Aerobic Oxidative C-H Azolation of Indoles and One-Pot Synthesis of Azolyl Thioindoles by Flavin-Iodine-Coupled Organocatalysis

Article abstract of DOI:10.1021/acs.orglett.1c00241

The aerobic oxidative cross-coupling of indoles with azoles driven by flavin-iodine-coupled organocatalysis has been developed for the green synthesis of 2-(azol-1-yl)indoles. The coupled organocatalytic system enabled the one-pot three-component synthesis of 2-azolyl-3-thioindoles from indoles, azoles, and thiols in an atom-economical manner by utilizing molecular oxygen as the only sacrificial reagent.

Full text of DOI:10.1021/acs.orglett.1c00241

pubs.acs.org/OrgLett
Letter
Aerobic Oxidative C−H Azolation of Indoles and One-Pot Synthesis
of Azolyl Thioindoles by Flavin−Iodine-Coupled Organocatalysis
Kazumasa Tanimoto, Hayaki Okai, Marina Oka, Ryoma Ohkado, and Hiroki Iida*
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ABSTRACT: The aerobic oxidative cross-coupling of indoles with
azoles driven by flavin-iodine-coupled organocatalysis has been
developed for the green synthesis of 2-(azol-1-yl)indoles. The
coupled organocatalytic system enabled the one-pot three-
component synthesis of 2-azolyl-3-thioindoles from indoles, azoles,
and thiols in an atom-economical manner by utilizing molecular
oxygen as the only sacrificial reagent.
he indole ring system is the most ubiquitous heterocycle
dimethylpiperazine7,8 and I2/NH4OOCH (Scheme 1A).9
Hypervalent iodine reagents efficiently promoted the oxidative
C−N coupling reaction.10 There is only one approach on the
efficient catalytic azolation; in this reaction, the iodine-
catalyzed system required a stoichiometric amount of tert-
butylhydroperoxide (TBHP) as a terminal oxidant (Scheme
1B).11 Nicewicz and co-workers demonstrated the photo-
T
in nature and is also the most potent pharmacophore that
is found in a range of natural products.1 Thus, considerable
efforts have been made toward the development of method-
ologies for the efficient preparation and functionalization of
indole derivatives.2 Among the indole derivatives, 2-(azol-1-
yl)indoles are found in biologically and pharmaceutically active
compounds such as celogentin C3 and potent anticancer agents
I,4 II,5 and III6 (Figure 1). The direct C−N bond formation of
Scheme 1. (A and B) Previous and (C and D) Present
Methods for the Cross-Coupling of 1 with 2
Figure 1. Structures of biologically active 2-(azol-1-yl)indoles.
nonactivated simple indoles and azoles is an atom-economical
approach to access 2-(azol-1-yl)indoles; however, the oxidative
cross-coupling of indoles and azoles to form 2-(azol-1-
yl)indoles has been rarely reported. Although a number of
the metal-catalyzed oxidative coupling of indoles and azoles
has been developed, the C−C bond formation was performed
rather than the C−N bond formation.2a,c−e
Received: January 21, 2021
Published: March 3, 2021
The stoichiometric cross-coupling reactions were performed
using an excess amount of oxidant and base such as NCS/1,4-
https://dx.doi.org/10.1021/acs.orglett.1c00241
© 2021 American Chemical Society
Org. Lett. 2021, 23, 2084−2088
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a
catalytic aerobic C−H azolation of diverse aryl and heteroaryl
compounds, including indoles. However, indoles hardly
reacted, resulting in poor yields (up to 12%).12
Table 1. Synthesis of 3aa via cross-coupling of 1a with 2a
Green aerobic systems have drawn considerable attention
because molecular oxygen (O2) utilized in these systems is an
ideal oxidant with many advantages such as sustainable
abundance, safety, cost-effectiveness, atom-economy, and
minimal pollution.2e,13 Flavin catalysts, which are prepared
by mimicking the function of flavin-dependent monooxyge-
nase,14 have attracted significant interest because of their
biomimetic organocatalytic ability to activate O2.15,16 Inspired
by the aerobic system of the flavoenzymes, we recently
developed a novel strategy for green, oxidative transformations
by combining the flavin catalyst and iodine catalyst.17,18 The
flavin−iodine-coupled organocatalytic system successfully
promoted the aerobic oxidative sulfenylation of indole
analogues19 and imidazo[1,2-a]pyridine ring formation20
under metal-free conditions. In these reactions, the flavin
catalyst activated O2 through electron transfer from the
coupled iodine catalyst, thereby allowing a green oxidative
coupling reaction with O2 (1 atm or air). O2 was the only
sacrificial reagent, and no other oxidizing or reducing agents
were required for these reactions. On the basis of this coupled
organocatalysis, in this study we developed the first efficient
method for the aerobic cross-coupling of indoles 1 and azoles 2
through the catalytic C−H activation of 1 (Scheme 1C).
