Synthesis of Stilbenes by Rhodium-Catalyzed Aerobic Alkenylation of Arenes via C-H Activation

Article abstract of DOI:10.1021/jacs.0c03935

Arene alkenylation is commonly achieved by late transition metal-mediated C(sp2)-C(sp2) cross-coupling, but this strategy typically requires prefunctionalized substrates (e.g., with halides or pseudohalides) and/or the presence of a directing group on the arene. Transition metal-mediated arene C-H activation and alkenylation offers an alternative method to functionalize arene substrates. Herein, we report a rhodium-catalyzed oxidative arene alkenylation from arenes and styrenes to prepare stilbene and stilbene derivatives. The reaction is successful with several functional groups on both the arene and the olefin including fluoride, chloride, trifluoromethyl, ester, nitro, acetate, cyanide, and ether groups. Reactions of monosubstituted arenes are selective for alkenylation at the meta and para positions, generally with approximately 2:1 selectivity, respectively. Resveratrol and (E)-1,2,3-trimethoxy-5-(4-methoxystyryl)benzene (DMU-212) are synthesized by this single-step approach in high yield. Comparison with palladium catalysis showed that rhodium catalysis is more selective for meta-functionalization for monosubstituted arenes and that the Rh catalysis has better tolerance of halogen groups.

Full text of DOI:10.1021/jacs.0c03935

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Synthesis of Stilbenes by Rhodium-Catalyzed Aerobic Alkenylation
of Arenes via C−H Activation
Xiaofan Jia, Lucas I. Frye, Weihao Zhu, Shunyan Gu, and T. Brent Gunnoe*
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ABSTRACT: Arene alkenylation is commonly achieved by late
transition metal-mediated C(sp2)−C(sp2) cross-coupling, but this
strategy typically requires prefunctionalized substrates (e.g., with
halides or pseudohalides) and/or the presence of a directing group
on the arene. Transition metal-mediated arene C−H activation and
alkenylation offers an alternative method to functionalize arene
substrates. Herein, we report a rhodium-catalyzed oxidative arene
alkenylation from arenes and styrenes to prepare stilbene and
stilbene derivatives. The reaction is successful with several
functional groups on both the arene and the olefin including
fluoride, chloride, trifluoromethyl, ester, nitro, acetate, cyanide, and
ether groups. Reactions of monosubstituted arenes are selective for
alkenylation at the meta and para positions, generally with approximately 2:1 selectivity, respectively. Resveratrol and (E)-1,2,3-
trimethoxy-5-(4-methoxystyryl)benzene (DMU-212) are synthesized by this single-step approach in high yield. Comparison with
palladium catalysis showed that rhodium catalysis is more selective for meta-functionalization for monosubstituted arenes and that
the Rh catalysis has better tolerance of halogen groups.
potential advantages. However, in many cases of arene
alkenylation involving transition metal-mediated C−H activa-
tion, directing groups are required to enhance reactivity toward
arene C−H activation and/or promote regioselectivity. This
limits the scope of substrates that can be used for arene
alkenylation via C−H bond-breaking reactions. For example,
amines, amides, and carbamates have been used to allow site-
selective functionalization of C−H bonds with C−H activation
and subsequent alkenylation typically occurring at the ortho
position.20
Arene alkyl- and alkenylation provide an opportunity to
affect more atom-economical formation of carbon−carbon
bonds between inexpensive arenes and alkenes through
undirected C−H activation (Figure 1b). It has been reported
that Ni,21,22 Ru,23−33 Pt,27,34−40 and Ir41−45 complexes catalyze
olefin hydroarylation (nonoxidative) to produce saturated alkyl
arenes, and Pd46−52 and Rh53−61 catalyze oxidative arene
alkenylation using oxidants in many cases with functionalized
olefins. We envisioned a strategy in which the reaction between
arenes and styrenes in the presence of a rhodium catalyst
INTRODUCTION
■
The innovation of synthetic routes to stilbenes is of interest in
organic chemistry because stilbene derivatives are potentially
