Role of mono-N-protected amino acid ligands in palladium(II)-catalyzed dehydrogenative heck reactions of electron-deficient (hetero)arenes: Experimental and computational studies

Article abstract of DOI:10.1021/om400890p

We report here that mono-N-protected amino acids (MPAAs), an important environmentally compatible structural motif, enable acceleration of Pd(II)-catalyzed dehydrogenative Heck reactions between pyridines and electron-deficient arenes with simple alkenes, leading to diversely functionalized C3- or meta-selective alkenylated pyridines and benzenes via non-chelate-assisted C-H activation. A comprehensive theoretical study by DFT calculations discloses that the amino scaffold of the MPAA ligand facilely converts to an X-type ligand by an initial N-H activation, resulting in a relatively low activation barrier for the C-H cleavage of pyridine. Then a property reversal of the amino group from X-type to L-type ligand allows the alkene substitution to take place smoothly, while the carboxyl group enables the formation of an intramolecular hydrogen bond, significantly decreasing the activation barrier for the carbopalladation. The results of calculations and the kinetic isotopic effect measurement support a rate-limiting C-H activation by a mechanism involving a concerted metalation/deprotonation pathway, with an endothermicity of 31.0 kcal/mol in the process.

Full text of DOI:10.1021/om400890p

Article
pubs.acs.org/Organometallics
Role of Mono-N-protected Amino Acid Ligands in Palladium(II)-
Catalyzed Dehydrogenative Heck Reactions of Electron-Deficient
Hetero)arenes: Experimental and Computational Studies
(
†
,§
‡,§
,†
,†
Xuefeng Cong, Huarong Tang, Chao Wu,* and Xiaoming Zeng*
†
‡
Center for Organic Chemistry and Materials Physics Center, Frontier Institute of Science and Technology, and School of Materials
Science and Engineering, Xi’an Jiaotong University, Xi’an, Shaanxi, 710054, People’s Republic of China
*
S Supporting Information
ABSTRACT: We report here that mono-N-protected amino
acids (MPAAs), an important environmentally compatible
structural motif, enable acceleration of Pd(II)-catalyzed
dehydrogenative Heck reactions between pyridines and
electron-deficient arenes with simple alkenes, leading to
diversely functionalized C3- or meta-selective alkenylated
pyridines and benzenes via non-chelate-assisted C−H
activation. A comprehensive theoretical study by DFT
calculations discloses that the amino scaffold of the MPAA
ligand facilely converts to an X-type ligand by an initial N−H
activation, resulting in a relatively low activation barrier for the
C−H cleavage of pyridine. Then a property reversal of the amino group from X-type to L-type ligand allows the alkene
substitution to take place smoothly, while the carboxyl group enables the formation of an intramolecular hydrogen bond,
significantly decreasing the activation barrier for the carbopalladation. The results of calculations and the kinetic isotopic effect
measurement support a rate-limiting C−H activation by a mechanism involving a concerted metalation/deprotonation pathway,
with an endothermicity of 31.0 kcal/mol in the process.
INTRODUCTION
For ligand-promoted catalysis, a mechanistic understanding
of the role of ligands is fundamentally important for gaining
insight into the rational design of novel ancillary ligands. In
particular, a quadrangular metal intermediate A with the
■
Over the past decades, ligand-accelerated catalysis has emerged
as a powerful strategy and has been widely studied for the
synthesis of diversely functionalized molecules. Although
1
chelation of a directing group is thought to be involved in the9
significant advances have been achieved in ligand-promoted
reaction pathway of directed C−H activation (Scheme 1a).
2
traditional couplings using electron-rich phosphines and N-
Different from this coordinative model, the activation of non-
chelate-assisted C−H bonds mainly depends on the intrinsic
electronic properties of substrates, allowing the formation of
active intermediates without the assistance from a directing
group; thus, a distinct mechanism can be considered as
compared with the directed C−H activation. On the basis of
these considerations, we addressed our efforts in developing
MPAA ligand-accelerated transformations involving a non-
chelate-assisted C−H activation. Herein, we report that MPAA
ligands enable a significant improvement of the catalytic activity
3
heterocyclic carbenes, there is still a lack of general and highly
efficient ligands to enhance the catalytic activities of transition
metals in oxidative C−H activation reactions, which are highly
useful synthetic tools for forming carbon−carbon and carbon−
4
heteroatom bonds. This may be ascribed to the incompatibility
and sensitivity of various ligands to the oxidative and harsh
reaction conditions, resulting in decreased efficiency in catalysis.
Note that dramatic breakthroughs have recently been made by
Yu and co-workers, who discovered that mono-N-protected
amino acids (MPAAs), a class of inexpensive, readily available,
and environmentally compatible scaffolds, could enable the
acceleration of Pd(II)-catalyzed oxidative C−H cross-coupling
1
0
of Pd(II) in the dehydrogenative Heck reactions of pyridines
11
and electron-deficient benzenes, giving diversely function-
alized alkenylated (hetero)arenes via a non-chelate-assisted C−
5
12
reactions. However, these fantastic ligands are currently
H activation (Scheme 1b). Theoretical studies by density
applied in promoting the directed C−H functionalization
functional theory (DFT) show that the MPAA ligand plays a
crucial role in promoting the transformation, through two
property reversals between one electron donor (X-type) and
two electron donor (L-type) ligands for the amino scaffold and
1i−k,5,6
with directing group-bearing reactants,
thus limiting the
scope of accessible compounds (Scheme 1a). The performance
of these attractive ligands in non-chelate-assisted C−H
7
activation of simple (hetero)arenes is unexplored, despite a
known example showing a slight promotion of Pd(II)-catalyzed
arylation.
Received: September 4, 2013
Published: October 9, 2013
8
©
2013 American Chemical Society
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Scheme 1. MPAA Ligand-Promoted C−H Activation
Reactions with Palladium
weakly coordinative property of MPAA ligands may facilitate
carbopalladation, reductive elimination, and reoxidation for
regeneration of the catalytic species.
With this hypothesis in mind, the evaluation of MPAA
ligands was performed by treatment of pyridine with butyl
acrylate under a molecular oxygen atmosphere (Table 1). A
a,b
Table 1. Evaluation of MPAA Ligands
the formation of an intramolecular hydrogen bond with the
carboxyl group, resulting in relatively low activation barriers for
the steps of C−H activation and carbopalladation (Scheme 2).
a
Reaction conditions: 1a (8.0 mmol), 2a (0.5 mmol), Pd(OAc) (10
2
mol %), MPAA ligand (20 mol %), and KHCO (40 mol %) in tert-
amyl-OH (2.0 mL) at 130 °C for 12 h under O (1 atm). Isolated
yield of C3-selective product. GC yield using tridecane as the internal
standard. The regioisomeric ratio of C3-, C4-, and C2-selective
products was determined by H NMR analysis of the crude products
using 1,1,2,2-tetrachloroethane as the internal standard. The desired
3
b
2
c
a
Scheme 2. DFT Results for Key Elementary Steps
d
1
e
product was not detected by GC/MS analysis.
control experiment without an MPAA ligand shows the
formation of only a trace amount of the desired coupling
product 3a. Further studies showed that the N-protecting
groups on the amino scaffold strongly influence the trans-
formation. Using the protecting-group-free L-valine, the
reaction was proved not to occur. Mono-N-acetylated glycine
slightly promotes the conversion with formation of 3a in 10%
yield. It is noteworthy that the installation of bulky alkyl
substituents (e.g., Ala, Val, Ile, Leu, and Phe) on the α-position
of mono-N-acetyl-protected amino acids allows for a dramatic
increase of the rates of the transformation and selectivity. Of
these, α-isopropyl-substituted L-N-acetyl-valine (Ac-Val-OH)
was identified as the optimal ligand, giving rise to C3-selective
alkenylpyridine 3a in good yield (70%) with high regiose-
lectivity (C3/C4/C2 = 14/1/0). However, replacing the acetyl
group with the bulky tert-butoxycarbonyl (Boc) produced a
significantly decreased yield (9%). MPAA ligands containing
benzoyl and electron-donating alkyl protecting groups failed to
give the desired product.
Having established the optimal ligand of Ac-Val-OH (see
Supporting Information for specific parameter optimization),
we next examined the substrate scope for the synthesis of
diversely functionalized alkenylpyridines. As shown in Table 2,
a wide range of functional groups, including chloride,
trifluoromethyl, alkoxy, alkoxycarbonyl, amide, cyano, and
nitro, can be effectively incorporated into the frameworks of
the alkenylated pyridines. Numerous monosubstituted alkenes
allow facile coupling with pyridine, leading to C3-selective
a
Values in parentheses are relative Gibbs free energies
RESULTS AND DISCUSSION
■
Pd(II)-Catalyzed Dehydrogenative Heck Reactions of
Pyridines. MPAA Ligand Screening. Pyridines are syntheti-
cally useful structural motifs and are found in a variety of
biologically active natural products, pharmaceuticals, agro-
13
chemicals, and materials. Because of their electron-density-
poor nature, the direct C−H functionalization of pyridines
remains a significant challenge.
Hiyama’s, and Chatani’s pioneering works on the development
of phosphine
moted non-chelate-assisted C−H activation of pyridines, we
envisioned that N,O-supported MPAAs could serve as
cooperative ligands in adjusting the electron density and steric
circumstance around the palladium center. Meanwhile, the
14−16
Inspired by Sames’s, Yu’s,
1
4a−c,17
10a
and 1,10-phenanthroline
ligand-pro-
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Table 2. Pd(II)-Catalyzed Dehydrogenative Heck Reactions
of Pyridines
Pd(II)-Catalyzed Dehydrogenative Heck Reactions of
Electron-Deficient Arenes. MPAA Ligand Screening.