Moreover, the C−H azolation reaction was coupled with the
previously developed sulfenylation reaction, allowing the one-
pot three-component synthesis of 2-(azol-1-yl)-3-thioindoles 5
from 1, 2, and thiols 4 (Scheme 1D).
entry
flavin (mol %)
I2 (mol %)
atmosphere
yield (%)
1
2
3
4
5
6
6·TfO (5)
none
6·TfO (5)
6·TfO (5)
6·TfO (5)
none
I2 (5)
I2 (5)
none
I2 (5)
I2 (5)
I2 (120)
O2
O2
O2
N2
air
N2
78
21
none
4
56
1 (12)
b
a
Conditions: 1a (1.0 M), 2a (2.0 M), 6·TfO, I2, and CH3CN under
O2, N2, or air (1 atm, balloon) at 50 °C. Yield was determined by 1H
NMR or GC measurements with 1,1,2,2-tetrachloroethane or
triethylene glycol dimethyl ether as an internal standard. 3-Iodo
adduct 7aa was formed.
b
Scheme 2. Substrate Scope of Flavin−Iodine-Catalyzed
Aerobic Oxidative Cross-Coupling of 1 with 2
a
First, we examined the cross-coupling reaction of 1-
methylindole (1a) with pyrazole (2a) in the presence of a
range of flavin catalysts and iodine sources in diverse solvents
under an O2 atmosphere (Tables S1 and S2). The desired
compound, 2-azolylindole 3aa, was selectively obtained in 78%
yield when riboflavin-derived alloxazinium salt 6·TfO21 (5 mol
%) and I2 (5 mol %) were used as the catalysts under an O2 (1
atm, balloon) atmosphere in CH3CN at 50 °C (entry 1, Table
1). In the absence of 6·TfO, the yield of 3aa decreased to 21%,
suggesting that the flavin-catalyzed O2 activation played an
important role in the progress of this reaction (entry 2). I2 and
O2 were necessary for the catalytic transformation to 3aa
(entries 3 and 4). When air (1 atm, balloon) was used as the
oxidant, the yield was reasonably lower (56%) than that under
O2 (entry 5). When a stoichiometric amount of I2 was used in
the absence of 6·TfO and O2, the desired product 3aa was
hardly obtained; instead, the corresponding 3-iodo adduct 7aa
was formed in 12% yield (entry 6).
With the optimized reaction conditions in hand, we
examined the substrate scope and limitations of this cross-
coupling reaction (Scheme 2). A series of indoles bearing alkyl
substituents at the N1 position (1a−d) successfully reacted
with 2a to give the corresponding products 3aa−3da in 58−
80% yields.
To our delight, the coupling reactions of indoles that were
not substituted at the N1 positions (1e and 1f) with 2a also
proceeded smoothly to produce 3ea and 3fa. The presence of
substituents at the C3 (1e), C5 (1d, f), and C7 (1c) positions
of the indole ring did not prevent the azolation reaction.
Electron-rich indole 1g and electron-deficient indole 1h gave
the desired products (3gb and 3hb) in 73% and 65% yields,
respectively, although a relatively higher amount of 2 or I2 was
required. Indole bearing cyano group 1i gave the correspond-
a
Conditions: 1 (1 M), 2 (2 M), 6·TfO (5 mol %), and I2 (5 mol %)
in CH3CN under O2 (1 atm, balloon) atmosphere at 50 °C for 36 h.
b
c
1,4-Dioxane was used as the solvent. Four equiv of 2 was used.
d
e
Twenty-five mol % of I2 was used. Determined by 1H NMR
f
measurement. 1 (4 M), 2 (1 M), 6·TfO (5 mol %), and I2 (5 mol %)
in 1,4-dioxane under O2 (1 atm) atmosphere at 80 C °C for 72 h.
̊
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Letter
a
ing product 3ia in poor yields, suggesting that the electron-
deficient indoles were relatively less active for the present
azolation. The use of substituted pyrazole 2b, 1,2,4-triazole
(2c), and benzimidazole (2d) as the azole reagent for this
cross-coupling reaction afforded 3ab, 3ac, 3cc, and 3ad,
respectively. However, the reactivity of 2d was relatively low,
because of which 4 equiv of 1a and a higher temperature (80
°C) were needed for the coupling reaction to reach
completion. In contrast to 2a, 2c, and 2d, the pKa values of
which are 2.5,22a 2.2,22a and 5.3,22b respectively, relatively basic
and acidic azoles such as imidazole (2e, pKa = 7.0)22a and
1,2,3-triazole (2f, pKa = 1.2)22a were not effective for the
coupling with 1a, as apparent from the poor yields of the
corresponding products 3ae and 3af.
