A new approach to carbon-carbon bond formation: development of aerobic Pd-catalyzed reductive coupling reactions of organometallic reagents and styrenes

Article abstract of DOI:10.1016/j.tet.2009.03.096

Alkenes are attractive starting materials for organic synthesis and the development of new selective functionalization reactions is desired. Previously, our laboratory discovered a unique Pd-catalyzed hydroalkoxylation reaction of styrenes containing a phenol. Based upon deuterium labeling experiments, a mechanism involving an aerobic alcohol oxidation coupled to alkene functionalization was proposed. These results inspired the development of a new Pd-catalyzed reductive coupling reaction of alkenes and organometallic reagents that generates a new carbon-carbon bond. Optimization of the conditions for the coupling of both organostannanes and organoboronic esters is described and the initial scope of the transformation is presented. Additionally, several mechanistic experiments are outlined and support the rationale for the development of the reaction based upon coupling alcohol oxidation to alkene functionalization.

Full text of DOI:10.1016/j.tet.2009.03.096

Tetrahedron 65 (2009) 5074–5083
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
A new approach to carbon–carbon bond formation: development
of aerobic Pd-catalyzed reductive coupling reactions
of organometallic reagents and styrenes
,
Keith M. Gligorich a, Yasumasa Iwai b, Sarah A. Cummings c, Matthew S. Sigman a
*
a Department of Chemistry, University of Utah, 315 South 1400 East, Salt Lake City, UT 84112, USA
b Kyorin Pharmaceutical Co., Ltd, 1848 Nogi, Nogi-machi, Shimotuga-gun, Tochigi-ken 329-0114, Japan
c Department of Chemistry, University of Nevada, Reno, Reno, NV 89557, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
Alkenes are attractive starting materials for organic synthesis and the development of new selective
functionalization reactions is desired. Previously, our laboratory discovered a unique Pd-catalyzed hy-
droalkoxylation reaction of styrenes containing a phenol. Based upon deuterium labeling experiments,
a mechanism involving an aerobic alcohol oxidation coupled to alkene functionalization was proposed.
These results inspired the development of a new Pd-catalyzed reductive coupling reaction of alkenes and
organometallic reagents that generates a new carbon–carbon bond. Optimization of the conditions for
the coupling of both organostannanes and organoboronic esters is described and the initial scope of the
transformation is presented. Additionally, several mechanistic experiments are outlined and support the
rationale for the development of the reaction based upon coupling alcohol oxidation to alkene
functionalization.
Received 28 January 2009
Received in revised form 27 March 2009
Accepted 30 March 2009
Available online 5 April 2009
Keywords:
Catalysis
Cross-coupling
Molecular Oxygen
Palladium
Ó 2009 Elsevier Ltd. All rights reserved.
Mechanism
Pd-Catalyzed Hydroalkoxylation of Vinylphenols
1. Introduction
OEt
2.5 mol% Pd[(−)-sparteine]Cl2
(1)
Alkenes are attractive starting materials for organic synthesis
because they can be readily converted to a wide range of functional
groups.1 However, the utility of many alkene functionalization re-
actions is limited because of poor regioselectivity of the trans-
formation leading to a mixture of products. One strategy to
overcome this challenge is the use of metal catalysts to control the
selectivity of the functionalization. For example, Pd catalysts have
been successfully employed in the Wacker reaction, which selec-
tively oxidizes an alkene to a methyl ketone.2 Previously, our group
has developed more effective catalyst systems for the Wacker ox-
idation.3 As part of this ongoing effort, we were interested in ap-
plying these and related catalyst systems to the discovery of new
types of selective alkene functionalization reactions. As a result, we
discovered a unique PdII-catalyzed hydroalkoxylation reaction of
alkenes containing a phenol.4 For example, vinyl phenol (1) is
converted to ether 2 in 72% yield using catalytic Pd[(ꢀ)-sparteine]-
Cl2 and CuCl2 (Eq. 1).
7.5 mol% CuCl2
EtOH, O2, 3ÅMS, rt
OH
OH
72%, 2
1
While there have been numerous reports of metal-catalyzed
alkene hydroalkoxylation reactions,5 there were no examples that
employed PdII salts.6 This is most likely due to facile
b-hydride
elimination after initial oxypalladation, which would lead to
Wacker oxidation products.2 We initially hypothesized that the
phenolic substrate allowed for competitive protonation of the Pd–
carbon bond formed after initial oxypalladation of the alkene with
the alcoholic substrate.4 In order to test this hypothesis and probe
the origin of the hydrogen atom incorporated into the alkene
framework, we believed that conducting the reaction with
CH3CH2OD as the solvent should result in the incorporation of one
deuterium atom into the product at the site of Pd–carbon bond
protonation.5 However, subjecting vinyl phenol 3 to the reaction
conditions with CH3CH2OD as the solvent produced the unlabeled
ether product 2 (Fig. 1A). This result rules out the plausibility of
a Brønsted acid based mechanism. To further investigate the origin
of the hydrogen atom incorporated into the product, a similar re-
action was performed with CD3CD2OD as the solvent. This led to the
formation of isotopomers 4a and 4b in a 2.5 to 1 ratio, which
contain one deuterium atom incorporated into the alkene
* Corresponding author. Tel.: þ1 801 585 0774; fax: þ1 801 581 8433.
