Rhodium(III) and hexabromobenzene - A catalyst system for the cross-dehydrogenative coupling of simple arenes and heterocycles with arenes bearing directing groups

Article abstract of DOI:10.1002/anie.201205734

The biaryl scaffold is of great importance in many fields, such as biologically active molecules and materials. Lately, its synthesis has been greatly facilitated by the advent of crosscoupling reactions. Nevertheless, the development of more step-and ato

Full text of DOI:10.1002/anie.201205734

Angewandte
Chemie
DOI: 10.1002/anie.201205734
À
Double C H Activation
Rhodium(III) and Hexabromobenzene—A Catalyst System for the
Cross-Dehydrogenative Coupling of Simple Arenes and Heterocycles
with Arenes Bearing Directing Groups**
Joanna Wencel-Delord, Corinna Nimphius, Honggen Wang, and Frank Glorius*
The biaryl scaffold is of great importance in many fields, such
as biologically active molecules and materials. Lately, its
synthesis has been greatly facilitated by the advent of cross-
coupling reactions. Nevertheless, the development of more
step-and atom-economic transformations is highly desirable.
The development of direct arylation reactions (coupling of
a preactivated partner with a benzene derivative) was a first
approach to this goal.[1] However, more recently, catalyst
systems that enable the oxidative cross-dehydrogenative
coupling (CDC) of two non-prefunctionalized arenes have
emerged as an attractive alternative.[2] Initial studies in this
challenging field showed that palladium catalysts are partic-
ularly suited for this transformation.[3,4] Furthermore, very
this unique and crucial reactant opens the door for the
application of this modern strategy to the direct functional-
ization of synthetically useful heterocycles. Besides tremen-
dously expanding the scope of this CDC, the use of this
halogenated species allows the amount of the coupling
partner to be decreased (in some cases down to 3 equiv).
In regard to the rapidly growing interest in CDC reactions,
on the one hand, and their potential, highly promising
industrial applications, on the other, the development of
À
general CDCs involving an undirected C H activation of
simple arenes is an important goal. Thus, inspired by our
previous studies, we commenced with an evaluation of
different haloarenes and hypervalent iodine species as
additives/oxidants in the RhIII-catalyzed cross-coupling of
benzamide 1a with toluene.[11] An extensive optimization
study enabled polybrominated benzene derivatives to be
identified as the optimal, hardly toxic, and inexpensive
recently, [RhIIICp*]-catalyzed (Cp* = C5Me5) formations of
[5–8]
À
biaryls through twofold C H activation were developed.
The key to success was the application of aryl halides as the
C H coupling partner.[9] Indeed, these halogenated substrates
À
are believed to not only act as the coupling
partner, but also as the cooxidant and/or
catalyst modifier (Scheme 1).[10] This intriguing
and multiple role of the haloarenes was, how-
ever, a limitation of the catalyst system, since
only halogen-substituted benzene derivatives
could be used successfully. Herein, we report
an unprecedented application of hexabromo-
benzene (C6Br6) as the key additive that enables
a highly chemo- and regioselective dehydrogen-
ative cross-coupling of benzamides with a vari-
Scheme 1. DG=directing group. The newly formed bonds and the H atoms involved in
the coupling are shown in bold.
ety of simple benzene derivatives. Furthermore,
[*] Dr. J. Wencel-Delord,[+] C. Nimphius,[+] Dr. H. Wang,
Prof. Dr. F. Glorius
additives/cooxidants (used together with Cu(OAc)2) required
for the efficient formation of the desired biaryl scaffold.[12]
Notably, the addition of only two equivalents of C6Br6 was
Universitꢀt Mꢁnster, Organisch-Chemisches Institut
Corrensstrasse 40, 48149 Mꢁnster (Germany)
E-mail: glorius@uni-muenster.de
sufficient to achieve full conversion of 1a into the desired
biaryl moiety. Furthermore, the application of an additional
aromatic solvent such as 2-chloro-p-xylene turned out to be
beneficial, thus enabling the use of a smaller excess of the
simple arene coupling partner. In addition, the use of
a cosolvent also ensured a more robust reaction system and
opened up the possibility of using solid, high melting arenes as
coupling partners. Under the optimized conditions, the cross-
coupling reaction of benzamide 1a with benzene led to the
formation of biaryl 3a in 70% yield. The control reactions
carried out in the absence of either a rhodium source or
Cu(OAc)2 showed the catalyst system to be total inactive.
