Rh catalyzed c-h activation and oxidative olefination without chelate assistance: On the reactivity of bromoarenes

Article abstract of DOI:10.1021/ol202557w

A Rh catalyzed, no-chelate-assisted C-H activation/oxidative olefination reaction of bromoarenes has been discovered, in which the latter ones seem to act as a substrate, terminal oxidant, and catalyst modifier.

Full text of DOI:10.1021/ol202557w

ORGANIC
LETTERS
2011
Vol. 13, No. 24
6346–6349
Rh Catalyzed CÀH Activation and
Oxidative Olefination without Chelate
Assistance: On the Reactivity of
Bromoarenes
Frederic W. Patureau,‡ Corinna Nimphius,† and Frank Glorius*,†
€
€
€
Organisch-Chemisches Institut der Westfalischen Wilhelms-Universitat Munster,
Corrensstrasse 40, 48149 Mu€nster, Germany, and Fachbereich Chemie, Technische
€
Universitat Kaiserslautern, Erwin-Schrodinger-Strasse Geb. 52, 67663 Kaiserslautern,
€
Germany
glorius@uni-muenster.de
Received September 21, 2011
ABSTRACT
A Rh catalyzed, no-chelate-assisted CÀH activation/oxidative olefination reaction of bromoarenes has been discovered, in which the latter ones
seem to act as a substrate, terminal oxidant, and catalyst modifier.
Since its first introduction in 1969 by Fujiwara and
Moritani,1 the Pd catalyzed CÀH oxidative olefination
of arenes has received little attention comparedto the more
established MizorokiÀHeck reaction.2 However in the
past decade or so, the field of CÀH activation mediated
cross-coupling chemistry has considerably expanded.3
These reactions are highly useful because they obviate
the else wise required preactivation steps, leading to gen-
erally cheaper and greener synthetic methods. Mostly Pd,4
Ru,5 and lately Rh6 are found to be efficient catalysts in
these CÀH activation processes. However, the use of a
proximal chelate-assisting directing group is almost always
required for activity and selectivity, a serious limitation of
their synthetic utility. In this respect, the topography of the
substrate is crucial, as the proximal directing group must
possess the proper bonding strength and alignment toward
the targeted CÀH bond.
†
€
€
Organisch-Chemisches Institut der Westfalischen Wilhelms-Universitat
M€unster.
‡ The presented research was carried out at the WWU M€unster; current
address of F.P.: TU Kaiserslautern.
(1) (a) Fujiwara, Y.; Moritani, I.; Danno, S.; Asano, R.; Teranishi, S.
J. Am. Chem. Soc. 1969, 91, 7166. For other selected references, see: (b)
Jia, C.; Piao, D.; Oyamada, J.; Lu, W.; Kitamura, T.; Fujiwara, Y.
Science 2000, 287, 1992. (c) Jia, C.; Kitamura, T.; Fujiwara, Y. Acc.
Chem. Res. 2001, 34, 633.
We and others have recently found that a number of
functional/directing groups were efficient for the Rh cata-
lyzed oxidativeorthoolefination reaction, including phenyl-
pyrazoles,6b acetanilides,6d benzamides, and phenones.6e
€
(2) For recent reviews on the MizorokiÀHeck reaction: (a) Brase, S.;
de Meijere, A. In Metal-Catalyzed Cross-Coupling Reactions; de Meijere,
A., Diederich, F., Eds.; Wiley-VCH: New York, 2004; p 217. (b) Nicolaou,
K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442.
r
10.1021/ol202557w
Published on Web 11/23/2011
2011 American Chemical Society

In contrast, only a few no-chelate assisted cases exist,
and these are limited to activated CÀH positions of some
specific heterocyclic structures.7
Scheme 1. Oxidative Olefination of Bromoarenesa
The pioneering work of Fujiwara (eq 1),1 Milstein
(eq 2),8 and others9 offer promising leads for these
challenges, although so far they are typically limited
to electron-rich arenes and usually activated acrylate
derivatives. Herein we wish to report the particular
reactivity of bromoarenes for the no-chelate assisted
CÀH activation and oxidative olefination with styrenes
(eq 3 and Scheme 1).
