Iridium(III) Catalysts with an Amide-Pendant Cyclopentadienyl Ligand: Double Aromatic Homologation Reactions of Benzamides by Fourfold C?H Activation

Article abstract of DOI:10.1002/anie.202003009

The synthesis, characterization, and catalytic performance of iridium(III) catalysts that bear an amide-pendant cyclopentadienyl ligand ([Cp^AIrI₂]₂) is reported. These [Cp^AIrI₂]₂ catalysts were obtained from the complexation of a Cp^A ligand precursor with [Ir(cod)OAc]₂ followed by oxidation. Double aromatic homologation reactions of benzamides with alkynes by fourfold C?H activation proceeded in good to high yield with these [Cp^AIrI₂]₂ catalysts, demonstrating their superior catalytic performance in this challenging transformation.

Full text of DOI:10.1002/anie.202003009

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Accepted Article
Title: Iridium(III) Catalysts with an Amide-pendant Cyclopentadienyl
Ligand: Double Aromatic Homologation Reactions of Benzamides
via Fourfold C–H Activation
Authors: Eiki Tomita, Kodai Yamada, Yu Shibata, Ken Tanaka,
Masahiro Kojima, Tatsuhiko Yoshino, and Shigeki Matsunaga
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To be cited as: Angew. Chem. Int. Ed. 10.1002/anie.202003009
Angew. Chem. 10.1002/ange.202003009
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10.1002/anie.202003009
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Iridium(III) Catalysts with an Amide-pendant Cyclopentadienyl
Ligand: Double Aromatic Homologation Reactions of Benzamides
via Fourfold C–H Activation.
Eiki Tomita,[a] Kodai Yamada,[a] Yu Shibata,[b] Ken Tanaka,[b] Masahiro Kojima,[a] Tatsuhiko Yoshino,*[a]
and Shigeki Matsunaga*[a]
Dedicated to Professor Shunichi Hashimoto on the occasion of his 70th birthday.
[a]
[b]
E. Tomita, K. Yamada, Dr. M. Kojima, Dr. T. Yoshino, Prof. Dr. S. Matsunaga
Faculty of Pharmaceutical Sciences
Hokkaido University
Kita-ku, Sapporo 060-0812, Japan
E-mail: tyoshino@pharm.hokudai.ac.jp; smatsuna@pharm.hokudai.ac.jp
Dr. Y. Shibata, Prof. Dr. K. Tanaka
Department of Chemical Science and Engineering
Tokyo Institute of Technology
O-okayama, Meguro-ku, Tokyo 152-8550, Japan
Supporting information for this article is given via a link at the end of the document.
Abstract: The synthesis, characterization, and catalytic
performance of iridium(III) catalysts that bear an amide-pendant
cyclopentadienyl ligand ([CpAIrI2]2) is reported. These [CpAIrI2]2
catalysts were obtained from the complexation of a CpA ligand
precursor with [Ir(cod)OAc]2 followed by oxidation. Double
aromatic homologation reactions of benzamides with alkynes
via fourfold C–H activation proceeded in good to high yield by
using [CpAIrI2]2 catalysts, demonstrating their high catalytic
performance for this challenging transformation.
(CpERhIII) catalyst and an amide-pendant cyclopentadienyl
rhodium (CpARhIII) catalyst (Figure 1b), which exhibited high
reactivity in several C–H functionalization reactions.[7,8] Both of
these electron-deficient rhodium(III) catalysts are synthesized by
direct complexation of RhCl3 with the corresponding fulvene
precursors, which in turn can be prepared by rhodium(I)-
catalyzed [2+2+1] cycloaddition reactions.
Despite such progress in the development of electron-
deficient Cp ligands, surprisingly little attention has been
focused on their applications to other group
9
metal
catalysis.[9,10] This dearth could possibly, at least in part, be
attributed to the decreased stability of electron-deficient CpMIII
complexes and the corresponding difficulties associated with
their synthesis. Rovis and co-workers have synthesized several
monoaryl- or diaryl-substituted cyclopentadienyl iridium catalysts
and revealed that a moderately electron-deficient Cp*((CF3)Ar)2IrIII
catalyst (Figure 1c) exhibits improved or unique chemoselectivity,
regioselectivity, and reactivity in olefin functionalization and non-
directed C–H functionalization reactions.[9] These pioneering
studies as well as the success of electron-deficient Cp ligands in
rhodium(III) catalysis suggest that further development of
electron-deficient CpMIII catalysts could lead to a significant
expansion of catalytic C–H functionalization reactions.