Inspired by the achievements of MPAA ligand-promoted
dehydrogenative Heck reactions of pyridines, we next turned
our attention to broadening the reaction scope for developing a
general synthetic procedure. In view of their electron-deficient
nature, analogous with pyridines, we chose strongly electron-
withdrawing group substituted benzenes as partners to react
with simple olefins. Different from the couplings of pyridines,
electron-deficient benzenes allow facile coupling with alkenes at
relatively low temperature (90 °C, Table 3). Similarly, the N-
a,b
Table 3. Influence of MPAA Ligands on the
Dehydrogenative Heck Coupling of Electron-Deficient
a
Benzene
b
entry
MPAA ligand
yield (%)
c
1
2
3
4
5
6
7
8
none
<2
c
Ac-Gly-OH
Ac-Ala-OH
Ac-Val-OH
Ac-Ile-OH
Ac-Leu-OH
Ac-Phe-OH
Boc-Val-OH
<2
6
64
85
75
43
28
a
a
Reaction conditions: 4a (10.0 mmol), 2b (0.5 mmol), Pd(OAc) (10
2
Reaction conditions: 1 (8.0 mmol), 2 (0.5 mmol), Pd(OAc) (10
2
mol %), MPAA ligand (20 mol %), and KHCO (40 mol %) in tert-
amyl-OH (1.0 mL) at 90 °C for 36 h under O (1 atm). Isolated
yields are shown. GC yield using tridecane as the internal standard.
3
mol %), Ac-Val-OH (20 mol %), and KHCO (40 mol %) in tert-amyl-
OH (2.0 mL) at 130 °C for 12 h under O (1 atm). Isolated yields
are shown. Ag CO (0.5 equiv) was used as the oxidant in DMA (1.0
3
b
b
2
2
c
c
2
3
d
e
mL) under air. 24 h. 36 h.
protecting groups and α-alkyl substituents on the MPAA
ligands heavily influence the catalytic activities of Pd(II) in the
transformation. α-Isobutyl-substituted Ac-Ile-OH was shown to
be superior to Ac-Val-OH, Ac-Leu-OH, and Ac-Phe-OH,
affording meta-selective alkenylated product 5h in 85% yield
products (3a−3h) in moderate to good yields (43−75%). Even
for the more challenging internal alkene partners, the reactions
occur with high regio- and stereoselectivities, leading to
synthetically important trisubstituted E-olefins (3i and 3j) as
the sole products. It is noted that a mixture of 3k and the
isomeric product 3k′ was observed when using 1,1′-
disubstituted butyl methacrylate.
(
entry 5). In addition, Boc-protected Val-OH also enabled
improvement of the transformation, albeit with lower yield
(
28%, entry 8).
With the optimal Ac-Ile-OH ligand, the scope of electron-
deficient arenes was explored by treatment with 2b (Table 4).
The reactions using electron-withdrawing trifluoromethyl-,
nitro-, and alkoxycarbonyl-incorporated benzenes furnish
meta-selective (E)-alkenylated products (5a−5c) as major
regioisomers (54−74% total yields, up to 4.88 m/p ratio). It
is worth mentioning that introducing the methoxy group to the
para-site of nitrobenzene dramatically increases the conversion,
leading to the desired product 5d in excellent yield (96%).
Using para-methyl and fluoride-substituted electron-deficient
benzenes, the desired alkenylbenzenes (5e−5h) can be easily
accessed with good yields (62−85%). In addition, 1,3-
bis(trifluoromethyl)benzene and pentafluorobenzene are also
efficient coupling partners in the transformation (5i and 5j).
Aryl fluorides and their derivatives are valuable synthetic
structural motifs because of their unique biological and
pharmaceutical activity; thus, the use of these chemicals as
starting materials to construct fluoride-incorporated complex
Subsequently, the scope of pyridines was probed by
treatment with butyl acrylate and N,N-dimethylacrylamide.
To our delight, various monosubstituted pyridines, no matter
the substituents placed at the C2-, C3-, and C4-position, react
easily with alkenes, giving the corresponding dehydrogenative
Heck coupling products (3l−3s) in moderate yields (35−61%).
Interestingly, the use of 2-methoxypyridine gives a mixture of
C3- and C5-selective alkenylpyridines (3t and 3t′) in a nearly
1
:1 regioisomeric ratio. Importantly, introducing an electron-
donating methoxy group into the skeleton of 3-trifluorome-
thylpyridine dramatically improves the transformation, leading
to C3-alkenylated products (3u and 3v) in satisfactory yields
(
76% and 80%). In contrast, replacement of trifluoromethyl
with nitro produces a lower performance in the reaction (3w).
In addition, symmetric 2,6-disubstituted pyridines are also
found to be suitable reactants (3x−3z). In particular, using
18
biologically active pyrimidine and quinoline, the related
coupling products 3aa and 3ab can be easily accessed by this
procedure, even though the yields are lower.
19
molecules is of significant interest. On the basis of this
consideration, we then employed para-fluoride-substituted
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Table 4. Pd(II)-Catalyzed Dehydrogenative Heck Reactions
of Electron-Deficient Arenes
N−H Bond Activation Mechanism (cp-1 → cp-4).
a,b
Following the pioneering mechanistic studies of Musaev, Yu,
9
and Blackmond, we envisioned that an analogous N−H
activation to convert to the related X-type ligand scaffold from
the L-type amino motif may initially take place. DFT
calculations show that an uncoordinated acetate anion
−
(
OAc ) can serve as a base to abstract the proton of the
amino group (Figure 1), which may be derived from a
a
Reaction conditions: 4 (4.0−10.0 mmol), 2 (0.5 mmol), Pd(OAc)2
(10 mol %), Ac-Ile-OH (20 mol %), and KHCO (40 mol %) in tert-
3
Figure 1. Free energy profiles for the N−H bond activation in
pentanol.
b
amyl-OH (1.0 mL) at 90 °C for 36 h under O (1 atm). Isolated
yields are shown. Using KHCO3 (1.0 mmol) and PivOH (0.25
mmol) for 48 h. Ag CO (0.5 equiv) was used as the oxidant in DMA
2
c
d
2
3
nucleophilic substitution of pyridine with a N,O-supported
palladium complex. A low-energy barrier (+4.1 kcal/mol) was
observed through the transition state TS-1, which undergoes
two consecutive exothermic processes leading to N,O-bound
Pd(pyridyl) σ-donor cp-4. Notably, without the N−H cleavage,
the following C−H bond activation was proved to be
thermodynamically unfavorable with a very high activation
barrier (+37.0 kcal/mol), which can be ruled out in the
transformation (see Supporting Information for specific
information).
(
1.0 mL) under air.
electron-deficient benzenes as reactants to explore the scope of
alkene partners. Substituted alkenes containing functional
groups, such as carbonyl, alkoxycarbonyl, phosphoryl oxygen,
and pentafluorophenyl, easily undergo this transformations,
giving meta-selective alkenylbenzenes (5k−5r) in good yields
(
48−83%). Interestingly, the internal alkene of trans-methyl
crotonate can also be used in the reaction, and the formation of
the single E-conformational product 5s was observed. Besides
electron-deficient arenes, benzene is also suitable, giving the
desired alkenylated benzene 5t in 78% yield.
C−H Activation Mechanism (cp-4 → cp-6). With the σ-
donor cp-4, a reversible ligand exchange may take place with an
endothermicity of 17.1 kcal/mol to overcome the energy
Computational Studies. For insight into the rational
design of new ancillary ligands, a mechanistic understanding of
the role of ligands in the reaction is important. In particular,
there are four mechanistic problems that need to be addressed
in the dehydrogenative Heck coupling of pyridines: (1)
understanding the role of the Ac-Val-OH ligand in the
transformation; (2) finding theoretical evidence to support
C3-regioselectivity; (3) theoretical proposing of a viable
mechanism for non-chelate-assisted C−H activation; and (4)
identifying the turnover-limiting step in the reaction.
10a,20
barrier, leading to π-donor cp-5 (Figure 2).
To our
knowledge, four kinds of possible mechanisms, including
1k,21
concerted metalation/deprotonation (CMD),
σ-bond
22
23
metathesis, oxidative addition, and electrophilic pallada-
tion, can be considered in the reaction pathway of Pd-
24
mediated C−H activation. Because of the achievement of a C3-
positional alkenylated product (eq 1), C3-selective C−H
activation was calculated for identifying the relevant mechanism
(
see Supporting Information for free energy profiles).
25
Analogously with Zhang’s report, a CMD mechanism is
suggested to be involved in the C−H activation step with a
relatively low activation barrier of +31.0 kcal/mol, because the
coordinated acetate moiety serves as an internal base to form a
six-membered-ring transition state, TS-2CMD (Figure 2). The
key bond lengths of Pd−Cipso, Cipso−H, and H−O2 are 2.19,
1.44, and 1.21 Å, respectively (see Supporting Information).
Clearly, a relatively strong alcohol binding with a slight
Because it is difficult to isolate and characterize stable Pd(II)
intermediates, computational studies by DFT were then
performed for the exploration of a plausible mechanism and
disentangling the problems in the catalytic cycle. Taking into
account the significant application value and interesting
mechanistic details, the dehydrogenative Heck coupling
between pyridine and ethyl acrylate was chosen as the reaction
model with the Ac-Val-OH ligand and Pd(OAc)2 under
standard conditions (eq 1).
lengthening of the C −H bond was observed in the
ipso
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cp-5, the activation barrier for the C4-selective transition state
TS-2′
is calculated to be +31.9 kcal/mol, which is only 0.9
CMD
kcal/mol higher than that for the C3-positional transition state
⧧
TS-2CMD (Figure 2). Such a small activation energy gap (ΔΔE
=
+0.9 kcal/mol) implies that the C4-selective alkenylated
product can also be produced, which is consistent with the
experimental result that the C4-positional compound was
1
detected by H NMR analysis of the crude products (C3/C4/
C2 = 8/1/0) (eq 1). However, the C2-positional transition
state TS-2″
has a much higher activation barrier (+32.4
kcal/mol), making it thermodynamically unfavorable.
CMD
Carbopalladation, β-Hydride Elimination, and Catalyst
Regeneration. Subsequently, a property reversal for the amino
scaffold from X-type to L-type ligand can be considered by the
abstraction of a proton from an external acetic acid, allowing
facile substitution with the alkene partner. Notably, the
coordinated acetic acid enables the formation of an intra-
molecular hydrogen bond with the carboxyl group on the Ac-
Val-OH ligand (Figure 3). Thus, a relatively low activation
barrier (+29.8 kcal/mol) for the insertion of alkene into the
Figure 2. Free energy profiles for site-selective activation of C−H
bonds of pyridine in pentanol.