E-mail address: sigman@chem.utah.edu (M.S. Sigman).
0040-4020/$ – see front matter Ó 2009 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2009.03.096

K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
5075
catalyzed cross-coupling wherein the catalyst initially oxidatively
adds an electrophilic organic compound, which generally contains
a carbon–halogen bond (R–X), that yields the oxidized species R–
PdII–X (Fig. 2A).2a A potential limitation of Pd0-catalyzed cross-
coupling reactions is the requirement of a substrate that is capable
of oxidizing Pd0 to PdII. Unconventional routes to access the req-
uisite R–PdII–X intermediate from starting materials that circum-
vent the need to oxidize Pd0 to PdII will increase the versatility and
scope of cross-coupling reactions.
A Deuterium Labeling Experiments
OEt
OH
2.5 mol% Pd[(−)-sparteine]Cl2
5 mol% CuCl2
No Deuterium
Incorporation
CH3CH2OD, O2, 3ÅMS, rt
OD
3
2
H
OCD CD
D
OCD CD
2
3
2
3
Instead
CH2D
CH3
+
CD3CD2OD
OH
OH
4b
4a
2.5 : 1
Based upon the deuterium labeling experiments performed on
the alkene hydroalkoxylation reaction,4 we hypothesized the cat-
alytic R–PdII–X intermediate could be generated from an alkene
(Fig. 2B and C).9 Specifically, oxidation of the alcoholic solvent with
PdII catalyst A will lead to the formation of PdII-hydride B. Co-
ordination and insertion of the alkene into the PdII-hydride yield
the PdII-alkyl intermediate D (or D0), which resembles the R–PdII–X
species formed via oxidative addition of an organic electrophile.2a
Transmetalation to form E and subsequent reductive elimination
generates the reductive coupling product as well as the reduced
catalyst F. Aerobic oxidation of Pd0 to PdII completes the catalytic
cycle.2,8 The sp2-hybridized carbon atoms of the alkene will be
transformed to sp3 atoms, which can be difficult to access with
B Proposed Mechanism
Alcohol Oxidation
OH
O
1
Cl
Cl
N
N
Cl
Cl
N
N
Cl
H
N
Ar
PdII
PdII
PdII
N H
A
B
C
Alkene Insertion
H
H
O
Cl
N
N
O
N
PdII
PdII
+
C
N
D
D'
Quinone Methide
traditional cross-coupling because of facile b
-hydride elimination.10
CuCl2
or O2
Initially, we anticipated the formation of undesired byproducts
arising from the oxidative Heck reaction11 and homocoupling of the
organometallic reagent,12 which are proposed to originate from
initial transmetalation of the PdII catalyst (Fig. 2D). The nature of
the catalyst, solvent, and coupling partners were thought to have
a significant impact on the formation of these byproducts by
modulating the relative rate of transmetalation compared to
2
EtOH
HCl
N
O
N
Pd0
D'
Pd0
A
N
N
E
F
Figure 1. (A) Deuterium labeling experiments. (B) Proposed mechanism of the alkene
hydroalkoxylation reactions involves coupling an alcohol oxidation to alkene
functionalization.
framework. This result suggests that the hydrogen atom originates
from the alkyl chain of ethanol rather than the acidic proton.
Based upon these results, we propose a mechanism wherein the
PdII catalyst A initially oxidizes the alcoholic solvent to generate the
Pd-hydride intermediate B (Fig. 1B). Coordination of the alkene
produces the cationic complex C. Based upon the formation of
isotopomers 4a and 4b, we propose that the alkene inserts into the
A Pd0-Catalyzed Cross-Coupling
catalytic Pd0
R1
X
R2
M
R1 R2
+
solvent
B PdII-Catalyzed Reductive Cross-Coupling Reaction
H
catalytic PdII
R2
M
R1
+
(CH3)2CHOH, O2
R1 R2
Pd-hydride at both the a- and b-position of the styrene yielding D
and D0. Since only the benzylic addition product is obtained, we
propose that intermediate D0 proceeds to product via formation of
an ortho-quinone methide intermediate with concomitant re-
duction of PdII to Pd0 and generation of E.7 Ethanol subsequently
reacts with the quinone methide intermediate to liberate the ether
product and the Pd0 species F, which is reoxidized by CuCl2 or O2.2,8
While the deuterium labeling experiments suggest a unique
alcohol oxidation coupled alkene functionalization process, the
scope of the reaction is limited to substrates that contain a phenol.