applicable in the pharmaceutical industry and in materials
science.1 Many stilbene derivatives exhibit photophysical and
photochemical properties that render them useful in dyes,
liquid crystals, and LEDs.2−5 In addition, some products of
medicinal interest possess stilbene (i.e., 1,2-diarylethylene)
structures. For example, resveratrol is commonly used as a
dietary supplement that has been observed to possess
chemopreventive and cytostatic properties against a variety
of human tumor cell lines, including several prostate cancer cell
lines.6,7 Some resveratrol derivatives, such as DMU-212, have
been shown to possess cytotoxic activity in ovarian, breast, and
colorectal cell lines.8
Synthetic routes to stilbenes feature cross-coupling of arenes
and styrenes,9,10 but these methods frequently require
substrates to be activated with a functional group, resulting
in undesirable multistep substrate synthesis and byproducts
from the stilbene synthesis (Figure 1a).11 For example, the
synthesis of alkenyl arenes has been achieved with halo-,
diazonium-, and sulfone-substituted arenes, as well as carboxyl-
and nitroalkenes, but these processes produce stoichiometric
amounts of waste.12−19 In addition, there are synthetic
inefficiencies associated with the generation of the initial
functionalized substrates. Thus, introducing arenes and olefins
into C−C bond-forming processes via C−H bond-breaking
(rather than C−halogen bond activation, for example) offers
Received: April 10, 2020
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A

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Table 1. Comparison of Different Rh Precursors and
Optimization of Reaction Conditions Using [Rh(μ-
OAc)(η2-C2H4)2]2 (1)
HOPiv temp
d
c
e
entry
[Rh]
solvent
(equiv ) (° C) additive yield
1
2
3
4
5
6
7
8
9
RhCl3·H2O
benzene
benzene
benzene
benzene
benzene
C6F6
240
240
240
800
1600
800
800
800
800
800
800
150
150
165
165
165
165
165
165
165
165
165
69
66
81
92
20
12
7
39
36
90
58
1
1
1
1
1
1
1
1
1
1
DMF
mestitylene
benzene
benzene
benzene
V2O5
10
11
4 Å MS
f
GO
a
b
56 mmol when using benzene as solvent. Catalyst amount is relative
c
to the limiting reagent styrene. Amounts of Cu(II) pivalate and
d
pivalic acid are relative to Rh. In each case 5 mL of solvent was used.
e
GC yield based on a calibration curve using hexamethylbenzene as
f
internal standard. GO = graphene oxide.
of carboxylate (either a Cu(II) salt or a carboxylic acid).53−57
When the reaction temperature is raised from 150 to 165 °C,
higher yield is observed after 24 h (81% vs 71%), although this
is accompanied by the conversion of the arene to aryl ester
(e.g., phenyl pivalate) due to a side reaction with copper(II)
pivalate. The yield of stilbenes was minimally affected when
styrene was used as a limiting reagent. Utilization of
dimethylformamide (DMF), hexafluorobenzene, or mesitylene
furnished lower yields (0%, 12%, and 11%, respectively), and
we suspect this is a result of slower C−H activation due to the
lower concentrations of arene. It has been reported that the
addition of vanadium(V) oxide will facilitate alkenylation
reactions;67,68 however, when V2O5 was added in equal
amount relative to copper(II) pivalate, yields were decreased
(see entry 9). It was reported that in our Pd-catalyzed olefin
alkenylation chemistry, the presence of water inhibits the
catalysis.48 We also examined the influence of drying agents;
however, neither molecular sieves nor graphene oxide (entries
10 and 11) improve the yield of stilbenes.
Under optimized conditions, we surveyed the scope and
limitations of the Rh-catalyzed process with a variety of
substituted styrene precursors (Table 2). The reactions
between substituted styrenes and benzene showed good
functional group tolerance and isolated yields. The tolerance
of some halogen group was witnessed as reactions with
halogenated styrenes afford expected stilbene derivatives 2f−
2k with isolated yields >68%. The reaction also leaves alkoxy
groups in 2o−2s untouched, which afforded an opportunity to
synthesize protected resveratrol and derivatives using this
approach (vide infra).