Pd−C bond was observed, affording Pd−alkyl species cp-9
ipso
transformation. Subsequent cleavage of the C −H bond
through a four-membered-ring transition state (TS-3). In
contrast, because of its very high activation barrier (+46.8 kcal/
mol) for the carbopalladation through the transition state TS-
3′, a direct ligand exchange by substitution with the alkene
ipso
produces the C-bound Pd(II) species cp-6 .
Int
A theoretical explanation for site-selective activation of C−H
bonds of pyridine was then carried out. Starting from π-donor
Figure 3. Free energy profiles for the steps for alkene insertion and catalyst regeneration in pentanol.
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partner to form cp-8′ can be ruled out in the reaction pathway
A comprehensive theoretical study for the mechanistic
understanding of the role of MPAA ligands by DFT
calculations discloses that the amino scaffold on the Ac-Val-
OH can convert to the X-type ligand by an initial N−H
activation, resulting in a relatively low activation barrier for the
C−H activation of pyridine. Then a property reversal of the
amino group from X-type to L-type ligand favors the
substitution with the alkene partner, while the carboxyl of the
MPAA ligand allows the formation of an intramolecular
hydrogen bond to largely decrease the activation barrier in
the carbopalladation step. The results of calculations and KIE
measurement support a rate-limiting C−H cleavage of pyridine
by a mechanism involving a CMD mechanism. In addition, the
C3-site selectivity of pyridine was also evidenced by the results
of computational studies. Further kinetic studies are ongoing in
our laboratory.
(
see Supporting Information for completely free energy profiles
of this route).
Following this, an intramolecular rotation followed by β-
hydride elimination may take place smoothly, giving rise to the
Pd(II)−hydride intermediate cp-10. By substitution with the
acetic acid, the desired alkenylated pyridine can be dissociated,
providing the hydrogen-bond-mediated complex cp-11, which
can undergo a reductive elimination giving a Pd(0) complex
(
cp-12). Finally, in the presence of molecular oxygen, the
Pd(II) cp-13 can be regenerated through a reoxidation with the
formation of water as the side product (exothermicity of 72.2
kcal/mol), which facilely transforms to the N,O-bound active
catalytic species cp-1 by a ligand exchange.
Overview of the Role of the MPAA Ligand and the Rate-
Limiting Step. From the results of our theoretical calculations,
the role of the Ac-Val-OH ligand can be addressed in the
following three ways: (1) it serves as an X-type ligand to bind
with Pd(II) by an initial N−H activation; (2) the amino
scaffold enables facile property reversal to convert to an L-type
ligand and thus favors the alkene substitution; (3) the carboxyl
group allows the formation of an intramolecular hydrogen bond
with an internal acetic acid, rendering the activation barriers in
the steps of C−H cleavage and carbopalladation largely
decreased.
EXPERIMENTAL SECTION
■
All reactions dealing with air- or moisture-sensitive compounds were
carried out in a flame-dried, sealed Schlenk reaction tube under an
atmosphere of nitrogen. Analytical thin-layer chromatography was
performed on glass plates coated with 0.25 mm 230−400 mesh silica
gel containing a fluorescent indicator (Merck). Flash silica gel column
chromatography was performed on silica gel 60N (spherical and
neutral, 140−325 mesh) as described by Still. NMR spectra were
measured on a Bruker AV-400 spectrometer and reported in parts per
As compared with other elementary steps, such as N−H
bond activation, carbopalladation, β-hydride elimination,
reductive elimination, and reoxidation, the C−H bond cleavage
million. 1H NMR spectra were recorded at 400 MHz in CDCl
referenced internally to tetramethylsilane as a standard, and C NMR
3
13
spectra were recorded at 100 MHz and referenced to the solvent
resonance. Analytical gas chromatography (GC) was carried out on a
Thermo Trace 1300 gas chromatograph, equipped with a flame
ionization detector. Mass spectra (GC-MS) were taken on a Thermo
Trace 1300 gas chromatograph mass spectrometer. High-resolution
through the six-membered ring TS-2
has the highest
CMD
⧧
activation barrier (ΔE = +31.0 kcal/mol), which is
thermodynamically unfavorable and can be considered as the
turnover-determining step in the transformation.
(
HR-MS) mass spectra were recorded by ESI-TOF. Melting points
Kinetic Isotope Effect (KIE) Experiment. To identify this, a
were determined with a Hanon MP-300. Unless otherwise noted,
materials were purchased from Tokyo Chemical Industry Co., Aldrich
Inc., and other commercial suppliers and used as received. Solvents
H/D KIE measurement was carried out next. Compared with
10a
Yu’s result (K /K = 4.0), a slightly lower KIE value of 3.0
H
D
was observed in our experiment (Scheme 3). This result is
were dried over CaH (for DMA, DCE, and DCM) or sodium (for
2
dioxane) by refluxing overnight and freshly distilled prior to use. tert-
Amyl-OH was purchased from commercial suppliers and used directly
without further purification. Mono-N-protected amino acid ligands
including Ac-Gly-OH, Ac-Ala-OH, Ac-Val-OH, Ac-Ile-OH, Ac-Leu-
OH, Ac-Phe-OH, Boc-Val-OH, Boc-Trp-OH, and PhCO-Val-OH
Scheme 3. H/D KIE Experiment
5
a,26
were prepared according to the literature.
General Procedure for MPAA Ligand-Promoted Dehydro-
genative Heck Reactions of Pyridines with Palladium(II). In a
dried Schlenk flask were placed pyridine derivative 1 (8.0 mmol),
alkene 2 (0.5 mmol), Pd(OAc) (11 mg, 10 mol %), Ac-Val-OH (16
2
mg, 20 mol %), and KHCO (20 mg, 0.2 mmol). Then 2 mL of tert-
3
amyl-OH was added with a syringe under molecular oxygen
atmosphere. The resulting mixture was stirred at room temperature
for 10 min and then heated at 130 °C for 12 h. After cooling to room
temperature, the reaction mixture was diluted with 5 mL of CH Cl
consistent with a thermodynamically unfavorable C−H
activation step, and it may indicate that the Ac-Val-OH ligand
enhances the electrophilic property of the palladium center in
promoting the C−H bond cleavage of pyridine.
2
2
and filtered through a plug of Celite, followed by washing with 10−20
mL of CH Cl . The combined residue was concentrated under
2
2
reduced pressure, and then the resulting crude product was purified by
column chromatography on silica gel to provide the C3-alkenylated
pyridine 3.
CONCLUSIONS
■
In summary, we have developed a general, practically useful
MPAA ligand-accelerated palladium(II) catalytic system for the
dehydrogenative Heck reactions of pyridines and electron-
deficient benzenes via non-chelate-assisted C−H activation.
The protocol features the use of inexpensive and readily
available Ac-Val-OH and Ac-Ile-OH as crucial ligands, environ-
mentally benign molecular oxygen as oxidant, high chemo-,
regio-, and stereoselectivities, and broad substrate scope with a
wide range of functional group tolerance.
(E)-3-(Pentafluorostyryl)pyridine (Table 2, 3h). The general
procedure was applied to pyridine (8.0 mmol) and 2,3,4,5,6-
pentafluorostyrene (97 mg, 0.5 mmol) at 130 °C for 12 h under 1
atm of O . The crude product was purified by column chromatography
2
on silica gel (EtOAc/PE, 1/9) to afford the title compound as a white
1
solid (91 mg, 67% yield). Mp: 96−98 °C. H NMR (400 MHz,
CDCl ): δ 8.73 (s, 1H), 8.56 (s, 1H), 7.86 (d, J = 7.2 Hz, 1H), 7.39 (d,
3
13
J = 16.8 Hz, 1H), 7.33 (s, 1H), 7.02 (d, J = 16.8 Hz, 1H); C NMR
(100 MHz, CDCl ): δ 149.9, 148.9, 146.3 (m), 143.8 (m), 141.6 (m),
3
139.2 (m), 136.7 (m), 133.4 (td, J = 9.0, 3.0 Hz), 133.1, 132.3, 123.8,
6
570
dx.doi.org/10.1021/om400890p | Organometallics 2013, 32, 6565−6575

Organometallics
Article
1
15.0 (d, J = 3.0 Hz), 111.7 (td, J = 14.0, 5.0 Hz). 19F NMR (377
MHz, CDCl ): δ −142.37 (dd, J = 21.1, 7.5 Hz, 2F), −155.19 (t, J =
(EtOAc/PE, 1/4) to afford the title compound as a white solid (40
1
mg, 35% yield). Mp: 51−53 °C. H NMR (400 MHz, CDCl ): δ 8.93
3
3
+
21.1 Hz, 1F), −162.51 (td, J = 21.9, 7.9 Hz, 2F). HRMS (ESI ): calcd
(s, 1H), 8.86 (s, 1H), 8.09 (s, 1H), 7.62 (d, J = 16.0 Hz, 1H), 6.56 (d, J
= 16.0 Hz, 1H), 4.22 (t, J = 6.4 Hz, 2H), 1.73−1.66 (m, 2H), 1.48−
+
for C H F N [M + H] 272.0499, found 272.0504.
13
6 5
1.39 (m, 5H), 0.95 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ):
(E)-Butyl 2-Methyl-3-(pyridin-3-yl)acrylate (Table 2, 3k). The
3
general procedure was applied to pyridine (8.0 mmol) and butyl 2-
methacrylate (71 mg, 0.5 mmol) at 130 °C for 12 h under 1 atm of O2.
The crude product was purified by column chromatography on silica
δ 165.8, 152.9, 152.4, 138.2, 137.3, 130.7, 123.4, 116.1, 110.6, 65.2,
+
+
30.7, 19.3, 13.9. HRMS (ESI ): calcd for C H N O [M + H]
13
14
2
2
231.1134, found 231.1131.
gel (EtOAc/PE, 1/4) to afford the title compound as a colorless oil
(E)-Butyl 3-(5-Ethoxycarbonylpyridin-3-yl)acrylate (Table 2, 3p).