Moreover, only trace amounts of products could be detected
Homepage: http://www.uni-muenster.de/Chemie.oc/glorius/
index.html
[+] These authors contributed equally to this work.
[**] We thank Nadine Kuhl and Prof. Frederic W. Patureau for helpful
discussions, Cornelia Weitkamp for valuable help, and Dr. Klaus
Bergander for special NMR experiments. This work was supported
by the European Research Council under the European Commun-
ity’s Seventh Framework Program (FP7 2007-2013)/ERC Grant
agreement no. 25936, and the Government of North Rhine-West-
phalia in the research network SusChemSys. The research of F.G.
has been supported by the Alfried Krupp Prize for Young University
Teachers of the Alfried Krupp von Bohlen und Halbach Foundation.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201205734.
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when the C6Br6 additive was omitted from
the reaction mixture. In contrast, the
absence of the silver salt led to the
formation of the expected product in
only a slightly lower yield (66% yield).
As a consequence of the high price of
silver, further studies were conducted
under silver-free conditions. Finally, it
was found that the presence of both pivalic
acid (PivOH) and cesium pivalate
(CsOPiv) is not essential, but they do,
however, improve the efficiency of the
Scheme 2. Reaction of benzamides with benzene and naphthalene. General reaction con-
overall transformation (3a was isolated in ditions: benzamide 1 (1.0 mmol, 1.0 equiv), 2 (20.0 mmol, 20 equiv), [{RhCp*Cl2}2]
(0.025 mol, 0.025 equiv), Cu(OAc)2 (2.2 mmol, 2.2 equiv), C6Br6 (2.0 mmol, 2.0 equiv), PivOH
(0.5 mmol, 0.5 equiv), CsOPiv (0.2 mmol, 0.2 equiv), 2-Cl-p-xylene (3 mL) 1408C, 21 h;
isolated yields; [a] 2 mL (22 mmol) of benzene and 0.1 mmol of AgSbF6 were used; [b] at
58 and 62% yield in the absence of pivalic
acid and cesium pivalate, respectively).
Under these optimized conditions, the
1608C; [c] product isolated together with 7% of another isomer (ratio determined by
cross-coupling of an array of synthetically
valuable benzamides with benzene was
examined (Scheme 2, 3a–k). A large range
of substituents at either the meta or para
position of the aromatic ring was well
tolerated. Electron-donating groups such
as Me or OMe in the para position led to
the formation of the desired coupling
product in good yields. Importantly, the
phenyl substituent was also well tolerated
on the aromatic ring of the benzamide,
with the additional sp2 carbon atoms not
perturbing the selectivity of the overall
transformation—the expected biaryl 3e
was obtained as a single regioisomer. The
arylation of the benzamides bearing
strongly electron-withdrawing CF3 groups
was slightly more sluggish, and an
increased reaction temperature (1608C)
was required to achieve full conversion.
Importantly, when brominated or chlori-
nated benzamides were submitted to the
standard reaction conditions, the expected
biaryl compounds 3h–j could be isolated
in synthetically useful yields, and no deha-
logenated products were detected. The
application of the benzamide bearing
a second potential directing group such
as an ester substituent led to the selective
coupling reaction in the ortho position
with respect to the amide moiety (3k).
Extending the substrate range from the
phenyl to the naphthyl system was also
tolerated, and the naphthyl-benzene biaryl
3l could be generated selectively as one
isomer in 55% yield. When the benzene
coupling partner was replaced by a naph-
thyl moiety, the desired product 3m was
1H NMR).
Scheme 3. CDC of benzamide 1a with a range of benzene derivatives. General reaction
conditions: see Scheme 2; isolated yields; [a] 0.5 mmol scale, 1 mL of toluene was used;
[b] at 1608C; [c] at 1508C; [d] reaction carried out on a 0.5 mmol scale; [e] product isolated
1
together with 10% of another isomer (ratio determined by H NMR); [f] product isolated
1
together with 7% of another isomer (ratio determined by H NMR).
formed in good selectivity (isolated product contains 7% of
another isomer).
