Non-redox metal ion promoted oxidative coupling of indoles with olefins by the palladium(II) acetate catalyst through dioxygen activation: Experimental results with DFT calculations

Article abstract of DOI:10.1039/c6ob00401f

Developing new catalytic technologies through C-H bond activation to synthesize versatile pharmaceuticals has attracted much attention in recent decades. This work introduces a new strategy in catalyst design for Pd(ii)-catalyzed C-H bond activation in wh

Full text of DOI:10.1039/c6ob00401f

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Biomolecular Chemistry
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Non-redox metal ion promoted oxidative coupling
of indoles with olefins by the palladium(II) acetate
catalyst through dioxygen activation: experimental
results with DFT calculations†
Cite this: DOI: 10.1039/c6ob00401f
Sicheng Zhang,a,b Zhuqi Chen,a,b Shuhao Qin,a,b Chenlin Lou,a,b Ahmed M. Senan,a,b
Rong-Zhen Liao*a,b and Guochuan Yin*a,b
Developing new catalytic technologies through C–H bond activation to synthesize versatile pharmaceuti-
cals has attracted much attention in recent decades. This work introduces a new strategy in catalyst
design for Pd(II)-catalyzed C–H bond activation in which non-redox metal ions serving as Lewis acids play
significant roles. In the oxidative coupling of indoles with olefins using dioxygen, it was found that
Pd(OAc)2 alone as the catalyst is very sluggish at ambient temperature which provided a low yield of the
olefination product, whereas adding non-redox metal ions to Pd(OAc)2 substantially improves its catalytic
efficiency. In particular, it provided bis(indolyl)methane derivatives as the dominant product, a category of
pharmacological molecules which could not be synthesized by Pd(II)-catalyzed oxidative coupling pre-
viously. Detailed investigations revealed that the reaction proceeds by heterobimetallic Pd(II)/Sc(III)-cata-
lyzed oxidative coupling of an indole with an olefin followed by Sc(III)-catalyzed addition with a second
indole molecule. DFT calculations disclosed that the formation of heterobimetallic Pd(II)/Sc(III) species
substantially decreases the C–H bond activation energy barrier, and shifts the rate determining step from
C–H bond activation of indole to the olefination step. This non-redox metal ion promoted Pd(II)-catalyzed
C–H bond activation may offer a new opportunity for catalyst design in organic synthesis, which has not
been fully recognized yet.
Received 21st February 2016,
Accepted 5th April 2016
DOI: 10.1039/c6ob00401f
www.rsc.org/obc
co-catalyst to re-oxidize the reduced Pd(0) back to the active
Pd(II) species.3,4 Sometimes, certain organic ligands were
Introduction
Activation and functionalization of the robust C–H bond offers employed to prohibit the formation of palladium black;
a promising protocol to synthesize versatile pharmaceutical however, due to the electron donating effect, these ligands gen-
molecules and functional materials. Among the late transition erally cause the decrease of the oxidizing power of the Pd(II)
metal ion mediated C–H activations, palladium is the most species. For example, we even found that in CO2-expanded tri-
attractive, and many palladium-based synthetic methodologies fluoroacetic acid (TFA) solvent, Pd(OAc)2 can catalyze benzene
have been developed in recent decades in which developing hydroxylation to biphenyl and phenol with dioxygen, and
new methods to synthesize indolyl containing compounds has adding copper(II) as an additive further improves its catalytic
attracted much attention.1,2 To achieve an efficient catalytic efficiency; however, adding phenanthroline or 2,2′-bipyridine
cycle of the palladium catalyst in oxidative C–H activation, as the ligand makes Pd(OAc)2 inactive in benzene hydroxy-
copper(II) is popularly employed as a stoichiometric oxidant or lation.5 Apparently, novel strategies in catalyst design are still
badly needed for efficient C–H bond activation at ambient
temperature.
aSchool of Chemistry and Chemical Engineering, Hubei Key Laboratory of Material
In nature, it is well known that certain non-redox metal
ions are involved in the oxidative processes of redox metallo-
Chemistry and Service Failure, Huazhong University of Science and Technology,
Wuhan 430074, PR China
bKey laboratory of Material Chemistry for Energy Conversion and Storage (Huazhong
enzymes like oxygen evolution of Photosystem II in which Ca2+
is one component of the active Mn4CaO5 center, and many
non-redox metal ions have been widely employed as additives
in heterogeneous redox catalysts to improve their stability and/
or modulate their reactivity.6,7 Although their roles in catalysis
have not been fully understood yet, it has inspired researchers
University of Science and Technology), Ministry of Education, PR China.
