Iridium/Acid Cocatalyzed Direct Access to Fused Indoles via Transfer Hydrogenative Annulation of Quinolines and 1,2-Diketones

Article abstract of DOI:10.1021/acs.orglett.0c00500

Herein, we present an unprecedented iridium/acid cocatalyzed construction of fused indoles via transfer hydrogenative annulation of nonactivated quinolines and 1,2-diketones. The products are assembled via initial reduction followed by selective coupling

Full text of DOI:10.1021/acs.orglett.0c00500

pubs.acs.org/OrgLett
Letter
Iridium/Acid Cocatalyzed Direct Access to Fused Indoles via Transfer
Hydrogenative Annulation of Quinolines and 1,2-Diketones
Guangpeng Lu, Feng Xie, Rong Xie, Huanfeng Jiang, and Min Zhang*
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ABSTRACT: Herein, we present an unprecedented iridium/acid
cocatalyzed construction of fused indoles via transfer hydrogenative
annulation of nonactivated quinolines and 1,2-diketones. The
products are assembled via initial reduction followed by selective
coupling of 1,2-diketones with the N and C8 sites of the quinolyl
skeleton. The developed synthetic method features operational
simplicity, readily available feedstocks, applicability for streamline
synthesis of functional molecules, high step and atom efficiency,
and generation of water as the byproduct.
Scheme 1. Previous Work and the New Finding
he indole core is ubiquitous in natural alkaloids (e.g.,
T
reserpine and strychnine),1 marketing drugs (e.g.,
indomethacin and pravadoline are used as analgesic and
nonsteroidal anti-inflammatory drugs (NSAID), respectively),2
dyes and functional materials.3 Consequently, the construction
of indole derivatives has long been an attractive subject in the
scientific community. Except for the well-established name
reactions (e.g., Fischer, Bartoli, Bischler, Nenitzescu, Larock et
al.),4 a range of alternative approaches via inter-5 or
intramolecular6 cyclization have also been developed to access
various indoles.
In comparison, less attention has been focused on the
construction of fused indoles. Generally, the functionalization
of two indolyl carbo sites is considered as a useful tool to
achieve the related end in this regard. For instance, the [3 + 2]
cycloaddition reactions of indoles with 2-aryl-N-tosylaziridines
or N-sulfonyl-1,2,3-triazoles were successively developed by
the Davies and Yang groups.7 Lei et al. demonstrated an
electrooxidative [3 + 2] cyclization reaction of phenols and
indole derivatives.8 Recently, we reported a synthesis of indole-
fused N-heterocycles through the annulation of diarylamines
and indoles.9 Via deaminative annulation of tetrahydroquino-
line-based hydrazines and internal alkynes, the Gade group
reported an interesting zirconium-catalyzed synthesis of fused
indoles by functionalization of both N and carbo sites (Scheme
1, eq 1).10 Despite the significant utility, many of the existing
synthetic approaches suffer from one or more limitations such
as the need for preinstallation of requisite reactants, the use of
less environmentally benign reagents, and low step and atom
efficiency. As such, the search for new methods, enabling direct
access to new fused indoles from readily available feedstocks,
would be highly desirable.
simplicity.11 In addition, such a tool has also been elegantly
employed to generate functional products via new bond
formations.12 For instance, the Li and Zeng groups have
successfully transformed phenol derivatives into cyclic amines
with HCOONa.13 Bruneau et al. reported the C(sp3)−H bond
alkylation of cyclic amines with formic acid.14 However, the
strategy, utilizing transfer hydrogened N-heteroarenes as the
coupling partners for the subsequent step of a given sequence,
remains a new subject to be explored, which would pave new
Received: February 7, 2020
In recent years, transfer hydrogenation has emerged as an
appealing tool in the reduction of unsaturated chemical bonds,
since it does not require high pressure H2 gas with operational
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© XXXX American Chemical Society
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A

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avenues to access novel functional products with structural
diversity.
