Catalytic C-H imidation of aromatic cores of functional molecules: Ligand-accelerated Cu catalysis and application to materials- and biology-oriented aromatics

Article abstract of DOI:10.1021/ja5130012

Versatile imidation of aromatic C-H bonds was accomplished. In the presence of copper bromide and 6,6′-dimethyl-2,2′-bipyridyl, a range of aromatics, such as polycyclic aromatic hydrocarbons, aromatic bowls, porphyrins, heteroaromatics, and natural produc

Full text of DOI:10.1021/ja5130012

Communication
pubs.acs.org/JACS
Catalytic C−H Imidation of Aromatic Cores of Functional Molecules:
Ligand-Accelerated Cu Catalysis and Application to Materials- and
Biology-Oriented Aromatics
Takahiro Kawakami,† Kei Murakami,† and Kenichiro Itami*,†,‡
†Institute of Transformative Bio-Molecules (WPI-ITbM) and Graduate School of Science, Nagoya University, Chikusa, Nagoya
464-8602, Japan
‡JST, ERATO, Itami Molecular Nanocarbon Project, Nagoya University, Chikusa, Nagoya 464-8602, Japan
S
* Supporting Information
ABSTRACT: Versatile imidation of aromatic C−H bonds
was accomplished. In the presence of copper bromide and
6,6′-dimethyl-2,2′-bipyridyl, a range of aromatics, such as
polycyclic aromatic hydrocarbons, aromatic bowls, por-
phyrins, heteroaromatics, and natural products, can be
imidated by N-fluorobenzenesulfonimide. A dramatic
ligand-accelerated copper catalysis and an interesting
kinetic profile were uncovered.
he introduction of amino groups can have dramatic effects
Ton the properties of aromatic molecules. Amino groups can
tune the optoelectronic properties of aromatic core structures by
changing the highest occupied and lowest unoccupied molecular
orbitals (HOMO/LUMO) and energies, introducing hydrogen-
bonding sites, and adding unique three-dimensionality to
otherwise flat structures. For these reasons, arylamines have
long been privileged structures in materials-oriented1 and
biology-oriented aromatics2 (Figure 1A). For example, arylamine
derivatives are key components in the recently emerging
perovskite-based solar cells1c,d and in live-cell super-resolution
imaging.2c
The development of new amination reactions for arenes has
thus made a significant impact in multidisciplinary fields of
science including materials, biological, and pharmaceutical
science. Conventionally, transition metal-catalyzed aminations
of carbon−halogen bonds in halogenated arenes are largely
regarded as reliable and versatile.3 As an emerging synthetic
Figure 1. (A) Functional molecules having arylamine cores. (B) C−H
imidation of functional aromatics.
route, transition metal-catalyzed aryl C−H aminations4−9 have
become an alternative to conventional amination. However, this
installation of directing groups is inherently difficult, methods to
directly aminate 1 equiv of aromatics through a directing-group-
free route is highly desirable.
Here, we describe a facile and versatile C−H imidation of
arenes with N-fluorobenzenesulfonimide (NFSI) as an imide
source that can be applied to a range of materials- and biology-
oriented aromatics (Figure 1B).7i,10 The combination of copper
bromide (I) and 6,6′-dimethyl-2,2′-bipyridyl (6,6′-Me2bpy)
showed outstanding catalytic activity for the C−H imidation of
a wide variety of substrates such as polycyclic aromatic
approach is still in its infancy and has several disadvantages such
as (1) the necessity for a directing group,5 (2) the requirement
for a large excess of arene,6 and (3) limited substrate scope
especially for 5-membered heterocycles.7 Recently, Ritter
reported a breakthrough in the form of a palladium-catalyzed
aromatic imidation with the arene as the limiting reagent,8a and
in 2014, Baran reported the ferrocene-catalyzed imidation.8b The
substrate scope of these reactions was wide enough to cover
benzene derivatives including bioactive molecules.8a,b Although
arylamine materials are equally important as bioactive molecules,
the synthetic chemistry community has paid less attention to the
development of direct amination methods for the preparation of
aromatic materials.1,9 Since π-aromatics are expensive and the
Received: December 21, 2014
© XXXX American Chemical Society
A
DOI: 10.1021/ja5130012
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Journal of the American Chemical Society
Communication
Figure 2. Scope of aromatic C−H imidation catalyzed by CuBr/6,6′-Me2bpy. (a) Arene (0.20 mmol), NFSI (1.3 equiv), 1,2-dichloroethane (3 mL), 70
°C, 12 h. (b) Fluoranthene (4.0 mmol), NFSI (1.3 equiv), CuBr (5.0 mol %), 6,6′-Me2bpy (6.0 mol %), 1,2-dichloroethane (20 mL), 12 h. (c) ORTEP
drawing. Thermal ellipsoids are drawn at the 50% probability level and hydrogen atoms are omitted for clarity. (d) NFSI (1.05 equiv). (e) Arene (2
mmol), NFSI (0.2 mmol), CuBr (20 mol %), 6,6′-Me2bpy (24 mol %), 1,2-dichloroethane (1 mL), 24 h. (f) Arene (0.20 mmol), NFSI (1.05 equiv), 1,2-
dichloroethane (1 mL), 9 h. (g) 2-Bromothiophene (4.0 mmol), NFSI (1.3 equiv), CuBr (5.0 mol %), 6,6′-Me2bpy (6.0 mol %), 1,2-dichloroethane (10
mL). (h) NFSI (1.3 equiv). (i) NFSI (1.5 equiv), CuBr (10 mol %), 6,6′-Me2bpy (12 mol %), 9 h, then additional CuBr (10 mol %), 6,6′-Me2bpy (12
mol %), 9 h. (j) Porphyrin (0.050 mmol), NFSI (1.3 equiv), CuBr (20 mol %), 6,6′-Me2bpy (24 mol %), 1,2-dichloroethane (2 mL), 12 h. (k) NFSI (2
equiv). (l) 25 °C, 15 h. (m) NFSI (1.05 equiv), CuBr (10 mol %), 6,6′-Me2bpy (12 mol %), 1,2-dichloroethane (1 mL), 8 h, then additional NFSI (1.05
equiv), CuBr (10 mol %), 6,6′-Me2bpy (12 mol %), 16 h.
