An efficient method for the preparation of styrene derivatives via Rh(III)-catalyzed direct C-H vinylation

Article abstract of DOI:10.1021/acs.orglett.5b00340

The development of a method for the Rh(III)-catalyzed direct vinylation of an aromatic C-H bond to give functionalized styrenes in good yield, using vinyl acetate as a convenient and inexpensive vinyl source, is reported. High functional group tolerance is demonstrated for electronically distinct arenes as well as different directing groups. Mechanistic investigation resulted in the characterization of a novel rhodium-metallacycle, which represents the first X-ray structure of a [1,2]-Rh(III)-alkenyl addition adduct.

Full text of DOI:10.1021/acs.orglett.5b00340

Letter
pubs.acs.org/OrgLett
An Efficient Method for the Preparation of Styrene Derivatives via
Rh(III)-Catalyzed Direct C−H Vinylation
Kate D. Otley and Jonathan A. Ellman*
Department of Chemistry, Yale University, 225 Prospect Street, New Haven, Connecticut 06520-8107, United States
S
* Supporting Information
ABSTRACT: The development of a method for the Rh(III)-
catalyzed direct vinylation of an aromatic C−H bond to give
functionalized styrenes in good yield, using vinyl acetate as a
convenient and inexpensive vinyl source, is reported. High
functional group tolerance is demonstrated for electronically
distinct arenes as well as different directing groups.
Mechanistic investigation resulted in the characterization of a
novel rhodium−metallacycle, which represents the first X-ray
structure of a [1,2]-Rh(III)-alkenyl addition adduct.
reaction temperature to 100 °C gave the styrene 2a in an
tyrenes are versatile and important synthetic intermediates
Sdue to the wide array of methods available for the rapid improved 65% yield (entry 9).
functionalization of the vinyl group such as cross-metathesis,1
Mizoroki−Heck cross-coupling,2 and asymmetric dihydroxyla-
tion, aminohydroxylation, and epoxidation.3 In addition,
styrenes are important inputs for the preparation of fine
chemicals and polymers.4
Traditional methods for the preparation of functionalized
styrene derivatives include dehydration of alcohols,5 carbonyl
olefination,6 and the partial reduction of terminal alkynes.7
More recently, efficient cross-coupling strategies have been
developed to afford functionalized styrene products.8 While
significant effort has been invested into methods of direct C−H
alkenylation through oxidative-Heck couplings,9 the prepara-
tion of styrenes through direct coupling with ethylene gas is
challenging. Examples of styrene synthesis by direct, oxidative
C−H vinylation in the literature are limited by low yields, poor
selectivity, and/or harsh reaction conditions.10
After developing conditions for vinylation of the 2-phenyl-
pyridine 1a in good yield, we focused on expanding the
directing group scope (Table 2). While reaction of amide
substrate 1b under the conditions developed for 1a did not
provide the styrene product (entry 1), decreasing the reaction
temperature to 65 °C gave 2b in 40% yield. NMR analysis
revealed decomposition of the vinyl acetate under the reaction
conditions, resulting in incomplete conversion of benzamide
1b. A range of vinyl acetate/methanol ratios were therefore
explored (entries 2,4−6), with a 1:1.5 ratio providing the
vinylated product in 66% yield (entry 6). The commercially
available preformed catalyst [Cp*Rh(CH3CN)3][SbF6]2 pro-
vided a 46% yield (entry 7). Importantly, the reaction proved
amenable to setup outside the glovebox to give styrene
derivative 2b in 61% yield (entry 8). Henceforward, all
reactions were performed without use of a glovebox.
Directing group scope was next explored (Scheme 1). In
addition to the vinylation of 2-phenylpyridine 1a and
pyrrolidine amide 1b, vinylated acetanilide 2c could also be
obtained in moderate yield. Amide groups with a range of
electronic and steric character (2d−g) were well-tolerated.
Notably, the electronically deactivated morpholine benzamide
2e, unhindered N,N-dimethyl benzamide (2f), and hindered
N,N-diisopropyl benzamide (2g) all underwent vinylation in
good yield.