E-mail: gyin@hust.edu.cn, rongzhen@hust.edu.cn
†Electronic supplementary information (ESI) available: NMR studies for mecha-
nisms, 1H and 13C NMR spectra for all the products, and optimized structures
and Cartesian coordinates for all the stationary points in DFT calculations. See
DOI: 10.1039/c6ob00401f
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to develop non-redox metal ion and organic Lewis acid pro- using an oxygen balloon as the oxidant source in acetonitrile
moted stoichiometric oxidations with the active redox metal at 30 °C. It was found that the reaction proceeds very slowly,
ions in high oxidation states.8–10 On investigating the oxidative offering a low isolated yield (6%) of (E)-methyl 3-(1H-indol-3-
relationships of the active metal oxo, hydroxo and hydroper- yl)acrylate as the product in 12 h (3aa, Table 1, entry 1). When
oxide intermediates in oxidations, we observed that increasing the Lewis acid Sc(OTf)3 (20 mol% relative to indole) was added
the positive net charge of the active metal intermediates to Pd(OAc)2 as an additive, no 3aa was detected through TLC
through protonation (Brønsted acid) can improve their capa- and 1H NMR analyses, however, another product, methyl
bility in electron transfer.11 Encouraged by these findings, we 3,3-di(1H-indol-3-yl)propanoate (4aa), was unexpectedly obtained,
explored non-redox metal ion (Brønsted acid vs. Lewis acid) and its isolated yield can be improved remarkably up to 63%
promoted catalytic oxidations with redox catalysts.12 In parti- (Table 1, entry 2). On the other side, on using Sc(OTf)3 alone
cular, we explored Al3+ promoted benzene hydroxylation by as the catalyst, there is no 4aa formation in the presence/
Pd(bpym)2+, whereas Pd(bpym)2+ alone is inactive (bpym: 2,2′- absence of oxygen (Table 1, entries 13 and 14). In addition, the
bipyrimidine).13 The recovered C–H bond activation ability of oxidative coupling reaction demonstrated here revealed that
the Pd(II) species was attributed to the binding of Al3+ to two the C–H bond activation occurs on the 3-position of indole,
remote nitrogen atoms of the bpym ligand, which increased while both 2 and 3-position coupled products were even
the net charge of the Al3+-bpym-Pd2+ unit and improved the reported for Pd(II)-catalyzed olefination of indoles which were
redox potential of the Pd(II) species, thus recovering its C–H highly reaction condition dependent.18,19
activation ability. Most recently, we further found that non-
In the literature, it has been reported that compounds con-
redox metal ions like Sc(III) can promote Wacker-type oxi- taining bis(indolyl) units have remarkable biological activities
dations even better than Cu(II), and both Sc(III) and Cu(II) can like anti-carcinogenic activity,15 and one route to obtain them
accelerate Pd(II)-catalyzed olefin isomerization in which the is acid-catalyzed alkyne addition with indoles in which alkynes
redox properties of Cu(II) are not necessary.14 These findings
clearly suggest that in addition to the redox properties, the
Lewis acid properties of Cu(II) may play a significant role in
Table 1 Optimization of the oxidative coupling of indole with methyl
acrylate using O2 as the oxidant sourcea
versatile Pd(II)-catalyzed C–H bond activations in which Cu(II)
was popularly employed as a stoichiometric oxidant or co-cata-
lyst to re-oxidize the reduced Pd(0). Notably, these findings
may have provided a novel strategy in catalyst design for redox
metal ion catalyzed C–H bond activations in organic synthesis.
Here, we reported an example of non-redox metal ions as
Lewis acids that can accelerate Pd(II)-catalyzed oxidative coup-
ling of indoles with acrylates through dioxygen activation.
Unexpectedly, in the presence of a Lewis acid, Pd(II)-catalyzed
oxidative coupling of indoles with acrylates leads to the domi-
nant formation of 3,3-bis(indolyl)propanoic esters, one cat-
egory of 3,3-bis(indolyl)methane derivatives, whereas Pd(II)
alone as the catalyst only provided olefination products of
indoles. To the best of our knowledge, prior to this work, there
has been no reported examples to demonstrate that redox tran-
sition metal ions like Pd(II) can catalyze oxidative coupling of
indoles with olefins to synthesize bis(indolyl)methane deriva-
tives, one category of molecules with antibacterial activity, gen-
otoxicity, antiviral activity, anti-inflammatory activity, coronary
dilatory properties and anti-carcinogenic properties;15 this cat-
egory of bioactive molecules is generally synthesized by the
condensation reaction of indoles with aldehydes/ketones, or
addition of indoles with alkynes.16,17
Entry
Pd(OAc)2 (mol%)
Sc(OTf)3 (mol %)
Sol.
Yieldb (%)
1
2
3
4
10
10
5
—
20
10
10
30
20
20
20
20
20
20
20
20
20
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
DMSO
DMF
6 (3aa)
63 (4aa)
45 (4aa)
34 (4aa)
55 (4aa)
61 (4aa)
56 (4aa)
8 (4aa)
7 (4aa)
20 (4aa)
30 (4aa)
51 (4aa)
N.D.