hydrocarbons (PAHs), aromatic bowls, porphyrins, heteroar-
omatics, and natural products. An interesting mechanistic insight
was gained through kinetic studies on this newly developed C−H
imidation catalysis.
respectively, with virtually complete regioselectivity. The
reaction of 9-bromoanthracene furnished 1d, leaving the
bromo group intact. Benzo[a]anthracene reacted regioselec-
tively at the less hindered position to provide 1e in 55% yield.
Corannulene, a unique bowl-shaped PAH, was also imidated to
afford 1f in reasonable yield. Though not high-yielding, simple
electron-neutral aromatics such as naphthalene and benzene
actually can be imidated under CuBr/6,6′-Me2bpy.
In addition to PAHs, a wide variety of 5-membered
heteroarenes that are ubiquitous in organic materials and
pharmaceutically relevant molecules could be regioselectively
functionalized. Various substituted thiophenes underwent
regioselective C−H imidation at the α-position to afford 2a−g
in high yields with good tolerance of functional groups (halide,
ketone, ester, and silyl groups). The reaction was also scalable,
The scope of the aromatic C−H imidation reaction is shown in
Figure 2. For example, treatment of fluoranthene with 1.3 equiv
of NFSI in the presence of a catalytic amount of CuBr (10 mol %)
and 6,6′-Me2bpy (12 mol %) in 1,2-dichloroethane at 70 °C for
12 h provided the corresponding imidated product 1a in 77%
yield as a single isomer. The structure of 1a was confirmed
unambiguously by X-ray crystallographic analysis. The reaction
was scalable such that 4 mmol of fluoranthene could be efficiently
converted to 1.59 g of 1a in 80% yield with a reduced loading of
CuBr (5 mol %) and 6,6′-Me2bpy (6 mol %). Pyrene and 2,7-
di(tert-butyl)pyrene were cleanly imidated to provide 1b and 1c,
B
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Journal of the American Chemical Society
Communication
and 4 mmol of 2-bromothiphene was smoothly converted to 2a
in 80% yield. 3-Phenylthiophene reacted regioselectively to
provide 2h. Other 5-membered heteroaromatics such as
thieno[3,2-b]thiophene, benzofuran, and oxazole derivatives
were efficiently converted into 2i−l. Nitrogen atoms contained
within heteroaromatic structures were not observed to play a role
as directing groups in the reaction. For example, benzo[h]-
quinolone was transformed to 2m as a mixture of regioisomers.
Electron-rich methoxy-substituted 6-membered arenes were also
viable substrates (2n). Along with PAHs and heteroarenes,
functional aromatic π-materials such as porphyrins could also be
employed as substrates. 5-Bromo-10,20-diarylporphyrin was
selectively imidated at the meso-position to produce 3a in 59%
yield. Although the yield was modest, 5,10,15,20-tetraarylpor-
phyrin also underwent selective imidation. Natural products
including caffeine, citropten, and flavone were smoothly
converted into the corresponding imidated products 4a−c.
During the course of our catalyst development process, we
discovered a significant substituent effect of bipyridyl- and
phenanthroline-based ligands that led to establishment of the
CuBr/6,6′-Me2bpy system for aromatic C−H imidation. Shown
in Figure 3 are the effects of representative ligands in the copper-
formation that not only is counterintuitive but also reflects the
unique role of N-bidentate ligands in the reaction mechanism.
To shed light on the reaction mechanism, we conducted
several kinetic experiments. First, a mixture of 2-phenyl-
thiophene and 2-(4-trifluoromethylphenyl)thiophene with
NFSI was subjected to copper catalysis in order to elucidate
the electronic preference of the reacting arenes (eq 1). Under
competitive conditions (equimolar amounts of the three
reagents), we observed the predominant formation of 2d,
which was generated from the more electron-rich 2-phenyl-
thiophene. Similarly, a competitive reaction between 2-phenyl-
thiophene and 2-acetylthiophene resulted in the exclusive
formation of 2d. Furthermore, sterically congested but more
electron-rich 2-acetyl-4-methylthiophene reacted faster than 2-
acetylthiophene to afford 2g as the predominant product (see the
Supporting Information for details). These results clearly
indicate that, in essence, the present imidation can be described
as a net electrophilic substitution of a nucleophilic arene.