exhibited the best catalytic performance and afforded the
desired product 3aa in 80% yield. However, the absence of
additives, hydrogen donor, or catalyst failed to yield compound
3aa (entries 5−7), showing that these three elements are
indispensable for product formation. Thus, we then used
[Cp*IrCl2]2 as the preferred catalyst and examined several
additives (entries 8−10), hydrogen donors (entries 11−13),
and solvents (entry 14), but the results showed that all of them
were inferior to CF3COOH, HCOOH, and p-xylene,
respectively. Further, the increase or decrease of reaction
temperature and catalyst loading diminished the yields (entries
15−16). Changing the loading amount of the hydrogen donor,
reactant 2a, and additive was unable to further improve the
product yields (entries 16−18). Hence, the optimal conditions
are as shown in entry 4.
From our sustained effort toward direct functionalization of
N-heterocycles,15 we have recently reported a direct reductive
quinolyl β-C−H alkylation by multispherical cavity carbon-
supported cobalt oxide nanocatalysts (Scheme 1, eq 2).15d
Inspired by this work, we envisioned a new reaction for the
synthesis of polycyclic N-heterocycle. As shown in eq 3 of
Scheme 1 employing the same catalyst system of eq 2, the first
transfer hydrogenation (1st TH) of quinoline 1a is expected to
generate enamine 1a′ in situ, which would be able to trap
cyclohexane-1,2-dione 2a at the β-site and generate iminium
3aa-1 under the assistance of acid. Then, the second transfer
hydrogenation (2nd TH) of the unreacted carbonyl group
followed by intramolecular nucleophilic addition (3aa-1) and
deprotonation gives rise to a fused tetrahydroquinoline 3aa-2.
However, after performing such a reaction, we observed that,
instead of the anticipated product 3aa-2, a structurally novel
fused indole 3aa was obtained in 3% yield. Based on this
finding, we wish herein to report, for the first time, a hydrogen-
transfer mediated access to fused indoles from nonactivated
quinolines and 1,2-diketones.
With the optimal reaction conditions in hand, we then
examined the substrate scope of the synthetic protocol. First,
1,2-diketone 2a in combination with various quinolines 1 (for
the structures of 1a−1q; see Scheme S2 in SI) was tested. As
illustrated in Scheme 2, all the reactions proceeded smoothly
Scheme 2. Variation of Quinolines
To formulate an efficient reaction system, we chose the
synthesis of product 3aa from quinoline 1a and 1,2-
cyclohexanedione 2a as a model system to evaluate different
reaction parameters (Table 1 and Table S1 in Supporting
Information (SI) for details). Initially, several catalysts
employed frequently for transfer hydrogenation reactions
were evaluated (Table 1, entries 1−4); only [Cp*IrCl2]2
a
Table 1. Optimization of the Reaction Conditions
Hydrogen
b
Entry
Catalyst
IrCl3
Ru3(CO)12
Pd(OAc)2
[Cp*IrCl2]2
[Cp*IrCl2]2
−
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
[Cp*IrCl2]2
donor
Additive
Yield of 3aa (%)
1
2
3
4
5
6
7
8
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
−
HCOOH
HCOOH
HCOOH
isopropanol
HCOONa
H2
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
HCOOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
−
CF3COOH
CF3COOH
P-TSA
Hf(OTf)3
Benzoic acid
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
CF3COOH
<5
0
0
80
0
0
0
<5
38
0
9
10
11
12
13
14
15
16
17
18
19
0
0
<5
c
d
(0, 32, 35, 0)
e
(61, 68)
(66, 80)
(70, 76)
(48, 76)
i
f
and furnished the desired products in moderate to good yield
upon isolation. Various functionalities (−Me, −OMe, −F, −Cl,
−Br, −CO2Me, −Ph) were well tolerated in the trans-
formation, which offers the potential for molecular complexity
via further chemical transformations. The electronic property
of the substituents on the quinolyl benzene ring affected the
product yields to some extent. In general, quinolines with a
strong electron-donating group (3ba, 3da) afforded the
products in relatively higher yields than those of electron-
deficient ones (3fa−3ia), presumably because electron-rich
quinolines result in more reactive intermediates arising from
the transfer hydrogenation process and favor the coupling
process. However, quinolines (1p and 1q) containing a strong
electron-withdrawing group (e.g., −NO2, −CN) failed to
g
h
79
a
Conditions: unless otherwise stated, all the reactions were performed
with 1a (0.20 mmol), 2a (0.30 mmol), catalyst (1 mol %), hydrogen
donor (5.0 equiv), additive (0.5 equiv), p-xylene (1.5 mL) at 120 °C
b
c
for 16 h. GC yield using hexadecane as an internal standard. H2
balloon. Yields obtained with H2O, tert-amyl alcohol, 1,4-dioxane,
and DMF as the solvents, respectively. Yields obtained at 110 and
130 °C, respectively. Yields obtained with catalyst loading of 0.8 mol
% and 1.2 mol %, respectively. Yields obtained with 4 and 6 equiv of
HCOOH, respectively. Yields obtained with 0.2 and 0.4 mmol of 2a,
respectively. CF3COOH: 1 equiv.
