Mechanistic investigations of a palladium-diene catalyzed Suzuki-Miyaura cross-coupling reaction

Article abstract of DOI:10.1021/om300115x

The mechanism of the first example of a palladium diene catalyzed asymmetric Suzuki-Miyaura cross-coupling reaction has been validated, with the key palladium intermediates captured and characterized. The identified species corresponding to each catalytic step were firmly associated with the diene ligand in our observations. In the ESI-MS/MS experiments by CID (collision-induced dissociation), the fragmentation of the gas-phase transmetalation species was consistent with the product-yielding process in the reductive elimination step and thus revealed the catalytically active species of the reaction system.

Full text of DOI:10.1021/om300115x

Communication
pubs.acs.org/Organometallics
Mechanistic Investigations of a Palladium-Diene Catalyzed Suzuki−
Miyaura Cross-Coupling Reaction
Xiaoshuang He, Shusheng Zhang, Yinlong Guo,* Haoyang Wang, and Guoqiang Lin*
Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, People's Republic of
China
*
S Supporting Information
ABSTRACT: The mechanism of the first example of a
palladium diene catalyzed asymmetric Suzuki−Miyaura cross-
coupling reaction has been validated, with the key palladium
intermediates captured and characterized. The identified
species corresponding to each catalytic step were firmly
associated with the diene ligand in our observations. In the
ESI-MS/MS experiments by CID (collision-induced dissocia-
tion), the fragmentation of the gas-phase transmetalation
species was consistent with the product-yielding process in the reductive elimination step and thus revealed the catalytically active
species of the reaction system.
he Pd-catalyzed cross-coupling process between organo-
boron compounds and organic halides, known as the
Before conducting our investigations into the reaction in Table
1, we first proposed its catalytic cycle, which involves four
8
T
Suzuki−Miyaura reaction, has been used widely in C−C bond
consecutive steps of precatalyst activation, oxidative addition,
transmetalation, and reductive elimination, shown in Scheme 1.
On the basis of our experience, the ionic Pd species in this
scheme would be detectable with the isotopic clusters of Pd in
ESI-MS spectra, and the neutral Pd intermediates bearing an+
aldehyde moiety could also be observed in the form of Cs
formation, particularly for constructing asymmetric biaryls.
1
Since its discovery in 1979, chemists have made continuing
efforts to improve the productivity and enantioselectivity of this
2
reaction by applying elaborately designed chiral ligands, and by
3
far, phosphorus ligands have remained the favorite choice.
9
However, most phosphines show extreme sensitivity to air and
moisture. In addition, the degradation of the P−C bond at
increased temperature could lead to the aggregation of Pd
species and consequently retard the overall reaction process.
In recent years, a diverse set of C - and C -symmetric chiral
adducts when Cs CO was used as a base in the reaction. In
2
3
order to monitor the reaction process, we decided to use each
catalyst separately and detect the reaction solution in two steps:
(
1) detection of the precatalyst activation step in the absence of
1
2
aryl bromide 3 and (2) monitoring of the reaction after the
addition of aryl bromide 3. In our assumptions, the Pd(0)
complex I could be detected at the precatalyst activation step,
while the intermediates formed in the following oxidative
addition step and the transmetalation step could be detected
after the addition of compound 3.
diene ligands with rigid bicyclic or polycyclic skeletons have4
been successfully introduced to asymmetric reaction systems.
Despite their great catalytic efficiency, the metals used were
limited to Rh and Ir. Moreover, a Pd-diene catalyzed reaction
has remained a difficult issue because of possible Pd black
formation due to the weaker interaction between the double
bond and the Pd metal center. In order to diminish the Pd
black and enhance the overall reaction, finding well-designed
ligands that possess the proper binding affinity to Pd is of
significant importance.
Among the five catalysts, 2d was first chosen to catalyze the
Suzuki−Miyaura cross-coupling reaction presented in Table 1.
The ESI-MS studies on the reaction were started with the
10
precatalyst activation step. Boronic acid 4 (0.30−0.45 mmol,
1
.5 equiv), Cs CO (0.5−0.75 mmol, 2.5 equiv), and catalyst
2
3
In 2010, our group reported the first example of a Pd-diene5
2d in 1.0 mL of dry toluene were mixed into a Schlenk flask at
room temperature under the protection of nitrogen. After 5
min, two Pd(II) species were easily observed by two strong
isotopic clusters centered at m/z 547 and 588. The two signals
catalyzed asymmetric Suzuki−Miyaura cross-coupling reaction.
Following the previous mechanistic study, we investigated the
reaction in detail by using ESI-MS techniques. Electrospray
ionization mass spectrometry (ESI-MS) is a soft ionization tool,
which smoothly transfers the ions present in solution into a gas-
respectively matched the theoretical isotopic distribution
+
6
patterns of (IVd − Cl) (m/z 547) and [(IVd
−
phase environment for characterization, and therefore, it has
+
Cl)·(CH CN)] (m/z 588), and their structures were also
3
rapidly become a major tool in identifying reactive
intermediates and has achieved great success in mechanistic
characterized by the tandem mass spectrometric (ESI-MS/MS)
7
investigations.