Herein, we report the synthesis of moderately electron-
deficient cyclopentadienyl iridium(III) catalysts with a pendant
amide moiety ([CpAIrI2]2) and their high catalytic activity in
aromatic homologation reactions of benzamides and four
alkynes via fourfold C–H activation to provide highly substituted
anthracene derivatives (Scheme 1c: This work).[11-13] A stepwise
synthetic route to the [CpAIrI2]2 catalysts involves the
complexation of [Ir(cod)OAc]2 and CpAH precursors that can be
obtained from the reduction of the corresponding fulvenes.[14]
The fourfold C–H activation/functionalization reactions of
benzamides proceeded in good to excellent yield only when the
[CpAIrI2]2 catalysts were employed.
Group 9 metal complexes with a pentamethylcyclopentadienyl
ligand (Cp*MIII; M = Co, Rh, Ir) have been widely used for
catalytic C–H functionalization reactions and enabled a variety of
atom- and step-economical organic transformations (Figure
1a).[1] While Cp*RhIII catalysts are the most general and
frequently used among the triad, Cp*CoIII and Cp*IrIII often
exhibit reactivity and selectivity that are different from those of
Cp*RhIII and may thus be
a complementary option when
examining unprecedent C–H functionalization reactions.[1d,e] On
the other hand, as electronic and steric effects of ancillary
ligands are also important factors in metal-catalyzed
transformations, several research groups have developed
modified Cp ligands to achieve high and/or unique reactivity and
selectivity.[2-9] Besides steric modifications that forge a steric bias
around the piano-stool structure of CpMIII complexes,[2] including
chiral Cpx ligands for enantioselective reactions,[3] the
introduction of electron-withdrawing groups on the Cp ligands to
render the metal catalysts electron-deficient is the most
successful approach (Figure 1b).[2,4,5,6a,b,7,8] Rovis and co-
workers have developed a series of RhIII catalysts that bear
electronically-tuned Cp ligands and examined their catalytic
properties,[2,5] revealing that Cp*CF3RhIII catalysts exhibit higher
reactivity in [4+2] annulation reactions of oxime derivatives to
provide (dihydro)pyridines via olefinic C–H activation.[5a,b] Some
of the authors of this manuscript (Y.S. and K.T.) have developed
a
bis-(ethoxycarbonyl)-substituted cyclopentadienyl rhodium
1
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Figure 1. Cp*MIII (M = Co, Rh, Ir) catalysts and representative examples of their electron-deficient analogues.
We first investigated the direct complexation of IrCl3 with a
CpA ligand (Scheme S1 in the Supporting Information). The
reductive complexation of fulvene 1a, which effectively afforded
[CpARhCl2]2 catalysts in a previous study,[8a] failed to furnish the
desired iridium(III) complex. We also attempted a standard
synthetic procedure for [CpIrCl2]2 complexes using diene 2a
obtained from the reduction of 1a using NaBH4, which was again
ineffective. Only the CpA precursor (1a or 2a) was recovered
along with some decomposed material in both cases.
In contrast, the mild preparation protocol for CpxRhI and CpxIrI
complexes developed by Cramer and co-workers[14] was
successful, even when using electron-deficient CpA ligands
(Scheme 1). Namely, when the reduced CpA precursor 2a was
treated with [Ir(cod)OAc]2 in toluene and MeOH, the
corresponding iridium(I) complex bearing a cod ligand (3a) was
obtained in 79% yield. The structure of 3a was unambiguously
allowed the preparation of both more electron-rich (5d) and
electron-deficient (5e) catalysts.
With several such [CpAIrI2]2 catalysts with different
functionalities in hand, we turned our attention to their
applications in catalytic C–H functionalization reactions.