Therefore, our laboratory was interested in taking advantage of this
distinctive mechanistic motif in the realm of new reaction discov-
ery. Specifically, we wanted to develop a PdII-catalyzed reductive
coupling reaction, which employs alkenes that do not contain
a phenol in combination with an organometallic reagent to gen-
erate a new carbon–carbon and carbon–hydrogen bond under
aerobic conditions. Herein, we present the development of an
aerobic reductive coupling reaction of alkenes with both organo-
stannanes and organoboronic esters as well as experiments that
showcase the unique mechanism.
C Mechanistic Proposal
Alcohol Oxidation
OH
O
H
X
R1
X
R1
L PdIIX2
A
L PdII
L PdII
n
n
n
H
B
H
C
Alkene Insertion
X
X
L PdII
D
C
L PdII
D'
+
R1
n
n
H
R1
O2
H
H
Transmetalation
R2M
XM
R1 R2
R2
L PdII
E
L Pd0
F
R1
D
A
n
n
H
D Competitive Oxidative Heck Pathway
catalytic PdII, O2
R2
R2SnBu3
R1
+
R1
X
R2
2. Approach
L PdII
R1
n
Initial Transmetalation
We were interested in developing a reductive coupling reaction
of alkenes and organometallic reagents that utilizes an alcohol
oxidation to initiate the catalysis and generate a Pd-hydride.
Mechanistically, this type of transformation differs from Pd0-
Figure 2. (A) Traditional Pd0-catalyzed cross-coupling with an organic oxidant. (B)
Proposed aerobic PdII-catalyzed reductive coupling reaction and (C) mechanistic hy-
pothesis. (D) Competitive oxidative Heck pathway.

5076
K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
alcohol oxidation/alkene insertion. Therefore, we initially decided
to employ the Pd[(ꢀ)-sparteine]Cl2 catalyst because of its ability to
readily oxidize alcohols and alkenes.3b,13
(18% GC yield), which is proposed to originate from initial trans-
metalation of the PdII catalyst.11d Interestingly, the diarylation
product 12, which is the addition of two aryl groups across the
alkene, was formed in 20% GC yield. The diarylation product is
believed to originate from the same PdII-alkyl intermediate that
Previously, our laboratory has shown that exposing a simple
styrene substrate to the alkene hydroalkoxylation reaction condi-
tions with ethanol as the solvent leads to the acetal product 6
(Fig. 3A).14 Since the proposed mechanism of acetal formation in-
volves initial nucleophilic addition of the alcohol to the metal bound
alkene, we thought a less nucleophilic secondary alcohol, such as
isopropanol (IPA), would not readily undergo acetal formation.
However, performing the reaction with IPA as the solvent un-
expectedly produced the hydroalkoxylation product 815 along with
the Wacker oxidation product 7, which most likely originates from
a H2O2 mediated pathway (Fig. 3B).16 Further investigation of these
results demonstrates that the hydroalkoxylationproduct 8 forms via
initial hydrochlorination of the alkene followed by nucleophilic
substitutionwith the alcohol.15 Interestingly, decreasing the amount
of CuCl2 slows the formation of the hydroalkoxylationproduct. Thus,
we believed that IPA would be an effective solvent and hydride
source for the reductive coupling reaction as long as the concen-
tration of CuCl2 was low enough to prevent formation of 8.
leads to the Heck product. However, instead of undergoing b-hy-
dride elimination, the PdII-alkyl species reacts with another
equivalent of the organostannane and subsequent reductive elim-
ination generates the product. While diarylation of alkynes and
norbornene has been previously reported, this is the first example
of a diarylation reaction of a styrene derivative.20 This unique
transformation is currently under further investigation in our lab-
oratory. Additionally, the oxidative homocoupling product 1312 was
formed in 9% GC yield and the Wacker oxidation product 714–16 was
generated in 3% GC yield.
2.5 mol% Pd[(−)-sparteine]Cl2
PhSnBu3 (9a)
7.5 mol% CuCl2
+
1.5 equiv.
IPA, 3ÅMS, O2, rt
5a
Ph
Ph
Ph
Ph
In addition to the solvent, the nature of the coupling partners
should play an important role in the outcome of the reaction.
Therefore, styrene derivatives were selected because of the in-
ability of the olefin to isomerize.17 Previously, our laboratory has
found styrenes to be excellent model substrates for the de-
velopment of new reactions and catalyst systems. Information
garnered from the use of styrene substrates can subsequently be
employed to expand the scope of these systems to include a wide
variety of alkenes.3 Furthermore, the second coupling partner
needed to readily undergo transmetalation and had to be stable to
the alcoholic solvent and O2 atmosphere. Many organometallic
reagents require a base to facilitate transmetalation with PdII,2a but
the presence of exogenous base has been found to affect the rate of
alcohol oxidation.13 Therefore, PhSnBu3 (9a) was initially selected
as the organometallic coupling partner because it should be stable
under the reaction conditions and does not require base to facilitate
transmetalation.18
+
+
(2)
23%,10a
18%, 11
20%, 12
O
+
9%, 13
3%, 7
Since the major byproducts originate from either the oxidative
Heck or diarylation reactions, we focused our attention on mini-
mizing the formation of these compounds. Based upon the pro-
posed mechanism, a decrease in the relative rate of initial
transmetalation compared to alcohol oxidation/alkene insertion
was desired to improve the selectivity for the reductive coupling
product. Previously, the addition of Cu salts to Pd0-catalyzed Stille
couplings had been shown to facilitate transmetalation.18a There-
fore, CuCl2 was removed from the catalytic conditions leading to
a decrease in conversion, which was attributed to catalyst de-
composition (Table 1, entry 2). However, the ratio of 10a to 11
improved to 2.4:1 and, thus, Cu-free conditions were pursued.