Scheme 3. One-Pot Three-Component Synthesis of 5
On the basis of the results of the aerobic C−N bond
formation, we explored the one-pot three-component synthesis
of 2-(azol-1-yl)-3-thioindoles 5. The aerobic one-pot, multi-
step, and multicomponent reaction will be an atom- and step-
economical strategy to meet the acute demands of green and
sustainable chemistry. Development of the O2-mediated
multistep reactions is one of the most rewarding challenges
in synthetic organic chemistry. However, this often suffers
from the low selectivity of the aerobic process. Previously, we
demonstrated a green and efficient method for the direct
aerobic oxidative sulfenylation of 1 with 4, in which the aerobic
oxidation of 4 and the following aerobic oxidative sulfenylation
of 1 were selectively promoted under mild conditions via
flavin-iodine coupled catalysis.19a Consequently, we expected
that the present aerobic oxidative azolation of 1 with 2 would
proceed in the same time as the previous aerobic sulfenylation
with 4, thus the target biofunctionalized indole 5 would be
produced via the three-component coupling reaction of 1, 2,
and 4 (Scheme 1D).23 We first attempted the reaction of 1a,
2a, and 4a in the presence of 6·TfO and I2; only 3-sulfenylated
indole 8 was obtained in 97% yield, without the generation of
bifunctionalized indole 5aaa (Scheme 3). This suggested that
the 2-azolation reaction was relatively slower than the 3-
sulfenylation reaction, and there was no azolation after
sulfenylation. Therefore, we carried out the one-pot
bifunctionalization reaction in a sequential mannerthe
azolation of 1 with 2 was performed first, following which
sulfenylation was performed by adding 4 into the reaction
mixture. Consequently, a series of compound 5 was obtained
in 63−78% yield via the three-component reaction of 1, 2, and
4. To the best of our knowledge, this is the first example of the
direct one-pot synthesis of 5 from simple compounds 1, 2, and
4. This would provide a novel green way to readily access
diverse compound 5, which is of biological and pharmaco-
logical importance. For example, the potent anticancer agent
IIIb has been prepared by the inefficient multistep reaction
through the chemoselective iodination and azolation of 1i with
2c, followed by the microwave-assisted sulfenylation with 9d,
which was prepared by the stoichiometric oxidation of 4d, thus
generating copious amounts of wastes (Scheme 4A).6,24 In
sharp contrast, the present flavin-iodine-catalyzed three-
component reaction of 1i, 2c, and 4d afforded the desired
compound IIIb in 78% yield through a one-pot reaction,
generating only water as the sole waste (Scheme 4B). This
clearly established the merit of the present green method.
On the basis of the experimental results and relevant
literature, a plausible mechanism of the present dual catalytic
system is proposed in Scheme 5. Initially, the reaction of
nucleophilic 1 with I2 affords corresponding iodonium 10 and
a
Conditions: A mixture of 1 (1 M), 2 (2 M), 6·TfO (5 mol %), and I2
(5 mol %) in CH3CN was stirred under O2 (1 atm, balloon)
atmosphere at 50 °C for 36 h, following which 4 (1.2 M) was added,
b
and the mixture was stirred at 50 °C for 24 h. Condition: A mixture
of 1 (1 M), 2 (2 M), 4 (1.2 M), 6·TfO (5 mol %), and I2 (5 mol %)
in CH3CN was stirred under O2 (1 atm, balloon) atmosphere at 50
1
°C for 36 h. The yield was determined by H NMR measurement.
c
Stirred for 48 h before the addition of 4.
Scheme 4. (A) Conventional Multistep Synthesis and (B)
Present One-Pot Three-Component Synthesis of IIIb
3-iodo iminium 11, which are electrophilically activated (step
i).9,11a Then, the nucleophilic attack of 2 at the C2 positions of
10 and 11 and the following elimination of H+ and I− afford
the 2-azolated product 3 (step ii). The generated H+ and I− are
efficiently converted to I2 and water by the flavin 6-catalyzed-
aerobic oxidation.17 Furthermore, in the presence of 4, flavin
catalysis promotes the aerobic oxidation of 4 to 9 (step iii),
which readily reacts with I2 to give sulfenyl iodide 12 (step
iv).19 Reactive intermediate 12 undergoes nucleophilic attack
by 3, producing the 3-sulfenylated product 5 along with H+
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Hayaki Okai − Department of Chemistry, Graduate School of
Natural Science and Technology, Shimane University,
Matsue 690-8504, Japan
Scheme 5. Plausible Mechanism for the Catalytic Synthesis
of 3 and 5
Marina Oka − Department of Chemistry, Graduate School of
Natural Science and Technology, Shimane University,
Matsue 690-8504, Japan
Ryoma Ohkado − Department of Chemistry, Graduate School
of Natural Science and Technology, Shimane University,
Matsue 690-8504, Japan
Complete contact information is available at:
https://pubs.acs.org/10.1021/acs.orglett.1c00241
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported in part by JSPS/MEXT KAKENHI
(Grant-in-Aid for Scientific Research (C), 19K05617) and the
Electric Technology Research Foundation of Chugoku.
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ASSOCIATED CONTENT
* Supporting Information
■
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AUTHOR INFORMATION
Corresponding Author
■
Hiroki Iida − Department of Chemistry, Graduate School of
Natural Science and Technology, Shimane University, Matsue
690-8504, Japan; orcid.org/0000-0002-7114-0364;
Email: iida@riko.shimane-u.ac.jp
Authors
Kazumasa Tanimoto − Department of Chemistry, Graduate
School of Natural Science and Technology, Shimane
University, Matsue 690-8504, Japan
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