Iridium- and Rhodium-Catalyzed Directed C-H Heteroarylation of Benzaldehydes with Benziodoxolone Hypervalent Iodine Reagents

Article abstract of DOI:10.1021/acs.orglett.8b00337

The C-H heteroarylation of benzaldehydes with indoles and pyrroles was realized using the benziodoxolone hypervalent iodine reagents indole- and pyrroleBX. Functionalization of the aldehyde C-H bond using either an o-hydroxy or amino directing group and catalyzed by an iridium or a rhodium complex allowed the synthesis of salicyloylindoles and (2-sulfonamino)benzoylindoles, respectively, with good to excellent yields (74-98%). This new transformation could be carried out under mild conditions (rt to 40 °C) and tolerated a broad range of functionalities, such as ethers, halogens, carbonyls, or nitro groups.

Full text of DOI:10.1021/acs.orglett.8b00337

Letter
pubs.acs.org/OrgLett
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
Iridium- and Rhodium-Catalyzed Directed C−H Heteroarylation of
Benzaldehydes with Benziodoxolone Hypervalent Iodine Reagents
Erwann Grenet and Jerome Waser*
́
̂
́
Laboratory of Catalysis and Organic Synthesis, Institute of Chemical Sciences and Engineering, Ecole Polytechnique Federale de
Lausanne, EPFL SB ISIC LCSO, BCH 4306, 1015 Lausanne, Switzerland
S
* Supporting Information
ABSTRACT: The C−H heteroarylation of benzaldehydes with indoles and pyrroles was realized using the benziodoxolone
hypervalent iodine reagents indole- and pyrroleBX. Functionalization of the aldehyde C−H bond using either an o-hydroxy or
amino directing group and catalyzed by an iridium or a rhodium complex allowed the synthesis of salicyloylindoles and (2-
sulfonamino)benzoylindoles, respectively, with good to excellent yields (74−98%). This new transformation could be carried out
under mild conditions (rt to 40 °C) and tolerated a broad range of functionalities, such as ethers, halogens, carbonyls, or nitro
groups.
Indoles and pyrroles are ubiquitous in medicinal chemistry and
natural products.1 Aryl indolyl ketones have attracted strong
interest due to their interesting biological activities, in
particular, through interactions with the cannabinoid receptor.2
Among them, the subclass in which the aryl moiety wears a
hydroxy or an amino group in the ortho position to the
carbonyl showed in addition diverse biological activities (Figure
1). Polymethoxylated indole derivatives 1 were cytotoxic
Scheme 1. Classical vs Umpolung Approaches for the
Synthesis of 3-Arylcarbonyl Indoles
Lewis acids (Et2AlCl,6a,b imidazolium chloroaluminate,6c or
ZrCl46d), reaction with nitrilium salts,7 or the use of
hexafluoroisopropanol as solvent.8 Furthermore, the nucleo-
philicity of the heterocycles can be enhanced by conversion
into Grignard or other organometallic reagents, which can then
be added directly to electrophiles or used in metal-catalyzed
cross-couplings.9 Recently, direct C−H acylation catalyzed by
transition metals has also been reported.10 The synthesis of 3-
salicyloylindoles was either not reported in these works, or
required the protection/deprotection of the hydroxy group.
Therefore, developing a more direct access to these compounds
would be highly desirable. In this respect, only limited success
has been achieved by the ring-opening of chromones,11,12 1,3-
dipolar cycloaddition, followed by decarboxylation,13 and
alkylation of indoles with nitroolefins, followed by oxidative
C−C bond cleavage.14
Figure 1. Synthetic and natural bioactive compounds with a 2-hydroxy
or 2-amino benzoyl indole or pyrrole core.
against KB, MKN45, MCF-7, and colon HT-29 cells.3 3-(2-
Aminobenzoyl)indole 2 led to VEGFR-2 inhibition.4 Fur-
thermore, the salicyloylpyrrole core is present in bhimamycins
3, antibiotic natural products isolated from the bacteria
Streptomyces sp.5
Due to their occurrence in biologically active compounds, the
efficient synthesis of 3-benzoylindoles or -pyrroles is important.