However, without CuCl2 to promote catalyst regeneration, we
needed to identify an additive to help stabilize the catalyst.
3. Results and discussion
3.1. Organostannanes optimization and scope
Exposure of 4-methylstyrene (5a) and PhSnBu3 (9a) to a solu-
tion of catalytic Pd[(ꢀ)-sparteine]Cl2 and CuCl2 in IPA under an O2
atmosphere led to the desired hydroarylation product 10a in 23%
GC yield as a >25:1 mixture of regioisomers (Eq. 2).9,19 As expected,
a significant amount of the oxidative Heck product 11 was formed
Table 1
Optimization for the hydroarylation product 10a, which led to the discovery of
a possible inhibitor
2.5 mol% Pd[(−)-sparteine]Cl2
Ph
X mol% (−)-sparteine
Ph
+
Y mol% MnO2
IPA, O2, 20h
5a
10a
11
Heck
+
A Acetal Formation with Ethanol
PhSnBu3 (9a)
1.5 equiv.
Hydroarylation
O
4 mol% Pd[(−)-sparteine]Cl2
EtO OEt
5 mol% CuCl2
+
Entrya
1e
2
X
Y
Temp
Conv.b (%)
10ac (%)
10a:11d
EtOH, O2, 3ÅMS, rt, 24h
5a
6
7
0
0
0
0
0
0
0
rt
rt
rt
85
67
40
63
37
30
>99
26
23
23
17
45
30
22
81
19
1.3:1
2.4:1
28:1
27:1
12:1
7.4:1
35:1
7.7:1
0
40
40
20
40
40
40
85% yield, 12:1, 6:7
3
4
60 ꢁC
B Hydroalkoxylation With Isopropanol via Hydrochlorination
5f
6f
7
60 ꢁ
60 ꢁ
C
C
O
O
75
75
60 ꢁC
5 mol% Pd[(−)-sparteine]Cl2
8f
60 ꢁ
C
20 mol% CuCl2
+
a
IPA, O2, 3ÅMS, 40 °C, 24 h
Reaction performed on a 0.2 mmol scale.
b
c
d
e
f
20% yield, 8
50% yield
Percent conversion measured by GC using an internal standard.
GC yield.
Ratio of GC yields.
7.5 mol % CuCl2 was added.
20 mol % (ꢀ)-sparteine-N-oxide was added.
Figure 3. (A) Exposing styrene 5a to the alkene hydroalkoxylation conditions with
ethanol leads to the formation of the acetal 6. (B) Employing IPA as the solvent with
similar reaction conditions unexpectedly produced the hydroalkoxylation product 8.

K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
5077
Previously our laboratory conducted mechanistic studies on the
aerobic oxidation of alcohols with Pd[(ꢀ)-sparteine]Cl2, which
demonstrated a significant rate enhancement and improved cata-
lyst stability when exogenous (ꢀ)-sparteine was used.13 Based
upon these data, 40 mol % exogenous (ꢀ)-sparteine was evaluated
and led to an increase in selectivity for the hydroarylation product
compared to Heck with a w28:1 ratio in low conversion (entry 3).
Since the aerobic oxidation of alcohols with Pd[(ꢀ)-sparteine]Cl2 is
normally conducted at elevated temperatures,13 the reaction was
performed at 60 ꢁC, which led to 63% conversion of 5a and a 45% GC
yield of the hydroarylation product (entry 4).
Considering only 63% conversion of the substrate was observed,
a time course analysis of the reaction was performed (Fig. 4A). A
significant retardation of the rate was observed as the reaction
progressed, suggesting either catalyst decomposition or inhibition.
Previously, Waymouth and co-workers21 and Stahl and co-
workers22 have demonstrated that ligands commonly employed in
Pd oxidase catalysis can be consumed via oxidation. Therefore, we
hypothesized that a possible inhibitor could originate from oxida-
tion of (ꢀ)-sparteine. In the past, (ꢀ)-sparteine-N-oxide (14a and b)
has been synthesized by treating (ꢀ)-sparteine with H2O2, which is
the product of O2 reduction (Fig. 4B).23 To test our hypothesis, two
experiments were performed with added 20 mol % (ꢀ)-sparteine-
N-oxide at two different concentrations of (ꢀ)-sparteine. With both
sets of conditions, a comparable decrease in the conversion of 5a
was observed (Table 1, compare entries 4–6). These results suggest
that (ꢀ)-sparteine-N-oxide can inhibit the catalysis (entry 6).