After establishing good directing group scope, we inves-
tigated benzamides with a range of electronic and steric
properties (Scheme 2). Benzamides without substitution on the
arene could be monovinylated with high or complete selectivity
and in excellent yield as demonstrated for the piperidine and
diisopropyl benzamides 2h and 2i, respectively. Electron-
Herein, we report Rh(III)-catalyzed vinylation for the direct
synthesis of styrenes without an external oxidant using vinyl
acetate as a convenient and economical surrogate for
ethylene.11
We began our exploration of the reaction conditions by
coupling 2-phenylpyridine in the presence of an excess of
inexpensive vinyl acetate with [Cp*RhCl2]2 as a catalyst (Table
1, entry 1). The use of a cationic Rh(III) source resulted in a
large increase in yield (entry 2). A variety of cosolvents were
explored with MeOH proving to be optimal (entries 2−5). We
−
further established that the noncoordinating B(C6F5)4
counterion resulted in an increase in reaction yield (entries
6−7). With 2-phenylpyridine as a reaction substrate, we
observed a mixture of single and double C−H activation
products (2 and 3). Because meta-substituted substrate 1a gave
a comparable yield of vinylated product and effectively
prevented over-vinylation (entry 8), we used this substrate
for the remainder of our optimization efforts. Decreasing the
Received: February 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b00340
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Organic Letters
Letter
Table 1. Optimization of Reaction Conditions with 2-Phenylpyridine Substrate
a
b
b
entry
R
Rh(III)-catalyst
[Cp*RhCl2]2
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*Rh(CH3CN)3][SbF6]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
[Cp*RhCl2]2
silver salt
solvent
temperature (°C)
yield 2 (%)
yield 3 (%)
1
2
3
4
5
6
7
8
9
H
−
−
−
−
MeOH
MeOH
toluene
DCE
120
120
120
120
120
120
120
120
100
25
40
14
13
0
0
4
H
H
4
H
2
H
−
neat
37
7
H
AgSbF6
AgB(C6F5)4
AgB(C6F5)4
AgB(C6F5)4
MeOH
MeOH
MeOH
MeOH
43
50
45
65
H
8
Me
Me
0
0
a
Conditions: 0.2 mmol scale, 2-phenylpydridine (1.0 equiv), Rh(III) (10 mol %), Ag salt (20 mol %), vinyl acetate (0.5 mL), solvent (0.5 mL), in
b
glovebox, 24 h. Yields determined by NMR relative to pentafluorobenzaldehyde external standard.
a b
,
Table 2. Optimization with Benzamide Substrate
Scheme 1. Directing Group Scope
a
b
entry
vinyl acetate/MeOH (mol/mol)
temperature (°C)
yield
1
2
3
4
5
6
1:2.3
1:2.3
1:2.3
1:1
100
65
45
65
65
65
65
0
40
24
60
<5
66
46
61
4:1
1:1.5
1:1.5
1:1.5
c
7
d
8
65
a
b
Conditions: 0.2 mmol scale, 0.2 M, in glovebox. Yields determined
c
by NMR relative to pentafluorobenzaldehyde external standard. With
[Cp*Rh(CH3CN)3][SbF6]2. Outside glovebox, 40 h.
d
donating (2k), electron-withdrawing (2l), and halogen (2m,
2n) substituents were well tolerated at the para position. While
ortho substitution was incompatible with the developed
conditions, a series of meta-substituted substrates was examined
with the regioselectivity of vinylation depending largely on the
nature of the meta substituent. Noncoordinating substituents
promote vinylation at the more remote position, as is
demonstrated by the regiospecific vinylation for substrates
bearing meta-methyl (2g), trifluoromethyl (2o), and naphthyl
(2q) functionality. On the other hand, small, coordinating
groups at the meta position, such as fluoro (2p), resulted in
selective vinylation at the proximal position. This observation is
consistent with previous mechanistic studies on the regiose-
lectivity of Rh(III)-catalyzed C−H activation conducted by
Jones and co-workers.12
a
b
Yields for isolated products. Conditions: 0.4 mmol scale, vinyl
c
acetate (1.2 mL), MeOH (0.8 mL), on benchtop. Conditions: 0.4
mmol scale, 2-phenylpydridine (1.0 equiv), vinyl acetate (0.5 mL),
solvent (0.5 mL), on benchtop, 100 °C, 24 h.
We depict a plausible mechanism for the observed
transformation in Scheme 3. The pathway begins with C−H
activation and formation of rhodacycle A, followed by [1,2]-
insertion of the C−Rh bond into the alkene to generate the
seven-membered metallacycle B. We propose that metallacycle
B undergoes β-hydride elimination to give rhodium-hydride C.
Reinsertion of the Rh−H bond gives the more stable six-
membered metallacycle D,13 which is poised to undergo
elimination of acetate, resulting in styrene product 2.14 While
we believe the proposed pathway to be most likely, an
alternative pathway proceeding through elimination of acetate
The vinyl acetate coupling partner is used in excess, which
for practical considerations necessitates that it be both
inexpensive and volatile. While isopropenyl acetate meets
these specifications, coupling with N,N-diisopropyl benzamide
1a was inefficient (<5%).