The general procedure was applied to ethyl nicotinate (8.0 mmol) and
butyl acrylate (64 mg, 0.5 mmol) at 130 °C for 36 h under 1 atm of
1
(
15 mg, 14% yield). H NMR (400 MHz, CDCl ): δ 8.64 (s, 1H), 8.54
3
(
6
d, J = 2.8 Hz, 1H), 7.69 (d, J = 8.0 Hz, 1H), 7.62 (s, 1H), 7.32 (t, J =
.4 Hz, 1H), 4.21 (t, J = 6.4 Hz, 2H), 2.12 (s, 3H), 1.74−1.68 (m,
O . The crude product was purified by column chromatography on
2
13
2
H), 1.49−1.40 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H). C NMR (100
silica gel (EtOAc/PE, 1/4) to afford the title compound as a white
MHz, CDCl ): δ 168.3, 150.7, 149.2, 136.5, 135.0, 131.9, 131.1, 123.4,
1
3
solid (64 mg, 46% yield). Mp: 52−54 °C. H NMR (400 MHz,
+
6
5.2, 30.8, 19.4, 14.3, 13.9. HRMS (ESI ): calcd for C H NO [M +
13 17 2
CDCl ): δ 9.18 (s, 1H), 8.87 (s, 1H), 8.43 (s, 1H), 7.68 (d, J = 16.0
3
+
H] 220.1338, found 220.1335.
Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 4.41 (q, J = 7.2 Hz, 2H), 4.21 (t, J
Butyl 2-(Pyridin-3-ylmethyl)acrylate (Table 2, 3k′). The crude
=
6.4 Hz, 2H), 1.73−1.66 (m, 2H), 1.48−1.41 (m, 5H), 0.94 (t, J = 7.2
product was purified by column chromatography on silica gel (EtOAc/
13
Hz, 3H). C NMR (100 MHz, CDCl ): δ 166.3, 164.9, 153.0, 151.8,
3
PE, 1/4) to afford the title compound as a colorless oil (30 mg, 28%
1
39.8, 135.1, 130.2, 126.6, 121.9, 65.0, 61.9, 30.8, 19.3, 14.4, 13.9.
1
yield). H NMR (400 MHz, CDCl ): δ 8.47 (s, 2H), 7.51 (d, J = 7.6
+
+
3
HRMS (ESI ): calcd for C H NO [M + H] 278.1392, found
15 19 4
Hz, 1H), 7.20 (d, J = 6.4 Hz, 1H), 6.27 (s, 1H), 5.51 (s, 1H), 4.09 (t, J
2
78.1390.
E)-N,N-Dimethyl 3-(5-Ethoxycarbonylpyridin-3-yl)acrylamide
(Table 2, 3q). The general procedure was applied to ethyl nicotinate
8.0 mmol) and N,N-dimethylacrylamide (50 mg, 0.5 mmol) at 130
=
0
6.4 Hz, 2H), 3.62 (s, 2H), 1.63−1.56 (m, 2H), 1.37−1.28 (m, 2H),
(
.88 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ 166.6, 150.5,
3
1
48.0, 139.4, 136.5, 134.4, 126.9, 123.4, 65.0, 35.5, 30.6, 19.2, 13.8.
(
+
+
HRMS (ESI ): calcd for C H NO [M + H] 220.1338, found
13
17
2
°C for 36 h under 1 atm of O . The crude product was purified by
2
2
20.1337.
column chromatography on silica gel (acetone/PE, 3/7) to afford the
(
E)-Butyl 3-(5-Methylpyridin-3-yl)acrylate (Table 2, 3l). The
title compound as a white solid (60 mg, 48% yield). Mp: 133−135 °C.
general procedure was applied to 3-methylpyridine (8.0 mmol), and
1
H NMR (400 MHz, CDCl ): δ 9.14 (s, 1H), 8.85 (s, 1H), 8.41 (s,
3
butyl acrylate (64 mg, 0.5 mmol) at 130 °C for 12 h under 1 atm of
1
6
H), 7.66 (d, J = 15.6 Hz, 1H), 7.02 (d, J = 15.6 Hz, 1H), 4.40 (q, J =
O . The crude product was purified by column chromatography on
13
2
.8 Hz, 2H), 3.19 (s, 3H), 3.07 (s, 3H), 1.40 (t, J = 6.8 Hz, 3H).
C
silica gel (EtOAc/PE, 1/4) to afford the title compound as a colorless
NMR (100 MHz, CDCl ): δ 165.7, 165.1, 153.0, 151.1, 137.6, 134.8,
1
3
oil (67 mg, 61% yield). H NMR (400 MHz, CDCl ): δ 8.54 (d, J =
+
3
1
31.1, 126.5, 120.9, 61.9, 37.6, 36.1, 14.4. HRMS (ESI ): calcd for
C H N O [M + H] 249.1239, found 249.1236.
2
1
(
.0 Hz, 1H), 8.42 (d, J = 1.6 Hz, 1H), 7.65−7.61 (m, 2H), 6.47 (d, J =
+
13
16
2
3
6.4 Hz, 1H), 4.19 (t, J = 6.4 Hz, 1H), 1.72−1.65 (m, 1H), 1.47−1.38
m, 1H), 0.94 (d, J = 7.2, 1H); 13C NMR (100 MHz, CDCl ): δ 166.6,
(E)-Butyl 3-(4-Methylpyridin-5-yl)acrylate (Table 2, 3r). The
general procedure was applied to 4-methylpyridine (8.0 mmol) and
butyl acrylate (64 mg, 0.5 mmol) at 130 °C for 12 h under 1 atm of
3
1
1
2
51.6, 147.0, 141.1, 134.8, 133.5, 129.9, 120.4, 64.8, 30.8, 19.3, 18.5,
+
+
3.9. HRMS (ESI ): calcd for C H NO [M + H] 220.1338, found
13
17
2
O . The crude product was purified by column chromatography on
2
20.1339.
E)-Butyl 3-(5-Chloropyridin-3-yl)acrylate (Table 2, 3m). The
silica gel (EtOAc/PE, 1/4) to afford the title compound as a colorless
(
1
oil (54 mg, 49% yield). H NMR (400 MHz, CDCl ): δ 8.72 (s, 1H),
3
general procedure was applied to 3-chloropyridine (8.0 mmol) and
8
1
1
.44 (d, J = 5.2 Hz, 1H), 7.86 (d, J = 16.0 Hz, 1H), 7.13 (d, J = 5.2 Hz,
butyl acrylate (64 mg, 0.5 mmol) at 130 °C for 12 h under 1 atm of
H), 6.43 (d, J = 16.0 Hz, 1H), 4.22 (t, J = 6.8 Hz, 2H), 2.44 (s, 3H),
O . The crude product was purified by column chromatography on
2
13
.74−1.67 (m, 2H), 1.49−1.40 (m, 2H), 0.96 (t, J = 7.2 Hz, 3H).
C
silica gel (EtOAc/PE, 1/9) to afford the title compound as a white
1
NMR (100 MHz, CDCl ): δ 166.7, 150.3, 147.9, 146.0, 139.3, 130.1,
solid (55 mg, 46% yield). Mp: 84−86 °C. H NMR (400 MHz,
3
+
1
25.5, 121.3, 64.8, 30.8, 19.5, 19.3, 13.9. HRMS (ESI ): calcd for
CDCl ): δ 8.60 (s, 1H), 8.55 (s, 1H), 7.82 (s, 1H), 7.59 (d, J = 16.0
3
+
C H NO [M + H] 220.1338, found 220.1337.
Hz, 1H), 6.49 (d, J = 16.0 Hz, 1H), 4.20 (t, J = 6.8 Hz, 2H), 1.72−1.65
13 17
2
1
3
(E)-N,N-Dimethyl 3-(4-Methylpyridin-5-yl)acrylamide (Table 2,
s). The general procedure was applied to 4-methylpyridine (8.0
(
m, 2H), 1.47−1.38 (m, 2H), 0.94 (t, J = 7.2 Hz, 3H). C NMR (100
3
MHz, CDCl ): δ 166.1, 149.8, 147.4, 139.3, 133.8, 132.6, 131.5, 122.1,
3
+
mmol) and N,N-dimethylacrylamide (50 mg, 0.5 mmol) at 130 °C for
6
5.0, 30.8, 19.3, 13.9. HRMS (ESI ): calcd for C H ClNO [M +
12 14 2
+
12 h under 1 atm of O . The crude product was purified by column
H] 240.0791, found 240.0799.
E)-Butyl 3-(5-Trifluoromethylpyridin-3-yl)acrylate (Table 2, 3n).
2
chromatography on silica gel (acetone/PE, 3/7) to afford the title
(
1
compound as a white solid (55 mg, 58% yield). Mp: 124−126 °C. H
The general procedure was applied to 3-(trifluoromethyl)pyridine (8.0
mmol) and butyl acrylate (64 mg, 0.5 mmol) at 130 °C for 36 h under
NMR (400 MHz, CDCl ): δ 8.68 (s, 1H), 8.39 (d, J = 2.8 Hz, 1H),
3
7
.82 (d, J = 15.6 Hz, 1H), 7.10 (d, J = 3.2 Hz, 1H), 6.84 (d, J = 15.2
1
atm of O . The crude product was purified by column
2
1
3
Hz, 1H), 3.18 (s, 3H), 3.07 (s, 3H), 2.40 (s, 3H). C NMR (100
chromatography on silica gel (EtOAc/PE, 1/4) to afford the title
1
MHz, CDCl ): δ 166.1, 149.8, 147.4, 145.9, 137.1, 131.1, 125.4, 120.5,
compound as a white solid (68 mg, 50% yield). Mp: 52−54 °C. H
3
+
+
3
7.6, 36.1, 19.5. HRMS (ESI ): calcd for C H N O [M + H]
NMR (400 MHz, CDCl ): δ 8.92 (s, 1H), 8.86 (s, 1H), 8.05 (s, 1H),
11 14 2
3
1
91.1184, found 191.1181.
