Undirected arene and chelate-assisted olefin C-H bond activation: [Rh IIICp*]-catalyzed dehydrogenative alkene-arene coupling as a new pathway for the selective synthesis of highly substituted Z olefins

Article abstract of DOI:10.1002/asia.201101018

Undirected/Directed Cross-Coupling: A new dehydrogenative Rh ^III-catalyzed cross-coupling reaction between bromoarenes bearing no directing group and vinylic substrates substituted by a chelating group is reported. An original reaction mechanism enables the use of internal alkenes in a Z-selective coupling. The application of 1,3-disubstituted or 1,2-homodisubstituted arenes leads to the formation of highly functionalized, complex, and valuable olefins as one single isomer. Copyright

Full text of DOI:10.1002/asia.201101018

DOI: 10.1002/asia.201101018
Undirected Arene and Chelate-Assisted Olefin C-H Bond Activation:
[RhIIICp*]-Catalyzed Dehydrogenative Alkene–Arene Coupling as a New
Pathway for the Selective Synthesis of Highly Substituted Z Olefins
Joanna Wencel-Delord,[a] Corinna Nimphius,[a] Frederic W. Patureau,[b] and
Frank Glorius*[a]
In the 21st century, the direct formation of carbon–carbon
bonds from carbon–hydrogen bonds, traditionally consid-
ered as inert moieties, has emerged as a challenging but
highly valuable synthetic tool.[1,2] In the context of green
coupling partners. In the presence of an alkene coupling
partner, however, either alkylation[6a,b,d,e,7a,b] or diene-
type[7i,8a,b,e,h,i,j] products are generally formed. Recently, cat-
ionic RhIII complexes turned out to be good catalysts for the
À
À
and sustainable chemistry, the direct functionalization of C
vinylic C H bond functionalization, thus enabling an effi-
H bonds obviates the need of prefunctionalized coupling
partners, limiting therefore steps and waste production. The
oxidative olefination reaction, pioneered by Fujiwara and
Moritani in 1969 and rediscovered at the beginning of this
century,[3] is among the best studied transformations using
cient synthesis of linear 1,3-butadienes and di-unsaturated
a-amino acid derivatives.[7i] However, in the quest for new
and valuable synthetic methods, the application of directed
À
C H bond activation of vinylic substrates, as key intermedi-
ates of new cross-coupling reactions leading to the forma-
tion of valuable, highly substituted olefins, remains still an
important challenge. Herein, we report an original dehydro-
genative cross-coupling reaction between alkenes bearing
a directing group and arenes without a chelating group; this
reaction constitutes a novel synthetic method for the effi-
cient and Z-selective[10] synthesis of arene-substituted olefins
(Figure 1).
À
direct C H bond functionalization. Very recently, thanks to
the contributions by Satoh and Miura, Bergman and
Ellman, Glorius and others, Rh-catalysts were found to be
particularly suitable for this transformation, leading to the
development of very efficient (low catalyst loading) catalytic
systems that are highly tolerant to functional groups and
active in the coupling of electron-neutral olefins.[4] This
strategy suffers, however, from important limitations such as
exclusive generation of E olefins and the general need of
Guided by our recent discovery of the particular reactivity
of arylhalides for nonchelate-assisted C H bond activa-
À
tion[5h] and the aptitude of the cationic RhIII species to cata-
lyze dehydrogenative cross-coupling reactions of arenes,[11]
we envisioned to use this strategy for the direct coupling of
vinylic substrates bearing a directing group with bromoar-
enes. N,N-Diisopropylmethacrylamide and bromobenzene
were selected as standard coupling partners.[12] We were de-
lighted to find out that in the presence of an electrophilic
Rh-species (generated in situ from [RhCp*Cl2]2 and
AgSbF6), a stoichiometric amount of pivalic acid, a catalytic
amount of cesium pivalate as an additive, and an excess of
À
chelate assistance for the C H bond activation of the arene
coupling partner.[5]
À
While directed C H bond activation of arenes is well
known, the efficient directed C H bond activation on vinyl-
À
ic substrates is more challenging, probably due to the in-
creased reactivity and versatility of olefins. Over the last
decade several reports concerning the direct functionaliza-
tion of olefins using Ru,[6] Rh,[7] Pd[8], or Ir[9] catalysts have
been published. Indeed, this strategy revealed itself as a con-
venient synthetic pathway for the preparation of pyridine[7j,e]
and 2-pyridone[6f,7h] derivatives, while alkynes were used as
[a] Dr. J. Wencel-Delord, C. Nimphius, Prof. Dr. F. Glorius
Organisch-Chemisches Institut
der Westfꢀlischen Wilhelms-Universitꢀt Mꢁnster
Corrensstrasse 40, 48149 Mꢁnster (Germany)