B
DOI: 10.1021/acs.orglett.5b00340
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a b
,
Scheme 2. Arene Scope with Amide Directing Group
Scheme 4. Preparation of Proposed Metallacycle
ab
,
Intermediate
a
b
−
0.06 mmol scale. For clarity, hydrogens and B(C6F5)4 counterion
have been omitted from the ORTEP view of metallacycle 4.
To establish the relevance of rhodacycle 4 in catalysis, we
1
monitored by H NMR a catalytic vinylation reaction of 2-
phenylpyridine and observed that 4 is present throughout the
reaction at a level comparable to Rh(III) loading (10 mol %).
This result is consistent with 4 as a catalyst resting state. To
further determine whether or not rhodacycle 4 is a catalytically
competent species, the vinylation of 2-phenylpyridine 1a with
vinyl acetate in the presence of 10 mol % of 4 was next explored
(Scheme 5). Vinylated product 2a was obtained in 55% yield
a b
,
Scheme 5. Reaction with 4 as Catalyst
a
b
Yields for isolated products. Conditions: 0.4 mmol scale, vinyl
c
acetate (1.2 mL), MeOH (0.8 mL), on benchtop. Isolated ratio of
single to double C−H activation products. 24 h reaction time.
d
a
Conditions: 0.2 mmol scale, vinyl acetate (0.5 mL), methanol (0.5
b
mL), on benchtop. Yields determined by GC relative to tetradecane
Scheme 3. Proposed Reaction Pathway
external standard.
along with 5% of styrene 5, which is derived from rhodacycle 4.
These results clearly establish that 4 is a competent vinylation
catalyst.
In summary, the developed method enables rapid access to
functionalized styrenes through direct, Rh(III)-catalyzed C−H
vinylation. Vinyl acetate serves as a cost-effective and
convenient vinyl source for a range of substrates. Mechanistic
investigation resulted in the characterization of a seven-
membered rhodacycle formed by [1,2]-insertion of the Rh−C
bond into vinyl acetate. This type of alkene insertion
intermediate has not previously been structurally characterized
for other Rh(III)-catalyzed oxidative Heck reactions.
ASSOCIATED CONTENT
■
from B to give a rhodium-carbene intermediate cannot be
completely ruled out.
S
* Supporting Information
To investigate the reaction mechanism, a room temperature
reaction of 2-phenylpyridine with vinyl acetate was performed
and resulted in isolation of rhodacycle 4 in 87% yield based
upon Cp*RhCl2 (Scheme 4). Single crystals of 4 were
prepared, and the structure was determined by X-ray
diffraction. For Rh(III)-catalyzed oxidative Heck reactions,
similar seven-membered rhodacycle intermediates for the [1,2]-
insertion of Rh−C bonds into alkenes have generally been
proposed.8,15 However, to the best of our knowledge,
metallacycle 4 is the first such [1,2]-Rh(III)-alkenyl addition
adduct to be isolated and characterized.
Full experimental details; characterization data; crystallographic
data (CIF) for 4. This material is available free of charge via the
Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: jonathan.ellman@yale.edu.
Notes
The authors declare no competing financial interest.
C
DOI: 10.1021/acs.orglett.5b00340
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Organic Letters
Letter
Lett. 2014, 16, 4718. (b) Zhang, M.; Zhang, H.-J.; Han, T.; Ruan, W.;
Wen, T.-B. J. Org. Chem. 2015, 80, 620.
(12) (a) Tsang, J. Y. K.; Buschhaus, M. S. A.; Legzdins, P.; Patrick, B.
O. Organometallics 2006, 25, 4215. (b) Li, L.; Brennessel, W. W.;
Jones, W. D. Organometallics 2009, 28, 3492.
(13) A similar mechanistic pathway has been proposed by Jones and
co-workers for the stoichiometric formation of a Rh(III)-[1,1]-
insertion adduct formed by the coupling of 2-phenylpyridine and
ethylene. Li, L.; Jiao, Y.; Brennessel, W. W.; Jones, W. D.
Organometallics 2010, 29, 4593.
ACKNOWLEDGMENTS
■
This work was supported by the NIH (GM069559). We
gratefully acknowledge Dr. Brandon Mercado (Yale University)
for solving the crystal structure of 4 and Dr. Yajing Lian
(currently at Pfizer Inc.) for work on initial experiments.
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