E)-Butyl 3-(2-Methoxypyridin-3-yl)acrylate (Table 2, 3t). The
7
.67 (d, J = 16.4 Hz, 1H), 6.58 (d, J = 16.0 Hz, 1H), 4.22 (t, J = 6.4
Hz, 2H), 1.73−1.66 (m, 2H), 1.48−1.39 (m, 2H), 0.95 (t, J = 7.2 Hz,
H). 13C NMR (100 MHz, CDCl ): δ 166.0, 152.5, 147.44 (q, J = 4.0
(
general procedure was applied to 2-methoxypyridine (8.0 mmol) and
butyl acrylate (64 mg, 0.5 mmol) at 130 °C for 12 h under 1 atm of
3
3
Hz), 139.1, 131.21 (q, J = 4.0 Hz), 130.5, 126.60 (q, J = 33.0 Hz),
1
9
1
24.6, 122.7, 121.9, 65.1, 30.8, 19.3, 13.9. F NMR (377 MHz,
O
2
. The crude product was purified by column chromatography on
+
+
CDCl ): δ −62.64. HRMS (ESI ): calcd for C H F NO [M + H]
silica gel (EtOAc/PE, 1/9) to afford the title compound as a colorless
3
13 14
3
2
1
2
74.1055, found 274.1060.
oil (39 mg, 33% yield). H NMR (400 MHz, CDCl ): δ 8.16 (d, J =
3
(
E)-Butyl 3-(5-Cyanopyridin-3-yl)acrylate (Table 2, 3o). The
3.6 Hz, 1H), 7.77 (d, J = 16.4 Hz, 1H), 7.72 (d, J = 8.8 Hz, 1H), 6.90
(t, J = 4.8 Hz, 1H), 6.59 (d, J = 16.0 Hz, 1H), 4.19 (t, J = 6.4 Hz, 2H),
4.03 (s, 3H), 1.73−1.66 (m, 2H), 1.48−1.39 (m, 2H), 0.94 (t, J = 7.6
general procedure was applied to nicotinonitrile (8.0 mmol), butyl
acrylate (64 mg, 0.5 mmol), Pd(OAc) (11 mg, 0.05 mmol), Ac-Val-
OH (16 mg, 0.1 mmol), KHCO (20 mg, 0.2 mmol), and Ag CO (70
mg, 0.25 mmol) in DMA (1 mL) at 130 °C for 36 h under air. The
crude product was purified by column chromatography on silica gel
2
Hz, 3H). 13C NMR (100 MHz, CDCl
): δ 167.4, 162.1, 148.2, 139.0,
3
2
3
3
+
138.1, 120.9, 118.2, 117.2, 64.6, 53.9, 30.9, 19.3, 13.9. HRMS (ESI ):
+
calcd for C H NO [M + H] 236.1287, found 236.1287.
13
17
3
6
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dx.doi.org/10.1021/om400890p | Organometallics 2013, 32, 6565−6575

Organometallics
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1
3
(
E)-Butyl 3-(2-Methoxypyridin-5-yl)acrylate (Table 2, 3t′). The
crude product was purified by column chromatography on silica gel
EtOAc/PE, 1/9) to afford the title compound as a colorless oil (37
C NMR (100 MHz, CDCl ): δ 167.5, 163.3, 161.1, 141.2, 136.9,
3
+
116.4, 110.4, 101.8, 53.8, 53.7, 37.5, 36.0. HRMS (ESI ): calcd for
C H N O [M + H] 237.1239, found 237.1235.
+
(
12
16
2
3
1
mg, 31% yield). H NMR (400 MHz, CDCl ): δ 8.26 (s, 1H), 7.75 (d,
J = 8.8 Hz, 1H), 7.60 (d, J = 16.0 Hz, 1H), 6.75 (d, J = 8.8 Hz, 1H),
(E)-N,N-Dimethyl 3-(5-Pyrimidyl)acrylamide (Table 2, 3aa). The
3
general procedure was applied to pyrimidine (8.0 mmol) and N,N-
dimethylacrylamide (50 mg, 0.5 mmol) at 130 °C for 36 h under 1 atm
of O . The crude product was purified by column chromatography on
silica gel (EtOAc/PE, 1/4) to afford the title compound as a white
solid (24 mg, 27% yield). Mp: 175−177 °C. H NMR (400 MHz,
CDCl ): δ 9.16 (s, 1H), 8.87 (s, 2H), 7.57 (d, J = 15.6 Hz, 1H), 7.02
(d, J = 15.6 Hz, 1H), 3.19 (s, 3H), 3.08 (s, 3H). C NMR (100 MHz,
CDCl ): δ 165.4, 158.8, 155.5, 135.1, 129.3, 121.6, 37.6, 36.2. HRMS
(
6
1
.31 (d, J = 16.0 Hz, 1H), 4.18 (t, J = 6.8 Hz, 2H), 3.96 (s, 3H), 1.72−
13
.65 (m, 2H), 1.47−1.38 (m, 2H), 0.94 (t, J = 7.2 Hz, 1H). C NMR
2
(
1
[
100 MHz, CDCl ): δ 167.1, 165.4, 148.4, 141.0, 136.5, 124.0, 117.4,
3
+
1
11.7, 64.6, 54.0, 30.9, 19.3, 13.9. HRMS (ESI ): calcd for C H NO
13
17
3
+
M + H] 236.1287, found 236.1288.
E)-Butyl 3-(2-Methoxy-5-trifluoromethylpyridin-3-yl)acrylate
Table 2, 3u). The general procedure was applied to 2-methoxy-5-
trifluoromethyl)pyridine (8.0 mmol) and butyl acrylate (64 mg, 0.5
3
13
(
(
(
3
+
+
ESI ): calcd for C H N O [M + H] 178.0980, found 178.0979.
9 11 3
mmol) at 130 °C for 12 h under 1 atm of O . The crude product was
purified by column chromatography on silica gel (EtOAc/PE, 1/9) to
afford the title compound as a white solid (115 mg, 76% yield). Mp:
3−45 °C. H NMR (400 MHz, CDCl ): δ 8.43 (s, 1H), 7.94 (s, 1H),
.75 (d, J = 16.4 Hz, 1H), 6.65 (d, J = 16.0 Hz, 1H), 4.21 (t, J = 6.4
2
General Procedure for MPAA Ligand-Promoted Dehydro-
genative Heck Reactions of Electron-Deficient Arenes with
Palladium(II). In a dried Schlenk flask were placed electron-deficient
arene derivative 4 (4.0−10.0 mmol), alkene 2 (0.5 mmol), Pd(OAc)
(11 mg, 10 mol %), Ac-Ile-OH (17 mg, 20 mol %), and KHCO (20
1
4
3
2
7
3
Hz, 1H), 4.09 (s, 3H), 1.74−1.65 (m, 2H), 1.49−1.40 (m, 2H), 0.95
mg, 0.2 mmol). Then 1 mL of tert-amyl-OH was added with a syringe
under a molecular oxygen atmosphere. The resulting mixture was
stirred at room temperature for 10 min and then heated at 90 °C for
36 h. After cooling to room temperature, the reaction mixture was
(
t, J = 7.2 Hz, 3H); 13C NMR (100 MHz, CDCl ): δ 166.8, 163.8,
3
145.5 (q, J = 4.0 Hz), 137.3, 134.6 (q, J = 3.0 Hz), 127.9, 125.2, 122.7,
1
22.5, 120.1 (q, J = 33.0 Hz), 119.8, 118.3, 64.8, 54.7, 30.9, 19.3, 13.9.
1
9
+
F NMR (377 MHz, CDCl ): δ −61.58. HRMS (ESI ): calcd for
diluted with 5 mL of CH
followed by washing with 10−20 mL of CH
2
Cl
2
and filtered through a plug of Celite,
Cl . The combined
3
+
C H F NO [M + H] 304.1161, found 304.1160.
2
2
14
16
3
3
(
E)-N,N-Dimethyl 3-(2-Methoxy-5-trifluoromethylpyridin-3-yl)-
residue was concentrated under reduced pressure, and then the
resulting crude product was purified by column chromatography on
silica gel to provide the meta-selective alkenylated benzene 5.
(E)-N,N-Dimethyl 3-(2-Methoxy-5-nitrophenyl)acrylamide (5d).
The general procedure was applied to 4-nitroanisole (8.0 mmol)
and N,N-dimethylacrylamide (50 mg, 0.5 mmol) at 90 °C for 36 h
acrylamide (Table 2, 3v). The general procedure was applied to 2-
methoxy-5-(trifluoromethyl)pyridine (8.0 mmol) and N,N-dimethyla-
crylamide (50 mg, 0.5 mmol) at 130 °C for 12 h under 1 atm of O2.
The crude product was purified by column chromatography on silica
gel (EtOAc/PE, 1/4) to afford the title compound as a white solid
1
(
110 mg, 80% yield). Mp: 111−113 °C. H NMR (400 MHz, CDCl ):
under 1 atm of O . The crude product was purified by column
3
2
δ 8.39 (s, 1H), 7.89 (s, 1H), 7.70 (d, J = 15.6 Hz, 1H), 7.11 (d, J =
chromatography on silica gel (acetone/PE, 1/4) to afford the title
5.6 Hz, 1H), 4.06 (s, 3H), 3.18 (s, 3H), 3.07 (s, 3H). 13C NMR (100
compound as a white solid (120 mg, 96% yield). Mp: 122−124 °C. H
1
1
MHz, CDCl ): δ 166.4, 163.7, 144.65 (q, J = 5.0 Hz), 135.1, 134.32 (q,
NMR (400 MHz, CDCl ): δ 8.39 (s, 1H), 8.20 (d, J = 8.8 Hz, 1H),
3
3
J = 2.0 Hz), 125.2, 122.5, 122.0, 119.96 (q, J = 43.0 Hz), 119.2, 54.6,
7.89 (d, J = 15.6 Hz, 1H), 7.00 (d, J = 15.6 Hz, 1H), 6.96 (d, J = 9.2
Hz, 1H), 3.97 (s, 3H), 3.19 (s, 3H), 3.07 (s, 3H); C NMR (100
7.6, 36.1. 19F NMR (377 MHz, CDCl ): δ −61.48. HRMS (ESI ):
+
13
3
3
+
calcd for C H F N O [M + H] 275.1007, found 304.1010.