Figure 1. Stilbene synthesis via transition-metal-catalyzed arene
alkenylation between arenes and vinylarenes. (a) Current synthetic
strategies for the preparation of stilbene and stilbene derivatives. (b)
Aerobic arene alkenylation catalyzed by Rh via a C−H activation
pathway. (c) Proposed catalytic cycle for late transition metal-
catalyzed oxidative arene alkenylation to produce stilbene and stilbene
derivatives.
precursor would form stilbene products through a rhodium-
mediated C−H activation followed by vinyl arene insertion, β-
hydride elimination, and catalyst regeneration by an air-
recyclable copper(II) oxidant (Figure 1c). Herein, we report
the aerobic Rh-catalyzed synthesis of stilbenes from styrenes
and arenes with good functional group tolerance. Under
optimized conditions, these products can be obtained in
moderate to good yields using dioxygen from the air as a
terminal oxidant. For select cases, we compared the efficacy of
Rh- and Pd-based catalysis and find that there are notable
differences between those two metals in both selectivity and
reactivity.
RESULTS AND DISCUSSION
■
We examined benzene and styrene as model substrates to
determine if there are differences using various Rh catalyst
precursors. The catalysis between the commercially available
RhCl3·H2O and [Rh(μ-OAc)(η2-C2H4)2]2 (1) was first
compared (Table 1, entries 1 and 2). The Rh(I) dimer 1
gave better yield (71% vs 65%) perhaps because the presence
of the acetate groups facilitates C−H activation via a concerted
metalation/deprotonation (CMD) mechanism.54,62−66 Previ-
ously, we have shown that Rh-catalyzed arene alkenylation
using hydrocarbons does not occur in the absence of a source
We also examined extension of this method to α- and β-
substituted styrenes (Scheme 1) and found that both α-
methylstyrene and trans-β-methylstyrene gave the desired
product 2t, along with products 2u and 2v, which are likely
produced by a rhodium-mediated isomerization reaction. We
propose two possible olefin isomerization routes to generate
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Table 2. Vinyl Arene Scope for Benzene Alkenylation Catalyzed by [Rh(μ-OAc)(η2-C2H4)2]2(1) in Neat Benzene and Isolated
Yields
a
b
c
Catalyst amount is relative to the limiting reagent styrene. Amounts of copper pivalate and pivalic acid are relative to single Rh. Reactions were
performed for 48 h.
2u and 2v (Scheme 2). We attribute the production of 2u to a
side isomerization reaction from product 2u to 2v via a Rh
hydride-mediated process and production of 2v to a similar
process that converts β-methylstyrene to allyl benzene, which
likely served as the precursor to 2v.
Scheme 1. Alkenylation Using Vinyl-Substituted Styrene of
Benzene
a
Table 3 shows the isolated yields for catalytic reactions using
substituted arenes and styrene. A range of monosubstituted
arenes are functionalized to give products 3a−3d, 3i−3n, 3r,
3u, and 3v, with electronic character ranging from electron-
rich anisole (3r) to electron-deficient α,α,α-trifluorotoluene.
Regardless of the arene substituent identity, the reaction
regioselectivity is catalyst-directed for the formation of meta
and para products, generally with an approximately 2:1 ratio.
For 3a, 3j, 3l, and 3v, the meta- and para-functionalized
isomers were separated using column chromatography to give
∼2:1 isolated yields of meta:para products. These results
indicate that the C−H activation step is sensitive to steric
hindrance, with even small fluoro or methyl groups almost
a
Conditions: 0.25 mol % of [Rh(μ-OAc)(η2-C2H4)2]2 (1) (0.5 mol %
for single rhodium), 160 equiv of copper pivalate, 800 equiv of pivalic
acid, 60 psig of N2, 15 psig of air, 5 mL of benzene as solvent, 165 °C,
24 h.
Scheme 2. Rh-Mediated Olefin Isomerization That Produces Unexpected Products 2u and 2v
C
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k
Table 3. Arene Scope of Oxidative Styrene Hydroarylation Catalyzed by [Rh(μ-OAc)(η2-C2H4)2]2(1) in Neat Arene Solution
a
b
c
Catalyst amount is relative to the limiting reagent styrene. Amounts of Cu(II) pivalate and pivalic acid are relative to Rh. Total yield is
d
e
f
calculated prior to isomer separation. o:m:p value is calculated on the basis of GC-FID peak areas. Reaction was performed for 48 h. Mesitylene
g
(2.5 mL) was added to the reaction mixture. The o:m:p value is calculated on the basis of 19F NMR spectroscopy due to poor resolution of isomers
h
in the GC. The yield was calculated on the basis of the integration of the vinyl protons of bromostilbene relative to the internal standard CH3NO2.
i
The crude reaction mixture was washed with base and analyzed by 1H NMR spectroscopy. The yield was calculated on the basis of the integration
j
of the vinyl protons of iodostilbene relative to the internal standard CH3NO2. Reactions were performed at 135 °C for 96 h with reactors opened
to air every 24 h. All yields are isolated.
k
totally suppressing ortho functionalization. When dialkylben-
zenes and trialkylbenzene 3e−3h were used as the substrates,
we observed the same influence of sterics on the selectivity.