(3) For recent reviews on CÀH activation, see: (a) Wencel-Delord, J.;
€
Droge, T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (b)
Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (c) Satoh, T.;
Miura, M. Chem.;Eur. J. 2010, 16, 11212. (d) Lyons, T. W.; Sanford,
M. S. Chem. Rev. 2010, 110, 1147. (e) Colby, D. A.; Bergman, R. G.;
Ellman, J. A. Chem. Rev. 2010, 110, 624. (f) Xu, L.-M.; Yang, Z.; Shi, Z.-
J. Chem. Soc. Rev. 2010, 39, 712. (g) Sun, C.-L.; Li, B.-J.; Shi, Z.-J. Chem.
Commun. 2010, 46, 677. (h) Li, C.-J. Acc. Chem. Res. 2009, 42, 335. (i)
Ackermann, L.; Vicente, R.; Kapdi, A. R. Angew. Chem., Int. Ed. 2009,
48, 9792. (j) Chen, X.; Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2009, 48, 5094. (k) Giri, R.; Shi, B.-F.; Engle, K. M.;
Maugel, N.; Yu, J.-Q. Chem. Soc. Rev. 2009, 38, 3242. (l) Li, B.-J.; Yang,
S.-D.; Shi, Z.-J. Synlett 2008, 949. (m) Kakiuchi, F.; Kochi, T. Synthesis
2008, 3013. (n) Satoh, T.; Miura, M. Top. Organomet. Chem. 2008, 24,
61. (o) Alberico, D.; Scott, M. E.; Lautens, M. Chem. Rev. 2007, 107, 174.
(4) For selected (chelate assisted) Pd catalyzed examples, see: (a) Cai,
G.; Fu, Y.; Li, Y.; Wan, X.; Shi, Z. J. Am. Chem. Soc. 2007, 129, 7666. (b)
Cho, S. H.; Hwang, S. J.; Chang, S. J. Am. Chem. Soc. 2008, 130, 9254.
(c) Garcia-Rubia, A.; Arrayas, R. G.; Carretero, J. C. Angew. Chem.,
Int. Ed. 2009, 48, 6511. (d) Zhang, H.; Ferreira, E. M.; Stoltz, B. M.
€
Angew. Chem., Int. Ed. 2004, 43, 6144. (e) Wurtz, S.; Rakshit, S.;
€
Neumann, J. J.; Droge, T.; Glorius, F. Angew. Chem., Int. Ed. 2008,
47, 7230. (f) Boele, M. D. K.; van Strijdonck, G. P. F.; de Vries, A. H. M.;
Kamer, P. C. J.; de Vries, J. G.; van Leeuwen, P. W. N. M. J. Am. Chem.
Soc. 2002, 124, 1586. See also: (g) Li, J.-J.; Mei, T.-S.; Yu, J.-Q. Angew.
Chem., Int. Ed. 2008, 47, 6452. (h) Wang, D.-H.; Engle, K. M.; Shi, B.-F.;
Yu, J.-Q. Science 2010, 327, 315. (i) Shi, B.-F.; Zhang, Y.-H.; Lam, J. K.;
Wang, D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 460. (j) Nishikata,
T.; Lipshutz, B. H. Org. Lett. 2010, 12, 1972. (k) Engle, K. M.; Wang, D.-H.;
Yu, J.-Q. Angew. Chem., Int. Ed. 2010, 49, 6169. (l) Engle, K. M.; Wang,
D.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 14137. (m) Lu, Y.; Wang,
D.-H.; Engle, K. M.; Yu, J.-Q. J. Am. Chem. Soc. 2010, 132, 5916. (n)
Garcia-Rubia, A.; Fernandez-Ibanez, M. A.; Arrayas, R. G.; Carretero,
J. C. Chem.;Eur. J. 2011, 17, 3567. (o) Dai, H.-X.; Stepan, A. F.;
Plummer, M. S.; Zhang, Y.-H.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 7222.
(5) Arguably, there are very few oxidative examples based on Ru
catalysts; see for example: (a) Ueyama, T.; Mochida, S.; Fukutani, T.;
Hirano, K.; Satoh, T.; Miura, M. Org. Lett. 2011, 13, 706. (b) Ackermann,
L.; Pospech, J. Org. Lett. 2011, 13, 4153. (c) Kwon, K.-H.; Lee, D. W.; Yi,
C. S. Organometallics 2010, 29, 5748. (d) Padala, K.; Jeganmohan, M. Org.
Lett.2011,13, 10.1021/ol202580e. (e) Hashimoto, Y.; Ueyama, T.; Fukutani,
T.; Hirano, K.; Satoh, T.; Miura, M. Chem. Lett. 2011, 40, 1165. However, a
number of interesting (chelate assisted) CÀH activation processes that couple
arenes with olefins exist. For selected examples, see: (f) Murai, S.; Kakiuchi,
F.; Sekine, S.; Tanaka, Y.; Kamatani, A.; Sonoda, M.; Chatani, N. Nature
1993, 366, 529. (g) Martinez, R.; Chevalier, R.; Darses, S.; Genet, J.-P.
