Catalytic Carbon-Carbon Bond Activation of Saturated and Unsaturated Carbonyl Compounds via Chelate-Assisted Coupling Reaction with Indoles

Article abstract of DOI:10.1021/acscatal.0c01245

The chelate assistance strategy was devised to promote a highly regioselective catalytic C-C bond activation reaction of saturated and unsaturated carbonyl compounds. The cationic Ru-H complex 1 was found to be an effective catalyst for mediating the coupling reaction of 1,2-disubstituted indoles with α,β-unsaturated aldehydes and ketones, in which the regioselective Cα-Cβ activation of the carbonyl substrates has been achieved in forming the 3-alkylindole products. The analogous coupling reaction of indoles with saturated aldehydes and ketones directly led to the Cα-Cβ cleavage of the carbonyl substrates in forming the 3-alkylindole products. The coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one and 2-propanol-d8 showed 20-22percent of deuterium incorporation to both α-and β-CH2 of the 3-alkylindole product. The coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one exhibited the most significant carbon kinetic isotope effect on the α-carbon of the product (Cα = 1.046). The Hammett plot constructed from the reaction of 1,2-dimethylinole with a series of para-substituted enones p-X-C6H4CH=CHCOCH3 (X = OMe, Me, H, Cl, CF3) showed a modest promotional effect by an electron-donating group (ρ =-0.2 ± 0.1). Several catalytically relevant Ru-H species were detected by NMR from a stoichiometric reaction mixture of the Ru-H complex 1 with 1,2-dimethylindole and (E)-3-nonen-2-one in CD2Cl2. These results support a mechanism of the catalytic coupling reaction via conjugate addition of indoles to enones followed by the C-C bond activation and hydrogenolysis steps.

Full text of DOI:10.1021/acscatal.0c01245

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Article
Catalytic Carbon–Carbon Bond Activation of Saturated and Unsaturated
Carbonyl Compounds via Chelate-Assisted Coupling Reaction with Indoles
Nuwan Pannilawithana, and Chae S. Yi
ACS Catal., Just Accepted Manuscript • DOI: 10.1021/acscatal.0c01245 • Publication Date (Web): 22 Apr 2020
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Catalytic Carbon–Carbon Bond Activation of Saturated and Unsaturated Carbonyl
Compounds via Chelate-Assisted Coupling Reaction with Indoles
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Nuwan Pannilawithana and Chae S. Yi*
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Department of Chemistry, Marquette University, Milwaukee, Wisconsin 53233 United States
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ABSTRACT: The chelate assistance strategy was devised to promote a highly regioselective catalytic C–C
bond activation reaction of saturated and unsaturated carbonyl compounds. The cationic Ru–H complex 1
was found to be an effective catalyst for mediating the coupling reaction of 1,2-disubstituted indoles with -
unsaturated aldehydes and ketones, in which the regioselective C–C activation of the carbonyl substrates
has been achieved in forming the 3-alkylindole products. The analogous coupling reaction of indoles with
saturated aldehydes and ketones directly led to the C–C cleavage of the carbonyl substrates in forming the
3-alkylindole products. The coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one and 2-propanol-d8
showed 20-22% of deuterium incorporation to both - and -CH2 of the 3-alkylindole product. The coupling
reaction of 1,2-dimethylinole with (E)-3-nonen-2-one exhibited the most significant carbon kinetic isotope
effect on the -carbon of the product (C = 1.046). The Hammett plot constructed from the reaction of 1,2-
dimethylinole with a series of para-substituted enones p-X-C6H4CH=CHCOCH3 (X = OMe, Me, H, Cl, CF3)
showed a modest promotional effect by an electron-donating group (ρ = -0.2 ± 0.1). Several catalytically
relevant Ru–H species were detected by NMR from a stoichiometric reaction mixture of the Ru–H complex 1
with 1,2-dimethylindole and (E)-3-nonen-2-one in CD2Cl2. These results support a mechanism of the catalytic
coupling reaction via conjugate addition of indoles to enones followed by the C–C bond activation and
hydrogenolysis steps.