Encouraged by the good tolerance of our catalyst system
towards different functional groups, the scope of simple
benzene derivatives as coupling partners was evaluated
(Scheme 3). Unsurprisingly, the standard benzamide 1a
underwent the CDC smoothly in the presence of monosub-
stituted benzene derivatives and led to the formation of the
expected biaryl products (4a–4e) in satisfying yields but,
independent of the nature of substituents, as mixtures of meta
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and para products. However, the application of o- and m-
xylene as the coupling partner enabled the regioselective
formation of biaryl products 4 f and 4g, respectively.[13] In
contrast, when 3-fluorotoluene was used as the coupling
partner, the formation of a second, minor isomer could be
detected (4h and 4h’ were isolated in a 5.0:1 ratio), probably
arising from the lower steric hindrance of the ortho position
because of the fluoro substituent. The complete selectivity
was reinstalled when 3-bromo- and 3-chlorotoluene were
used. Importantly, even the iodo substituent was tolerated on
the arene coupling partner.[14] Unlike the majority of palla-
dium-catalyzed CDC transformations, the application of the
less electron-rich toluene derivatives was also possible: the
coupling of 3-(trifluoromethyl)toluene was efficient at a reac-
tion temperature of 1408C. Notably, the toluene derivative
Scheme 5. Application of the RhIII-catalyzed direct arylation for the
synthesis of 8, key intermediate of Bixafen. 7% of the diarylated
product was isolated.
À
bearing an ester group underwent a nonchelate-assisted C H
activation that led to the meta-selective coupling reaction
with 1. Intriguingly, the coupling reaction of benzamide 1 with
3-bromoanisole was sluggish, and the expected product 4n
was formed in moderate yield. However, good reactivity
could be reinstalled by introducing two chloro substituents in
the 2- and 6-positions of anisole (4r was isolated in 71%).
This observation would suggest that the coordination ability
of the OMe group is, at least partially, responsible for the
lower activity of anisole derivatives. Similarly, 2,6-substituted
nitrobenzene and cyanobenzene derivatives smoothly under-
went the arylation reaction.
makes the direct transformations of this class of compounds
of prime importance. Despite considerable effort in this field
over the past few years, these reactions remain rare. In
particular, highly efficient and selective methods for the
direct arylation of heterocycles are still an enormous chal-
lenge.[2e] Up to now, palladium has been the most generally
À
used metal for the direct C H activation of heterocycles,
while the potential of RhIII catalysts for this transformation
was highlighted only recently.[15] To our delight, the coupling
between 1 and benzothiophene turned out to be highly
efficient and selective even if only five equivalents of the
heterocycle were used. The corresponding product 10a could
be isolated in 79% yield as a single isomer (Scheme 6). The
crucial role of the C6Br6 additive was also confirmed for this
transformation: only traces of the desired product could be
detected in the absence of this cooxidant. Benzofuran also
turned out to be a suitable coupling partner; however, a larger
amount (10 equiv) was required for the isolation of 10b in
a satisfying yield of 66%. Furthermore, this catalyst system
could be applied to selectively and efficiently install an
aromatic ring at the 2-position of a series of 2- and 3-
substituted thiophenes, challenging substrates for CDC. In
To our delight, the efficiency of this catalytic system was
also conserved when the amide directing group was replaced
by a ketone. Indeed, the carbonyl substrate 5 underwent the
Scheme 4. CDC of ketone 5 with benzene.
monoarylation reaction smoothly to give the
expected, biphenyl ketone 6 in a synthetically useful
yield (Scheme 4).
The undeniable potential of this strategy could be
further illustrated by its application in the synthesis of
biaryl 8—the key intermediate of the fungizid mol-
ecule Bixafen. Under non-optimized conditions, this
highly valuable product could be prepared in one step
from commercially available and inexpensive 4-
fluoroacetanilide
7
and
1,2-dichlorobenzene
(Scheme 5). Even though the efficiency of this trans-
formation is still limited, it shows clearly the potential
of this reaction for the atom- and step-economic
À
industrial applications of the twofold C H activation.
