Aerobic, Metal-Free, and Catalytic Dehydrogenative Coupling of Heterocycles: En Route to Hedgehog Signaling Pathway Inhibitors

Article abstract of DOI:10.1021/acs.orglett.8b00521

The nitrosonium ion-catalyzed dehydrogenative coupling of heteroarenes under mild reaction conditions is reported. The developed method utilizes ambient molecular oxygen as a terminal oxidant, and only water is produced as byproduct. Dehydrogenative coupl

Full text of DOI:10.1021/acs.orglett.8b00521

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Aerobic, Metal-Free, and Catalytic Dehydrogenative Coupling of
Heterocycles: En Route to Hedgehog Signaling Pathway Inhibitors
Luis Bering,†,‡ Felix M. Paulussen,‡ and Andrey P. Antonchick*,†,‡
†Max-Planck-Institute of Molecular Physiology, Department of Chemical Biology, Otto-Hahn-Straße 11, 44227 Dortmund, Germany
‡TU Dortmund, Faculty of Chemistry and Chemical Biology, Chemical Biology, Otto-Hahn-Straße 4a, 44227 Dortmund, Germany
S
* Supporting Information
ABSTRACT: The nitrosonium ion-catalyzed dehydrogen-
ative coupling of heteroarenes under mild reaction conditions
is reported. The developed method utilizes ambient molecular
oxygen as a terminal oxidant, and only water is produced as
byproduct. Dehydrogenative coupling of heteroarenes trans-
lated into the rapid discovery of novel hedgehog signaling
pathway inhibitors, emphasizing the importance of the developed methodology.
salts or oxidants are often drawbacks of double C−H bond
functionalization. Kita and co-workers pioneered the metal-free
coupling of pyrroles and thiophenes using hypervalent
iodine(III) reagents (Figure 1B).9 The reaction takes advantage
of the low oxidation potential and the high intrinsic
nucleophilicity of the heteroarene substrates.10 Radical coupling
of arenes was reported using 2,3-dichloro-5,6-dicyano-1,4-
benzoquinone (DDQ).11,12 Although the described metal-free
methodologies represent great improvements in terms of
environmental compatibility, the use of high molecular weight
oxidants still leads to stoichiometric amounts of waste.
Early studies by Radner and, later, by Tanaka enlightened
Scholl-type reactions through nitrosonium ion-catalyzed
coupling.13 Because of the growing importance of sustainable
chemistry, and the ongoing interest of our group in the
development of novel metal-free reaction methodologies,
nitrosonium salts have attracted our attention.14 Molecular
oxygen is considered the ideal oxidant due to its natural
occurrence, inexpensive character, and safe handling.15 To our
surprise, the employment of nitrosonium salts in oxidative C−
C bond formation remained almost untouched.16 Herein, we
demonstrate the efficient dehydrogenative coupling of hetero-
cycles under mild reaction conditions using nitrosonium
tetrafluoroborate as sustainable catalyst and ambient molecular
oxygen as oxidant (Figure 1C).
xidative coupling through C−H bond functionalization
Orepresents one of the most efficient synthetic strategies
for the construction of carbon−carbon bonds.1 Selective
functionalization of abundant and inert C−H bonds is in
high demand.2 Various approaches using transition-metal
catalysts and directing groups have been widely reported,
which often require additional functionalization of the starting
materials.3 Direct oxidative C−C bond formation serves as an
alternative strategy.4 Double C−H bond functionalization offers
the unique advantage of making the requirement for
prefunctionalization of both coupling partners unnecessary.5
Early reports demonstrated the oxidative coupling of hetero-
cycles using palladium salts.6 Mori and co-workers7 reported
the palladium-catalyzed coupling of thiophenes in the presence
of AgF and a stoichiometric oxidant (Figure 1A), and Wang
and co-workers8 disclosed the palladium-catalyzed coupling
under aerobic conditions. Elevated temperatures, prolonged
reaction times, and the stoichiometric use of either palladium
Initially, we hypothesized an analogy between nitrosonium
salts and hypervalent iodine(III) reagents due to a comparable
redox potential.17 We selected an initial set of compounds
according to their oxidation potential and were pleased to find
2-phenylbenzofuran (1a) as a suitable substrate.18 We chose 1a
as model substrate, since no methodology was known, which
covers metal-free, catalytic, and dehydrogenative coupling
conditions at once.19 2-Arylbenzofurans and their homodimers
are associated with useful biological activities.20
Figure 1. Direct oxidative coupling of heterocycles via C−H bond
functionalization.