Keywords: C–C bond activation, indole, carbonyl compound, ruthenium catalyst
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INTRODUCTION
Designing selective C(sp3)–C(sp3) bond activation methods of saturated hydrocarbon compounds has
been regarded as one of the most challenging problems in contemporary catalysis field.1 It has been widely
recognized that the selective catalytic C–C bond activation methods would not only entail new opportunities
for economically feasible and environmentally sustainable technologies ranging from petroleum and biomass
reforming processes but also provide a powerful tool for the synthesis of complex organic molecules.1,2 In
industrial cracking and reforming processes, heterogeneous metal catalysts are commonly used to convert
petroleum and biomass feedstocks into high-value hydrocarbon commodities such as olefins, alcohols and
ethers.3 Since such processes are inherently energy intensive and often lead to unselective products, they are
seldomly employed for the synthesis of complex organic products requiring selective C–C bond cleavage
reaction. Since Milstein’s pioneering discovery on a direct arene C(sp2)–CH3 bond activation reaction
mediated by a pincer-ligated Rh complex,4 a number of catalytic C–C bond activation methods have been
devised by using soluble transition metal complexes. Chelate assistance methodology has been shown to be
a particularly effective strategy for mediating regioselective CO–C bond activation reactions of arylketones
and imines, where nitrogen chelate groups have been successfully employed for the synthesis of complex
organic molecules via C–C bond cleavage.5 Ackermann and co-workers recently devised a chelation-assisted
C–C activation protocol by using a non-precious transition metal catalyst.6 By channeling a relief of strain
energy as the driving force, catalytic C–C bond cleavage methods of cyclopropane and strained cyclic ketone
derivatives have been shown to be a versatile synthetic tool for constructing a variety of cyclic compounds,7
as exemplified by recent asymmetric synthesis of biologically active chiral organic molecules.8 Catalytic -
carbon elimination method has also been shown to be effective for promoting regioselective C–C bond
cleavage reactions for saturated and unsaturated hydrocarbon substrates bearing oxygen functional group.9
Dong and co-workers recently reported a series of catalytic C–C bond activation methods that are either
driven by a relief of ring stain or are accompanied by insertion and elimination reactions.10 Despite such
remarkable advances, the development of selective catalytic C(sp3)–C(sp3) bond activation methods of
unstrained aliphatic compounds still largely remains as an elusive goal in homogeneous catalysis field, as
most of the current catalytic C–C cleavage technologies are either employ strained cyclic substrates or limited
to C(sp2)–C(sp2) and C(sp2)–C(sp3) activation reactions on unsaturated hydrocarbons and carbonyl
substrates.11
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Scheme 1. Mechanistic Hypothesis for Chelate Assisted Catalytic C–C Cleavage Reaction.
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Inspired by both metal-organic cooperative catalysis and merging C−H and C−C bond activation
methods,5,12 we envisioned a general strategy that exploits both arene and heteroatom chelate groups to
promote unstrained C(sp3)–C(sp3) bond activation reactions, as illustrated in Scheme 1. We reasoned that a
regioselective C–C bond activation reaction might be feasible when a metal catalyt can directly interact with
the C–C -orbital without the interference from C–H bond orbitals, and this could be achieved when a metal
catalyst is assisted by two chelate groups. By employing recently developed catalytic C–H coupling protocols
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-
using a well-defined cationic ruthenium-hydride catalyst [(C6H6)(PCy3)(CO)RuH]+BF4 (1),13 we have been
exploring a number of catalytic coupling reactions of arenes with carbonyl compounds as a way to screen
suitable template groups for promoting C–C cleavage reaction. Here we report a generally applicable catalytic
coupling reaction of indoles with saturated and unsaturated carbonyl compounds, in which regioselective C–
C activation of the carbonyl compounds has been realized without employing any reactive reagents or
forming toxic byproducts.