The most straightforward approach is based on the innate
reactivity of the heterocycles as nucleophiles combined with an
electrophilic acylation reagent (Scheme 1a). However, Friedel−
Crafts acylation of indoles under standard conditions usually
leads to a complex mixture of mono-, diacylated, and
oligomerization products due to their high electron density.1a
This issue can be partially resolved by the introduction of
electron-withdrawing protecting groups, the use of milder
Received: January 30, 2018
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.8b00337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
As an alternative strategy, we envisaged an Umpolung
pathway involving a nucleophilic acyl metal intermediate
generated via Csp2−H activation of an aldehyde15 and an
electrophilic indole (Scheme 1b). Concerning the nucleophilic
partners, benzaldehydes substituted with oxygen or nitrogen
heteroatoms in the ortho position are privileged substrates, as
the directing group is necessary for C−H activation under mild
conditions.15a As electrophilic partners, we considered hyper-
valent iodine(III) reagents, which have been extensively used as
Umpolung reagents in numerous transformations.16 In fact,
both aryl iodoniums and ethynylbenziodoxolones (EBX) have
been used to introduce phenyl or alkyne derivatives via cross-
coupling on salicylaldehydes.17 However, there are only few
methods for the synthesis of indole-and pyrrole-based
iodonium salts.18 Furthermore, due to their limited stability,
these compounds have found only very limited use in
transition-metal catalysis. Recently, our and Yoshikai’s group
reported the synthesis of bench-stable indole− and pyrrole−
benziodoxolones (indoleBX and pyrroleBX).19 We further
demonstrated that the new indole- and pyrroleBX reagents
could be used for directed C−H functionalization with rhodium
or ruthenium catalysts, whereas iodonium salts were not
successful.19a Herein, we report the C−H functionalization of
2-hydroxy and 2-amino benzaldehydes derivatives with indole-
and pyrroleBX reagents using either iridium or rhodium
catalysts to give access to important indole and pyrrole building
blocks.
1, entry 3). Variation of the amount of KOAc revealed that a
superstoichiometric amount was not necessary (Table 1, entry
4). However, the yield decreased when the base was used in a
substoichiometric quantity (Table 1, entry 5), and without base
only 56% yield was obtained, even if full conversion was still
observed (Table 1, entry 6). Finally, we were able to reduce the
catalyst loading to 1 mol % without significant change in yield,
demonstrating the robustness of the catalyst (Table 1, entry 7).
A scale-up to 1.20 mmol allowed us to decrease the iridium
catalyst loading to 0.5 mol %, giving 93% yield of 6a in the
same reaction time (Table 1, entry 8). Control experiments
indicated that the transition-metal complex is essential for the
reaction.20 When 3-bromo-1-methylindole and 3-iodo-1-meth-
ylindole were used as reagents, the desired compounds were
obtained in 59% and 53% yield, respectively, but only after
heating overnight at 80 °C.20 This result further highlights the
exceptional reactivity of indoleBX reagents.
The scope of the reaction was then studied (Scheme 2). The
effect of substituents in the para position to the hydroxy group
Scheme 2. Ir(III)-Catalyzed C−H Indolation of 2-
ab
,
Hydroxybenzaldehydes.
We initiated the studies on C−H indolation with the
optimization of the reaction conditions for the coupling of
salicylaldehyde 4a with Me-indoleBX 5a (Table 1). While
a
Table 1. Optimization Studies
b
entry
catalyst
base (equiv)
yield (%)
c
1
2
3
4
5
6
7
8
[RhCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
[IrCp*Cl2]2
CsOAc (1.2)
CsOAc (1.2)
KOAc (1.2)
KOAc (1.0)
KOAc (0.5)
-
traces
91
90
90
86
56
d
KOAc (1.0)
KOAc (1.0)
94
e
93
a
Reactions conditions: 4a (0.05 mmol), 5a (0.05 mmol), [IrCp*Cl2]2
b
(3 mol %), base, and methanol (0.5 mL) at rt for 10 min. Isolated
c
yield after column chromatography. Reaction performed at 80 °C.
d
e
[IrCp*Cl2]2 (1 mol %). Yield at a 1.20 mmol scale with 0.5 mol %
[IrCp*Cl2]2.
a
Reactions conditions: 4 (0.15 mmol), 5 (0.15 mmol), [IrCp*Cl2]2 (1
mol %), KOAc (0.15 mmol), methanol (1.5 mL) at rt for 10 min.
b
c
[RhCp*Cl2]2 as catalyst gave only traces of the desired product
6a (Table 1, entry 1), we were pleased to see that the use of
[IrCp*Cl2]2 led to formation of 6a in excellent 91% yield in the
presence of cesium acetate at room temperature (Table 1, entry
2). This is the first example of the use of an iridium catalyst
with indoleBX reagents. Furthermore, the reaction did not
require any particular precautions concerning the presence of
water or oxygen. Complete conversion was reached after 10
min at room temperature. Cheaper potassium acetate could
also be used to give 90% yield of the ketone product 6a (Table
Isolated yield after column chromatography. 93% yield for a reaction
d e f
at 1.20 mmol scale. 30 min. 1 h. Reaction performed at 50 °C for 2
h. Reaction performed at 70 °C for 2 h.
g
was examined first (6a−i). In terms of electronic effect, both
electron-donating alkyl and ether groups (6b and 6c) and
electron-withdrawing halogens, aldehyde, and nitro groups
(6d−i) were well tolerated. The exclusive formation of product
6h starting from a bis-formylated benzene confirmed the
requirement of a directing group for C−H activation.21 In term
B
DOI: 10.1021/acs.orglett.8b00337
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
of substitution pattern of the benzene ring, a methoxy group
was tolerated also in all other positions (6j−l).