Therefore, we needed to identify an additive to disproportionate
H2O2 in order to reduce the amount of (ꢀ)-sparteine-N-oxide
generated during the catalysis. Previously, MnO2 has been shown to
disproportionate H2O2.24 Excitingly, use of 75 mol % MnO2 led to
10a in 81% GC yield at >99% conversion (entry 7). Interestingly,
addition of MnO2 and (ꢀ)-sparteine-N-oxide led to similar con-
version and GC yield compared to the absence of MnO2 (entry 8). It
should be noted that the reaction does not effectively proceed
without the addition of (ꢀ)-sparteine even in the presence of
MnO2.
To test our hypothesis that MnO2 was reducing the amount of
(ꢀ)-sparteine-N-oxide, two reductive coupling reactions were
performed using the optimal catalytic conditions except one
reaction did not contain MnO2 (Table 1, entries 4 and 7). After
completion of the reaction, the crude mixtures were analyzed by
ESI-MS. Both (ꢀ)-sparteine-N-oxide and (ꢀ)-sparteine were ob-
served and the ratio of the respective peak heights was measured.
However, the peak heights are dependent on ionization potential
and do not directly reflect the absolute quantity of each species in
the mixture. The ratio of peak heights of (ꢀ)-sparteine-N-oxide to
(ꢀ)-sparteine was found to be 0.50 for the reaction performed with
75 mol % MnO2 compared to 0.64 for the MnO2 free conditions,
which is an approximate 28% difference. These data support our
hypothesis that MnO2 disproportionates H2O2 and reduces the
amount of (ꢀ)-sparteine-N-oxide generated during the catalysis.
Attempts to scale the reaction from 0.2 to 1 mmol led to in-
consistent conversion and GC yields of 10a. For example, the re-
ductive coupling reaction performed on 0.2 mmol scale produced
10a in 81% GC yield (Table 2, entry 1). However, conducting the
same reaction on 1 mmol scale produced 10a in only 24% GC yield
(entry 2). This discrepancy led us to question if there is not enough
O2 present in the liquid phase and causes catalyst decomposition.
Previously, Stahl and co-workers have found that a large liquid to
gas surface area is required to achieve effective mass transport of O2
into solution in the PdII-catalyzed aerobic oxidation of alcohols
with DMSO, which could be a problem in this case.25 Additionally,
the solubility of O2 in isopropanol may be decreased at 60 ꢁC.26
In order to test our hypothesis, the pressure of O2 was increased
from balloon (w1.1 atm) to 25 psi (1.7 atm), and this led to a sig-
nificant improvement of the GC yield of 12a on 1 mmol scale (Table
2, entry 3). Even with the increased O2 pressure, MnO2 was still
required to achieve effective catalysis (compare entries 3 and 4).
The optimization studies demonstrate that ligand oxidation can
inhibit the catalysis and efficient mass transport of O2 is required to
prevent catalyst decomposition.27 Even with the improved catalytic
conditions, a large diameter flask is still required to obtain ac-
ceptable yields of the reductive coupling product. Since this is
a triphasic reaction, vigorous stirring is also essential to ensure
a sufficient dispersion of MnO2 and efficient mass transport of O2.
After identifying suitable catalytic conditions, the initial scope of
the PdII-catalyzed reductive coupling of arylstannanes and styrenes
was explored. This methodology can be utilized to access a variety of
diarylmethine containing compounds, which are prevalent in bi-
ologically active small molecules.28 Many of these compounds
would be difficult to selectively synthesize using other types of
Table 2
Optimization for the reductive coupling product on 1 mmol scale
2.5 mol% Pd[(−)-sparteine]Cl2
Ph
40 mol% (−)-sparteine
Ph
+
Y mol% MnO2
IPA, O2, 60 °C, 20h
5a
10a
11
Heck
+
PhSnBu3 (9a)
Hydroarylation
1.5 equiv.
Entry
Scalea
Y
O2
Conv.b (%)
10ac (%)
10a:11d
1
0.2
1.0
1.0
1.0
75
0
0
Balloon
Balloon
25 psi
>99
40
63
81
24
46
86
35:1
16:1
26:1
22:1
2
3e
4e
75
25 psi
94
a
Scale in mmol.
b
c
Percent conversion measured by GC using an internal standard.
GC yield.
Ratio of GC yields.
Reaction was performed in a sealed thick-wall glass pressure vessel.