RESULTS AND DISCUSSION
While searching for a suitable heteroarene substrate that could serve as a chelate directing group for
promoting C–C cleavage reactions, we initially discovered that the treatment of 1,2-dimethylindole with (E)-3-
nonen-2-one in the presence of the catalyst 1 led to the regioselective C–C bond cleavage of the enone
substrate in forming the coupling product 2a (eq 1). The formation of acetone byproduct was also detected by
GC-MS in the crude reaction mixture. We subsequently found that the addition of both 2-propanol and 1,2-
benzoquinone substantially improved the product yield of 2a, and from a series of optimization study, we were
able to establish the standard conditions for the coupling reaction of 1,2-dimethylindole with (E)-3-nonen-2-
one (Table 1). Notably, we screened a number of different hydrogen source for the coupling reaction, in which
both H2 (5 atm) and 2-propanol were equally effective as the hydrogen source, while other potential hydrogen
donors such as formic acid and ethanol were completely ineffective in mediating the coupling reaction (entries
6,7). The catalyst 1 was found to exhibit the highest activity among the selected ruthenium catalysts (entries
8-13), and no catalytic activity was observed without Ru catalyst or with an acid catalyst (entries 14-16). 1,2-
Dichloroethane was found to be the most suitable solvent for the coupling reaction among selected organic
solvents. The catalytic method features a highly regioselective cleavage of unstrained C–C bond of the
enone substrate in forming the coupling product 2a.
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Table 1. Catalyst and Additive Screening for the Coupling of 1,2-Dimethylindole with (E)-3-Nonen-2-onea
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entry
catalyst
deviation from the standard 2a (%)b
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none
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with H2 (5 atm)
in 2-propanol (1 mL)
no 2-propanol
no BQ
with HCO2H (0.3 mmol)
with EtOH (0.3 mmol)
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[(PCy3)2(CO)(CH3CN)2RuH]BF4
[(PCy3)(CO)RuH]4(O)(OH)2/HBF4·OEt2
(PCy3)2(CO)RuHCl/HBF4·OEt2
RuCl2(PPh3)3/HBF4·OEt2
Ru3(CO)12/HBF4·OEt2
[(COD)RuCl2]x/HBF4·OEt2
PCy3/HBF4·OEt2
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AlCl3
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<5
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Standard conditions: 1,2-dimethylindole (0.25 mmol), (E)-3-nonen-2-one (0.30 mmol), 2-propanol
(0.25 mmol), catalyst (5 mol %), BQ (10 mol %), 1,2-dicholoroethane (1 mL), 125 °C, 36 h. b The product yield
was determined by GC-MS by using hexamethylbenzene as an internal standard. BQ = 3,4,5,6-tetrachloro-
1,2-benzoquinone.
Reaction Scope. We examined the substrate scope for the C–C cleavage reaction under the
optimized standard conditions (Table 2). For the sake of convenience, 2-propanol was used as the hydrogen
source in most cases, even though both H2 and 2-propanol were found to be equally effective in giving the C–
C cleavage products. Electron-rich 1,2-dimethylindole was found to be a suitable substrate for the coupling
with both alkyl- and aryl-substituted enones to form the C–C cleavage products 2a-o (entries 1-18). Both -
aryl-substituted aliphatic enones and aryl-substituted enones reacted smoothly with 1,2-dimethylindole, in
which the C–C bond of the enone substrates has been selectively cleaved in forming the coupling products
2e-i and 2j-g, respectively (entries 6-15). The coupling of 1,2-dimethylindole with 2-alkenylcyclic ketones
selectively formed the C–C cleavage products 2e,f along with the cyclic ketone byproducts (entries 24-26). A
number of biologically active enone substrates such as (E)--ionone, 4-(1-methyl-1H-indol-2-yl)but-3-en-2-one
and piperonylacetone predictively afforded the corresponding C–C cleavage products 2s,t,u in good yields
(entries 22, 23 and 27). Sterically demanding and electron-rich indole substrates were found to be essential
for promoting the C–C cleavage reaction, as the analogous coupling reaction of 1-methylindole or 2-
methylindole with the enones afforded less than 15% of the C–C cleavage products.
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Table 2. Catalytic C–C Cleavage Reaction of -Unsaturated Ketones from the Coupling with
Indolesa
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a Reaction conditions: indole (0.25 mmol), ketone (0.30 mmol), 2-propanol (0.25 mmol), 1 (5 mol %),
3,4,5,6-tetrachloro-1,2-benzoquinone (10 mol %), 1,2-dichloroethane (1 mL), 125 °C, 36 h.