Because all four arene C−H bonds in p-xylene (3e) are
adjacent to a methyl group, the reaction gave a low yield of
only 22%. For m-xylene (3f) and o-xylene (3g), better yields
(>70%) are obtained because they have more sterically
accessible arene C−H bonds. 1,2,3-Trimethylbenzene has a
steric profile similar to that of meta-xylene (i.e., an accessible
C−H bond that is meta to methyl groups), and the reaction
gave 67% isolated yield of the desired product (3h) after a
prolonged reaction time (48 h).
to C−X bond functionalization competing with C−H
activation. Thus, along with the desired products bromo-
(3m) and iodostilbene (3n), (E)-stilbene (2a) is formed. The
reactions work well for pentafluorobenzene (3o), ortho-
dichlorobenzene (3p), and meta-dibromobenzene (3q, under
135 °C) giving 61%, 74%, and 74% isolated yields, respectively.
When using the arenes with methoxy groups (3v−3y), a
decrease in yield at 165 °C is observed. Yet the yields can be
improved by lowering the reaction temperature to 135 °C and
extending the reaction time to 96 h. We expanded the scope of
the catalysis to polycyclic arenes and heteroaromatic
substrates. The reactions with naphthalene (3s) and furan
(3t) are selective and generate the expected alkenylation
products in moderate to good yields.
With respect to halogenated arenes, the reactions proceed
for fluoro- and chlorobenzene with total isolated yields (all
isomers) of 82% (3k) and 87% (3l), respectively. However,
reactions are less successful with bromo- and iodobenzene due
It has been reported that polyphenolic compounds and
methyl ether derivatives possess possible anticancer bio-
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activity.6−8,69−87 Among those molecules, resveratrol and
DMU-212 are two widely studied compounds. Current
synthetic routes for resveratrol and derivatives use Wittig
reactions, Perkin condensations, alkene metathesis, and cross-
coupling.70,72,77,80,88−90 Decarbonylative Heck coupling and
Perkin condensations can produce polyhydroxystilbenes at
moderate yields (∼50%) in four and two steps, respec-
tively.70,88 Alkene metathesis can generate polymethoxystil-
benes in two steps at high conversions, but with low selectivity
against self-metathesis products.91 Wittig reactions can
generate polymethoxystilbenes in one step with high yield,
but require aqueous conditions and the in situ formation of
trialkylphosphonium salts.92 Via our method, DMU-212 and
resveratrol can be prepared from polymethoxybenzene and
vinyl anisole in 68% and 71% yield by a single- or two-step
conversion(s), respectively (Figure 2a).
substrates could produce more than 20 different polymethox-
ystilbenes.
Hyperbaric dinitrogen pressure is used for arenes with
boiling points lower than the reaction temperature. For
selected high-boiling-point arene substrates, the catalysis
could be performed under ambient pressure, which allows us
to use simple reaction setups equipped with a continuous air
feed to enable larger scale synthesis. As shown in Scheme 3,
the reaction between 1,3-dimethoxybenzene and 4-vinylanisole
yields 62% (838 mg) of the desired product (E)-1,3-
dimethoxy-5-(4-methoxystyryl)benzene (trimethylresveratrol).
The continuous air flow created a stable O2 concentration, and
lower copper loading is possible. As shown in Scheme 3, the
Cu(II) loading was reduced to 8 equiv (relative to Rh) in the
reaction between dichlorobenzene, and an isolated yield of
84% (1.05 g) of the desired product 3p was achieved.
We also examined aerobic arene alkenylation for stilbene
production using Pd(OAc)2 (4), previously reported to serve
as a catalyst for arene alkenylation despite low selectivity.48,49
We first investigated the regioselectivity of palladium catalysis.