10
10
10
10
10
10
10
10
10
—
—
5
6c
7d
8
9
10
11e
12f
13
14g
THF
CH3CN
CH3CN
CH3CN
CH3CN
Results and discussion
Optimization of the oxidative coupling of indole with methyl
N.D.
acrylate by the Pd(OAc)2/Sc(OTf)3 catalyst
a Reaction conditions: 1a (0.2 mmol), 2a (1 mmol) under stirring for
12 h with an O2 balloon in 2 mL solvent. b Isolated yields (average of
two runs) of 3aa for entry 1, and 4aa for others. c 0.4 mmol of 2a was
added. d 1.6 mmol of 2a was added. e At 10 °C. f At 50 °C. g Under an
Initially, we investigated the oxidative coupling reaction of
N-unprotected indole (1a) and methyl acrylate (2a) with 10 mol%
Pd(OAc)2 as the catalyst, and the reaction was conducted by argon atmosphere. N.D. = not detected by TLC.
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are much more expensive than the corresponding olefins.17 NaOTf slightly improved the yield of 3aa to 7%, and using
While in Pd(II)-catalyzed indole coupling with olefins, it gener- 60 mol% of NaOTf offered 14% of 3aa. Notably, there was only
ally provided olefination products with no bis(indolyl) unit a trace amount of 4aa generated by adding NaOTf as an addi-
products reported.18,19 Therefore, the method demonstrated tive. In the case of adding bivalent metal ions like Zn2+, Ca2+
here may have a chance to offer a new strategy for the synthesis and Ba2+, the oxidative coupling reaction changed sharply. For
of bis(indolyl)methane derivatives from cheap olefins and example, adding Zn(OTf)2 offered 59% of 4aa as the product
indoles. Accordingly, this Pd(II)/Lewis acid catalyzed indole with only a trace amount of 3aa detected, which is distinctly
coupling with olefins was investigated in detail. Solvents may different from using Pd(II) alone or adding NaOTf as an addi-
play significant roles in catalysis through their coordination tive. More importantly, using trivalent metal ions as additives
with the active metal species, or through the potential hydro- provided even better yield of 4aa with no 3aa formation. For
gen bond network.20 Here, the synergistic effect between Pd(II) example, adding 20 mol% of Sc(OTf)3 or Y(OTf)3 offered 63%
and Lewis acids is critical for efficient oxidative coupling, or 62% of 4aa, respectively, and Al(OTf)3 also offered 51% of
therefore a valid solvent should not block their interactions in 4aa with no 3aa formation as those offered by adding Sc(III) or
catalysis. After solvent screening, acetonitrile was found to Y(III). In control experiments, 60 mol% loading of HOTf, which
be the most efficient (entries 8–10), and investigating the has an identical amount of OTf− anions to that of adding
Sc(OTf)3 loading next revealed that both the increase of the 20 mol% Sc(OTf)3, gave neither 3aa nor 4aa. Together with the
amount of Sc(OTf)3 to 30 mol% and the decrease to 10 mol% results from adding NaOTf, it clearly shows that the pro-
led to a drop in the 4aa yield (55% vs. 34%, entries 4, 5). The motional effect originates from the non-redox metal ion as a
yield of 4aa was almost doubled by elevating the temperature Lewis acid, rather than from the OTf− anion or Brønsted acid
from 10 to 30 °C (entry 11), while a further elevation showed (H+) which can be potentially generated through hydrolysis of
no positive effect (entry 12). In addition, a four-fold excess of the added Lewis acid. In particular, the promotional effect is
acrylate was necessary for the formation of 4aa in higher yield, highly Lewis acid strength dependent, that is, a stronger
due to its easy evaporation from the solution into the oxygen Lewis acid offers a better efficiency. Similar Lewis acid
balloon which makes it become insufficient in the solution.
