Rhodium(II)-catalyzed nondirected oxidative alkenylation of arenes: Arene loading at one equivalent

Article abstract of DOI:10.1002/anie.201310539

A bimetallic Rh^II catalyst promoted the C-H alkenylation of simple arenes at 1.0 equivalent without the use of a directing group. A phosphine ligand as well as cooperative reoxidation of Rh^II with Cu(TFA)₂ and V₂O₅ proved essential in providing monoalkenylated products in good yields and selectivities, especially with di- and trisubstituted arenes. Down to one: A C-H alkenylation of simple arenes without the need for an excess amount of the arene was possible with a bimetallic Rh^II catalyst (see scheme). A phosphine ligand as well as a combination of the oxidants Cu(TFA)₂ and V₂O₅ proved essential for the efficient synthesis of monoalkenylated products with good selectivity, especially for di- and trisubstituted arene substrates.

Full text of DOI:10.1002/anie.201310539

Angewandte
Chemie
DOI: 10.1002/anie.201310539
À
C H Functionalization
Rhodium(II)-Catalyzed Nondirected Oxidative Alkenylation of
Arenes: Arene Loading at One Equivalent**
Harit U. Vora, Anthony P. Silvestri, Casper J. Engelin, and Jin-Quan Yu*
Abstract: A bimetallic RhII catalyst promoted the C H
alkenylation of simple arenes at 1.0 equivalent without the
use of a directing group. A phosphine ligand as well as
cooperative reoxidation of RhII with Cu(TFA)2 and V2O5
proved essential in providing monoalkenylated products in
good yields and selectivities, especially with di- and trisubsti-
tuted arenes.
yield.[8c] Additionally, Glorius and co-workers were able to
À
effect the alkenylation of bromobenzene under RhIII cata-
lysis.[8d] Although these studies showcase the ability of a wide
range of metals to perform arene alkenylation, nondirected
À
C H functionalization reactions are still plagued by the need
for very high arene loadings and a lack of selectivity in the
metalation step (Scheme 2). We therefore directed our efforts
À
T
he functionalization of C H bonds holds great potential for
the late-stage diversification of complex molecules.[1]
A
common strategy relies on the use of directing groups to
overcome issues of selectivity and reactivity inherent to the
[2]
À
targeting of C H bonds. Typically, these directing groups
may be existing functionality; alternatively, they may be
installed and then removed postfunctionalization.[3] In the
absence of directing groups,[4] the functionalization of C H
À
bonds becomes considerably more challenging, as the require-
ment for high arene loadings and a lack of selectivity in the
metallation step manifest themselves (Scheme 1).
Scheme 1. Challenges associated with nondirected functionalization.
Scheme 2. Relevant examples of nondirected alkenylation.[8] Cp*=pen-
tamethylcyclopentadienyl, Cy=cyclohexyl, DCE=1,2-dichloroethane,
EWG=electron-withdrawing group, Piv=pivaloyl.
The oxidative coupling between arenes and activated
alkenes, as described by Fujiwara et al.,[5a] has been the
standard against which catalytic systems with Pd,[5] Rh,[6] and
Ru[7,8a] have been measured. Our research group has shown
that electron-deficient arenes are suitable substrates for this
process with palladium and a 2,6-dialkyl-substituted pyridine
ligand under aerobic conditions.[8b] Similarly, Sanford and co-
workers have shown that crotonic acid ester derivatives
participate readily to afford b-disubstituted acrylates in good
toward the development of highly reactive catalysts that can
À
activate C H bonds when one equivalent of the arene is used,
and investigated novel bimetallic RhII catalytic systems that
would tolerate lower substrate loadings.
Our interest in a Rh salt was predicated on the work of
Grushin et al., who reported that an electrophilic Rh(TFA)3
salt was a viable catalyst for the selective carboxylation of
arenes with CO.[9] Subsequent investigations into the mech-
anism of this reaction revealed that the electrophilic catalyst
is highly susceptible to a disproportionation event that
renders the catalyst inactive. We hypothesized that a bimet-
allic RhII catalyst might provide an entrance point to an active
RhIII species through oxidation.[10] Cotton et al. also reported
that RhII has an affinity for h2 arene coordination, which could
be beneficial in increasing effective molarity and promoting
selectivity.[11] Moreover, the use of a bimetallic RhII catalyst in
[*] Dr. H. U. Vora, A. P. Silvestri, C. J. Engelin, Prof. Dr. J.-Q. Yu
Department of Chemistry, The Scripps Research Institute (TSRI)
10550 North Torrey Pines Road, La Jolla, CA 92037 (USA)
E-mail: yu200@scripps.edu
Homepage: http://www.scripps.edu/chem/yu
[**] We gratefully acknowledge The Scripps Research Institute and the
US NSF (CHE-1011898) for financial support. C.J.E. gratefully
acknowledges the Technical University of Denmark, Knud Høj-
gaards Fond, Oticon Foundation, and Otto Monsteds Fond for
financial support.