MHz, CDCl ): δ 166.3, 162.5, 141.4, 135.2, 126.3, 125.3, 123.5, 120.7,
12
13
3
2
2
3
+
+
(
E)-N,N-Dimethyl 3-(2-Methoxy-5-nitropyridin-3-yl)acrylamide
111.0, 56.5, 37.6, 36.1. HRMS (ESI ): calcd for C H N O [M + H]
12 14 2 4
(
Table 2, 3w). The general procedure was applied to 2-methoxy-5-
251.1032, found 251.1039.
nitropyridine (8.0 mmol) and N,N-dimethylacrylamide (50 mg, 0.5
(E)-N,N-Dimethyl 3-(2-Fluoro-5-nitrophenyl)acrylamide (5e). The
general procedure was applied to 1-fluoro-4-nitrobenzene (10.0
mmol) and N,N-dimethylacrylamide (50 mg, 0.5 mmol) at 90 °C
mmol) at 130 °C for 12 h under 1 atm of O . The crude product was
2
purified by column chromatography on silica gel (EtOAc/DCM, 1/9)
to afford the title compound as a white solid (25 mg, 20% yield). Mp:
for 36 h under 1 atm of O . The crude product was purified by column
2
1
1
1
1
37−139 °C. H NMR (400 MHz, CDCl ): δ 9.02 (d, J = 2.4 Hz,
chromatography on silica gel (EtOAc/PE, 1/1) to afford the title
3
1
H), 8.51 (d, J = 2.8 Hz, 1H), 7.73 (d, J = 15.6 Hz, 1H), 7.13 (d, J =
compound as a white solid (98 mg, 82% yield). Mp: 120−122 °C. H
5.6 Hz, 1H), 4.13 (s, 3H), 3.20 (s, 3H), 3.09 (s, 3H). 13C NMR (100
NMR (400 MHz, CDCl ): δ 8.44 (dd, J = 6.4, 2.8 Hz, 1H), 8.23−8.19
3
MHz, CDCl ): δ 165.9, 164.8, 144.2, 139.7, 134.1, 131.6, 123.0, 119.5,
(m, 1H), 7.73 (d, J = 15.6 Hz, 1H), 7.28−7.24 (m, 1H), 7.11 (d, J =
3
+
+
13
5
5.4, 37.6, 36.1. HRMS (ESI ): calcd for C H N O [M + H]
15.6 Hz, 1H), 3.21 (s, 3H), 3.09 (s, 3H); C NMR (100 MHz,
11
13
3
4
2
52.0984, found 252.0990.
E)-Butyl 3-(2,6-dimethylpyridin-3-yl)acrylate (Table 2, 3x). The
CDCl ): δ 165.6, 162.9, 144.6 (d, J = 2.0 Hz), 132.5 (d, J = 1.0 Hz),
3
(
125.9 (d, J = 10.0 Hz), 124.8 (d, J = 14.0 Hz), 124.5 (d, J = 5.0 Hz),
1
9
general procedure was applied to 2,6-dimethylpyridine (8.0 mmol)
123.1 (d, J = 7.0 Hz), 117.2 (d, J = 25.0 Hz), 37.6, 36.1. F NMR
+
and butyl acrylate (64 mg, 0.5 mmol) at 130 °C for 12 h under 1 atm
(377 MHz, CDCl ): δ −104.23. HRMS (ESI ): calcd for
3
+
of O . The crude product was purified by column chromatography on
C H FN O [M + H] 239.0832, found 239.0831.
2
11 11
2
3
silica gel (EtOAc/PE, 1/4) to afford the title compound as a colorless
(E)-N,N-Dimethyl 3-[2-Methyl-5-(ethoxycarbonxyl)phenyl]-
acrylamide (5f). The general procedure was applied to ethyl 4-
methylbenzoate (8.0 mmol), N,N-dimethylacrylamide (50 mg, 0.5
1
oil (85 mg, 73% yield). H NMR (400 MHz, CDCl ): δ 7.88 (d, J =
3
16.0 Hz, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.02 (d, J = 8.0 Hz, 1H), 6.32
(
d, J = 15.6 Hz, 1H), 4.21 (t, J = 6.8 Hz, 2H), 2.64 (s, 3H), 2.54 (s,
mmol), Pd(OAc) (11 mg, 10 mol %), Ac-Ile-OH (17 mg, 20 mol %),
2
3
H), 1.73−1.66 (m, 2H), 1.49−1.40 (m, 2H), 0.95 (t, J = 7.2 Hz, 3H).
KHCO (100 mg, 1.0 mmol), and PivOH (26 mg, 0.25 mmol) at 90
3
1
3
C NMR (100 MHz, CDCl ): δ 166.9, 159.5, 156.9, 140.8, 134.1,
°C for 48 h under 1 atm of O . The crude product was purified by
3
2
+
1
26.0, 121.4, 120.1, 64.7, 30.8, 24.6, 22.8, 19.3, 13.9. HRMS (ESI ):
column chromatography on silica gel (acetone/PE, 1/4) to afford the
+
calcd for C H NO [M + H] 234.1494, found 234.1496.
title compound as a white solid (81 mg, 62% yield). Mp: 82−84 °C.
14
19
2
1
(
E)-N,N-Dimethyl 3-(2,6-Dimethoxypyridin-3-yl)acrylamide
Table 2, 3z). The general procedure was applied to 2,6-
dimethoxypyridine (8.0 mmol) and N,N-dimethylacrylamide (50 mg,
.5 mmol) at 130 °C for 12 h under 1 atm of O . The crude product
H NMR (400 MHz, CDCl ): δ 8.20 (s, 1H), 7.95−7.98 (m, 2H),
3
(
7.26−7.25 (m, 1H), 6.87 (d, J = 15.2 Hz, 1H), 4.36 (q, J = 7.2 Hz,
2H), 3.14 (s, 6H), 2.47 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). C NMR
13
0
(100 MHz, CDCl ): δ 166.5, 142.7, 139.3, 134.8, 130.9, 130.0, 128.7,
2
3
+
was purified by column chromatography on silica gel (EtOAc/PE, 1/
) to afford the title compound as a white solid (81 mg, 69% yield).
127.4, 119.9, 61.1, 37.5, 36.3, 20.2, 14.5. HRMS (ESI ): calcd for
C H NO [M + H] 262.1443, found 262.1439.
+
4
15
19
3
1
Mp: 133−135 °C. H NMR (400 MHz, CDCl ): δ 7.67 (d, J = 15.6
Hz, 1H), 7.64 (d, J = 8.0 Hz, 1H), 6.92 (d, J = 15.6 Hz, 1H), 6.30 (d, J
=
(E)-N,N-Dimethyl 3-[2-Fluoro-5-(ethoxycarbonxyl)phenyl]-
acrylamide (5g). The general procedure was applied to ethyl 4-
fluorobenzoate (8.0 mmol) and N,N-dimethylacrylamide (50 mg, 0.5
3
8.0 Hz, 1H), 4.00 (s, 3H), 3.93 (s, 3H), 3.14 (s, 3H), 3.04 (s, 3H).
6
572
dx.doi.org/10.1021/om400890p | Organometallics 2013, 32, 6565−6575

Organometallics
Article
+
mmol) at 90 °C for 36 h under 1 atm of O . The crude product was
purified by column chromatography on silica gel (EtOAc/PE, 1/1) to
MHz, CDCl ): δ −107.21. HRMS (ESI ): calcd for C H FO [M +
2
3
15 17
3
+
H] 265.1240, found 265.1247.
afford the title compound as a white solid (86 mg, 65% yield). Mp:
(E)-tert-Butyl 3-(2-Fluoro-5-acetylphenyl)acrylate (5n). The gen-
eral procedure was applied to 4-fluoroacetophenone (10.0 mmol) and
tert-butyl acrylate (64 mg, 0.5 mmol) at 90 °C for 36 h under 1 atm of
1
7
1
1
3
1
5
3−75 °C. H NMR (400 MHz, CDCl ): δ 8.22 (dd, J = 7.2, 2.0 Hz,
3
H), 8.01−7.98 (m, 1H), 7.72 (d, J = 15.6 Hz, 1H), 7.16−7.11 (m,
H), 7.05 (d, J = 15.6 Hz, 1H), 4.35 (q, J = 7.2 Hz, 2H), 3.18 (s, 3H),
O . The crude product was purified by column chromatography on
2
.07 (s, 3H), 1.38 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ
silica gel (EtOAc/PE, 1/9) to afford the title compound as a white
3
1
66.3, 165.4, 165.2, 162.6, 134.1, 132.2 (d, J = 10.0 Hz), 131.1 (d, J =
.0 Hz), 127.1 (d, J = 3.0 Hz), 123.6 (d, J = 13.0 Hz), 121.5 (d, J = 7.0
solid (104 mg, 79% yield). Mp: 68−70 °C. H NMR (400 MHz,
CDCl ): δ 8.14 (d, J = 7.2 Hz, 1H), 7.96−7.93 (m, 1H), 7.68 (d, J =
3
19
1
(
6.0 Hz, 1H), 7.14 (t, J = 9.2 Hz, 1H), 6.52 (d, J = 16.4 Hz, 1H), 2.60
Hz), 116.3 (d, J = 23.0 Hz), 61.4, 37.5, 36.2, 14.4. F NMR (377
MHz, CDCl ): δ −107.96. HRMS (ESI ): calcd for C H FNO [M
+
s, 3H), 1.53 (s, 9H). 13C NMR (100 MHz, CDCl ): δ 196.2, 165.8,
+
3
3
14 16
3
+
1
1
1
65.3, 162.7, 135.1 (d, J = 2.0 Hz), 133.8 (d, J = 4.0 Hz), 131.6 (d, J =
H] 266.1192, found 266.1192.
0.0 Hz), 129.6 (d, J = 5.0 Hz), 124.2 (d, J = 6.0 Hz), 123.1 (d, J =
(
E)-N,N-Dimethyl 3-(2-Fluoro-5-acetylphenyl)acrylamide (5h).
19
2.0 Hz), 116.4 (d, J = 23.0 Hz), 81.1, 28.3, 26.7. F NMR (377 MHz,
The general procedure was applied to 4-fluoroacetophenone (10.0
mmol) and N,N-dimethylacrylamide (50 mg, 0.5 mmol) at 90 °C for
+
+
CDCl ): δ −107.48. HRMS (ESI ): calcd for C H FO [M + H]
2
3
15 17
3
65.1240, found 265.1245.