Angew. Chem., Int. Ed. 2006, 45, 8232. (h) Simon, M.-O.; Genet, J.-P.;
Darses, S. Org. Lett. 2010, 12, 3038. (i) Watson, A. J. A.; Maxwell, A. C.;
Williams, J. M. J. Org. Lett. 2010, 12, 3856.
(6) For selected (chelate assisted) Rh catalyzed examples, see: (a)
Lenges, C. P.; Brookhart, M. J. Am. Chem. Soc. 1999, 121, 6616. (b)
Umeda, N.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2009, 74,
7094. (c) Ueura, K.; Satoh, T.; Miura, M. Org. Lett. 2007, 9, 1407. (d)
Patureau, F. W.; Glorius, F. J. Am. Chem. Soc. 2010, 132, 9982. (e)
Patureau, F. W.; Besset, T.; Glorius, F. Angew. Chem., Int. Ed. 2011, 50,
1064. (f) Rakshit, S.; Grohmann, C.; Besset, T.; Glorius, F. J. Am. Chem.
Soc. 2011, 133, 2350. (g) Tsai, A. S.; Brasse, M.; Bergman, R. G.; Ellman,
J. A. Org. Lett. 2011, 13, 540. (h) Wang, F.; Song, G.; Du, Z.; Li, X. J.
Org. Chem. 2011, 76, 2926. (i) Gong, T.-J.; Xiao, B.; Liu, Z.-J.; Wan, J.;
Xu, J.; Luo, D.-F.; Fu, Y.; Liu, L. Org. Lett. 2011, 13, 3235. (j) Mochida,
S.; Hirano, K.; Satoh, T.; Miura, M. J. Org. Chem. 2011, 76, 3024. (k)
Park, S. H.; Kim, J. Y.; Chang, S. Org. Lett. 2011, 13, 2372. (l) Chen, J.;
Song, G.; Pan, C.-L.; Li, X. Org. Lett. 2010, 12, 5426. (m) Wang, F.;
Song, G.; Li, X. Org. Lett. 2010, 12, 5430. (n) Willwacher, J.; Rakshit, S.;
Glorius, F. Org. Biomol. Chem. 2011, 9, 4736. (o) Besset, T.; Kuhl, N.;
Patureau, F. W.; Glorius, F. Chem.ÀEur. J. 2011, 17, 7167.
a Isolated yields, run on a 1 mmol scale; the bromoarene (5 mL) is
engaged neat. ε < 5%. λ: not determined. Ortho-regioisomers typically
account for less than 1%; in the cases of 3i and 7j,k, they account for less
than 5%. bReaction time: 48 h. cIn the case of 7l, at least six of the seven
possible regioisomers were found. d55% isolated yield, which is a
mixture of 0.29 mmol of 3o/4o and 0.26 mmol of 5o.
While originally investigating the prospective potential
of Rh catalysts for the C(sp3)ÀH bond activation of some
pivalic derivatives, we were surprised to discover that the
(7) For no-chelate assisted CÀH oxidative olefination of some
specific heterocyclic structures, see for example: (a) Grimster, N. P.;
Gauntlett, C.; Godfrey, C. R. A.; Gaunt, M. J. Angew. Chem., Int. Ed.
2005, 44, 3125. For reviews, see: (b) Beck, E. M.; Gaunt, M. J. Top. Curr.
Chem. 2010, 292, 85. (c) Seregin, I. V.; Gevorgyan, V. Chem. Soc. Rev.
2007, 36, 1173 and references cited therein.