À
C H bond functionalization was shown previously by Chang
and co-workers, who demonstrated the arylation of quinoli-
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310539.
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ne[12a] and benzo[h]quinoline.[12b] We thus sought to develop
a nondirected alkenylation of simple arenes with a bimetallic
RhII complex.
[Rh2(oct)4] provided 3 in 68% yield (entry 9). The use of
[Rh2(tfa)4] (tfa = trifluoroacetate) yielded 3 in 14% yield
(Table 1, entry 10). Importantly, the use of either RhI or RhIII
catalysts resulted in negligible product yields (Table 1,
entries 11–14). In the absence of tricyclohexyl phosphine or
in the presence of its oxide, 3 was obtained in less than 10%
yield (Table 1, entries 15 and 16). These results highlight one
reason why rigorous exclusion of oxygen is necessary. In the
presence of PPh3 or P(o-tolyl)3, 3 was obtained in 58% yield
(Table 1, entries 17 and 18). Similarly, the use of more
electron deficient P(C6F5)3 provided 3 in only 15% yield
(Table 1, entry 19). Arene-derived phosphines were not
pursued further, as they are susceptible to competitive
alkenylation.
We found that the use of toluene (1; 1 equiv) as the model
substrate with n-butyl acrylate (2; 1.0 equiv), [Rh2(OAc)4]
(5.0 mol%), PCy3 (5.0 mol%), Cu(TFA)2 (1.0 equiv), and
V2O5 (1.0 equiv) provided the desired product 3 in 74% yield
with 1:1 selectivity for the meta and para isomers (Table 1,
entry 1). The use of V2O5 is crucial for this reaction. Other
solvents gave significantly lower yields. An increase in the
arene loading to 10 equivalents led to the formation of the
product in 84% yield (Table 1, entry 2).
Table 1: Deviation from standard reaction conditions.
Next, we looked at the effect of the oxidants and the
pivotal role they play. In the absence of Cu(TFA)2 or when
Cu(TFA)2 was replaced with Cu(OAc)2, the desired product 3
was obtained in low yield (Table 1, entries 20 and 21). When
the alkenylation was carried out without vanadium oxide,
a negligible amount of product 3 was generated (Table 1,
entry 22). The important role of vanadium oxide in this
transformation is attributed to its ability to oxidize low-valent
rhodium and copper salts generated during the course of the
reaction.[14] Interestingly, during the optimization of this
reaction, we observed that the use of 10 equivalents of
bromobenzene in the absence of V2O5 yielded the cinnamate
5 in 61% yield (Scheme 3). As the oxidative addition of aryl
halides with RhII and RhIII salts is thought to be difficult,[15] we
Entry
Deviation from standard
reaction conditions
T
[8C]
Yield
[%][a]
Selectivity
(o/m/p)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
none
PhMe (10 equiv)
3 ꢀ mol. sieves
temperature
no [Rh2(OAc)4]
140
140
140
130
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
140
74
84
55
45
NR
58
<5
<5
68
14
<5
14
<5
<5
<5
<10
58
58
15
15
<5
<5
0:1:1
0:1:1
0:1:1
0:1:1
NA
0:1:1
NA
NA
0:1:1
0:1:1
NA
0:1:1
NA
[Rh2(OAc)4] (2.5 mol%)
[Rh2(cap)4] (5.0 mol%)
[Rh2(esp)2] (5.0 mol%)
[Rh2(oct)4] (5.0 mol%)
[Rh2(tfa)4] (5.0 mol%)
[{Rh(cod)Cl}2] (5.0 mol%)
[HRh(PPh3)3CO] (5.0 mol%)
[(RhCp*Cl2)2] (5.0 mol%)
Rh(TFA)3 (5.0 mol%)
no PCy3
OPCy3 (5.0 mol%)
PPh3 (5.0 mol%)
P(o-tolyl)3 (5.0 mol%)
P(C6F5)3 (5.0 mol%)
no Cu(TFA)2
NA
NA
Scheme 3. Importance of vanadium oxide.
0:1:1
0:1:1
0:1:1
0:1:1
0:1:1
NA
attribute the formation of 5 to a rhodium-catalyzed sequential
À
C H olefination and copper(I)-mediated proteo-debromina-
tion process. Presumably, the CuI generated can oxidatively
insert into the aryl bromide and subsequently undergo
protonolysis in the presence of exogenous TFA. We hypothe-
size that V2O5 plays a role in the oxidation of CuI to CuII, thus
inhibiting proteo-dehalogenation.[16]
Cu(OAc)2
no V2O5
NA
[a] The yield was determined by NMR spectroscopy with 1,3,5-trimeth-
oxybenzene as an internal standard. cap=caprolactamate, cod=1,5-
cyclooctadiene, esp=a,a,a’,a’-tetramethyl-1,3-benzenedipropionate,
oct=n-octyl, NA=not applicable, NR=no reaction.