Figure 4. (A) Time course analysis of the reductive coupling reaction. (B) The com-
pound (ꢀ)-sparteine-N-oxide can be synthesized using H2O2 and may inhibit the
catalysis.
d
e

5078
K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
hydroarylation methodologies.29 Notably, all of the reactions are
highly regioselective (>25:1) for addition of the arene to the -car-
A Base Facilitated Transmetalation with Boronic Esters
a
‡
R2-PdII-X
R1 B(OR)3
L PdII
R2
OR
bon of the styrene. A variety of arylstannanes were competent
coupling partners where the steric and electronic nature did not
have a significant impact upon the yield of the reaction (Fig. 5). In
contrast to many previously reported Lewis acid-catalyzed hydro-
arylation reactions,29 substrates that contain acid sensitive func-
tional groups can be employed. The scope of the reaction was not
limited to arylstannanes, but vinylstannanes were utilized to per-
form an overall hydrovinylation reaction.30 Under these conditions,
simple alkenes do not lead to appreciable yields of the desired
product because of alkene isomerization.17 Additionally, all of the
products were generated with <5% ee even though a chiral ligand
was employed.
R1B(OR)2
A
R1B(OR)3
B
X
n
C
B Base Modulates Rate of Alcohol Oxidation
OH
O
BH
X
X
X
X
X
H
L PdII
E
L PdII
F
L PdIIX2
D
L PdII
G
n
n
n
n
H
O
O
B
Figure 6. (A) A base is typically required to facilitate transmetalation of boronic esters
via a proposed four-member transition state. (B) The proposed mechanism of the Pd-
catalyzed aerobic oxidation of alcohols where exogenous base can modulate the rate.
3.2. Organoboronic esters optimization and scope
which should better stabilize the catalyst. Previously, our group has
shown that the use of N-heterocyclic carbene (NHC) ligands led to
highly active catalyst systems for the aerobic oxidation of alco-
hols.13d In this case, the [Pd(SiPr)Cl2]2 catalyst was employed to
couple 5a and BA in combination with exogenous (ꢀ)-sparteine and
tBuOK, which led to the desired product 10a in 8% GC yield (Fig. 7).
Even with the use of an NHC ligand, catalyst decomposition was
observed. This led us to question if the acidityof the boronic acid was
inhibiting the reaction or was causing catalyst decomposition.
To test our hypothesis, we evaluated the pinacol derived phenyl
boronic ester (PE) under the same conditions. This led to a higher
yield of the desired product and through further optimization it was
found that the use of 2.5 equiv of PE produced 10a in 64% GC yield.
Even though the yield was significantly improved, the reaction re-
quired 24 h, which led us to question if the large size of PE was re-
ducing the rate of the reaction. Therefore, both the propanediol (PD)
and the ethylene glycol (EG) derived boronic esters were evaluated.
Interestingly, PD yielded the desired product in 32% GC yield, but the
use of 3 equiv of EG generated 10a in 91% GC yield.
After identifying the optimal boronic ester derivative for the re-
ductive coupling reaction, the nature of the exogenous base was
evaluated. Initially, a significant number of nitrogen containing ba-
ses were tested, but all of the bases, except (ꢀ)-sparteine, did not
lead to effective catalysis. However, without (ꢀ)-sparteine, only 2%
conversion of 5a was measured and suggests that (ꢀ)-sparteine is
playing an important role in the reaction (Table 3, entries 1 and 2).
Therefore, we optimized the concentration of (ꢀ)-sparteine and
found 6 mol % produced the highest yield of the desired product.
Interestingly, removal of tBuOK led to >99% conversion of 5a and
78% GC yield of 10a (entry 3). The lower selectivity for the reductive
coupling product suggests that both bases are required to achieve
higher yields. Based upon these results, we evaluated higher con-
centrations of tBuOK, which decreased the yield of 10a (entries 4 and
5). After identifying the optimal concentration of tBuOK, we
In addition to the use of organostannanes, we were interested in
expanding the scope of the reductive coupling reaction to include
organoboronic acids or esters. Boronic acids are highly attractive
coupling partners because of the low toxicity of the byproducts and
excellent functional group compatibility.31 However, the mecha-
nism of transmetalation is proposed to be more complex as com-
pared to organostannanes. For example, an exogenous base is
typically required to activate the organoboronic acid or ester (A),
which yields intermediate B (Fig. 6A).32 The activated species then
reacts with R–PdII–X via a proposed four-membered transition
state C. Integrating an exogenous base to facilitate transmetalation
of an organoboronic acid or ester into the reductive coupling re-
action was thought to be a significant challenge. The reason for this
was based upon the proposed mechanism for the aerobic Pd-cat-
alyzed oxidation of alcohols wherein exogenous base has been
shown to accelerate the rate of alcohol oxidation.13 The proposed
mechanism entails initial coordination of the alcohol to the active
catalyst D, which leads to species E. Subsequent deprotonation of
the bound alcohol by an exogenous base produces Pd-alkoxide F,
which undergoes b-hydride elimination to generate Pd-hydride G.