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Table 3. Catalytic C–C Cleavage Reaction of -Unsaturated Aldehydes from the Coupling with Indolesa
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a
Reaction conditions: indole (0.25 mmol), aldehyde (0.30 mmol), 2-propanol (0.25 mmol), 1 (5 mol
%), 3,4,5,6-tetrachloro-1,2-benzoquinone (10 mol %), 1,2-dichloroethane (1 mL), 125 °C, 36 h.
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We next surveyed the aldehyde substrate scope by using the standard conditions (Table 3). Electron-
rich 1,2-dimethylindole was found to be a suitable substrate for the coupling with both alkyl- and aryl-
substituted -unsaturated aldehydes to selectively give the C–C cleavage products 2 (entries 1-8). The
coupling of 1,2-dimethylindole with 2-methylcinnamaldehyde also efficiently installed the C–C cleavage
products 2e (entry 9). The analogous coupling of 1,2,5-trisubstituted indoles with alkyl- and aryl-substituted
enals predictively afforded the corresponding coupling products 2l,p,r,y, which are resulted from the
regioselective C–C cleavage reaction (entries 12-15). Compared to the enone substrates, a substantially
higher C–C cleavage product yield was obtained with the aldehydes in most cases. The coupling reaction of
1,2-dimethylindole with other carbonyl compounds such as acrylic esters and amides gave a low C–C
cleavage product yield (<20%) under the similar conditions.
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In light of the previously developed dehydrogenation of saturated of ketones and amines,14 we sought
to combine the dehydrogenation and the coupling reaction to achieve a direct C–C bond cleavage of the
saturated carbonyl substrates. Thus, the treatment of 1,2-dimethylindole (0.25 mmol) with 4-phenyl-2-
butanone (0.30 mmol) in the presence of 1 (5 mol %) and rac-1,1’-bi-2-naphthol (rac-BINOL; 10 mol %) in 1,2-
dicholoroethane (1.0 mL) at 125 °C smoothly formed a mixture of the coupling product 2e and 3a (eq 2). In
this case, no hydrogen donor additive was necessary for the coupling reaction. We screened a number of
redox-active additives to promote the dehydrogenation of the ketone substrate, and found that rac-BINOL is
most effective in promoting the C–C cleavage reaction among selected catechol and benzoquinone additives
(Table S3, SI).
The substrate scope of saturated carbonyl compounds was explored by using the optimized reaction
conditions as described in eq 2 (Table 4). The coupling of 1,2-dimethylindole with both alkyl- and aryl-
substituted saturated aldehydes smoothly formed the C–C cleavage products 2 (entries 1-11). In contrast, the
coupling of 1,2-dimethylindole with saturated ketone substrates afforded a mixture of the products 2e-g,h,l,r,z
and 3a-c (entries 12-18), in which 3-(2-propyl)indole product 3 was resulted from the coupling reaction with
acetone byproduct. The coupling of 1,2-dimethylindole with 2-benzylcyclohexanone resulted in the C–C
cleavage product 2e and cyclohexanone byproduct. Compared to the unsaturated carbonyl substrates, a
much narrower substrate scope of the saturated ketones was realized, as neither aliphatic ketones nor aryl-
substituted ketones gave the desired C–C cleavage products presumably due to the difficulty in promoting the
dehydrogenation for these saturated ketones. Moreover, the coupling reaction was quite sluggish for these
saturated ketones, resulting the formation of the product 3 from the coupling of unreacted indole with acetone
byproduct. All of the C–C cleavage products were readily isolated after silica gel column chromatographic
separation, and their structure was completely established by standard spectroscopic methods. To the best of
our knowledge, the catalytic method represents a unique set of examples for achieving regioselective C(sp3)–
C(sp3) cleavage of unstrained saturated carbonyl compounds.