Aromatic homologation via sequential C–H activations has been
extensively studied as a powerful strategy to rapidly access
extended aromatic -conjugated organic materials since the
seminal report by Satoh, Miura, and co-workers in 2008.[12a] To
evaluate the potential of the newly developed [CpAIrI2]2 catalysts,
we selected N,N-dimethylbenzamide 6a as the model substrate
and
investigated
its
homologation
reaction
with
diphenylacetylene 7a. Eventually, we found that the reaction of
6a and four equivalents of alkyne 7a using [CpA1IrI2]2 5a/AgSbF6
as the catalyst and Cu(OAc)2 as the terminal oxidant in PhCl
afforded polyphenylated anthracene derivative 8aa in almost
quantitative yield (Table 1, entry 1). The structure of 8aa was
determined by a single-crystal X-ray diffraction analysis (for
details, see the Supporting Information). It is noteworthy that
one-pot double aromatic homologation reactions via fourfold C–
H activation have scarcely been reported to date. Although
Satoh, Sato, Miura, and co-workers, as well as Li and co-
workers have reported this type of reactions using a Cp*RhIII
catalyst, the applicable substrates were limited to those bearing
a strongly coordinating azole-type directing group.[12a,d,e] With
this background in mind, we examined different [CpAIrI2]2
catalysts as well as other CpMIII catalysts under the optimized
reaction conditions (Table 1, entries 2-9). While [CpA3IrI2]2 5c
and [CpA4IrI2]2 5d exhibited similarly high reactivity, [CpA2IrI2]2 5b
and [CpA5IrI2]2 5e afforded lower yields (entries 2-5). We
speculate that the poor reactivity of 5b might be due to its poor
solubility, and the more electron-deficient nature of 5e might
lead to low stability. When a standard [Cp*IrCl2]2 was used as
the catalyst, only a naphthalene derivative 9 was observed in
moderate yield (<50%), indicating the inferior activity of the
[Cp*IrCl2]2 catalyst especially in the second aromatic
homologation (entry 6). On the other hand, Cp*Co(CO)I2 and
[Cp*RhCl2]2 did not afford any aromatic homologation products
(entries 7 and 8) and [CpA1RhCl2]2 resulted in the formation of a
complex mixture (entry 9) probably due to their lower or different
chemoselectivity compared to the [CpAIrI2]2 catalysts. All these
determined by
Subsequently, we examined the oxidation of this intermediate to
form catalytically active iridium(III) species. While the
a single-crystal X-ray diffraction analysis.
a
treatment of 3a with I2 at ambient temperature resulted in a
complex mixture containing a dissociated CpA ligand, lowering
the reaction temperature to –78 °C and using two equivalents of
I2 led to a clean and complete conversion. The 1H NMR
spectrum of the resulting compound, however, indicated the
unexpected presence of a coordinating cod ligand. Based on a
report by Kudinov and co-workers,[15] we speculated that cationic
intermediate 4a was generated under these conditions.
Gratifyingly, intermediate 4a gradually converts in CH2Cl2 into
the desired complex 5a without a cod ligand. The X-ray
diffraction analysis of a single crystal obtained from a solution of
5a in CH2Cl2 confirmed its dimeric structure in the solid state (for
details, see the Supporting Information). On the other hand, the
1H NMR spectrum of 5a in CDCl3 exhibited a 5.6:1 mixture of
two different species. As the addition of DMSO to the solution
resulted in a single DMSO adduct, 5a can be expected to exist
as an equilibrium mixture with different coordination structures in
solution. The established stepwise synthetic protocol was
applied to other CpA precursors, providing several [CpAIrI2]2
catalysts (5b-5e; for details, see the Supporting Information). It
should be noted that a moderately acidic NH moiety did not
interfere with the catalyst synthesis (5b). The protocol also
2
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10.1002/anie.202003009
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Scheme 1. Established synthetic route to and the structures of CpAIrIII catalysts.
6c did not afford the double aromatic homologation product.
Diarylalkynes that bear an electron-withdrawing group exhibited
good reactivity and the corresponding products were obtained in
high yield (8ab-8af). Potentially reactive functional groups for
further derivatization, such as an aryl bromide and ester, were
also compatible (8ad, 8af). The use of DCE as the solvent was
required for 8af due to the poor solubility of the naphthalene
intermediate in PhCl. Although relatively electron-rich alkynes
are somewhat less reactive, the corresponding products were
obtained in moderate to high yield upon increasing the catalyst
loading and changing the solvent to 1,4-dioxane (8ag-8ai).
Disappointingly, neither aliphatic alkynes nor terminal alkynes
afforded the desired homologation products.
Table 1. Aromatic double homologation reactions of benzamide 6a with alkyne
7a via fourfold C–H activation: Optimized conditions and control
experiments.[a]
Entry
Catalyst
% Yield[b]
We envisioned that successive first and second aromatic
homologation reactions using different alkynes could provide
unsymmetrically substituted anthracene derivatives, which would
rapidly expand the easily accessible chemical space (Scheme 4).