Specifically, the rate limiting step of the Pd[(ꢀ)-sparteine]Cl2 cat-
alyzed oxidation of alcohols with low concentrations of exogenous
base was found to be deprotonation of intermediate E.13 However,
when an exogenous base is employed, an acceleration of the rate of
the reaction is observed, which is attributed to a change to b-hy-
dride elimination of F as the rate limiting step.
With this additional requirement in mind, we attempted to
identify catalytic conditions for the reductive coupling of styrenes
and organoboronic acids. Initially, we evaluated PhB(OH)2 (BA) with
the conditions developed for organostannanes.9 This led to the de-
sired product 10a in poor yield.33 During the course of the reaction,
a black precipitate was observed, which suggested decomposition of
the Pd catalyst. Therefore, we decided to evaluate different ligands,
2.5 mol% Pd[(−)-sparteine]Cl2
40 mol% (−)-sparteine
R1 R2
R2SnBu3
R1
+
1.5 equiv.
75 mol% MnO2
10a-j
Alkene
9a-h
5a-f
IPA, 25 psi O2, 60 °C, 18h
OMe
CF3
Cl
OMe
76%, 10a
70%, 10b
TBSO
67%, 10c
OMe
59%, 10d
65%, 10e
OMe
OMe
O
O
Boc
N
H
58%, 10f
55%, 10g
63%, 10h
52%, 10i
50%, 10j
OMe
OMe
Figure 5. The initial scope of the reductive coupling reaction of styrenes and organostannanes.

K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
5079
2.5 mol% [Pd(SiPr)Cl2]2
5-7 mol% (−)-sparteine
5-7 mol% tBuOK
esters, we had several mechanistic questions. The first question we
addressed was where does the hydrogen atom incorporated into
the alkene framework originate from? This was explored utilizing
two isotopic labeling experiments similar to those used for the al-
kene hydroalkoxylation reaction (Fig. 1A).4 The reductive coupling
of 5a and 9a was performed with (CH3)2CH(OD) as the solvent
(Fig. 9).9 As expected, no deuterium was incorporated into the
product 10a, which rules out the involvement of acidic protons in
the catalysis. In contrast, employment of (CH3)2CD(OH) as the
solvent led to three hydroarylation products, which were quanti-
fied by 1H NMR and GC/MS. Isotopomers 16a and 16b account for
70% and 22% of the isolated products, respectively, and the
remaining 8% is the unlabeled product 10a.
Ph
Ph
+
5a
+
10a
11
Heck
IPA, O2
50 °C, 8-24 h
PhB(OR)2
Hydroarylation
O
O
OH
OH
O
Ph
B
Ph B
Ph
B
O
1.3 equiv. (BA)
18% Conv.
8% GC yield of 10a
2.5 equiv. (PE)
>99% Conv.
64% GC yield of 10a
2.5 equiv. (PD)
46% Conv.
32% GC yield of 10a
O
Ph
B
iPr
iPr
N
O
N
The labeling studies support our original mechanistic proposal
wherein oxidation of the alcoholic solvent initiates the catalysis
and yields the PdII-hydride intermediate B (Fig. 2C). The formation
of two isotopomers suggests that the alkene inserts into the PdII-
3 equiv. (EG)
>99% Conv.
91% GC yield of 10a
iPr
iPr
SiPr
Figure 7. Identification of the optimal organoboronic ester.
hydride species at both the
a
- and
b
-position. This leads to in-
termediates D and D0, which equilibrate via
b
-hydride elimination.
questioned if other inorganic bases would be more effective.
Therefore, we evaluated five different inorganic bases, which led to
lower yields of 10a compared to tBuOK (entries 6–10). The optimi-
zation studies showcase the importance of the nature of the boronic
ester derivative and that both (ꢀ)-sparteine and tBuOK are required
to achieve optimal yields of the reductive coupling product.
However, when (CH3)2CD(OH) is employed as the solvent, deute-
rium is incorporated into the styrene during the course of the re-
action, which suggests that the alkene can dissociate from C. This
process implies that the PdII-deuteride can exchange with the al-
kene substrate via an insertion/b-hydride elimination pathway to
generate a PdII-hydride intermediate. This may account for the
formation of 8% of the hydroarylation product, which does not
contain any deuterium.
Using the optimized catalytic conditions, the scope of the re-
ductive coupling of boronic ester derivatives was investigated. All of
the diarylmethine containing compounds synthesized with this
method had >25:1 selectivity. The electronic nature of the styrene
did not significantly impact the yield of the transformation (Fig. 8).
However, electron donating groups on the arylboronic ester re-
duced the rate of the reaction leading to lower yields. Acid sensitive
functional groups, such as an acetal, are stable under the conditions
and are readily removed during workup. Unfortunately, under
these conditions vinylboronic ester derivatives did not undergo
reductive coupling. Additionally, straight chain alkenes rapidly
isomerize.17 Finally, considering that the chiral substance
(ꢀ)-sparteine is employed, the enantioselectivity was measured for
several reductive coupling products revealing less than 5% ee using
either boronic ester derivatives or organostannanes.