Fax : (+49)251-83-33202
E-mail: glorius@uni-muenster.de
[b] Prof. Dr. F. W. Patureau
Fachbereich Chemie-Organische Chemie
Technische Universitꢀt Kaiserslautern
Erwin-Schrçdinger-Straße, Geb. 52
67633 Kaiserslautern (Germany)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/asia.201101018.
Figure 1. Oxidative olefination strategies
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COMMUNICATION
copper acetate, the desired coupling product was formed
and could be isolated in 65% yield as a mixture of meta and
para regioisomers of the olefinated bromobenzene deriva-
tive. Remarkably, this coupling reaction occurred with com-
plete Z selectivity. This stereoselectivity is highly valuable
because of its potential synthetic applications. Moreover, it
proves the crucial role of the directing group in this coupling
process. Control reactions showed that omission of either
the Rh precatalyst or the copper salt resulted in total inac-
tivity of this catalytic system.
Encouraged by this result, we evaluated the potential of
this transformation for the synthesis of different tri- and tet-
rasubstituted olefins. 1,2-Disubstituted vinylic substrates
bearing either a methyl or a phenyl group in trans-position
(1b and 1c) could also undergo the cross-coupling reaction
with bromobenzene (Scheme 1, 3b and 3c). As expected, in
pensated by replacing the pivalic acid with 2,4,6-triisopro-
pylbenzoic acid (41% isolated yield). Thus, the potential of
this new strategy for the formation of highly substituted al-
kenes, which are generally difficult to access, could be
proven.
Moreover, in the course of our endeavor towards the de-
velopment of efficient and selective dehydrogenative cross-
coupling reactions, we continued our study using 1,3-disub-
stituted bromobenzene derivatives or 1,2-dibromobenzene
as coupling partners. Indeed, our previous research[11]
showed that steric hindrance at 1,3-disubstituted arenes pre-
À
vents C H bond activation at the ortho position, and there-
À
fore only one out of four aromatic C H bonds is available
for the coupling reaction. Consequently, the coupling reac-
tion of 1a with different 1,3-disubstituted arenes occurred
smoothly (however, an increased reaction temperature of
1608C was required), giving access to only one isomer of the
desired product (Scheme 2). First, we turned our attention
to dihalogen-substituted arenes as coupling partner. 1-
Bromo-3-chlorobenzene and 1,3-dibromobenzene turned
out to be suitable coupling partners, leading to the forma-
tion of 4b and 4c in moderate yields (60 and 58% respec-
tively). By contrast, the steric hindrance of the fluoro-sub-
stituent in 1-bromo-3-fluorobenzene was insufficient, and
therefore the coupling product was obtained as a mixture of
two isomers (4a/4aꢀ, 3.8:1). The highly electron-poor arene
1-bromo-3-trifluoromethylbenzene gave a comparable reac-
tivity in this coupling reaction. By contrast, the application
of a more electron-rich coupling partner, 3-bromotoluene,
Scheme 1. Cross-coupling of di- and trisubstituted vinylic amides with
bromobenzene. General conditions: vinylic amide (1 mmol), bromoben-
zene (5 mL), [{RhCp*Cl2}2] (2.5 mol%), AgSbF6 (10 mol%), CuACTHNUTRGNEN(UG OAc)2
(2.2 mmol), PivOH (1.1 mmol), CsOPiv (0.2 mmol), 21 h. [a] Reaction
run at 1408C. [b] Reaction run at 1608C. [c] PivOH was replaced by
2,4,6-triisopropylbenzoic acid.