After several preliminary examinations, we found that the single
aromatic homologation reaction of benzamide 6a using two
equivalents of alkyne 7a afforded naphthalene 9 in 88% yield in
1
2
3
4
5
6
7
8
9
[CpA1IrI2]2 5a (5 mol %)
[CpA2IrI2]2 5b (5 mol %)
[CpA3IrI2]2 5c (5 mol %)
[CpA4IrI2]2 5d (5 mol %)
[CpA5IrI2]2 5e (5 mol %)
[Cp*IrCl2]2 (5 mol %)
[Cp*RhCl2]2 (5 mol %)
Cp*Co(CO)I2 (10 mol %)
[CpA1RhCl2]2 (5 mol %)
>95
9
>95
>95
65
<5
0
the presence of
1 mol % of catalyst 5a. The second
homologation reactions also smoothly proceeded with both
electron-rich and electron-deficient alkynes to provide densely
and unsymmetrically substituted anthracenes (10a-10e).
As the standard [Cp*IrCl2]2 catalyst promoted the first
homologation step under the conditions in Table 1 to afford
naphthalene 9 in moderate yield, we wondered whether it could
promote the second homologation when isolated 9 was used as
the starting material. When 9 and alkyne 7c were subjected to
the same conditions for the second homologation except for
using the [Cp*IrCl2]2 as the catalyst, only trace amounts of
anthracene 10a were observed. The C–H activation of
naphthalene 9 directed by the amide moiety would cause severe
steric repulsion between the N-Me groups and the peripheral
phenyl group, and thus the second homologation from 9 would
be much more difficult than the first homologation. Thus, the
high reactivity of the [CpAIrI2]2 catalysts would be crucial for the
0
<5
[a] Reaction conditions: 6a (0.025 mmol), 7a (0.113 mmol), [CpA1IrI2]2 5a
(0.00125 mmol), AgSbF6 (0.005 mmol), and Cu(OAc)2 (0.105 mmol) in PhCl
(0.25 mL) at 100 °C for 24 h under an argon atmosphere. [b] Yields were
determined by 1H NMR analysis of the crude mixture using 1,1,2,2-
tetrachloroethane as the internal standard.
results suggest that both the iridium metal center and the CpA
ligand are essential for this challenging double aromatic
homologation reaction.
We next examined the scope of the double aromatic
homologation reactions (Scheme 3). Both acyclic (8aa, 8da) and
cyclic amides (8ea, 8fa) effectively work as the directing groups,
providing the desired anthracene products in 60–96% isolated
yields. While p-fluorobenzamide 6b furnished the desired fully
substituted anthracene (8ba) in 83% yield, p-methoxybenzamide
second step. Moreover,
a
[CpA1RhCl2]2 catalyst afforded
significantly lower yield than 5a together with other byproducts,
which indicates that its selectivity is insufficient. Although we
assume that the higher reactivity of the [CpAIrI2]2 catalysts could
3
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Scheme 4. Successive aromatic homologation reactions for the synthesis of
unsymmetrical anthracenes. [a] DCE was used as the solvent instead of PhCl.
[b] [CpA1IrI2]2 5a (5 mol %) and AgSbF6 (20 mol %) were used.
Acknowledgements
Scheme 3. Scope of double aromatic homologation reactions of benzamides
with alkynes. Reaction conditions: 6 (0.20 mmol), 7 (0.90 mmol), [CpA1IrI2]2 5a
(0.01 mmol), AgSbF6 (0.04 mmol), and Cu(OAc)2 (0.84 mmol) in PhCl (2 mL)
at 100 °C for 24 h under an argon atmosphere. Isolated yields after silica gel
column chromatography are given. [a] DCE was used as the solvent instead of
PhCl. [b] 6 (0.10 mmol), 7 (0.45 mmol), [CpA1IrI2]2 5a (0.01 mmol), AgSbF6
(0.02 mmol), and Cu(OAc)2 (0.42 mmol) in 1,4-dioxane (1 mL) at 100 °C for 24
h under an argon atmosphere.
This work was supported in part by JSPS KAKENHI Grant
Number JP15H05802 in Precisely Designed Catalysts with
Customized Scaffolding, JP18H04637 in Hybrid Catalysis, and
JP19K16306.
Keywords: iridium • cyclopentadienyl ligand • C–H activation •
aromatic homologation • anthracene
possibly be attributed to their higher electrophilicity, further
studies on their properties and reactivity are necessary.
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[13] For notable reactivity and selectivity of Cp*IrIII catalysts, see selected
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10.1002/anie.202003009
Angewandte Chemie International Edition
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Moderately electron-deficient cyclopentadienyl iridium(III) catalysts bearing a pendant-amide group ([CpAIrI2]2) were developed.
These new iridium catalysts efficiently promoted double aromatic homologation reactions of benzamides with alkynes via fourfold C–
H activation, for which standard rhodium, cobalt, and iridium catalysts were ineffective.
Institute and/or researcher Twitter usernames: @yakuzou_hokudai
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