Org. Lett., Vol. 13, No. 24, 2011
6347

lower reactivity and conversion.12 Intriguingly, the reac-
tion displays a very long and arguably unusual incubation
time, presumably linked to the formation of the “true”
active species (Figure 1). The fact that only halogenated
arenes are suitable substrates (reactivity: F < Cl , Br),
tends to indicate that cleavage of the halideÀcarbon bond
may be important. To probe this hypothesis, a 1:1 mixture
of bromobenzene and toluene was engaged in the reaction
with 4-tBu-styrene, leading to low conversion of the
expected olefinated bromoarene as well as olefinated
toluene, approximately in a 1:1 ratio.13 This clearly indi-
cates that the intrinsic halogenated character of the sub-
strate is essential for catalyst reactivity. We propose that
the excess amount of bromoarene serves as a terminal
oxidant by CÀBr bond cleavage.14 In order to probe the
postulated reversibility of the CÀH activation event, an
H/D scrambling experiment was carried out by engaging
bromobenzene and bromobenzene-d5 (1:1) under identical
reaction conditions, but without the olefin coupling part-
ner (eq 4). Considering the large excess of bromobenzene
(used as solvent), the detection of low levels of H/D
scrambling is difficult. The small amounts of H/D
scrambled products observed were within the margin of
error10 (linked to the initial isotopic purity and distribution
of the commercial starting materials), at least indicating
that the CÀH activation/back reaction sequence is not
rapidly entertained. In addition, a strong H/D kinetic
isotope effect (KIE: kH/kD = 3.4, eq 5) was observed,
leaving little doubt that the CÀH activation event is also
the rate-limiting step of the catalytic cycle.15À17 The initial
TOF (measured between 9 and 12 h, Figure 1) amounts to
∼1.3 hÀ1, a very modest rate compared to chelate assisted
CÀH activation.18 On the basis of these experiments, we
propose that the CÀH activation is the result of a “random
collision” between the active Rh species and the most
accessible CÀH positions, followed by classical olefin
insertion and β-hydride elimination. We propose that the
Figure 1. Formation of 3b/4b as a function of time. The 9 and 12
h yields were determined by 1H NMR integration; the later ones
were isolated.
CÀH activation and subsequent oxidative olefination of
bromobenzene (5 mL, 48 mmol) with styrene (1 mmol) is
possible at 140 °C, using Cp*Rh(SbF6)2 as the catalyst,
Cu(OAc)2, and pivalic acid. Bromostilbene 3a/4a was
obtained in 66% yield as a 2:1 meta/para mixture
(Scheme 1).10 Interestingly, the ortho bromostilbene is
almostnotdetected(<1%),10 while debrominatedstilbene
and linear 1,4-diene (5 and 6, respectively) are inseparable
side products, albeit usually in small quantities (Scheme 1).
Omission of pivalic acid leads to low conversion and
omission of Cu(OAc)2 shuts down the reactivity, demon-
strating the importance of these two components.11 Chlor-
obenzene affords only traces of the desired product, and
fluorobenzene does not react at all (neither does toluene).
Iodobenzene showed good reactivity, but unacceptably
large amounts of deiodinated product was typically ob-
served in the mixture (3o/4o/5o, Scheme 1). In general, the
regioisomeric ratios obtained are found “quasi-statistical”;
that is all (nonsterically shielded) CÀH positions have an
almost equal chance of reacting. In other words bromo-
benzene tends to afford a 2:1 meta/para mixture of pro-
ducts, 1,2-disubstituted bromoarenes tend toward 1:1
meta/para mixtures (1,2,4 and 1,2,5), and 1,3-disubstituted
arenes tend toward the single meta regioisomer (1,3,5),
although this steric effect typically comes at the cost of
(13) We are very interested in this reactivity transfer phenomenon,
but our initial attempts in this direction remain unsatisfactory. For
instance, engaging a 1:1 mixture of 1,3,5-bromoxylene (sterically
shielded oxidant) and toluene (as the C-H activation substrate) with
4-tBu-styrene only led to traces of products (isomeric mixture of (tBu-
styryl)-toluene), even with an extended 48 h reaction time.
(14) The usage of bromobenzene as reoxidant in Rh catalysis was
previously postulated; for example see: (a) Barrett, A. G. M.; Itoh, T.;
Wallace, E. M. Tetrahedron Lett. 1993, 34, 2233. See also: (b) Bouffard,
J.; Itami, K. Top. Curr. Chem. 2010, 292, 231.
(15) It is interesting to note that a detectable H/D scrambling did
occur in the products of the experiment of eq 5. In particular, the D3-
product represents 7% of the total amount of 3p/4p (expected as a D4-
product), probably due to PivOH being an important proton source; see
experimental details in the Supporting Information.