Initially, we chose five analogous ligands in order to evaluate
their catalytic activities. The results are shown in Table 1.
Received: February 13, 2012
Published: March 27, 2012
©
2012 American Chemical Society
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Organometallics
Communication
a
Table 1. Representative Suzuki−Miyaura Cross-Coupling Reactions Catalyzed by Five Pd(II)-Diene Catalysts
b
c
entry
diene ligand
1a (Ar = Ph)
time (h)
yield (%)
ee (%)
1
2
3
4
5
18
24
24
12
30
49
47
48
90
24
73
63
74
87
62
1b (Ar = 4-FPh)
1c (Ar = 4-MeOPh)
1d (Ar = 3,5-(Me) Ph)
2
1e (Ar = 3,4,5-(MeO) Ph)
3
a
Conditions: aryl bromide (0.2−0.3 mmol, 1.0 equiv), boronic acid (0.3−0.45 mmol, 1.5 equiv), Cs CO (0.5−0.75 mmol, 2.5 equiv), and toluene
2
3
b
c
(
1.0−1.5 mL). Isolated yield. Determined by HPLC on chiral stationary phases.
Scheme 1. Proposed Catalytic Cycle of the Suzuki−Miyaura
Cross-Coupling Reaction
gratification, after 30 min of reaction, three new signals with
isotopic envelopes characteristic for mononuclear Pd species
appeared in the spectra. In addition, they were also observed
after reacting for 43, 66, 75, and 90 min (see the Supporting
Information). According to the simulations of the theoretical
isotopic distribution patterns, the three cluster signals were
+
+
assigned to (II − Br) (m/z 539), [(II ·CsCl) − Br] (m/z
d
d
+
7
07), and (III ·Cs) (m/z 799), respectively. ESI-MS/MS
d
experiments were also conducted to reconfirm their structures.
In our speculations, the Cs+ adduct ions of (III ·Cs)
+
d
demonstrated the transmetalation step in the catalytic cycle
7
g,12
and such metal adduct species had been reported before.
As
+
+
for the observed ions of (II − Br) and [(II ·CsCl) − Br] ,
they probably indicated the existence of the oxidative addition
d
d
intermediate of II , which was undetectable in the form of
d
+
(
II ·Cs) (m/z 751) during the whole performance. As an
d
+
explanation, (II − Br) was generated via bromide loss from
d
+
the neutral intermediate of II , and [(II ·CsCl) − Br] was
d
d
formed when Br− of intermediate II was replaced by Cl
−
d
1
3
existing in the solution.
As mentioned above, the Pd(0) intermediate I was not
d
observed in the whole ESI-MS detection. Further efforts were
made by replacing the boronic acid 4 with (2-formylphenyl)-
boronic acid 6. With the absence of aryl bromide 3, the sample
solution was analyzed by GC-MS. Excitedly, a homocoupling
byproduct of the boronic acid 8 (see the Supporting
Information) was detected. As Scheme 2 shows, this byproduct
1
1
results. On the basis of previous reports, the detected ions of
+
+
of 8 was possibly formed together with Pd(0) intermediate Id
(
IV − Cl) (m/z 547) and [(IV − Cl)·(CH CN)] (m/z
88) were probably formed by the heterolysis of the Pd(II)-
d
d
3
by reductive elimination of the presumed precursor 7, and thus
5
it might indicate the existence of Pd(0) intermediate I . At this
diene precursor IVd in the ionization process. To our
disappointment, however, no signals corresponding to Pd(II)
intermediate V or Pd(0) intermediate I in the catalytic cycle
d
stage, we have successfully validated the proposed catalytic
cycle in Scheme 1 involving catalyst 2d. In addition, we also
monitored the 2d-catalyzed Suzuki−Miyaura cross-coupling
reaction with NMR spectrometers; however, no intermediate
species were identified except for the substrate and the product
d
d
could be observed.
When the solution turned dark red (indicating the activation
of the precatalyst), aryl bromide 3 (0.2−0.3 mmol, 1.0 equiv)
was added, and then the reaction solution was sampled and
detected by ESI-MS at different time intervals. To our
1
3
19
in the C and F NMR spectra (see the Supporting
Information).
2
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Organometallics
Communication
Scheme 2. Investigations of the Precatalyst Activation Step by GC-MS
We next conducted analogous experiments by using the
other four catalysts separately. As shown in Table 2, each
Table 2. Detected Species of Reactions Catalyzed by
Different Pd-Diene Catalysts by ESI-MS
activated precat. ion of oxidative addition ion of transmetalation+
+
+
(
IV − Cl) and [(IV −
(II − Br) and [(II − ion of (III·Cs)
+
+
cat.