Having identified a set of optimized reaction conditions,
we began our investigations into the scope of the reaction
with respect to the Michael acceptor. After trying a variety of
coupling partners, including vinyl phosphonates, acrylo-
nitriles, substituted acrylates, crotonates, and vinyl ketones,
we found that only simple acrylates were competent sub-
strates.[17] When 1.0 equivalent of benzene was subjected to
the reaction with 2, 5 was obtained in 62% yield (Scheme 4).
The use of cumene provided 6 in 78% yield and a 1:2 ratio of
meta and para isomers. Halogenated arenes suffered from
suppressed reactivity, and much lower yields were observed.
We presume this lower reactivity to be a consequence of
decreased arene electron density: less h2 coordination and
more Lewis basic coordination to the metal. Indeed, when
bromobenzene and fluorobenzene were subjected to the
We next focused our attention on the importance of
molecular sieves in the reaction. Substitution of 3 ꢀ for 5 ꢀ
molecular sieves led to a decrease in the yield to 55% with no
change in selectivity (Table 1, entry 3).[13] A change in the
temperature from 140 to 1308C provided 3 in 45% yield
(Table 1, entry 4). In the absence of RhII, no product was
obtained (Table 1, entry 5), whereas a reduction in the
amount of [Rh2(OAc)4] from 5 to 2.5 mol% provided 3 in
58% yield (entry 6). Moreover, the use of the alternative RhII
catalysts [Rh2(cap)4] and [Rh2(esp)4] resulted in the formation
of only small quantities of 3 (Table 1, entries 7 and 8), whereas
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Scheme 4. Scope of the oxidative alkenylation of monosubstituted
arenes. The yields given are for the isolated product as a mixture of
regioisomers.
optimized reaction conditions, 4 and 7 were obtained in 41
and 36% yield, respectively, as mixtures of regioisomers.
Similarly, the use of methylbenzoate provided 8 in 50% yield
with functionalization occurring in a 1:2 ratio at the meta and
para positions. The formation of cis-olefinated arenes in 2–
10% yield was also observed (see the Supporting Informa-
tion), the cause of which remains to be investigated.
Scheme 5. Scope of the oxidative alkenylation of 1,2-disubstituted
arenes. The yields given are for the isolated product as a mixture of
regioisomers.
We next surveyed symmetrical and nonsymmetrical 1,2-
disubstituted arenes and their reactivity in this reaction
(Scheme 5). The use of electron-rich arenes without Lewis
basic functional groups provided the desired products 9, 10,
and 11 in good yields (68–78%) as single regioisomers
(Scheme 5). When substrates bearing Lewis basic groups
were subjected to the reaction, lower yields were observed.
When nonsymmetrical 2-fluoroanisole was used in the
reaction, the desired product 12 was obtained in only 40%
yield, with functionalization occurring primarily in the para
position to the methoxy group. In the case of chromone,
however, 13 could be obtained as a single regioisomer in
satisfactory 62% yield. The use of dichlorobenzene, 2-
bromochlorobenzene, and 2-(trifluoromethyl)toluene pro-
vided the respective products 14, 15 and 16 in 40, 47, and
38% yield.
Scheme 6. Scope of the oxidative alkenylation of 1,3- and 1,2,3-
substituted arenes. The yields given are for the isolated product as
a mixture of regioisomers.
Having established the scope of the reaction with mono-
and 1,2-disubstituted arenes at 1.0 equivalent, we next
examined the scope of reaction with 1,3-disubstituted and
1,2,3-trisubstituted arenes (Scheme 6). When meta-xylene
was subjected to the reaction conditions, 17 was obtained in
64% yield as predominantly a single regioisomer (1:9 ortho/
meta). Similarly, the use of m-bromotoluene resulted in the
formation of 18 in 52% yield as a single regioisomer. With
and affects the oxidation potential of the bimetallic com-
plex.[18] Additionally, the exchange of the equatorial ligands
generates a vacant site for acrylate coordination. Concurrent
oxidation of the bimetallic complex, effected by Cu(TFA)2 or
V2O5, would generate a RhIII species, C H activation by
À
which would generate the aryl rhodium species. Carbometa-
lation of the acrylate, followed by b-hydride elimination,
would yield the product and a rhodium hydride, which, after
reductive elimination, would be reoxidized to generate the
active catalyst.
2,6-dimethylanisole, 19 was obtained as
regioisomers (1:9 meta/para) in 60% yield.
a mixture of
We put forth the following reasonable mechanistic
proposal for the bimetallic RhII alkenylation: Initial coordi-
nation of tricyclohexylphosphane to dirhodium tetraacetate
facilitates ligand exchange of the equatorial acetate groups
In summary, we have developed a method for the
alkenylation of arenes at 1.0 equivalent by utilizing a bimet-
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allic RhII complex. In many cases involving 1,2- and 1,3-
disubstituted arenes, products can be obtained in good yields
and selectivities. Currently, effort towards elucidating the
mechanism and developing this reaction to tolerate other
nondirected functionalization reactions is ongoing in our
laboratory.
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À
Keywords: alkenylation · bimetallic catalysts · C H activation ·
.
homogeneous catalysis · rhodium
À
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À
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À
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