promoted catalytic oxidations were previously observed in
PdII(bpym)-catalyzed benzene hydroxylation, and manganese
complex catalyzed oxygenations of olefins and sulfides in
laboratories.4,12,13
Scanning Lewis acids for Pd(II)-catalyzed oxidative coupling
reaction
After the optimization of coupling conditions, the influence of
different Lewis acids on Pd(II)-catalyzed indole coupling with
methyl acrylate was investigated, and the results are summar-
ized in Table 2. In the absence of a Lewis acid, using Pd(OAc)2
alone as the catalyst showed very sluggish activity, providing
only 6% of 3aa with no 4aa formation. Adding 20 mol% of
The substrate scope of Lewis acid promoted Pd(II)-catalyzed
indole couplings
Table 3 lists the tested substrate scope of this Lewis acid pro-
moted coupling reaction between indoles and acrylates. It is
worth emphasizing that in the absence of a Lewis acid, using
Pd(OAc)2 alone as the catalyst provided only mono-indole
coupled products, that is olefination products of indoles 3
with no formation of 4 as well as those in Tables 1 and 2. In
contrast, adding Sc(OTf)3 to Pd(OAc)2 offered bis(indolyl)pro-
panoic esters as product 4 with no 3 detected. In particular, in
the absence of Sc(OTf)3, Pd(OAc)2 alone as the catalyst demon-
strated a very poor efficiency, offering a very low yield of 3,
while adding Sc(OTf)3 to Pd(OAc)2 provided products 4 in
moderate to high yields (54–77%), and the following discus-
sions for the substrate scope are based on using Pd(OAc)2/
Sc(OTf)3 as the catalyst.
Table 2 Screening of Lewis acids for the oxidative coupling of indoles
with methyl acrylatea
Entry
Additives
Yield 3aab (%)
Yield 4aab (%)
For free (NH)-indoles (1a, 1e) as substrates, the yield of 4
increased with the larger size of the alkyl group on acrylates,
for example, with the size of the group increasing from
methyl, ethyl to n-butyl, the yield of 4a increased in the series
of 63%, 70% and 74% (4aa, 4ab and 4ac). On the other hand,
for the N-substituted indoles (1b and 1c), substituted by
methyl remarkably improved the yield from 63% to 77% (4aa
vs. 4ba), while further replacement by larger n-butyl caused the
yield to decrease to 68% (4ba vs. 4ca). Notably, almost no
product was generated when indole bears an electron-with-
drawing group like acetyl in acetylindole. In the case of meth-
oxyl substituted indole (4d), the yields are lower than those of
1
—
6
7
14
<2
<2
<2
<2
N.D.
N.D.
N.D.
N.D.
<2
<2
21
30
59
62
63
51
2
NaOTf
NaOTf
Ba(OTf)2
Ca(OTf)2
Zn(OTf)2
Y(OTf)3
Sc(OTf)3
Al(OTf)3
HOTf
3c
4
5
6
7
8
9
10c
N.D.
a Reaction conditions: 1a (0.2 mmol), 2a (1 mmol), Pd(OAc)2 (10 mol%),
and Lewis acid (20 mol%) with an O2 balloon in CH3CN (2 mL), stirring
at 30 °C for 12 h. b Isolated yields are the average of two runs. c 60 mol%
additive was used. N.D. = not detected by TLC.
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Table 3 Substrate scope of Pd(II)/Sc(III)-catalyzed oxidative coupling of indoles with acrylatesa,b
Organic & Biomolecular Chemistry
a Reaction conditions: 1 (0.2 mmol), 2 (1 mmol), Pd(OAc)2 (10 mol%), and Sc(OTf)3 (20 mol%) with an O2 balloon in CH3CN (2 mL), stirring at
30 °C for 12 h. b Isolated yields are the average of two runs and are estimated to be >95% pure by 1H NMR analysis.
free (NH)-indoles, while for bromide substituted indole (4e), pathway A, the bis(indolyl) product is formed by the nucleo-
using methyl acrylate as the olefin offered slightly lower yield philic addition of an indole to an acrylate ester followed by
(61%) than that of free (NH)-indoles (63%), but higher yield in sp3–sp2 coupling with another indole molecule. Alternatively
the case of ethyl and n-butyl acrylates (both obtained in 75% in pathway B, the bis(indolyl) product is obtained by sp2–sp2
yield). Apparently, the substituent effects are very complicated coupling followed by nucleophilic addition. Addition of
in this Pd(OAc)2/Sc(OTf)3 catalyzed oxidative coupling reaction. indoles to the CvC double bond has been proposed in the
Finally, it is worth mentioning that the compatibility of this reaction of indoles with alkynes,17 while olefinations of
reaction with the substituent like Br on the indole molecule indoles are well-known in Pd(II)-catalyzed Heck reactions21 and
(1e) may offer the opportunity of further cross-coupling reac- oxidative couplings.18,19
tions to be performed on the products.
To distinguish between pathways A and B in this work,
several control experiments have been conducted as follows.
First, 10 mol% of Pd(OAc)2 was employed to catalyze the reac-
tion of indole with 3aa which was synthesized on a large scale
Possible pathways for bis(indolyl)propanoic ester product
formation
Taking the whole process into consideration, there are two according to the literature;19f however, the formation of
new C–C bonds generated in the oxidative coupling reaction to 4aa was not observed. In another case, adding 20 mol% of
form bis(indolyl)propanoic ester products. Accordingly, two Sc(OTf)3 does catalyze the reaction of indole with 3aa to form
possible pathways can be expected as shown in Scheme 1. In the final product 4aa with an isolated yield of 91% (Scheme 2).