both cases the desired products were obtained, as meta/para
mixtures of Z-trisubstituted olefins. However, the introduc-
tion of the substituent in b position resulted in a significant
decrease in the efficiency of this transformation. These
somewhat lower yields are probably due to the degradation
of the starting material under the reaction conditions; no
starting material could be recovered at the end of the reac-
tion.[13] Impressively, even when the sterically congested
1,1ꢃ,2-trisubstituted vinylic amides 1d and 1e were submit-
ted to the reaction conditions, the desired tetrasubstituted
olefins 3d and 3e could be formed. When substrate 1d bear-
ing a methyl substituent in both a and b position was ap-
plied, the corresponding arylated olefin 3d was isolated in
comparable yield (49%). A somewhat lower isolated yield
(37%) was observed when the cinnamic acid derivate 1e
was used as substrate. This decrease could be slightly com-
Scheme 2. Cross-coupling of di- and trisubstituted vinylic benzamides
with 1,3-disubstituted bromoarenes and 1,2-dibromobenzene. General
conditions: see Scheme 1. [a] Reaction run at 1608C. [b] Reaction run at
1408C. [c] Reaction run on a 5 mmol scale. [d] Reaction run on a 3 mmol
scale. [e] PivOH was replaced by 2,4,6-triisopropylbenzoic acid.
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Frank Glorius et al.
resulted in a significant decrease in the reaction efficiency.
Finally, 1,2-dibromobenzene was selected as substrate and
the expected trisubstituted olefin was obtained in compara-
ble yield. The vinylic amide substrates bearing no substitu-
ent in the a position have also proven to be adequate sub-
strates. Compound 1b coupled with 1-bromo-3-chloroben-
zene and 1,2-dibromobenzene gave 4g and 4h, respectively,
in 47 and 49% yield. The cinnamic acid derivative 1c
turned out to be a slightly less good substrate, and the de-
sired Z olefins were obtained in lower yields (4i=27% and
4j=35%). Very similar results have also been obtained
when trisubstituted alkenes 1d and 1e were employed as
substrates; three tetrasubstituted olefins 4k, 4l, and 4m
were generated.
Scheme 4. Isomerization test.
21 hours, 4c was recovered unchanged in 87% yield. Nei-
ther isomerization of the double bond nor significant H/D
scrambling between the olefinic proton and the solvent were
observed. These results suggest that in the case of the
amide-directing group, vinylic C H bond activation can
occur exclusively in the Z position with regard to the direct-
ing group. This observation is consistent with the hypothesis
of chelate-assisted vinylic C H bond activation and occur-
rence of this step before arene C H activation.
À
To further establish the power of this methodology, the
compatibility of this cross-coupling reaction with vinylic sub-
strates bearing an ester-directing group was examined
(Scheme 3). Surprisingly, when butyl methacrylate (5a) was
À
À
To obtain some further mechanistic information, we sub-
sequently examined the influence of the electronic proper-
ties of the bromoarenes on the efficiency of this cross-cou-
pling reaction. We have therefore performed a competition
experiment between 3-bromotoluene and 1-bromo-3-tri-
fluoromethylbenzene, in which amide 1a was used as the
coupling partner (Scheme 5). The reaction, run under other-
Scheme 3. Dehydrogenative cross-coupling of vinylic esters and bromoar-
enes. General conditions: see Scheme 1. [a] Reaction run at 1408C.
[b] Reaction run at 1608C.
submitted under optimized reaction conditions, the GC–MS
profile of the crude reaction mixture suggested the forma-
tion of two isomers of arylated product along with an signifi-
cant quantity of diarylated alkene. To obviate this problem
of double vinylic C-H activation, the corresponding b-substi-
tuted acrylate 5b was synthesized. The cross-coupling reac-
tion of this substrate with bromobenzene led to the forma-
tion of the desired tetrasubstituted olefin 6a in 40% isolated
yield. The coupling product was exclusively obtained as Z
isomer, though as a mixture of meta and para regioisomers
(with regard to the bromine substituent on the aromatic
ring). This regioselectivity issue could be tackled by the judi-
cious choice of 1,3-disubstituted arenes as coupling partners.
Scheme 5. Competition experiment.
wise standard conditions, led to the formation of the two ex-
pected products, 4d and 4e. After purification, the NMR
analysis allowed to determine the ratio between the two
products as 3.6:1 in favor of the electron-deficient arene 4d.
This result shows clearly that this dehydrogenative cross-
coupling is faster for electron-poor arenes. This observation
is of crucial importance because it highlights the difference
between our catalytic system and others, with Pd-catalyzed
cross-dehydrogenative coupling (CDC) being generally com-
patible with electron-rich aromatic rings. Moreover, this ob-
servation suggests that our transformation occurs via a real
À
Indeed, C C bond formation between the methacrylate de-
rivative 5b and 1-bromo-3-trifluoromethylbenzene or 1-
bromo-3-chlorobenzene permitted to synthesize selectively
the corresponding olefin (6b and 6c), albeit with low yield
(45 and 46% isolated yield).