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Table 4. Catalytic C–C Cleavage Reaction of Saturated Aldehydes and Ketones from the Coupling with
Indolesa
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a
Reaction conditions: indole (0.25 mmol), carbonyl compound (0.30 mmol), 1 (5 mol %), rac-1,1′-bi-
2-naphthol (10 mol %), 1,2-dichloroethane (1 mL), 125 °C, 36 h.
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To probe whether the coupling reaction actually involves a direct C(sp3)–C(sp3) bond cleavage, we
monitored the progress of coupling reaction of 1,2-dimethylindole with (E)-3-nonen-2-one by GC-MS. We
observed a rapid formation of the initial coupling product 4, which was isolated in 95% yield after the reaction
was stopped at 30 min (eq 3). The treatment of the isolated 4 under the standard conditions slowly led to the
C–C cleavage product 2a. This experiment clearly demonstrates that the formation of the product 2a was
resulted from a two-step reaction sequence involving the initial conjugate addition of the indole to the carbonyl
compounds, followed by the regioselective C(sp3)–C(sp3) bond hydrogenolysis.
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Deuterium Labeling Study. We have chosen the coupling reaction of 1,2-dimethylindole with (E)-3-
nonen-2-one to probe the mechanism of the C–C cleavage reaction. First, the H/D exchange pattern was
examined from the coupling reaction of 1,2-dimethylinole (0.25 mmol) with (E)-3-nonen-2-one (0.30 mmol)
and 2-propanol-d8 (99.5% D, 0.25 mmol) in the presence of complex 1 (5 mol %) in 1,2-dichloroethane (1 mL),
which was heated at 125 °C for 36 h (eq 4). In this case, benzoquinone was not added to the reaction mixture
to avoid any potential complications. The isolated product 2a-d showed nearly 20-22% of deuterium on both
1
2
- and -CH2 of the alkyl group as analyzed by H and H NMR spectroscopic methods (Figure S1, SI). A
significant amount of deuterium (14% D) was also incorporated to the 2-methyl group of the product 2a-d. In a
control experiment, the treatment of isolated product 2a (0.25 mol) with 2-propanol-d8 (0.25 mmol) under
otherwise standard conditions led to <5% deuterium on both - and -CH2 groups of 2a, but with a
substantially higher amount of deuterium incorporation to the 2-methyl group (9% D) (Figure S2, SI). These
results suggest that an extensive H/D scrambling on both - and -alkyl carbons occurs during the C–C bond
hydrogenolysis step from the exchange with 2-propanol-d8.
Carbon Isotope Effect Study. To discern the rate limiting step of the reaction, we next measured the
carbon kinetic isotope effect from the coupling reaction of 1,2-dimethylinole with (E)-3-nonen-2-one by
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employing Singleton’s high-precision NMR technique (eq 4).15 We obtained a high conversion sample of 2a
from three separate treatments of 1,2-dimethylindole (0.25 mmol), with (E)-3-nonen-2-one (0.30 mmol), 2-
propanol (0.25 mmol) and complex 1 (5 mol %) in 1,2-dichloroethane (1 mL), which was compared with the
low conversion sample of 2a isolated from three separate 2.0 mmol scale of the reaction. The most significant
carbon isotope effect was observed on the -carbon of the indole product 2a when the 13C ratio of the product
from a high conversion was compared with the sample obtained from a low conversion (13C(avg 87%
conversion)/13C(avg 11% conversion) at C = 1.046; average of three runs) (Table S4, SI). The significant
carbon isotope effect on the -carbon is consistent with the turnover limiting C–C bond cleavage step for the
coupling reaction.
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0.12
OMe
Me
0.06
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-0.06
-0.12
Cl
H
CF3
-0.4
-0.2
0
0.2
0.4
0.6
σp
Figure 1. Hammett Plot from the Reaction of 1,2-Dimethylindole with p-X-C6H4CH=CHCOCH3 (X =
OMe, Me, H, Cl, CF3).