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Scheme 1 Possible pathways of Pd(II)/Sc(III)-catalyzed bis(indolyl)propanoic ester formation.
Scheme 2 The possible last steps to 4aa product.
Fig. 1 1H NMR studies on the reaction of indole (1a) with Pd(OAc)2 and/
or Sc(OTf)3 in the presence/absence of methyl acrylate in CD3CN at
25 °C.
Therefore, it is Sc(OTf)3 rather than Pd(OAc)2 that catalyzes the
addition of indoles with 3aa to form 4aa. Second, using
10 mol% of Pd(OAc)2 and 20 mol% of Sc(OTf)3 together as cata-
lysts did not catalyze the reaction between indole and methyl
3-(1H-indol-3-yl)propanoate (5aa), which was synthesized on a
large scale according to the literature,22 to form 4aa, indicating
that Pd(II)/Sc(III) does not catalyze sp3–sp2 coupling as shown
in the second step of pathway A. Altogether, these control
experiments have clearly evidenced that the oxidative coupling
step is prior to the nucleophilic addition in the whole process
as shown in pathway B.
time in air (Fig. 1b and c). However, adding Pd(OAc)2 with
Sc(OTf)3 to indole caused the immediate broadening of its peaks
(Fig. 1d), clearly indicating that the synergistic effect occurs
between Pd(II) and Sc(III) in activating the C–H bond of indole.
With the reaction proceeding, several groups of new peaks
gradually appeared and the remaining faded away to make the
baseline flat (Fig. 1e). However, adding methyl acrylate into
the above resulting mixture did not lead to the formation of
3aa or 4aa, suggesting that, in the absence of methyl acrylate,
1H NMR studies on Lewis acid promoted Pd(II)-catalyzed
indole couplings
1
The H NMR spectra of indole and methyl acrylate in CD3CN activation of indole by Pd(OAc)2/Sc(OTf)3 leads to the for-
disclosed seven groups of chemical shifts for indoles from mation of other products which have not yet been identified.
6.49 to 9.31 ppm and three groups for methyl acrylate from In another series of 1H NMR studies, the bis(indolyl)propanoic
5.87 to 6.39 ppm, respectively (Fig. 1a and S1a†). All these ester, 4aa, can be generated by introducing Sc(OTf)3 into the
peaks did not show any change after adding 1 equiv. of mixture of an equivalent amount of 1a and 3aa in CD3CN
Pd(OAc)2 or Sc(OTf)3, even after the mixture was kept for a long (Fig. 2a–d), clearly confirming that Sc(III)-catalyzed olefin
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Fig. 2 1H NMR kinetics of the reaction between (E)-methyl 3-(1H-indol-3-yl)acrylate (3aa) and indole (1a) in the presence of Sc(OTf)3 in CD3CN
at 25 °C.
addition of 1a with 3aa occurs as one step in Pd(II)/Sc(III) bonyl of the acetate bridge in the 13C NMR spectrum were
catalyzed oxidative coupling of indole with methyl acrylate to tentatively attributed to the disturbance of the OTf− anions
4aa as evidenced by independent synthetic tests demonstrated which are attached to the Sc(III) cation, and this heterobimetal-
above. In the literature, Wang and co-workers reported that lic Pd(II)/Sc(III) moiety was assigned as the key active species for
adding a Brønsted acid like TFA to the Pd(OAc)2 catalyst can the improved catalytic efficiency in Wacker type oxidation. In
also accelerate the olefination of indoles to provide 3-position the literature, similar heterobimetallic Pd(II) complexes with
coupled products, and the role of TFA was attributed to the Ba2+, Sr2+, Ca2+, Mn2+, Co2+, Ni2+, Cd2+, Nd2+, Zn2+ and Ce4+
in situ formation of the active Pd(O2CCF3)+ as disclosed in with an acetate bridge had been reported elsewhere, and some
their mechanism.19f Clearly, the role of TFA in their system is of them were identified with X-ray structures.23 Here, DFT cal-
distinctly different from the Lewis acid role of non-redox metal culations were conducted for Pd(II)/Sc(III) catalyzed oxidative
ions in this work. Here, the added non-redox metal ions as coupling, and it further indicated that adding Sc(III) can sub-
Lewis acids play a dual role including accelerating Pd(II)-cata- stantially decrease the activation energy barrier of oxidative
lyzed C–H activation and catalyzing the addition of the second coupling reaction, and shift the rate determining step from
indole molecule to the alkenylated indole.