3
6 h under 1 atm of O . The crude product was purified by column
2
(E)-Ethyl 3-(2-Fluoro-5-acetylphenyl)acrylate (5o). The general
chromatography on silica gel (acetone/PE, 1/4) to afford the title
1
procedure was applied to 4-fluoroacetophenone (10.0 mmol) and
ethyl acrylate (50 mg, 0.5 mmol) at 90 °C for 36 h under 1 atm of O2.
The crude product was purified by column chromatography on silica
compound as a white solid (100 mg, 85% yield). Mp: 96−98 °C. H
NMR (400 MHz, CDCl ): δ 8.14 (dd, J = 7.2, 2.4 Hz, 1H), 7.94−7.90
3
(
1
m, 1H), 7.72 (d, J = 15.6 Hz, 1H), 7.19−7.15 (m, 1H), 7.07 (d, J =
5.6 Hz, 1H), 3.19 (s, 3H), 3.08 (s, 3H), 2.61 (s, 3H). 13C NMR (100
gel (DCM/PE, 1/1) to afford the title compound as a white solid (78
1
mg, 66% yield). Mp: 57−59 °C. H NMR (400 MHz, CDCl ): δ 8.15
3
MHz, CDCl ): δ 196.4, 166.2, 165.3, 162.7, 134.1, 133.8 (d, J = 3.0
3
(
d, J = 6.8 Hz, 1H), 7.97−7.94 (m, 1H), 7.77 (d, J = 16.4 Hz, 1H),
Hz), 131.1 (d, J = 10.0 Hz), 129.9 (d, J = 5.0 Hz), 123.8 (d, J = 13.0
1
9
7.15 (t, J = 9.2 Hz, 1H), 6.59 (d, J = 16.4 Hz, 1H), 4.25 (q, J = 6.8 Hz,
Hz), 121.7 (d, J = 7.0 Hz), 116.4 (d, J = 23.0 Hz), 37.6, 36.1, 26.7.
F
2H), 2.60 (s, 3H), 1.32 (t, J = 7.2 Hz, 3H). 13C NMR (100 MHz,
+
NMR (377 MHz, CDCl ): δ −107.19. HRMS (ESI ): calcd for
3
+
CDCl
): δ 196.1, 166.5, 165.3, 162.7, 136.1 (d, J = 3.0 Hz), 133.9 (d, J
3
C H FNO [M + H] 236.1087, found 236.1080.
13
14
2
=
3.0 Hz), 131.8 (d, J = 10.0 Hz), 129.8 (d, J = 5.0 Hz), 122.9 (d, J =
(E)-Butyl 3-(2-Fluoro-5-nitrophenyl)acrylate (5k). The general
1
2.0 Hz), 122.4 (d, J = 6.0 Hz), 116.6 (d, J = 22.0 Hz), 60.9, 26.7, 14.4.
procedure was applied to 1-fluoro-4-nitrobenzene (10.0 mmol) and
N,N-dimethylacrylamide (50 mg, 0.5 mmol) at 90 °C for 36 h under 1
1
9
+
F NMR (377 MHz, CDCl ): δ −107.21. HRMS (ESI ): calcd for
3
+
C H FO [M + H] 237.0927, found 237.0930.
13
13
3
atm of O . The crude product was purified by column chromatography
2
(E)-Diethyl 3-(2-Fluoro-5-acetylphenyl)phosphonate (5p). The
on silica gel (EtOAc/PE, 1/9) to afford the title compound as a white
1
general procedure was applied to 4-fluoroacetophenone (10.0
mmol) and diethyl vinylphosphonate (82 mg, 0.5 mmol) at 90 °C
solid (110 mg, 82% yield). Mp: 50−52 °C. H NMR (400 MHz,
CDCl ): δ 8.46 (dd, J = 6.0, 2.4 Hz, 1H), 8.27−8.23 (m, 1H), 7.77 (d,
3
for 36 h under 1 atm of O . The crude product was purified by column
2
J = 16.0 Hz, 1H), 7.30−7.26 (m, 1H), 6.64 (d, J = 16.4 Hz, 1H), 4.23
chromatography on silica gel (EtOAc/DCM, 3/7) to afford the title
(
=
t, J = 6.8 Hz, 2H), 1.74−1.67 (m, 2H), 1.49−1.40 (m, 2H), 0.95 (t, J
1
compound as a colorless oil (100 mg, 74% yield). H NMR (400
7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ 166.1, 165.6, 163.0,
3
MHz, CDCl ): δ 8.13 (d, J = 7.2 Hz, 1H), 7.94 (t, J = 6.4 Hz, 1H),
3
1
44.6, 134.5, 124.6 (d, J = 5.0 Hz), 124.01 (d, J = 11.0 Hz), 123.95 (d,
7
1
6
.56 (dd, J = 23.2, 17.6 Hz, 1H), 7.15 (t, J = 9.2 Hz, 1H), 6.43 (t, J =
19
J = 2.0 Hz), 117.4 (d, J = 24.0 Hz), 65.1, 30.8, 19.3, 13.9. F NMR
7.6 Hz, 1H), 4.18−4.11 (m, 4H), 2.60 (s, 3H), 1.34 (t, J = 7.2 Hz,
+
(
377 MHz, CDCl ): δ −107.96. HRMS (ESI ): calcd for C H FNO
13
3
13 14
4
H). C NMR (100 MHz, CDCl ): δ 196.2, 165.1, 162.5, 139.9 (q, J
+
3
[
M + H] 268.0985, found 268.0980.
E)-1-Pentafluorophenyl-2-(2-fluoro-5-nitrophenyl)ethane (5l).
=
3.0 Hz), 133.9 (d, J = 3.0 Hz), 131.9 (d, J = 10.0 Hz), 129.4 (d, J =
(
4
1
.0 Hz), 123.2 (q, J = 13.0 Hz), 120.0 (d, J = 6.0 Hz), 118.0 (d, J =
The general procedure was applied to 1-fluoro-4-nitrobenzene (10.0
mmol) and 2,3,4,5,6-pentafluorostyrene (97 mg, 0.5 mmol) at 90 °C
19
3.0 Hz), 116.6 (d, J = 23.0 Hz), 62.3, 62.2, 26.7, 16.6, 16.5. F NMR
19
(
−
377 MHz, CDCl ): δ −108.24. F NMR (377 MHz, CDCl ): δ
3
3
for 36 h under 1 atm of O . The crude product was purified by column
+
+
2
107.96. HRMS (ESI ): calcd for C H FO P [M + H] 301.1005,
14 18 4
chromatography on silica gel (DCM/PE, 1/19) to afford the title
found 301.0990.
1
compound as a white solid (120 mg, 72% yield). Mp: 113−115 °C. H
(E)-1-(2-Fluoro-5-acetylphenyl)pent-1-en-3-one (5q). The general
NMR (400 MHz, CDCl ): δ 8.52 (d, J = 6.0 Hz, 1H), 8.23−8.19 (m,
3
procedure was applied to 4-fluoroacetophenone (10.0 mmol) and 1-
penten-3-one (42 mg, 0.5 mmol) at 90 °C for 36 h under 1 atm of O2.
The crude product was purified by column chromatography on silica
1
H), 7.54 (d, J = 17.2 Hz, 1H), 7.30−7.26 (m, 1H), 7.18 (d, J = 17.2
13
Hz, 1H). C NMR (100 MHz, CDCl ): δ 165.0, 162.4, 146.5 (m),
3
144.7, 144.0 (m), 142.1 (m), 139.3 (m), 136.6 (m), 127.3 (m), 125.9
gel (EtOAc/PE, 1/9) to afford the title compound as a white solid (53
(
1
d, J = 14.0 Hz), 125.5 (d, J = 11.0 Hz), 123.2 (d, J = 5.0 Hz), 118.2,
17.2 (d, J = 24.0 Hz), 111.3 (td, J = 14.0, 4.0 Hz). F NMR (377
1
mg, 48% yield). Mp: 69−71 °C. H NMR (400 MHz, CDCl ): δ 8.19
3
19
(
d, J = 6.8 Hz, 1H), 7.95 (t, J = 6.8 Hz, 1H), 7.67 (d, J = 16.4 Hz, 1H),
MHz, CDCl ): δ −106.26 (s, 1F), −141.66 (dd, J = 21.9, 8.3 Hz, 2F),
3
7.17 (t, J = 9.2 Hz, 1H), 6.88 (d, J = 16.4 Hz, 1H), 2.70 (q, J = 7.2 Hz,
2
H), 2.61 (s, 3H), 1.16 (t, J = 7.6 Hz, 3H). 13C NMR (100 MHz,
−
153.80 (t, J = 21.1 Hz, 1F), −162.05 (td, J = 21.1, 7.2 Hz, 2F).
+
+
HRMS (ESI ): calcd for C H F NO [M + H] 334.0303, found
CDCl ): δ 200.7, 196.2, 165.5, 162.9, 133.9 (d, J = 4.0 Hz), 133.5 (d, J
14
5
6
2
3
334.0315.
= 3.0 Hz), 131.9 (d, J = 10.0 Hz), 129.6 (d, J = 4.0 Hz), 129.3 (d, J =
6.0 Hz), 123.1 (d, J = 13.0 Hz), 116.4 (d, J = 23.0 Hz), 34.6, 26.7, 8.2.
(E)-Butyl 3-(2-Fluoro-5-acetylphenyl)acrylate (5m). The general
1
9
+
procedure was applied to 4-fluoroacetophenone (10.0 mmol) and
butyl acrylate (64 mg, 0.5 mmol) at 90 °C for 36 h under 1 atm of O2.
The crude product was purified by column chromatography on silica
F NMR (377 MHz, CDCl ): δ −107.40. HRMS (ESI ): calcd for
3
+
C H FO [M + H] 221.0978, found 268.0979.