Hammett Study. To probe electronic influence on the C−C cleavage reaction, we compared the
reaction rates of 1,2-dimetylindole with a series of para-substituted enones p-X-C6H4CH=CHCOCH3 (X =
OMe, Me, H, Cl, CF3) under the standard conditions. The kobs for each reaction was determined from a first-
order plot of -ln[(1,2-dimethylindole)t/(1,2-dimethylindole)0] vs time. The Hammett plot of log(kX/kH) vs σp
showed a linear correlation, in which the coupling reaction is moderately promoted by an electron-donating
group (ρ = -0.2 ± 0.1) (Figure 1). A relatively small electronic effect from the -aryl substituent of the enone
substrate suggests of a metal-mediated non-electrophilic C−C cleavage process. Similar moderate electronic
effect with a relatively low Hammett  value has been observed for metal-mediated non-electrophilic cleavage
reactions of C−H, C−C and C−Si bonds.16
Scheme 2. The Reaction of 1 with 1,2-Dimethylindole and (E)-3-Nonen-2-one
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Figure 2. Partial 1H NMR Spectra from the Reaction of 1 with 1,2-Dimethylindole and (E)-3-Nonen-2-
one. Complex 1 (▲), complex 5 () and complex 6 (●).
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Spectroscopic Detection of Catalytically Relevant Species. In an effort to detect catalytically
relevant species, we monitored the coupling reaction of 1,2-dimethylindole with (E)-3-nonen-2-one by
employing NMR spectroscopic technique (Scheme 2). Thus, a stoichiometric mixture of the complex 1 (0.10
mmol), 1,2-dimethylindole (0.20 mmol), (E)-3-nonen-2-one (0.20 mmol) and 2-propanol (0.20 mmol) was
dissolved in CD2Cl2 (0.5 mL) in a resealable NMR tube. The reaction tube was immersed in an oil bath set at
125 °C and was taken out periodically to record the NMR spectrum at an ambient temperature. After just 5 s
of heating at 125 °C, four new sets of Ru-H signals rapidly appeared at  -12.1 (d, JPH = 27.2 Hz), -12.2 (d, JPH
= 27.6 Hz), -12.8 (d, JPH = 27.2 Hz) and -12.9 (d, JPH = 27.4 Hz) ppm in a 1:1:2.5:2.5 ratio as monitored by the
1H NMR, which were assigned to four diastereomeric mixtures of the arene-coordinated Ru–H complex 5
(Figure 2). The formation of free benzene molecule was also observed by the 1H NMR. The same
diastereomeric mixture of the complex 5 was independently generated from the treatment of 1 with the
isolated product 4. The 13C{1H} NMR of independently formed 5 exhibited three sets of carbonyl peaks, at 
207.5, 206.6 and 207.0 ppm, which are also consistent with four diastereomeric mixtures resulting from two
chiral centers (the peak at  207.5 ppm is consisted of two overlapping carbonyl peaks)(Figure S4, SI). Upon
further heating for 120 s at 125 °C, a new set of Ru–H peaks began to appear at  -12.4 (J = 27.5 Hz) and -
12.8 (d, JPH = 27.3 Hz) ppm at the expense of the peaks due to 5. These Ru–H peaks were identified as a
diastereomeric mixture of the product-coordinated complex 6, by comparing with an independently generated
ones from the treatment of 1 with the product 2a. Upon further heating for about 10 min, the peaks due to a
diastereomeric mixture of the product-coordinated complex 6 eventually predominated at the expense of both
1 and 5.
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Scheme 3. Proposed Mechanism of the Coupling Reaction of 1,2-Dimethylindole with an Enone
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Proposed Mechanism. We compiled a plausible mechanistic pathway for the coupling reaction of
1,2-dimethylindole with an enone substrate on the basis of these kinetic and spectroscopic data (Scheme 3).