As shown in Figure 3a, Pd catalysis leads to substantial
amounts of ortho functionalization in all six arenes investigated,
whereas ortho functionalization in rhodium-catalyzed reactions
was minimal. A directing group effect was observed when using
anisole as the substrate, but this effect was more heavily
pronounced for Pd than for Rh. Using 4 as the catalyst
precursor, the ortho:meta selectivity for 1,3-dimethoxybenzene
with styrene (Figure 3a) is 9:1 in favor of ortho
functionalization and with 4-methoxystyrene (Figure 3b) is
8:1 in favor of ortho functionalization. In contrast, ortho:meta
selectivities for 1,3-dimethoxylbenzene with styrene and 4-
methoxystyrene using the Rh catalyst 1 are both 1:8, favoring
the meta product.
Other than resveratrol and DMU-212, many other
polyphenolics and their methyl esters can be synthesized
using our strategy because we have demonstrated our method
works well on polymethoxybenzene (3v−3y) and vinyl-
methoxybenzenes (2o−2s). The reactions between these
We also investigated Pd catalysis using halogenated arenes as
substrate (Figure 3c) at 120 °C where the consumption of the
functionalized product (observed in Pd catalysis) is minimal.
Using chlorobenzene, the desired product mixture (ortho,
meta, and para isomers) can be obtained after 12 h under
reaction conditions, and the same product distribution
(approximately 1:2:2 ortho:meta:para) is observed. It has
been reported that Rh-catalyzed oxidative olefination of
bromoarene favors the formation of the C−H bond activation
product;93 we observe similar selectivity with Rh catalysis
when using bromo- or iodobenzene as the substrate, with Pd
showing much lower tolerance toward halide functionality. The
reaction of bromobenzene with 4 produces a large amount of
stilbene, with a 1:3 ratio of stilbene:bromostilbene, which likely
results from C−Br bond activation in lieu of C−H bond
activation. When using iodobenzene, the reaction produces
trace amounts of iodostilbene, which indicated that Pd favors
the activation of C−I over C−H bonds. In contrast, Rh has
shown better tolerance toward bromo and iodo functionalities.
Catalysis with 1 using bromobenzene still favors C−H
activation product bromostilbene over the C−Br activation
product stilbene, and the ratio of the former to the latter is
11:1. The reaction with iodobenzene is less selective, but still
slightly favors producing the C−H activation product (the
observed ratio of iodostilbene to stilbene is 1.1).
Figure 2. Rh-catalyzed direct synthesis of bioactive molecules. (a)
Synthesis of resveratrol and DMU-212. Yields are isolated.
Conditions: (i) 0.25 mol % of [Rh(μ-OAc)(η2-C2H4)2]2 (1) (0.5
mol % based on rhodium), 160 equiv of copper pivalate, 800 equiv of
pivalic acid, 60 psig of N2, 15 psig of air, 5 mL of arene as solvent, 500
μmol of 4-vinylanisole, 135 °C, 96 h, reactors were open to air every
24 h; (ii) BBr3, 0−30 °C, quant, overnight. (b) Building blocks for the
synthesis of future pharmaceutically relevant molecules.
SUMMARY AND CONCLUSIONS
■
We have developed a new, broadly applicable strategy for the
one-pot aerobic synthesis of stilbenes by Rh-catalyzed
oxidative arene alkenylation. Whereas conventional methods
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Scheme 3. Gram-Scale Syntheses of (E)-1,3-Dimethoxy-5-(4-methoxystyryl)benzene and (E)-1,2-Dichloro-4-styrylbenzene
a
(3p)
a
b
Catalyst amount is relative to the limiting reagent styrene. Amounts of Cu(II) pivalate and pivalic acid are relative to Rh.
optimization studies were determined by GC-FID analysis of the
crude reaction mixture using hexamethylbenzene as an internal
standard.
for arene alkenylation require prefunctionalized substrates, our
approach makes use of C−H bond activation, without the need
for prefunctionalization with a weaker bond C−X bond (X =
halide or pseudohalide) or directing group. The new arene
alkenylation chemistry is tolerant of fluoride, chloride,
trifluoromethyl, ester, nitro, acetate, cyanide, and ether groups
on both the arene and the alkene in uniformly good to high
yield and with predictable regioselectivity without the need to
identify or develop catalytic systems for each class of reagent.