C–H activation of indole to the olefination step. More impor-
tantly, the DFT calculations further proposed a more detailed
structure of the Pd(II)/Sc(III) dimer in which two OTf− anions
also serve as a bridge between Pd(II) and Sc(III) cations as well
DFT calculations of oxidative coupling by the Pd(II)/Sc(III)
catalyst
Previously in Wacker type oxidations with the Pd(II)/Sc(III) cata- as acetate.
lyst, we disclosed that adding Sc(OTf)3 to Pd(OAc)2 in aceto-
Pd(OAc)2-catalyzed oxidative coupling of indole with methyl
nitrile will generate a new Pd(II) species which has Sc(III) acrylate. In the literature, the crystal structure of Pd(OAc)2
bridged to the Pd(II) cation through a diacetate bridge.14 Mean- showed a trinuclear complex with nearly idealized D3h sym-
while, the multiple peaks of methyl with a singlet peak of car- metry, in which six bridging acetate groups coordinate to the
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three palladium(II) cations in a square planar fashion for each C3-arylation product. Coordination of the second substrate
metal ion.24 This trimer structure has also been suggested to methyl acrylate to Pd(II) leads to the formation of Int2, which
be the major species in benzene and acetic acid solutions.25,26 undergoes carbopalladation (TS2), intramolecular rotation,
Here we calculated the reaction energies for the conversion of and β-hydride elimination (TS3) to give a Pd(II)–hydride inter-
1/3Pd3(OAc)6 to 1/2Pd2(OAc)4, and further to Pd(OAc)2 (opti- mediate Int5 with the coupling product coordinated. TS2 was
mized structures see Fig. S6†) in acetonitrile. The calculations calculated to be 12.2 kcal mol−1 relative to React and features a
showed that Pd3(OAc)6 is the most stable species, and its con- typical four-membered ring transition state, as well as the clas-
versions to 1/2 Pd2(OAc)4 and Pd(OAc)2 are endergonic by 5.9 sical Pd(0)-catalyzed Heck reactions of aryl halides with
and 14.8 kcal mol−1, respectively. Therefore, Pd3(OAc)6 should olefins.33–36
be considered as the starting species for the whole catalytic
cycle, as well as the calculations on Pd(OAc)2-catalyzed other oxidize the Pd(II)–hydride intermediate. There generally exists
reactions.27–29
two mechanisms, including the Pd(II) pathway via direct hydro-
To regenerate the active Pd(II) catalyst, dioxygen is used to
From Pd(OAc)2, the indole substrate can coordinate to the gen atom transfer to dioxygen, and the Pd(0) pathway via
Pd(II) cation via its C2vC3 double bond to form React, which reductive elimination to form Pd(0) acetic acid, followed by O2
was calculated to be close to isogonic (Fig. 3). This is followed insertion.37–42 The choice of the pathway is ligand properties
by a concerted metalation/deprotonation (CMD)30–32 at C3 to dependent. Here we considered both mechanisms, and found
generate Int1 via TS1 (Fig. 4). TS1 was calculated to be that the Pd(0) pathway is preferred for the present system. As
13.9 kcal mol−1 relative to React. The barrier for the metalation shown in Fig. S7†, TS4 for the hydrogen atom transfer has a
of C2 was found to be 3.5 kcal mol−1 higher, suggesting that barrier of 16.2 kcal mol−1 relative to Int5. However, the barrier
the C3-arylation product is the major product. This agrees of TS5 for the alternative Pd(0) pathway is 10.5 kcal mol−1
quite well with our experimental results which only gives the lower than TS4. Finally, the (E)-methyl 3-(1H-indol-3-yl)acrylate
Fig. 3 Overall Gibbs free energy profile calculated at the B3LYP-D3 level of theory for the Pd(OAc)2-catalyzed oxidative coupling of indole with
methyl acrylate.
Fig. 4 Relevant key transition state structures involved in concerted metalation/deprotonation, migration insertion, and β-hydride elimination for
the Pd(OAc)2-catalyzed oxidative coupling of indoles with methyl acrylate.
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product and hydrogen peroxide dissociate from Pd(II) to regen- geometry while Sc(III) possesses a square pyramidal configur-
erate the active Pd(II) species.
ation. Quite unexpectedly, this reaction is exergonic by as
From the overall Gibbs free energy profile shown in Fig. 3, much as 20.9 kcal mol−1 (Fig. 5), suggesting that the Pd(II)/
it can be seen that TS1 is the rate-limiting step, with a total Sc(III) complex is the dominant species when mixing Pd(OAc)2
barrier of 28.4 kcal mol−1, and the whole reaction is exergonic and Sc(OTf)3 in acetonitrile solution. The calculated structure
by 22.0 kcal mol−1. The main reason for the high barrier also agrees with our H NMR studies which suggest an almost
1
comes from the large energetic penalty for the generation of symmetric environment for the two methyl groups. To bind
the active monomeric Pd(OAc)2 from the trimeric species. the indole substrate to form React′, one OTf− ligand has to
Indeed, extra ligands have been used to manipulate the become terminal creating an empty site at Pd(II), which
thermodynamics for this interconversion, thereby enhancing can then coordinate to the C2vC3 double bond of indole.
the catalysis in the literature.27–29,32,42 Here, we demonstrated As acetate is used as the general base to abstract a proton from
an alternative strategy to generate the monomeric Pd(II) the indole substrate, one acetate ligand has to dissociate
species in which a Lewis acid plays the critical role as shown from the Sc(III) center becoming monodentately coordinated
below.
