bond affords intermediate C, followed
by coordination of alcohol to form intermediate D, which finally
undergoes reductive elimination to yield product 3 and regenerates
pre-catalyst Rh(I).
2011, 2, 312; (i) B. Lopez, A. Rodriguez, D. Santos, J. Albert,
´
X. Ariza, J. Garcia and J. Granell, Chem. Commun., 2011, 47, 1054;
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T. Matsuo, T. Fukuyama, Y. Ie, F. Kakiuchi and N. Chatani,
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Chem. Soc., 2009, 131, 729; (c) S. Inoue, H. Shiota, Y. Fukumoto
and N. Chatani, J. Am. Chem. Soc., 2009, 131, 6898.
In summary, we have developed a Rh-catalyzed reaction
protocol for the direct carbonylation of indoles to form
indole-3-carboxylates. This [Rh(COD)Cl]2/K2S2O8 catalyst
system showed high regioselectivity and good substance tolerance
under mild conditions. These features demonstrated by current
methodology also point out a way forward to develop direct
carbonylations of heteroarenes with other partners. Current
experiments in our laboratory are directed at extending the
reaction scope and gaining more information on the
mechanism.
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8 T. Itahara, Chem. Lett., 1982, 1151.
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We thank The Chinese Academy of Sciences and the
National Natural Science Foundation of China (21002106
and 21133011) for financial support.
c
This journal is The Royal Society of Chemistry 2011
Chem. Commun., 2011, 47, 12553–12555 12555