Cl)·(CH CN)] (m/z)
Br)·CsCl)] (m/z)
(m/z)
3
2
2
2
2
2
a
b
c
491 and 532
527 and 568
551 and 592
547 and 588
671 and 712
803
799
923
d
e
539 and 707
spectrum obtained at the precatalyst activation step also
showed two strong respective signals, which corresponded to
the activated Pd(II) catalyst IV and their CH CN adducts. In
3
addition, in the cases of catalysts 2c,e, signals given by
+
+
(
III ·Cs) (m/z 803) were observed at 40 min and (III ·Cs)
c
e
(m/z 923) at 35 min after aryl bromide 3 was added, both of
which corresponded to the transmetalation step. However, such
species were undetectable when catalysts 2a,b were used. In
comparison to catalyst 2d, oxidative addition species were
missed in the spectra by using any one of these four catalysts.
Thus far, we have identified and characterized the key
intermediates concerning the five PdCl (diene) catalysts.
2
Figure 1. ESI-MS/MS spectra for the transmetalation species: (a)
According to Table 2, the intermediates corresponding to the
oxidative addition step were more difficult to detect (only
observed in the case of 2d) than those corresponding to the
transmetalation step (observed in the cases of 2c−e), strongly
indicating that the oxidative addition species of II were
transient, while the transmetalation species of III were formed
immediately and accumulated before being slowly consumed
and transformed in the reductive elimination step. Recalling
previous studies on this reaction by in situ IR, an unknown
peak occurred upon the addition of bromide 3 and disappeared
when the reaction finished, in addition to the detectable 3 and
+
+
MS/MS of (III ·Cs) at m/z 803; (b) MS/MS of (III ·Cs) at m/z
c
d
+
7
99; (c) MS/MS of (III ·Cs) at m/z 923.
e
+
(
m/z 923) all produced (5·Cs) (m/z 379) by the consecutive
loss of the diene ligand and palladium upon being subjected to
a collision energy of 20 eV (Scheme 3). These results matched
the product-yielding process in the reductive elimination step
perfectly. Furthermore, for these three species, the ratios of
+
peak intensities of the parent ions of (III·Cs) and the product
+
ions of (III·Cs − diene) were respectively 42:100 (1c), 30:100
(
1d), and 100:20 (1e), implying that the binding energy of the
5. This new peak also explained the existence of intermediate
diene ligand to palladium was 1d < 1c < 1e, and this was quite
consistent with the product yields shown in Table 1: 1d (90%)
> 1c (48%) > 1e (24%). Therefore, the fragment patterns of
these gas-phase species in the ESI-MS/MS experiments
III at the transmetalation step. As a result, different from the
widely accepted note that transmetalation step is the rate-
14
determining step of the Suzuki−Miyaura reaction, the rate of
this Pd-diene catalyzed Suzuki reaction should depend on the
reductive elimination step, because the precursor ions of this
step accumulated before being transformed into biaryl 5 and
Pd(0)-diene I. Similar conclusions had been reported in the
9
,10
represented their relative intrinsic catalytic activities.
In summary, we have successfully validated the catalytic cycle
for the Pd-diene catalyzed Suzuki−Miyaura cross-coupling
reaction, with the key palladium intermediates captured and
characterized. Our observations demonstrate the catalytically
active species of the reaction by the fragmentation patterns of
the transmetalation species. In particular, the reductive
elimination step determines the rate of the whole process.
We believe that this protocol provides a valuable tool for fast
12
self-coupling reaction of arylboronic acids.
As mentioned above, ESI-MS/MS experiments have been
conducted for characterizing all the detected intermediates.
Interestingly, on reviewing the three intermediates formed in
the transmetalation step (Figure 1), the parent ions of
+
+
+
(
III ·Cs) (m/z 803), (III ·Cs) (m/z 799), and (III ·Cs)
c d e
2
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Organometallics
Scheme 3. Fragmentation of (III·Cs) in the ESI-MS/MS Experiments
Communication
+
screening of the well-defined ligands and thus contributes to
the transition-metal-catalyzed asymmetric system.
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ASSOCIATED CONTENT
Supporting Information
Text, figures, and tables giving experimental procedures,
structures, mass spectra, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
■
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f) Chevrin, C.; Bras, J. L.; Hen
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́
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1
AUTHOR INFORMATION
Corresponding Author
E-mail: ylguo@sioc.ac.cn (Y.G.); lingq@sioc.ac.cn (G.L.). Tel:
86-021-54925300. Fax: +86-021-64166128.
■
(
*
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K. J. Chem. Soc., Dalton Trans. 1999, 19, 3507. (c) Wang, H. Y.;
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W. L.; Guo, Y. L.; Metzger, J. O. Organometallics 2012, 31, 1627.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was supported by research grants from the NSFC
20902104, 21072215, 21172250), CAS (YZ200938 and
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Bioorganic and Natural Product Chemistry.
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