This performance presents an opportunity for the large-scale
organic synthesis of commercially relevant stilbenes, including
those with medicinal properties.
Scope of Vinyl Arenes. Under an atmosphere of dry nitrogen, di-
μ-acetatotetrakis(dihaptoethene)dirhodium(I) (1) (2.5 μmol, 550
μg), copper(II) pivalate (400 μmol, 106 mg), and pivalic acid (2
mmol, 204 mg) were added into a dried Andrews Glass Lab-Crest
Fisher-Porter tube with a stir bar. Vinyl arene (500 μmol) and
benzene (5 mL) were then added via syringe. The tube then was
opened to air, sealed, and pressurized with dinitrogen (60 psig). The
mixture was stirred at 165 °C. After 24 h, the reaction was allowed to
cool to room temperature. The resultant mixture was diluted with
ethyl acetate (40 mL) and washed with saturated sodium carbonate
solution (50 mL). The aqueous and organic layers were separated.
The aqueous layer was extracted with ethyl acetate (3 × 40 mL), and
the combined organic layers were washed with water (3 × 10 mL),
dried over magnesium sulfate, filtered, and concentrated under
vacuum.
Scope of Arenes. Under an atmosphere of dry nitrogen, di-μ-
acetatotetrakis(dihaptoethene)dirhodium(I) (1) (2.5 μmol, 550 μg),
copper(II) pivalate (400 μmol, 106 mg), and pivalic acid (2 mmol,
204 mg) were added to a dried Andrews Glass Lab-Crest Fisher-
Porter tube with a stir bar. Styrene (500 μmol) and arene (5 mL)
were then added via syringe. The tube was opened to air, sealed, and
pressurized with dinitrogen (60 psig). The mixture was stirred at 165
°C. After 24 h, the reaction was allowed to cool to room temperature.
The resultant mixture was diluted with ethyl acetate (40 mL) and
washed with saturated sodium carbonate solution (50 mL). The
aqueous and organic layers were separated. The aqueous layer was
extracted with ethyl acetate (3 × 40 mL), and the combined organic
layers were washed with water (3 × 10 mL) and dried over
magnesium sulfate, filtered, and concentrated under vacuum. The
concentrate was purified by column chromatography using hexanes as
eluent.
Synthesis of Bioactive Stilbene Derivatives. Under an
atmosphere of dry nitrogen, di-μ-acetatotetrakis(dihaptoethene)-
dirhodium(I) (1) (2.5 μmol, 550 μg), copper(II) pivalate (400
μmol, 106 mg), and pivalic acid (2 mmol, 204 mg) were added to a
dried Andrews Glass Lab-Crest Fisher-Porter tube with a stir bar.
Vinyl arene (500 μmol) and arene (5 mL) were then added via
syringe. The tube was opened to air, sealed, and pressurized with
dinitrogen (60 psig). The mixture was stirred at 135 °C for 96 h. After
every 24 h, the reaction was allowed to cool to room temperature, and
fresh air was purged into the reactor via a long needle. After the
reaction finished, the resultant mixture was diluted with ethyl acetate
(40 mL) and washed with saturated sodium carbonate solution (50
mL). The aqueous and organic layers were separated. The aqueous
layer was extracted with ethyl acetate (3 × 40 mL), and the combined
organic layers were washed with water (3 × 10 mL), dried over
magnesium sulfate, filtered, and concentrated under vacuum. The
concentrate was purified by column chromatography using 9:1
hexanes:ethyl acetate as eluent.