We propose that a catalytically active Ru–H species 7 is initially formed from the ligand substitution reaction
with the indole substrate. The conjugate addition of 7 with the enone substrate, which was shown to be
relatively facile under the catalytic conditions as illustrated in eq 3, would initially form the arene-coordinated
complex 5.17 Since the carbonyl coordination would require a vacant site on the Ru center, we hypothesize
that a carbonyl-coordinated Ru-3-indole species 8, which is the key intermediate species for the C–C
cleavage step, could be generated via an arene-to-indole coordination shift, in light of well-established ring-
slippage modes of indole and related arene ligands.18 The carbon kinetic isotope effect data clearly indicates
that the C–C bond cleavage is the turnover limiting step of the catalytic reaction. The subsequent C–C bond
hydrogenolysis would form the product-coordinated complex 6 and acetone byproduct. The exchange reaction
of 6 with another indole substrate would lead to the formation of the product 2 and the regeneration of 7. A
relatively moderate electronic effect from the -aryl group of the enone substrate as probed by Hammett study
supports a non-electrophilic C–C bond cleavage step, while the deuterium labeling data indicates that the
hydrogenolysis step may be rapid and reversible. Even with the direct spectroscopic detection of the Ru–H
complexes 5 and 6, which provides a supporting evidence for the proposed catalytic cycle, detailed kinetic,
spectroscopic as well as computational studies are warranted to decipher the exact C–C bond cleavage
mechanism.19
CONCLUSION
In summary, we have successfully developed a novel catalytic chelate assistance method to achieve
a regioselective C–C bond cleavage of saturated and unsaturated carbonyl compounds. We found that the
coupling reaction of indoles with -unsaturated aldehydes and ketones initially formed the coupling
products, which subsequently underwent the regioselective C(sp3)–C(sp3) cleavage reaction that is assisted
by both indole and ketone chelate directing groups. The analogous coupling reaction with saturated aldehydes
and ketones led to the similar C–C cleavage products, which are resulted from the initial dehydrogenation of
the carbonyl substrates prior to the coupling with indole substrates. We proposed a plausible mechanism of
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the coupling reaction on the basis of both kinetic and spectroscopic data, which features an initial conjugate
addition of the indole substrate, the chelate assisted C–C activation and hydrogenolysis steps. We are
continuing our efforts to explore other suitable double chelate groups for promoting selective catalytic C–C
bond activation reactions.
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EXPERIMENTAL SECTION
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General Procedure for the Coupling Reaction of an Indole with an Enone and 2-Propanol. In a
glove box, an indole (0.25 mmol), an enone (0.30 mmol), 2-propanol (0.25 mmol) and complex 1 (5 mol %)
were dissolved in 1,2-dichloroethane (1 mL) in a 25 mL Schlenk tube equipped with a Teflon stopcock and a
magnetic stirring bar. The tube was brought out of the glove box and was stirred in an oil bath set at 125 °C
for 36 h. The reaction tube was taken out of the oil bath and was cooled to room temperature. After the tube
was open to air, the solution was filtered through a short silica gel column by eluting with CH2Cl2 (10 mL), and
the filtrate was analyzed by GC-MS. Analytically pure product 2 was isolated by column chromatography on
silica gel (40-63 μm particle size, hexanes/EtOAc), and its structure was completely established by NMR and
GC-MS spectroscopic methods.
ASSOCIATED CONTENT
AUTHOR INFORMATION
Corresponding Author
*E-mail: chae.yi@marquette.edu
ORCID
Chae S. Yi: 0000-0002-4504-1151
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
Financial support from the National Science Foundation (CHE-1664652) is gratefully acknowledged.
Supporting Information. The Supporting Information is available free of charge on the ACS Publications
website. Experimental procedures, characterization data and NMR spectra for organic products (PDF).
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(17) Though the complex 7 was not detected in the reaction mixture, it was independently generated from the
reaction of 1 with 1,2-dimethylindole. The treatment of 7 with (E)-3-nonen-2-one rapidly formed the complex 5
within 30 min at 125 °C.
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the following experimental evidences are inconsistent with the acid-catalyzed mechanism. First, none of Lewis
and BrØnsted acid catalyst has been found to mediate the C−C cleavage reaction of the initially formed 4.
Second, the analogous coupling reaction of 1,2,5-trimethylpyrrole with (E)-3-nonen-2-one produced the
conjugate addition product 3-(1,2,5-trimethyl-1H-pyrrol-3-yl)-2-nonanone but with a trace amount of the C−C
cleavage product 1-(1,2,5-trimethyl-1H-pyrrol-3-yl)-2-propanone (<5%). This result indicates that the 6-arene
coordination of Ru catalyst is essential for promoting the C−C cleavage reaction.
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