Scheme 6. CDC of benzamide 1a with heterocycles. General reaction conditions:
see Scheme 2; yield of isolated product; [a] 5 mmol of heteroarene were used;
[b] 10 mmol of heteroarene were used; [c] 3 mmol of heteroarene were used;
[d] product isolated together with 5–7% of another isomer (ratio determined by
We then turned our attention to using hetero-
cycles as the coupling partners for this CDC reaction.
Indeed, the presence of heterocycles in pharmaceut-
ical, biologically active compounds and materials 1H NMR); [e] 30 h reaction time.
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this case, a further decrease in the
amount of the heterocyclic coupling
partner was possible (down to
3 equiv). Notably, bromo and chloro
substituents on the thiophene ring were
well tolerated, and led to the formation
of 10c, 10d, and 10g—highly valuable
building blocks for further functionali-
zation. Finally, an electron-deficient
furan was also efficiently coupled with
1 (10h).
To gain some mechanistic insight,
a series of deuteration experiments was
conducted. Significant kinetic isotope
effects (KIEs) were measured for both
coupling partners, thus indicating that
the reaction proceeds by a true twofold
[16,17]
À
C H activation mechanism.
Fur-
thermore, a comparison of the initial
rates of the reactions (using standard
and deuterated coupling partners) sug-
gests the involvement of the nonche-
À
Figure 1. Impact of C6Br6 on the rate of C H bond activation.
À
late-assisted C H activation in the rate-
determining step.[17]
Additionally, a few competition experiments were carried
out to gain more information about the influence of the
electronic properties of each coupling partner on the overall
reaction.[17] Firstly, treatment of 1:1 mixtures of differently
substituted benzamides with benzene clearly showed that this
CDC is enhanced for electron-rich benzamides. In contrast,
the role of both reagents is not limited to the reoxidation of
the rhodium catalyst after the reductive elimination of the
product. Furthermore, the activity of the catalyst system was
totally shut down by the replacement of Cu(OAc)2 by CuBr2,
thus indicating that CuBr2 is not the active species.
À
Finally, the impact of the presence of C6Br6 on the C H
À
the electronic influence on the nondirected C H activation
activation was investigated (Figure 1). A series of reactions
using D2O as the D source in the absence of any substrate 2
showed that H/D scrambling on the benzamide was slightly
enhanced in the presence of C6Br6 (Figure 1, conditions A
versus conditions B). Interestingly, when using [D10]-p-
xylene[13] as a coupling partner and the only D source, we
observed D transfer from [D10]-p-xylene to 1, which indicates
step is much less pronounced. When m-xylene and the
electron-poor 3-(trifluoromethyl)toluene were submitted to
the reaction conditions concomitantly (as substrate 2), both
expected products were formed in almost equal amounts. This
À
result suggests that neither an Ar H deprotonation pathway
nor a SEAr mechanism is plausible for this step. The
observation of a significant KIE for this coupling partner
led to the postulation of a s-bond metathesis-type mecha-
nism.[18] Further competition experiments using 3-bromoto-
luene as another competing partner resulted in a twofold
increase in the reaction rate for this halogenated arene. While
the reason for this difference is still unclear, the influence of
À
that the C H activation of [D10]-p-xylene occurred but no
reductive elimination took place. However, the rate of the
À
undirected C H bond activation was significantly decreased
when this polybrominated reagent was omitted (Figure 1,
conditions C versus conditions D). These observations could
be interpreted as indirect proof of the key role of C6Br6 in the
À
À
the weak nonbonding C Br···p interactions between this
“activation” of the rhodium catalyst for the undirected C H
activation.
haloarene and the catalyst and/or benzamide cannot be
excluded.[19]
In conclusion, a new RhIII-catalyzed dehydrogenative
cross-coupling reaction of a large range of simple benzene
derivatives bearing arenes with directing groups is described.
The key feature of this catalyst system is the application of
Cu(OAc)2 together with C6Br6 as a complex catalyst modifier.