d
e
f
g
h
i
B
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afford the desired products, indicating that a relatively
electron-rich quinoline is essential in affording the desired
annulation product. Of note, the methyl group on the pyridyl
ring (3ca) gave a lower yield than that of quinoline with a
methyl group on the benzene ring (3ba), which is assigned to
the pyridyl methyl group disfavoring the transfer hydro-
genation process.
Scheme 4. Control Experiments
Subsequently, we turned our attention to the variation of
both coupling partners. Thus, various quinolines and 1,2-
diketones (for the structures of 2a−2d; see Scheme S2 in SI)
were tested for the transformation. As shown in Scheme 3, all
Scheme 3. Variation of Both Coupling Agents
Subjection of quinoline 1a and butane-2,3-diol 2b′′ under the
standard conditions failed to yield product 3ab (eq 6), whereas
the reaction of quinoline 1a with 3-hydroxybutan-2-one 2b′
afforded product 3ab in 60% GC yield (eq 7). These results
indicate that tetrahydroquinoline 1a′′ and α-hydroxylketone,
instead of vicinal diol, are involved in the reaction process.
Further, the reaction of 6-methoxyquinoline 1d and cyclo-
hexane-1,2-dione 2a by replacing HCOOH with DCOOD
gave product 3da-dn in 84% yield with different deuterium
ratios on the product, supporting that the reaction undergoes a
transfer hydrogenative annulation pathway (eq 8).
Based on the above findings, a plausible reaction pathway is
depicted in Scheme 5. The presence of an iridium catalyst and
Scheme 5. Plausible Reaction Pathway
a
Temperature: 130 °C.
of the substrates underwent efficient transfer hydrogenative
annulation reaction, delivering the desired products in
moderate to good isolated yields. Noteworthy, the reactions
employing unsymmetrical 1,2-diketone 2c exhibited unique
regioselectivity (3ac vs 3ac′, 3bc vs 3bc′, 3dc vs 3dc′, and 3oc
vs 3oc′), and the major products were obtained by reacting the
sterically less-hindered carbonyl group with the quinolyl N-site,
which suggests that the N-site of the transfer hydrogenated
intermediate is initially involved in the annulation process.
However, employing greatly hindered compound phenyl-
glyoxal 2e failed to form the desired product.
In an effort to gain mechanistic insights into the reaction, we
conducted several control experiments (Scheme 4). Inter-
ruption of the model reaction after 3 h generated product 3aa
and enamino ketone 3aa-1 in 30% and 13% GC yields,
respectively (eq 4). Prolonging the reaction time to 16 h led to
full consumption of 3aa-1 to product 3aa, showing that 3aa-1
is a reaction intermediate. Then, tetrahydroquinoline 1a′′ was
able to react with 2a and afforded 3aa in 82% GC yield (eq 5).