Received: February 12, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00521
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Organic Letters
Letter
We initiated our systematic optimization by treating 1a with
substoichiometric amounts of nitrosonium tetrafluoroborate
(NOBF4) in the presence of trifluoroacetic acid (TFA) (Table
1). Chlorinated solvents yielded the desired product 2a in 39%
Scheme 1. Scope of the Catalytic Dehydrogenative Coupling
of 2-Phenylbenzofurans
a
Table 1. Optimization of Reaction Conditions
b
entry
solvent
acid (ratio)
catalyst (mol %)
yield (%)
1
CH2Cl2
C6H5Cl
EtOH
TFA (4/1)
TFA (4/1)
TFA (4/1)
TFA (4/1)
TFA (4/1)
TFA (4/1)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NaNO2 (20)
NOBF4 (10)
NOBF4 (10)
NOBF4 (10)
NOBF4 (20)
NOBF4 (5)
NOBF4 (10)
39
80
2
3
nd
nd
62
4
THF
5
CH3NO2
CH3CN
CH3CN
6
85
7
traces
14
8
TFA
9
HFIP
31
10
11
12
13
14
15
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CH3CN
CF3SO3H
CF3SO3H
TFA (5/1)
TFA (3/1)
TFA (4/1)
TFA (4/1)
TFA (4/1)
62
21
79
64
82
32
c
16
78
a
Reaction conditions: 1a (0.1 mmol, 1 equiv), catalyst (see table),
solvent (0.1 M), 0 °C, 2−18 h under air atmosphere (SI for the
b
details). Yields are given for isolated products after column
c
d
chromatography. Reaction performed at rt. nd = not detected.
and 80% yields, respectively (entries 1 and 2). We were pleased
to observe an increased yield of 2a, when acetonitrile was used
as solvent (entry 6), while protic solvents and ethers did not
yield any product (entries 3 and 4). Absence of acid yielded
traces of 2a due to electrophilic nitration.21 A high excess of
acid proved to be unfavorable for the course of reaction.
Conducting the reaction in HFIP yielded product 2a in 32%,
which underpins the requirement for a strong acid (entry 9).
Further screening of solvents in the presence of acid did not
improve the outcome of the reaction (Table S1). Cationic
nitrosonium species were also generated by treating sodium
nitrite with triflic acid, which allowed the isolation of 2a in 62%
yield (entry 10). The yield of 2a even further decreased when
nitrosonium tetrafluoroborate and triflic acid were applied
(entry 11). Next, we also examined the amount of acid, which
was found to be already optimal (entries 12 and 13). Increased
loading of nitrosonium tetrafluoroborate led to a decreased
yield of 2a, and lowering the catalyst loading resulted in an
incomplete conversion of starting material (entries 14 and 15).
Finally, different temperatures and concentrations were also
explored, but no further improvements were found (entry 16
and Table S1).
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), NOBF4 (0.1 equiv),
b
CH3CN/TFA (0.1 M), 0 °C, 1−8 h under air atmosphere. Yields are
given for isolated products after column chromatography. CH2Cl2/
TFA (4/1) was used as solvent.
c
on the 2-phenyl group were well tolerated on all accessible
positions (Scheme 1, 2b−k). Next, a set of polysubstituted
products was synthesized in good to excellent yield, depending
on the electronic properties of the substituents (Scheme 1, 2l−
p). Interestingly, product 2p was selectively formed, while the
naphthalene substituent remained untouched under the
reaction conditions. The dehydrogenative coupling of 5-
substituted substrates was accomplished (Scheme 1, 2q−s).
To stress the synthetic value of our newly developed reaction,
we performed the dehydrogenative coupling using 5 mmol of
1a. To our delight, product 2a was isolated in only slightly
reduced yield, demonstrating the facile scalability of the
coupling reactions.
Having the optimized conditions in hand, we started to
explore the scope of this catalytic dehydrogenative coupling
reaction. The reaction proved to be robust and versatile and
allowed the synthesis of a broad range of bibenzofurans
(Scheme 1). Several starting materials suffered from poor
solubility in acetonitrile. Changing the solvent to dichloro-
methane allowed the straightforward isolation of the products
in satisfying yield and short reaction times. Functional groups
After confirming the scope of 2-arylbenzofurans, we moved
our attention to the dehydrogenative coupling of benzothio-
phenes and indoles (Scheme 2). Bibenzothiophenes 4a−d were
isolated in good yields and short reaction times, revealing
similar trends in functional group compatibility compared,
B
DOI: 10.1021/acs.orglett.8b00521
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Letter
with low oxidation potentials entail higher nucleophilicity and
preferentially undergo homocoupling.
Scheme 2. Scope of the Catalytic Dehydrogenative Coupling
of 2-Phenylbenzothiophenes and 3-Phenylindoles
On the basis of the conducted control experiments, a
reaction mechanism is proposed and outlined in Figure 2.
Figure 2. Proposed reaction mechanism.
Initially, 1a is oxidized via single-electron-transfer (SET),
generating radical cation A and nitrogen monoxide. Sub-
sequently, A reacts with a second molecule of 1a by means of
radical SEAr to generate intermediate B. A second SET leads to
rearomatization and formation of product 2a, while producing a
second molecule of nitrogen monoxide. Nitrogen monoxide is
oxidized by molecular oxygen generating nitrogen dioxide.
Nitrogen dioxide dimerizes to form dinitrogen tetroxide, which
is in equilibrium with NONO3 through disproportionation. In
the presence of acid water, a nitrosonium and a nitronium ion
are released upon protonation. Finally, the nitronium ion is able
to oxidize nitrogen monoxide instead of molecular oxygen,
maintaining the catalytic cycle.