Pd(OAc)2/Sc(OTf)3-catalyzed oxidative coupling of indole
to Pd(II).
From React′, the reaction proceeds via a very similar mech-
with methyl acrylate. When Sc(OTf)3 is added, it reacts with anism as that from React, in which Sc(OTf)3 is not involved.
Pd3(OAc)6 to form a heterobimetallic Pd(II)/Sc(III) complex in Therefore, only essential differences will be discussed herein.
which two acetate and two OTf− ligands bridge the Pd(II) and For the first CMD step, TS1′ (structure see Fig. 6) was
Sc(III) cations together, and the third OTf− coordinates to the calculated to be 13.4 kcal mol−1 relative to React′ (Fig. 5).
Sc(III) cation alone. Consequently, Pd(II) adopts a square planar This is very close to that for TS1, the barrier of which is
Fig. 5 Overall Gibbs free energy profile calculated at the B3LYP-D3 level of theory for the Pd(OAc)2/Sc(OTf)3-catalyzed oxidative coupling of
indoles with methyl acrylate.
Fig. 6 Relevant key transition state structures involved in concerted metalation/deprotonation, migration insertion, and β-hydride elimination for
the Pd(OAc)2/Sc(OTf)3-catalyzed oxidative coupling of indoles with methyl acrylate.
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13.9 kcal mol−1. In addition, the C2 metalation has a barrier of mediate I forms the intermediate II which further generates
17.1 kcal mol−1, that is, 3.7 kcal mol−1 higher than that for the the coupling intermediate III, and it is the rate determining
C3 metalation. This is in agreement with our experimental step in this Pd(II)/Sc(III) catalyzed oxidative coupling. β-Hydro-
findings which show only the C3-arylation product observed. gen elimination of the intermediate III releases the product
However, significant difference can be seen for the second 3aa, which further proceeds indole addition catalyzed by the
carbopalladation step. The binding of methyl acrylate becomes Sc(III) cation to generate the final product 4aa. After β-hydrogen
endergonic and the barrier for the following migration inser- elimination, the generated Pd(II)–hydride intermediate prefers
tion increases. The participation of Sc(OTf)3 changes the rate- the reduction elimination to form Pd(0) which is next oxidized
limiting step from the first CMD step to the second carbopalla- by dioxygen to regenerate the active Pd(II)/Sc(III) species. The
dation step. The involvement of Sc(OTf)3 somehow disfavors formation of H2O2 was also evidenced by HPLC analysis with
the second step and increases the barrier, however, it signifi- authentic samples.
cantly reduces the energetic cost for the formation of the reac-
tant complex React′. Together, the total barrier decreases from
28.4 kcal mol−1 to 25.4 kcal mol−1
.
Experimental
The following β-hydride elimination step has a barrier of
12.6 kcal mol−1 relative to Int3′. Similarly to that without
Sc(OTf)3, two possible pathways have been considered for the
oxidation of the Pd(II)–hydride intermediate Int5′. The direct
hydrogen atom transfer pathway has a much higher barrier
than the reductive elimination pathway. The oxidation of
Pd(II)–hydride to regenerate the catalyst is kinetically unimpor-
tant as it is not rate-limiting for the whole catalytic reaction.
Altogether, DFT calculations have also supported that the
addition of the Lewis acid Sc(OTf)3 plays a crucial role in
enhancing the reaction rate of Pd(II)-catalyzed oxidative coup-
ling as demonstrated in the above experimental tests.
Combining the results from experimental tests and DFT cal-
culations, a simplified complete mechanism has been pro-
posed for this Pd(II)/Sc(III) catalyzed oxidative coupling
(Scheme 3). In this mechanism, the heterobimetallic Pd(II)/
Sc(III) moiety (abbreviated as PdII/ScIII in Scheme 3) serves as
the key active species for the oxidative coupling of indole with
methyl acrylate. First, activation of the C-3 C–H bond of indole
by Pd(II)/Sc(III) species generates the palladation intermediate
of indole, I. Then, coordination of methyl acrylate to the inter-
General experimental details
Pd(OAc)2 was purchased from Strem Chemicals Inc., and
Sc(OTf)3 was from Accela ChemBio Co., Ltd. All indoles and
acrylates were purchased from Credit-Chem Co., Ltd and used
without further purification except that 1-methylindole (1b),
1-benzylindole (1c) and the intermediate methyl 3-(1H-indol-
3-yl)propanoate (5aa) were synthesized according to the pub-
lished procedures.22,43 Acetonitrile was dehydrated via 4 Å MS
(activated at 300 °C for 2 h in a muffle furnace) before use.