hydrogen donor HCOOH initially forms the metal hydride
species [IrH2] with liberation of CO2.14 Upon two rounds of
transfer hydrogenation (TH) by [IrH2], quinoline 1 is
transformed to tetrahydroquinoline 1′′.16 Meanwhile, the
TH of diketone 2 gives hydroxylketone 2′. Then, 1′′
condenses with the carbonyl group of 2′ and affords α-
amino ketone 3-2 via tautomerization of the coupling adduct
3-1. Alternatively, 3-2 can also be afforded via the
condensation of tetrahydroquinoline 1′′ and diketone 2
followed by a TH process. Then, the acid-catalyzed intra-
molecular cyclization between the electron-rich aryl ring and
carbonyl group gives intermediate 3-4. Finally, dehydration-
C
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induced aromatization and deprotonation give rise to product
3. In addition, TH of the carbonyl group of 3-2 followed by an
acid-catalyzed intramolecular Fridel-Crafts type cyclization also
rationalizes the product formation. It is important to note that,
with the present catalyst system, TH of quinoline to
tetrahydroquinoline is faster than the reduction of 1,2-diketone
to 1,2-diol, thus offering high chemoselectivity.
To demonstrate the synthetic utility of the developed
chemistry, a gram scale synthesis of compound 3aa was
achieved by scaling the quinoline amount to 6 mmol, which
still afforded high product yield upon isolation (Scheme 6,
Engineering, South China University of Technology, Guangzhou
510641, P. R. China; School of Biotechnology and Health
Sciences, Wuyi University, Jiangmen 529020, China;
orcid.org/0000-0002-7023-8781; Email: minzhang@
scut.edu.cn
Authors
Guangpeng Lu − Key Lab of Functional Molecular Engineering
of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou
510641, P. R. China
Feng Xie − School of Biotechnology and Health Sciences, Wuyi
University, Jiangmen 529020, China
Scheme 6. Synthetic Utility
Rong Xie − Key Lab of Functional Molecular Engineering of
Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou
510641, P. R. China
Huanfeng Jiang − Key Lab of Functional Molecular Engineering
of Guangdong Province, School of Chemistry and Chemical
Engineering, South China University of Technology, Guangzhou
510641, P. R. China; orcid.org/0000-0002-4355-0294
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.0c00500
80%, 1.01 g). Then, the treatment of 3aa with DDQ resulted in
product 4aa,17a a key intermediate applied for the preparation
of drug molecules such as 5-HT3 receptor antagonist17b and
serotonin agents.17c Such a synthesis is far superior to the
reported protocol that requires 4 steps to give only 42% of
overall product yield.17b Further, subjection of 3aa in DMSO
with molecular I2 generated a carbazole derivative 5aa via
dehydroaromatization of 3aa.18 Noteworthy, the obtained
product constitutes the core structure of many kinds of oxime
ester photoinitiators with high activity and high thermo-
stability.19
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the National Key Research and Development
Program of China (2016YFA0602900), National Natural
Science Foundation of China (21971071), and the Foundation
of Education Department of Guangdong Province
(2017KZDXM085) for financial support.
In summary, we have developed an unprecedented iridium/
acid cocatalyzed transfer hydrogenative annulation reaction of
nonactivated quinolines with 1,2-diketones, which allows direct
access to a wide array of fused indoles, a class of valuable
compounds with the potential for further discovery and
creation of functional molecules. The products are furnished
via initial reduction followed by selective coupling of 1,2-
diketones with the N and C8 sites of the quinolyl skeleton. The
developed chemistry proceeds with the merits of operation
simplicity, high step and atom efficiency, broad substrate
scope, liberation of water as the byproduct, and applicability
for streamline synthesis of functional molecules. In consid-
eration of the significant importance of indole-fused N-
heterocycles in biological, medicinal, and synthetic organic
chemistry, the present work has the potential to be applied for
various purposes, and the hydrogen transfer-mediated coupling
strategy will pave new avenues for the transformation of inert
organic systems into functional frameworks.
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/acs.orglett.0c00500.
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Experimental details, NMR spectra (PDF)
AUTHOR INFORMATION
Corresponding Author
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