Dimeric scaffolds can be found in numerous natural products
and represent a promising source for the discovery of
biologically active compounds.22 We continued our inves-
tigation by testing all substances (1−4) in cell-based screening
assays. To our delight, we discovered the bisindoles 4f−i as
potent and novel inhibitors of the hedgehog (Hh) signaling
pathway (Table 2 and SI). Inhibition of the Hh signaling
pathway is a promising approach for the treatment of cancers,
such as basal cell carcinoma and medulloblastoma.23 A primary
structure−activity relationship was observed with IC50 values in
the low micromolar range, while the monomeric starting
a
Reaction conditions: 1 (0.2 mmol, 1 equiv), NOBF4 (0.1−0.2 equiv),
b
solvent (0.1 M), 0 °C, 0.5−2 h under air atmosphere. Yields are given
for isolated products after column chromatography. CH3CN was used
as solvent. CH3CN/TFA (4/1) was used as solvent.
c
d
although the overall yield was lower. Furthermore, 3-arylindoles
were successfully coupled under the developed reaction
conditions. Functional groups with electron-donating or
electron-withdrawing effects were well tolerated on the 3-
phenyl ring and the 5-position of indole (Scheme 2, 4e−j). To
our surprise, the coupling of unprotected indole did not require
any acid, while products 4k and 4j were synthesized using the
optimized reaction conditions. To the best of our knowledge,
an efficient undirected coupling of 3-arylindoles via C−H bond
functionalization has not been described before.
Table 2. Selected Examples of Identified Inhibitors of the
b
Hedgehog (Hh) Signaling Pathway
To investigate the course of the reaction, we conducted
several control experiments (see the SI for the details). Only
traces of products 2a were detected when the reaction was
performed under argon atmosphere. This result underlines the
importance of oxygen to maintain the catalytic cycle. In
contrast, when the reaction was conducted under oxygen
atmosphere, only traces of product were formed as well due to
overoxidation of reactive intermediates. Next, a radical-
scavenging experiment was performed using butylated hydrox-
ytoluene (BHT). While product 2a was not detected, formation
of a radical scavenging product could be confirmed. Finally, we
also performed a competition experiment, but only minor
formation of a heterocoupling product was detected. This
finding is in accordance to the general tendency that substrates
b
c
entry
R1
R2
4
IC50 (μM)
viability
1
2
3
4
o-MeOC6H4
m-ClC6H4
m-FC6H4
C6H5
H
4f
5.42 0.49
6.18 1.58
4.39 0.95
8.11 1.26
inactive
inactive
inactive
inactive
H
4g
4h
4i
H
Me
a
b
See the SI for biological methods. Mean IC50 value for the inhibition
of the Hh signaling pathway (see Table S2 for full details).
Compound referred to as “inactive” showed more than 80% cell
c
viability at 10 μM.
C
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heteroarenes under mild conditions. The desired products were
formed smoothly with a fast reaction rate using molecular
oxygen as the stoichiometric oxidant, while water is formed as a
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ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00521.
■
S
General experimental procedures, detailed optimization
studies, details on control experiments, mechanistic
studies and biological methods and characterization of
starting materials and products (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: andrey.antonchick@mpi-dortmund.mpg.de.
ORCID
Andrey P. Antonchick: 0000-0003-0435-9443
Notes
(19) (a) Auzias, M.; Neuburger, M.; Wegner, H. Synlett 2010, 2010,
2443−2448. (b) Wirtanen, T.; Makela, M. K.; Sarfraz, J.; Ihalainen, P.;
̈
̈
Hietala, S.; Melchionna, M.; Helaja, J. Adv. Synth. Catal. 2015, 357,
3718−3726. (c) Wirtanen, T.; Muuronen, M.; Hurmalainen, J.;
Tuononen, H. M.; Nieger, M.; Helaja, J. Org. Chem. Front. 2016, 3,
1738−1745.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
(20) (a) Delogu, G. L.; Matos, M. J.; Fanti, M.; Era, B.; Medda, R.;
Pieroni, E.; Fais, A.; Kumar, A.; Pintus, F. Bioorg. Med. Chem. Lett.
2016, 26, 2308−2313. (b) Pu, W.; Yuan, Y.; Lu, D.; Wang, X.; Liu, H.;
Wang, C.; Wang, F.; Zhang, G. Bioorg. Med. Chem. Lett. 2016, 26,
5497−5500.
A.P.A. acknowledges the support of DFG (Heisenberg
scholarship AN 1064/4-1) and the Boehringer Ingelheim
Foundation (Plus 3). L.B. is supported by the Verband der
Chemischen Industrie e.V. We thank Dr. S. Sievers and the
Compound Management and Screening Center (COMAS,
Dortmund) for biological testing.
(21) Tanaka, M.; Muro, E.; Ando, H.; Xu, Q.; Fujiwara, M.; Souma,
Y.; Yamaguchi, Y. J. Org. Chem. 2000, 65, 2972−2978.
(22) (a) Lian, G.; Yu, B. Chem. Biodiversity 2010, 7, 2660−2691.
(b) Wezeman, T.; Masters, K.-S.; Brase, S. Angew. Chem., Int. Ed. 2014,
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