1H and 13C NMR spectra were recorded on a Bruker AV-400
using TMS as an internal reference. High-resolution mass
spectra (HRMS) were obtained on Brüker Bruker Compass
Data Analysis 4.0.
General procedures for oxidative coupling of indoles with
acrylates by the Pd(OAc)2 catalyst
Pd(OAc)2 (4.5 mg, 0.02 mmol) was dissolved in anhydrous
CH3CN (3.0 mL) in a glass tube equipped with magnetic
stirring. Then indole (0.2 mmol) and acrylate ester (1 mmol)
were sequentially added to the system, and the reaction
mixture was stirred at 30 °C for 12 h with O2 balloon as the
oxidant source. After that, the acetonitrile solvent was removed
by rotary evaporation. The residue was next treated by prepara-
tive thin-layer chromatography (PTLC) by using a mixture of
ethyl acetate and petroleum ether (60–90 °C) as the eluting
solvent (EtOAc/P.E., v/v = 35 : 65) to obtain the C-3 olefination
product 3 as a yellow solid.
General procedures for oxidative coupling of indoles with
acrylates by Pd(OAc)2/Sc(OTf)3
Sc(OTf)3 (19.7 mg, 0.04 mmol) was added to a glass tube con-
taining Pd(OAc)2 (4.5 mg, 0.02 mmol) and anhydrous CH3CN
(3.0 mL). Then indole (0.2 mmol) and acrylate ester (1 mmol)
were sequentially added to the system, and the reaction
mixture was stirred at 30 °C for 12 h with O2 balloon as the
oxidant source. After that, the acetonitrile solvent was removed
by rotary evaporation. The residue was next treated by prepara-
tive thin-layer chromatography (PTLC) by using a mixture of
ethyl acetate and petroleum ether (60–90 °C) as the eluting
solvent (EtOAc/P.E., v/v = 35 : 65) to obtain the bis(indolyl)
products as a brown solid.
Scheme 3 Simplified full mechanism for Pd(II)/Sc(III) catalyzed oxidative
coupling of indole with acrylate.
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Computational details
and Testing Center of Huazhong University of Science and
Technology.
The quantum chemical calculations were made using the
B3LYP44 density functional as implemented in the Gaussian
09 package.45 For geometry optimizations, the def2-SVP46 basis
set (including the SDD47 pseudopotential for Pd) was used for Notes and references
all elements. The final and the solvation energies in aceto-
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the SDD pseudopotential for Pd). D3 dispersion corrections
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Grimme50 were also added at single-points. Analytical fre-
quency calculations were performed at the same level of theory
as the geometry optimizations to obtain Gibbs free energy cor-
rections and to confirm the nature of the various stationary
points. The latter implies no imaginary frequency for minima
and only one imaginary frequency for transition states. The
energies reported herein are the B3LYP-D3 energies including
Gibbs free energy corrections, solvation corrections, and D3
dispersion corrections.
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Conclusions
This work illustrated a new strategy in catalyst design for
Pd(II)-catalyzed C–H bond activation in which non-redox metal
ions can substantially improve the C–H bond activation
efficiency. Under the ambient conditions, Pd(OAc)2 alone as
the catalyst is very sluggish in the oxidative coupling of
indoles with acrylates, and only minor olefination products
were obtained. Adding non-redox metal ions like Sc(III) to
Pd(OAc)2 can substantially accelerate the oxidative coupling
reaction, and leads to the formation of bis(indoyl)methane
derivatives as the dominant product which possesses various
biological and pharmacological activities. Independent
control experiments with NMR studies revealed that the reac-
tion proceeds by Pd(II)/Sc(III) catalyzed olefination followed by
Sc(III)-catalyzed addition. Detailed DFT calculations indicated
that addition of Sc(OTf)3 to Pd(OAc)2 generated a heterobi-
metallic Pd(II)/Sc(III) moiety having both OAc− and OTf− anions
as the bridge which is more active than monomeric Pd(OAc)2.
Significantly, the rate determining step has been shifted from
C–H bond activation of indoles to the olefination step by
adding Sc(OTf)3 to Pd(OAc)2 as the catalyst, which substan-
tially decreases the activation energy barrier of oxidative coup-
ling reaction. The Lewis acid promoted oxidative coupling by
the Pd(II) catalyst demonstrated here may offer a new opportu-
nity in catalyst design for versatile C–H activation in organic
synthesis.
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