Notably, the discovery of this latter, less common additive
opens the door to expand this CDC transformation to regio-
and chemoselective arene–heteroarene cross-coupling reac-
tions. Moreover, the application of the heteroaromatic
reagents enables the amount of the coupling partner to be
decreased down to three equivalents, thus rendering this
transformation synthetically useful.
Furthermore, it should be mentioned that product for-
mation was always associated with the formation of C6HBr5
derived from the protodehalogenation of C6Br6, which
indicates the role of C6Br6 as an oxidant. Additional
mechanistic investigations were performed to further eluci-
date the roles of C6Br6 and Cu(OAc)2.[17] Firstly, a series of
stoichiometric reactions (utilizing only 5 mol% of 1a)
showed that omission of either C6Br6 or Cu(OAc)2 led to
a significant decrease in the reaction efficiency (yield of 36
and 21%, respectively, compared to 78% yield for the
stoichiometric reaction under otherwise identical reaction
conditions) and no reaction was observed in the absence of
both the Cu salt and C6Br6. These observations suggest that
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[6] RhIII-catalyzed intramolecular aryl – aryl coupling involving
Received: July 18, 2012
Revised: September 29, 2012
Published online: October 19, 2012
À
twofold C H activation: K. Morimoto, M. Itoh, K. Hirano, T.
Satoh, Y. Shibata, K. Tanaka, M. Miura, Angew. Chem. 2012,
124, 5455 – 5458; Angew. Chem. Int. Ed. 2012, 51, 5359 – 5362.
À
[7] For selected reviews on Rh-catalyzed C H activation, see
À
À
Keywords: biaryls · C C coupling · C H activation ·
cross-coupling · dehydrogenation
.
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À
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[11] For details see the Supporting Information.
[12] For comparison, the prices of several commonly used oxidants
À
for C H bond activation are: inorganic reagents: Na2S2O8 5.2 E/
mol; Cu(OAc)2·H2O 12.2 E/mol; Ag2CO3 573 E/mol; organic
reagents: C6Br6 84.6 E/mol; tBuOOH 212 E/mol (0.5–0.6m
solution in decane); PhI(OAc)2 385 E/mol; C6H2Br4 529.5 E/
mol; NFSI 955.3 E/mol.
[13] No reaction was observed when a 1,4-disubstituted benzene
derivative (p-xylene) was used, probably because of the steric
hindrance.
[4] For seminal reports on Pd-catalyzed CDCs involving heteroar-
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[5] J. Wencel-Delord, C. Nimphius, F. W. Patureau, F. Glorius,
Angew. Chem. 2012, 124, 2290 – 2294; Angew. Chem. Int. Ed.
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Chem. Asian J. 2012, 7, 1208 – 1212.
[14] The application of the benzamide bearing an iodo substituent in
the para position led to the formation of a mixture of the desired
product and a bromo-substituted biaryl product, the formation
of which probably occurs through a Finkelstein type reaction.
[15] For a recent report concerning RhIII-catalyzed C H activation of
À
indoles, see a) D. J. Schipper, M. Hutchinson, K. Fagnou, J. Am.
Chem. Soc. 2010, 132, 6910 – 6911; b) B. Zhou, Y. Yang, Y. Li,
Chem. Commun. 2012, 48, 5163 – 5165; for a recent report
concerning RhIII-catalyzed cross-coupling of heterocycles, see N.
Kuhl, M. N. Hopkinson, F. Glorius, Angew. Chem. 2012, 124,
8354 – 8358; Angew. Chem. Int. Ed. 2012, 51, 8230 – 8234.
[16] The deuteration experiments and their interpretation were
inspired by the recent work of Hartwig and Simmons: E. M.
Simmons, J. F. Hartwig, Angew. Chem. 2012, 124, 3120 – 3126;
Angew. Chem. Int. Ed. 2012, 51, 3066 – 3072.
[17] For details of this study see the Supporting Information.
[18] K. L. Hull, M. S. Sanford, J. Am. Chem. Soc. 2009, 131, 9651 –
9653.
[19] For a selected review on halogen bonding, see P. Metrangolo, H.
Neukirch, T. Pilati, G. Resnati, Acc. Chem. Res. 2005, 38, 386 –
395.
Angew. Chem. Int. Ed. 2012, 51, 13001 –13005
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www.angewandte.org 13005