EXPERIMENTAL SECTION
■
General Considerations. Unless otherwise noted, all synthetic
procedures were performed under aerobic conditions. Glovebox
purity was maintained by periodic nitrogen purges and was monitored
by an oxygen analyzer (O2 < 15 ppm for all reactions). Benzene was
1
purified by passage through a column of activated alumina. H NMR
spectra were recorded on a Varian 600 spectrometer. 1H NMR
spectra are referenced against residual proton signals (1H NMR) of
the deuterated solvents. GC/MS was performed using a Shimadzu
GCMS-QP2010 Plus system with a 30 m × 0.25 mm RTx-Qbond
column with 8 μm thickness using electron impact ionization. GC/
FID was performed using a Shimadzu GC-2014 system with a 30 m ×
90.25 mm HP5 column with 0.25 μm film thickness. For initial
catalytic experiments without isolation of product, stilbene yields were
quantified using linear regression analysis of gas chromatograms of
standard samples of authentic product. The slope, correlation
coefficient, and response factor of the regression line are 0.83, 0.99,
and 0.80 for stilbene. Copper(II) pivalate and di-μ-acetatotetrakis-
(dihaptoethene)dirhodium(I) (1) were synthesized according to a
published procedure.94,95 All other reagents were used as received
from commercial sources. High-resolution mass spectrometry was
performed at the University of Kansas Mass Spectrometry Lab.
Optimization of Reaction Conditions. Under an atmosphere of
dry nitrogen, di-μ-acetatotetrakis(dihaptoethene)dirhodium(I) (1)
(2.5 μmol, 550 μg), copper(II) pivalate (400 μmol, 106 mg), and
pivalic acid (2 mmol, 204 mg) were added into a dried Andrews Glass
Lab-Crest Fisher-Porter tube with a stir bar. Styrene (500 μmol, 57
μL) and benzene (5 mL) were then added via syringe. The tube was
opened to air, sealed, and pressurized with dinitrogen (60 psig), and
the mixture was stirred at 165 °C. After 24 h, the reaction was allowed
to cool to room temperature. The resultant mixture was diluted with
ethyl acetate (40 mL) and washed with saturated sodium carbonate
solution (50 mL). The aqueous and organic layers were separated.
The aqueous layer was extracted with ethyl acetate (3 × 40 mL), and
the combined organic layers were washed with water (3 × 10 mL)
and dried over magnesium sulfate. The resulting sample was subjected
to GC-FID analysis. All yields and ratios given during the
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removal of the reaction solvent, necessitating a long condenser). The
reaction mixture was stirred at optimized temperature for the arene.
After completion of the reaction, the flask was allowed to cool to
room temperature. The resultant mixture was diluted with ethyl
acetate (150 mL) and washed with saturated sodium carbonate
solution (200 mL). The aqueous and organic layers were separated.
The aqueous layer was extracted with ethyl acetate (3 × 200 mL), and
the combined organic layers were washed with water (3 × 200 mL),
dried over magnesium sulfate, filtered, and concentrated under
vacuum. The product was purified by flash column chromatography
using hexanes/ethyl acetate as the eluent.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge at
https://pubs.acs.org/doi/10.1021/jacs.0c03935.
■
sı
Full experimental details (PDF)
AUTHOR INFORMATION
Corresponding Author
■
T. Brent Gunnoe − Department of Chemistry, University of
Virginia, Charlottesville, Virginia 22904, United States;
orcid.org/0000-0001-5714-3887; Email: tbg7h@
virginia.edu
Authors
Xiaofan Jia − Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22904, United States; orcid.org/
0000-0003-0425-5089
Lucas I. Frye − Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22904, United States; orcid.org/
0000-0001-7713-7097
Weihao Zhu − Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22904, United States
Shunyan Gu − Department of Chemistry, University of Virginia,
Charlottesville, Virginia 22904, United States; orcid.org/
0000-0002-3625-1042
Complete contact information is available at:
https://pubs.acs.org/10.1021/jacs.0c03935
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was supported by the U.S. Department of Energy,
Office of Basic Energy Sciences, Chemical Sciences, Geo-
sciences, and Biosciences Division (DE-SC0000776). L.I.F.
was supported by a Beckman Scholar Award from The Arnold
and Mabel Beckman Foundation.
Figure 3. Difference between rhodium and palladium catalysis. (a)
a
Regioselectivity differences: [Rh] = 0.5 [Rh(μ-OAc)(η2-C2H4)2]2
b
(1) and [Pd] = Pd(OAc)2(4); amounts of Cu(II) pivalate and
pivalic acid are relative to [M]; c reaction temperature = 135 °C. (b)
New possibilities for bioactive molecule synthesis that benefit from
the selectivity differences between Rh and Pd. (c) Differences
between Pd and Rh catalysis on C−X versus C−H bond activation (X
= Cl, Br, I).
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