À
C H bond activation event and that the electrophilic substi-
tution pathway (often proposed in case of the Pd-catalyzed
CDC) is highly improbable in our case.
The surprising diarylation reactivity of 5a prompted us to
investigate the Z-selectivity observed in the case of the
amide-directing group. The arylated, trisubstituted olefin 4c
was therefore submitted to the reaction conditions, using
pentadeuterated bromobenzene (Scheme 4). However, after
Finally, to probe the synthetic value of this new dehydro-
genative cross-coupling, further transformations of the gen-
erated aryl-olefins were investigated. At first, the dibromi-
nated product 4c was submitted to a bromine/lithium ex-
change reaction, followed by an electrophilic trapping with
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Undirected Arene and Chelate-Assisted Olefin C-H Bond Activation
COMMUNICATION
water.[14] This sequence led to the formation of the valuable
meta-substituted (Z)-3-(3-bromophenyl)-N,N-diisopropyl-2-
methylacrylamide 7 in 49% yield under nonoptimized con-
ditions (Scheme 6).[15] The additional value of this method is
Experimental Section
General procedure: To a flame-dried screw-capped test tube equipped
with a magnetic stir bar were added [RhCp*Cl2]2 (15.5 mg, 0.025 mmol),
AgSbF6 (34.4 mg, 0.1 mmol), CuACHTUNTRGNENUG(OAc)2 (400 mg, 2.2 mmol), PivOH
(112.3 mg, 1.1 mmol), CsOPiv (46.8 mg, 0.2 mmol), and the vinylic amide
1 (1.0 mmol) under argon atmosphere. Subsequently, the bromo-arene
(5.0 mL) was added. The reaction mixture was stirred at the indicated
temperature for 21 h. The mixture was then cooled down to room tem-
perature, diluted with EtOAc (20 mL), and filtered through a pad of
silica gel using EtOAc (250 mL) as eluent. Evaporation of the solvent fol-
lowed by purification by flash chromatography (toluene/EtOAc; for de-
tails, see the Supporting Information) afforded the corresponding product
3.
Acknowledgements
We thank Nadine Kuhl for helpful discussions and Dr. Klaus Bergander
for assistance with some&&ok?&& NMR experiments. This work was
supported by the European Research Council under the European Com-
munityꢃs Seventh Framework Program (FP7 2007–2013)/ERC Grant
agreement number 25936 and by the Alexander von Humboldt Founda-
tion (F.W.P.). 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.
Scheme 6. Potential synthetic applications of generated aryl-amides 4b
and 4c. Reaction conditions for the Br/Li exchange: 4c (0.5 mmol),
tBuLi (1.6m solution in pentane, 0.55 mmol), THF (10 mL), À788C, 1 h,
then H2O (0.5 mL). Reaction conditions for the Suzuki coupling: 4b
(2 mmol), PhB(OH)2 (2.4 mmol), PdACTHNUGTRNEUNG(OAc)2 (3 mol%), PPh3 (30 mol%),
2m solution of Na2CO3 (4 mL), ethanol (4 mL), toluene (4 mL), 1008C,
overnight. Reaction conditions for the Buchwald–Hartwig Amination: 8
(1.1 mmol), PhNH2 (1.32 mmol), NaOtBu (1.32 mmol), PdACHTNUTRGNEUNG(OAc)2
À
Keywords: arenes · alkene–aryl bond formation · C H
activation · cross-coupling · rhodium
(3 mol%), XPhos (9 mol%), dioxane (1.5 mL), H2O (2 mol%).
À
[1] For a review on recent applications of the C H bond activation
a possible trapping of the lithiated intermediate with other
types of electrophiles, thus enabling a selective introduction
of different functional groups in meta position. Furthermore,
4b bearing a bromo- and a chloro-substituent on the aryl
ring was used as a substrate for sequential Suzuki and Buch-
wald–Hartwig couplings. The introduction of a second aryl
ring could be achieved using phenylboronic acid and a stan-
dard Pd-catalyst.[16] The desired product 8 was isolated in
68% yield. The subsequent amination reaction, catalyzed by
a Pd/X-Phos catalytic system[17] proceeded smoothly, leading
to the formation of the highly functionalized trisubstituted
olefin 9 in 67% yield.[18]
In conclusion, we have developed a new dehydrogenative
RhIII-catalyzed cross-coupling reaction between bromoar-
enes without chelate assisting-directing group and vinylic
substrates bearing a directing group. While the “traditional
oxidative olefination” concerns the E-selective coupling of
terminal olefins[19] and arenes,[4,5] an original reaction path-
way of this new transformation enables the use of the inter-
nal alkenes in a Z-selective coupling, leading to the forma-
tion of tri- and tetrasubstituted olefins. Therefore, even
though this new method is still limited by moderate yields,
the obtained selectivity, the generated molecular complexity,
the potential opportunities for further modifications (as
shown in this paper), and the value of the products render it
attractive for modern organic chemistry.