13
13
2
(E)-1-Pentafluorophenyl-2-(2-fluoro-5-acetylphenyl)ethane (5r).
gel (EtOAc/PE, 1/9) to afford the title compound as a white solid
The general procedure was applied to 4-fluoroacetophenone (10.0
mmol) and 2,3,4,5,6-pentafluorostyrene (97 mg, 0.5 mmol) at 90 °C
1
(
8
1
109 mg, 83% yield). Mp: 42−44 °C. H NMR (400 MHz, CDCl ): δ
3
.15 (d, J = 6.8 Hz, 1H), 7.97−7.94 (m, 1H), 7.77 (d, J = 16.0 Hz,
H), 7.16 (t, J = 9.2 Hz, 1H), 6.60 (d, J = 16.4 Hz, 1H), 4.20 (t, J = 6.8
for 36 h under 1 atm of O . The crude product was purified by column
2
chromatography on silica gel (DCM/PE, 1/9) to afford the title
1
Hz, 2H), 2.61 (s, 3H), 1.73−1.66 (m, 2H), 1.48−1.39 (m, 2H), 0.94
compound as a white solid (122 mg, 74% yield). Mp: 91−93 °C. H
(
t, J = 7.2 Hz, 3H). 13C NMR (100 MHz, CDCl ): δ 196.1, 166.6,
NMR (400 MHz, CDCl ): δ 8.21 (d, J = 6.8 Hz, 1H), 7.93−7.90 (m,
3
3
1
3
1
1
65.3, 162.7, 136.1 (d, J = 2.0 Hz), 133.9 (d, J = 4.0 Hz), 131.8 (d, J =
0.0 Hz), 129.8 (d, J = 5.0 Hz), 122.9 (d, J = 7.0 Hz), 122.4 (d, J = 6.0
1H), 7.54 (d, J = 17.2 Hz, 1H), 7.21−7.13 (m, 2H), 2.64 (s, 1H). C
NMR (100 MHz, CDCl ): δ 196.5, 164.7, 162.1, 146.4 (m), 143.8
3
19
Hz), 116.6 (d, J = 23.0 Hz), 64.9, 30.8, 26.7, 19.3, 13.9. F NMR (377
(m), 141.7 (m), 139.2 (m), 136.7 (m), 133.9 (d, J = 3.0 Hz), 130.7 (d,
6
573
dx.doi.org/10.1021/om400890p | Organometallics 2013, 32, 6565−6575

Organometallics
Article
J = 10 Hz), 128.8 (m), 128.1 (d, J = 5.0 Hz), 124.9 (d, J = 13.0 Hz),
(2) For recent reviews, see: (a) Wong, S. M.; Ming So, C. M.;
Kwong, F. Y. Synlett 2012, 1132. (b) Snelders, D. J. M.; van Koten, G.;
Gebbink, R. J. M. K. Chem.−Eur. J. 2011, 17, 42. (c) Li, W.; Hou, G.;
Sun, X.; Shang, G.; Zhang, W.; Zhang, X. Pure Appl. Chem. 2010, 82,
1429. (d) Martin, R.; Buchwald, S. L. Acc. Chem. Res. 2008, 41, 1461.
1
16.4 (d, J = 23.0 Hz), 111.9 (td, J = 14.0, 5.0 Hz), 26.7. 19F NMR
(
377 MHz, CDCl ): δ −109.43 (s, 1F), −142.15 (dd, J = 21.5, 7.5 Hz,
F), −155.04 (t, J = 21.1 Hz, 1F), −162.53 (td, J = 21.1, 7.5 Hz, 2F).
3
2
+
+
HRMS (ESI ): calcd for C H F O [M + H] 331.0558, found
16
8 6
3
31.0563.
(
e) Surry, D. S.; Buchwald, S. L. Angew. Chem., Int. Ed. 2008, 47, 6338.
3) For recent reviews, see: (a) Kumar, A.; Ghosh, P. Eur. J. Inorg.
Chem. 2012, 3955. (b) Nolan, S. P. Acc. Chem. Res. 2011, 44, 91.
c) Díez-Gonzalez, S.; Marion, N.; Nolan, S. P. Chem. Rev. 2009, 109,
3612. (d) Samojłowicz, C.; Bieniek, M.; Grela, K. Chem. Rev. 2009,
(
E)-Methyl 3-(2-Fluoro-5-acetylphenyl)but-2-enoate (5s). The
(
general procedure was applied to 4-fluoroacetophenone (10.0
mmol) and methyl crotonate (50 mg, 0.5 mmol) at 90 °C for 36 h
(
́
under 1 atm of O . The crude product was purified by column
2
chromatography on silica gel (DCM/PE, 1/1) to afford the title
1
3
09, 3708. (e) Poyatos, M.; Mata, J. A.; Peris, E. Chem. Rev. 2009, 109,
677. (f) Melaimi, M.; Soleilhavoup, M.; Bertrand, G. Angew. Chem.,
1
compound as a white solid (50 mg, 43% yield). Mp: 81−83 °C. H
NMR (400 MHz, CDCl ): δ 7.95−7.91 (m, 2H), 7.14 (t, J = 9.2 Hz,
3
Int. Ed. 2010, 49, 8810.
4) For selected reviews on oxidative C−H activation reactions, see:
a) Yeung, C. S.; Dong, V. M. Chem. Rev. 2011, 111, 1215. (b) Liu, C.;
Zhang, H.; Shi, W.; Lei, A. Chem. Rev. 2011, 111, 1780. (c) Le Bras, J.;
Muzart, J. Chem. Rev. 2011, 111, 1170. (d) Wencel-Delord, J.; Droge,
13
H), 6.03 (s, 1H), 3.77 (s, 3H), 2.60 (s, 3H), 2.54 (s, 3H); C NMR
(
3
(
4
.0 Hz), 131.3 (d, J = 15.0 Hz), 130.7 (d, J = 10.0 Hz), 130.0 (d, J =
5
.0 Hz), 121.1 (d, J = 3.0 Hz), 116.5 (d, J = 14.0 Hz), 51.5, 26.7, 19.5.
1
9
+
̈
F NMR (377 MHz, CDCl ): δ −106.88. HRMS (ESI ): calcd for
3
+
T.; Liu, F.; Glorius, F. Chem. Soc. Rev. 2011, 40, 4740. (e) Chen, X.;
Engle, K. M.; Wang, D.-H.; Yu, J.-Q. Angew. Chem., Int. Ed. 2009, 48,
C H FO [M + H] 237.0927, found 237.0937.
13
13
3
H/D KIE Experiment. The general procedure was applied to 1a
5
(
094.
5) (a) Shi, B.-F.; Maugel, N.; Zhang, Y.-H.; Yu, J.-Q. Angew. Chem.,
(
0.64 mL, 8.0 mmol), 1a-d (0.64 mL, 8.0 mmol), and butyl acrylate
5
2
a (71 μL, 0.5 mmol) at 130 °C for 12 h under 1 atm of O . The crude
2
1
Int. Ed. 2008, 47, 4882. (b) Wang, D.-H.; Engle, K. M.; Shi, B.-F.; Yu,
J.-Q. Science 2010, 327, 315.
(6) For selected recent examples on the use of MPAA ligands in
directed C−H activation reactions, see: (a) Wasa, M.; Engle, K. M.;
Lin, D. W.; Yoo, E. J.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133, 19598.
residue was analyzed by H NMR and then purified by column
chromatography on silica gel (EtOAc/PE, 1/4) to provide the mixed
1
compounds 3a and d -3a. The H NMR data of the mixture suggest
4
that the related KIE value is 3.0. The KIE measurements were
performed in three runs, giving the same result.
(
(
b) Leow, D.; Li, G.; Mei, T.-S.; Yu, J.-Q. Nature 2012, 486, 518.
c) Li, G.; Leow, D.; Wan, L.; Yu, J.-Q. Angew. Chem., Int. Ed. 2012,
ASSOCIATED CONTENT
■
5
2, 1247. (d) Cheng, X.-F.; Li, Y.; Su, Y.-M.; Yin, F.; Wang, J.-Y.;
*
S
Supporting Information
Sheng, J.; Vora, H. U.; Wang, X.-S.; Yu, J.-Q. J. Am. Chem. Soc. 2013,
135, 1236. (e) Dai, H.-X.; Li, G.; Zhang, X.-G.; Stepan, A. F.; Yu, J.-Q.
J. Am. Chem. Soc. 2013, DOI: 10.1021/ja400659s. (f) Huang, C.;
Chattopadhyay, B.; Gevorgyan, V. J. Am. Chem. Soc. 2011, 133, 12406.
Characterization data for the known coupling products, kinetic
isotope effect, detailed optimized geometries, and free energies.
This material is available free of charge via the Internet at
http://pubs.acs.org.
(
(
g) Cong, X.; You, J.; Gao, G.; Lan, J. Chem. Commun. 2013, 49, 662.
h) Pi, C.; Li, Y.; Cui, X.; Zhang, H.; Han, Y.; Wu, Y. Chem. Sci 2013,
4
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AUTHOR INFORMATION
■
Corresponding Authors
E-mail: chaowu@mail.xjtu.edu.cn.
E-mail: zengxiaoming@mail.xjtu.edu.cn
(
*
Angew. Chem., Int. Ed. 2012, 51, 10236.
(8) Wang, Y.-N.; Guo, X.-Q.; Zhu, X.-H.; Zhong, R.; Cai, L.-H.; Hou,
X.-F. Chem. Commun. 2012, 48, 10437.
(9) (a) Baxter, R. D.; Sale, D.; Engle, K. M.; Yu, J.-Q.; Blackmond, D.
G. J. Am. Chem. Soc. 2012, 134, 4600. (b) Musaev, D. G.; Kaledin, A.;
Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2012, 134, 1690.
(10) (a) Ye, M.; Gao, G.-L.; Yu, J.-Q. J. Am. Chem. Soc. 2011, 133,
*
Author Contributions
X. Cong and H. Tang contributed equally.
§
Notes
The authors declare no competing financial interest.
6
964. (b) Wen, P.; Li, Y.; Zhou, K.; Ma, C.; Lan, X.; Ma, C.; Huang, G.
Adv. Synth. Catal. 2012, 354, 2135.
11) (a) Zhang, Y.-H.; Shi, B.-F.; Yu, J.-Q. J. Am. Chem. Soc. 2009,
ACKNOWLEDGMENTS
■
(
Support for this work by the National Natural Science
Foundation of China [Nos. 21202128 (X.Z.), 21203143
C.W.)] is gratefully acknowledged.
1
2
31, 5072. (b) Kubota, A.; Emmert, M. H.; Sanford, M. S. Org. Lett.
012, 14, 1760. (c) Zhang, X.; Fan, S.; He, C.-Y.; Wan, X.; Min, Q.-Q.;
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