(16) During the preparation of this manuscript, an insightful report
appeared describing the Pd catalyzed arylation on monosubstituted
arenes: (a) Wang, X.; Leow, D.; Yu, J.-Q. J. Am. Chem. Soc. 2011,
133, 13864. In comparison with our work, their transformation is more
regioselective (up to 99% para selectivity), but their kinetic isotopic data
tend to indicate an electrophilic attack mechanism (kH/kD = 1). An early
work describing the carbonylation of arenes by Rh CÀH activation
reports a more related kH/kD = 3; see: (b) Grushin, V. V.; Marshall,
W. J.; Thorn, D. L. Adv. Synth. Catal. 2001, 343, 161.
(17) The reaction tolerates 1 equiv of TEMPO (2,2,6,6-tetramethyl-
piperidinooxy), although the conversion is then typically lower.
(18) In the Rh catalyzed oxidative olefination of acetanilides with
nBu-acrylate, a kinetic measurement situated the initial average TOF at
around 1080 hÀ1; see ref 6d.
(8) Weissman, H.; Song, X.; Milstein, D. J. Am. Chem. Soc. 2001,
123, 337.
(9) For other pioneering examples of no-chelate assisted CÀH oxi-
dative olefinations, see: (a) Matsumoto, T.; Yoshida, H. Chem. Lett.
2000, 1064. (b) Dams, M.; De Vos, D. E.; Celen, S.; Jacobs, P. A. Angew.
Chem., Int. Ed. 2003, 42, 3512. (c) Yokota, T.; Tani, M.; Sakaguchi, S.;
Ishii, Y. J. Am. Chem. Soc. 2003, 125, 1476. (d) Tani, M.; Sakaguchi, S.;
Ishii, Y. J. Org. Chem. 2004, 69, 1221. (e) Yamada, T.; Sakakura, A.;
Sakaguchi, S.; Obora, Y.; Ishii, Y. New J. Chem. 2008, 32, 738. (f) Zhang,
Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009, 131, 5072. (g) Ye,
M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 6964. (h)
Hickman, A. J.; Sanford, M. S. ACS Catal. 2011, 1, 170.
(10) See experimental details in the Supporting Information.
(11) Using only a catalytic loading of Cu(OAc)2, e.g., 20 mol%, is not
sufficient to effect reactivity (no conversion).
(12) 1,4-Disubstituted bromoarenes (like 4-bromotoluene), do not
react at all. 1,3-Dibromobenzene, 1,3-bromo-chlorobenzene, and 1,3-
bromo-fluorobenzene afford only low to very low conversions; 1,2-
dibromobenzene or 2-bromoanisole do not react at all. Activated
olefins, such as n-butylacrylate and styrenes that are functionalized with
polar substitutents (4-MeO-, 4-tBuO-), do not lead to any product
formation, maybe due to rapid olefin decay.
6348
Org. Lett., Vol. 13, No. 24, 2011

catalyst modifier). This sheds light on new Rh catalyzed
CÀH activation processes and will serve as the basis for
future investigations.
Scheme 2. Proposed Mechanism
Acknowledgment. We thank Dr. Joanna Wencel-Delord
€
reoxidation through CÀBr bond cleavage is responsible
for the formation of the active Rh intermediate, possibly
containing a bromide ligand, although the reason why this
might be important remains unclear. The very slow activa-
tion of the Cp*Rh(AgSbF6)2 precatalyst toward the active
species is not clear either. The traces of Ar-OPiv usually
found in the crude mixtures may be connected with this
event (Scheme 2).
In conclusion, we have discovered a unique type of
Rh-catalyzed CÀH activation reactivity, which does not
require a chelate-assisting directing group. We have de-
monstrated that bromoarenes are an essential component
ofthisreactivity(weassume asbotha terminaloxidant and
(WWU Munster) for discussions. The Alexander von
Humboldt Foundation (F.P.), and the Deutsche For-
schungsgemeinschaft are gratefully acknowledged for
financial support. The research of F.G. was supported by
the Alfried Krupp Prize for Young University Teachers of
the Alfried Krupp von Bohlen und Halbach Foundation.
This work was supported by the European Research
Council under the European Community’s Seventh Frame-
work Program / ERC Grant agreement no. 259368.
Supporting Information Available. Experimental and
characterization details. This material is available free of
charge via the Internet at http://pubs.acs.org.
Org. Lett., Vol. 13, No. 24, 2011
6349