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À
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À
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[5] The presence of the directing group helps to tackle two important
À
difficulties of the C H bond activation: the initial chelation between
À
a metal and a heteroatom ensures the proximity between the metal
[9] For selected example of Ir-catalyzed vinylic C H bond activation,
À
and the C H bond being activated and permits to control the regio-
see: H. He, W.-B. Liu, L.-X. Dai, S.-L. You, J. Am. Chem. Soc. 2009,
131, 8346.
À
selectivity of the C H bond activation event. The nonchelate-assist-
À
ed C H bond activation is therefore difficult to achieve and the con-
trol of the selectivity may be very challenging. For selected, recent
[10] In this article Z selectivity corresponds to the formation of highly
À
substituted olefins, in which C C bond formation between vinylic
À
examples of nonchelate-assisted C H bond activation, see: a) X.
and aromatic carbons occurs cis to the directing group.
[11] J. Wencel-Delord, C. Nimphius, F. W. Patureau, F. Glorius, Angew.
Chem. 2012, 124, 2290; Angew. Chem. Int. Ed. 2012, 51, 2247.
[12] The modification of the directing group had also an important
impact on the efficiency of this transformation; when methacryla-
mide was used as substrate, the formation of the desired product
was not observed and the application of the N-butyl methacrylamide
led to the formation of corresponding arylated product in poor
yield.
[13] GC–MS analysis of crude reaction mixtures indicated the total con-
version of the starting material for all experiments, and no impor-
tant side reaction was detected. The low yields are therefore proba-
bly due to the polymerization of the vinylic substrates under the re-
action conditions (see ref. [7i]).
[14] Experimental procedure inspired from: a) Q. Perron, A. Alexakis,
Adv. Synth. Catal. 2010, 352, 2611; b) L. Bonnafoux, F. R. Leroux, F.
Colobert, Beilstein J. Org. Chem. 2011, 7, 1278.
[15] In the crude reaction mixture, the presence of another isomer is pos-
sible. After purification, 7 was obtained as a single isomer.
[16] S. Bertini, A. De Cupertinis, C. Granchi, B. Bargagli, T. Tuccinardi,
A. Martinelli, M. Macchia, J. R. Gunther, K. E. Carlson, J. A. Katze-
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À
[6] For selected examples of Ru-catalyzed vinylic C H bond activation,
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À
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[18] The desired product was isolated together with 19% of the E
isomer.
[19] For an interesting example of intermolecular C-H olefination using
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1674 and ref. [4k].
Received: December 15, 2011
Published online: && &&, 0000
Chem. Asian J. 2012, 00, 0 – 0
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemasianj.org
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COMMUNICATION
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C H Activation
Joanna Wencel-Delord,
Corinna Nimphius,
Frederic W. Patureau,
Frank Glorius*
&&&& — &&&&
Undirected Arene and Chelate-
Assisted Olefin C-H Bond Activation:
[RhIIICp*]-Catalyzed Dehydrogenative
Alkene–Arene Coupling as a New
Pathway for the Selective Synthesis of
Highly Substituted Z Olefins
Undirected/Directed Cross-Coupling:
A new dehydrogenative RhIII-catalyzed
cross-coupling reaction between bro-
moarenes bearing no directing group
and vinylic substrates substituted by
a chelating group is reported. An origi-
nal reaction mechanism enables the
use of internal alkenes in a Z-selective
coupling. The application of 1,3-disub-
stituted or 1,2-homodisubstituted
arenes leads to the formation of highly
functionalized, complex, and valuable
olefins as one single isomer.
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www.chemasianj.org
ꢂ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Chem. Asian J. 0000, 00, 0 – 0
ÝÝ These are not the final page numbers!