Information for a mechanism proposal)15a,17c but also served as
handles for further modifications (Scheme 4). For example,
A longer reaction time of 30 min was observed only in case
of 2-hydroxy-6-methoxybenzaldehyde 4l to give 6l in 86% yield.
Alkyl-substituted products 6m and 6n were also obtained in
good yields. Naphthalene and estrone derivatives 6o and 6p
were isolated in excellent 91% and 98% yields respectively.
Pentacyclic compound 6q wearing a carbazole heterocycle was
obtained in 90% yield. Modification of the hypervalent iodine
reagent was then investigated. Changing the N-substitution
from methyl to pentyl or butenyl delivered indoles 6r−u. The
corresponding O-methylated compounds are reported synthetic
cannabinoids.22 A bromo substituent on the benzene ring was
well tolerated (6v).The N-H free compound 6w could be also
obtained with complete regioselectivity in 85% yield. For
products 6u and 6w, it was necessary to perform the reaction at
70 °C to reach full conversion. Importantly, the method could
be extended to the synthesis of pyrrole 6x using a pyrroleBX as
reagent.
Scheme 4. Product Modifications
We then turned to the use of nitrogen-based directing groups
for the activation of the aldehyde C−H bond. In the case of 2-
aminobenzaldehyde 7a bearing a N-tosyl directing group, a
Rh(III) dimer catalyst proved to be as effective as the Ir(III)
catalyst (Scheme 3), in contrast to what had been observed
phenol 6a was quantitatively transformed into the correspond-
ing triflate 9 by reaction with triflic anhydride. Suzuki−Miyaura
cross-coupling with phenyl boronic acid gave then biphenyl
derivative 10 in 89% yield over two steps. Alternatively, the
directing group could be fully removed by a palladium-
catalyzed reduction of the triflate to furnish 3-benzoylindole 11.
From N-sulfonylphenyl substituted ketones 8a and 8b, an
iodine-mediated oxidative C-2 amination generated tetracyclic
indolo-[2,3b]quinolinone 12a and 12b in quantitative yield for
tosyl 8a and 89% yield for nosyl 8b.23 The nosyl protecting
group was synthetically especially useful, as it could be removed
in the presence of thiophenol, either on the cyclized product
12b or the indolation product 8b to give the N-H free
heterocycles 13 and 14.
Scheme 3. Rh(III)-Catalyzed C−H Indolation of 2-
a b
,
Sulfonylaminobenzaldehydes
In summary, we have reported the first example of aldehyde
C−H heteroarylation giving highly useful indole and pyrrole
building blocks. The reaction proceeded under mild, neutral
conditions using either an alcohol or a sulfonylamide directing
group with an iridium or a rhodium catalyst, respectively, and
the cyclic hypervalent iodine reagents indole- and pyrroleBX.
This represented also the first use of an iridium catalyst with
indole- and pyrroleBX as reagents. As the reaction tolerated a
broad range of functional groups and the obtained versatile
indole and pyrrole building blocks could be easily further
modified, the method is expected to be highly useful in
synthetic and medicinal chemistry.
a
Reaction conditions: 7 (0.15 mmol), 5 (0.15 mmol), [RhCp*Cl2]2 (1
mol %), KOAc (0.15 mmol), methanol (1.5 mL) at 40 °C for 4 h.
Isolated yield after column chromatography. 80% yield for a reaction
b
c
at 0.80 mmol scale.
with salicylaldehyde 4a (Table 1). The reaction was best run in
MeOH at 40 °C during 4 h.20 Several N-sulfonyl groups (tosyl,
p-nosyl, and mesyl) could be used to direct the C−H
functionalization, giving products 8a−c in 80−88% yield. In
contrast, a N-Boc directing group was inefficient for this
transformation (result not shown). The reaction could be
perform in the presence of a chlorine atom on the phenyl ring
affording the product 8d with 91% yield. The thiophene-
derived compound 8e was isolated in an excellent 90% yield.
This rhodium-catalyzed reaction also tolerated a N-butenyl
substituent or a bromo group on the indole benzene ring,
giving the desired products 8f and 8g in 79% and 82% yields,
respectively.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.8b00337.
Experimental procedures, analytical data, optimization
tables, and NMR spectra for all compounds (PDF)
NMR data (ZIP)
AUTHOR INFORMATION
Corresponding Author
■
The directing groups not only were useful for allowing C−H
functionalization under mild conditions (see the Supporting
*E-mail: jerome.waser@epfl.ch.
C
DOI: 10.1021/acs.orglett.8b00337
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Organic Letters
ORCID
Letter
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Jerome Waser: 0000-0002-4570-914X
́
̂
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work is supported by the ERC starting grant 334840,
iTools4MC, and EPFL.
■
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DOI: 10.1021/acs.orglett.8b00337
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