Although the details remain unclear at present, we assume that
NFSI is the first-reacting agent with CuBr/6,6′-Me2bpy in the
productive pathway, generating an electrophilic imidyl radical as
an active species for the reaction.10c The thus-generated imidyl
radical reacts with arene to provide the corresponding product. It
is also possible that an imidyl cation or a metal-aminyl species12 is
an active species.
Two independent deuterium labeling studies for the reactions
of 2-phenylthiophene and 2-deuterio-5-phenylthiophene
showed the intermolecular kinetic isotope effect (KIE) value as
kH/kD = 0.91 (Scheme 1). Although the observation of an inverse
Scheme 1. Independent KIE Experiments
Figure 3. Dramatic ligand effect in Cu-catalyzed C−H imidation.
catalyzed imidation of fluoranthene and 3-phenylthiophene.
While the C−H imidation did not occur with catalytic amounts
of CuBr or CuI7i in the absence of ligands, we discovered a huge
rate-acceleration effect upon addition of ligands where one or
two methyl groups were attached at the 6-position(s) of the 2,2′-
bipyridyl backbone (6-Mebpy and 6,6′-Me2bpy). Interestingly,
methyl substitution at the 4- and 5-positions (4,4′-Me2bpy and
5,5′-Me2bpy) had little effect on the catalytic activity, indicating
that the observed rate-acceleration by 6,6′-Me2bpy is steric in
nature. The ligands having a phenanthroline backbone were
slightly less active than those with a bipyridyl backbone (2,9-
Me2phen vs 6,6′-Me2bpy). Phenanthroline having a bulkier n-
butyl group (2,9-n-Bu2phen) or phenyl group (2,9-Ph2phen)
retarded the reaction. Overall, this represents a unique, steric-
accelerated ligand effect in the copper-catalyzed C−H trans-
KIE value is rare in C−H functionalization chemistry, this
secondary and inverse KIE provides significant information. It
has been known that inverse secondary KIEs can be observed in
some reactions where a C−H (C−D) bond experiences sp2 →
sp3 rehybridization in the rate-determining step such as
electrophilic nitration of benzene and carbonyl addition
reactions.11 Thus, the observed inverse secondary KIE implicates
the addition of the imidyl radical to the arene as the rate-
determining step. Interestingly, the Ritter group recently
reported quite distinct KIE values in their palladium-catalyzed
aromatic C−H imidation.8a It was found that intermolecular and
intramolecular KIE values were 1.03 and 0.8, respectively, which
led them to conclude that irreversible substrate binding occurs
before C−N bond formation and that the rate-determining step
is the oxidation of the palladium catalyst with NFSI.
C
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Journal of the American Chemical Society
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mechanism of our copper-catalyzed C−H imidation as well as the
significance of the ligand effect in copper catalysis. Nevertheless,
with a direct method for activating/converting otherwise difficult
aromatic substrates in hand, we and others are now in a position
to synthesize a range of new functional arylamine materials.13
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ASSOCIATED CONTENT
■
S
* Supporting Information
Detailed experimental procedures and spectral data for all
compounds, including scanned images of H and 13C NMR
1
spectra. This material is available free of charge via the Internet at
http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*itami@chem.nagoya-u.ac.jp
■
Notes
The authors declare no competing financial interest.
(8) Reports on intermolecular C−H amination with 1 equiv of arenes:
(a) Boursalian, G. B.; Ngai, M.-Y.; Hojczyk, K. N.; Ritter, T. J. Am. Chem.
Soc. 2013, 135, 13278. (b) Foo, K.; Sella, E.; Thome, I.; Eastgate, M. D.;
Baran, P. S. J. Am. Chem. Soc. 2014, 136, 5279.
ACKNOWLEDGMENTS
■
This work was supported by the ERATO program from JST
(K.I.) and a Grant-in-Aid from JSPS (26888007 to K.M.). We
thank Dr. Yasutomo Segawa and Mr. Takehisa Maekawa for
assistance with X-ray crystallography, Dr. Keiko Kuwata with
HRMS measurement, and Mr. Kei Muto with KIE experiments.
Mr. Kyohei Ozaki is acknowledged for preparation of the starting
materials. We thank Dr. Ayako Miyazaki and Prof. Cathleen M.
Crudden for critical comments, and Prof. Jay Siegel for the
generous gift of corannulene. ITbM is supported by the World
Premier International Research Center (WPI) Initiative, Japan.
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J.; Glorius, F. Nat. Chem. 2013, 5, 369. (c) Segawa, Y.; Maekawa, T.;
Itami, K. Angew. Chem., Int. Ed. 2015, 54, 66.
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S.-L. RSC Adv. 2014, 4, 6173. (c) Zhang, H.; Song, Y.; Zhao, J.; Zhang, J.;
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