Since the deuterium labeling studies support the formation of
both intermediates D and D0, this led to the next mechanistic
question of why is the regioselectivity >25:1 for substitution of the
arene at the benzylic position of the styrene? The high regiose-
lectivity suggests that only D leads to product even though both
isomers are proposed to form. To account for this observation, we
thought intermediate D, which is a PdII-
stabilized by converting to a PdII-h3
-benzyl intermediate when
using a styrenyl substrate.34 To test our hypothesis, we believed
a conjugated diene substrate would lead to a similar PdII- 1-alkyl
intermediate that can be stabilized via a possible PdII-h3
-allyl
h
1-alkyl species, can be
-
p
h
-p
species (Fig. 10). Reaction of diene 17 with vinylstannane 9f yields
the reductive coupling product in 40% yield as a single regioisomer
and 1:1 mixture of diastereomers.
3.3. Mechanistic studies
The deuterium labeling experiments suggest the possible for-
mation of a well-defined PdII[(ꢀ)-sparteine](H)X intermediate B
(Fig. 2). Since the bidentate ligand (ꢀ)-sparteine is employed, this
causes the hydride and anionic ligand to be cis to each other, which
is the required geometry for the complex to undergo reductive
elimination to generate Pd0[(ꢀ)-sparteine]. To the best of our
knowledge, there are no known isolated cis-PdII-(H)X complexes,
which can be attributed to facile reductive elimination of HX.35 This
led to the question does the ligand, (ꢀ)-sparteine, in combination
with the polar alcoholic solvent facilitate chloride dissociation to
generate a cationic PdII-hydride intermediate, which does not
readily undergo reductive elimination?13 To investigate this ques-
tion, we attempted to synthesize and characterize a cationic
PdII[(ꢀ)-sparteine](H)(X) complex.
After exploring the initial scope of the reductive coupling re-
action of styrenes with both organostannanes and organoboronic
Table 3
Optimization of the exogenous base for the reductive coupling of 5a and EG
Entry
X (mol %)
Base
Conv.a (%)
10a (%)b
10a:11c
1
6
6
0
15
25
6
6
6
6
6
tBuOK
tBuOK
d
>99
2
>99
86
91
1
>30:1
4.3:1
23:1
>30:1
>30:1
>30:1
>30:1
17:1
2d
3
A variety of strategies have been previously reported to access
trans-PdII-hydrides and we believed the use of a non-coordinating
counterion, such as triflate, would help prevent reductive elimi-
nation of HX.35 However, attempts to synthesize PdII[(ꢀ)-
sparteine](H)(OTf) using a variety of different reported methods
to access trans-PdII-hydrides led to the formation of a black pre-
cipitate.36 These results suggest that the PdII-hydride may have
been generated, but underwent reductive elimination to yield
a Pd0 complex, which decomposed. Since the initial attempts did
not employ a polar alcoholic solvent, we decided to attempt to
synthesize the desired complex via an alcohol oxidation.35
78
76
49
85
85
73
75
74
4
5
6
7
8
9
10
tBuOK
tBuOK
Cs2CO3
K2CO3
KHCO3
Na2CO3
CsF
56
>99
>99
87
87
82
24:1
>30:1
a
Percent conversion measured by GC using an internal standard.
GC yield.
Ratio of GC yields.
No (ꢀ)-sparteine was added.
b
c
d

5080
K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
0.75 mol% [Pd(SiPr)Cl2]2
O
O
6 mol% (−)-sparteine
R2
B
R1
+
6 mol% tBuOK
R1 R2
10a,b,d, k-q
IPA, O2, 55 °C, 24h
Alkene
3 equiv
15a-h
Boc
N
H
OMe
F
81%, 10a
77%, 10n
91%, 10k
90%, 10l
58%, 10b
78%, 10m
O
O
O
OMe
Cl
68%, 10o
71%, 10p
68%, 10d
63%, 10q
O
Figure 8. The initial scope of the reductive coupling reaction of styrenes and ethylene glycol derived boronic ester derivatives.
Therefore, the PdII[(ꢀ)-sparteine](OTf)2 complex (20) was syn-
thesized by treatment of PdII[(ꢀ)-sparteine]Cl2 with 2 equiv of
AgOTf. The PdII[(ꢀ)-sparteine](OTf)2 complex was subsequently
dissolved in isopropanol, which unfortunately led to the forma-
tion of a black precipitate (Fig. 11A).
The formation of a black precipitate in all of our attempts sug-
gests that the PdII[(ꢀ)-sparteine](H)(X) complex is not stable and
undergoes facile reductive elimination to generate Pd0[(ꢀ)-spar-
teine] and HX. This led to the question how does the reductive
coupling reaction progress effectively if the proposed catalytic in-
termediate B readily undergoes reductive elimination (Fig. 2C)?
One of the key differences between the stoichiometric studies we
performed and the catalytic conditions is the presence of an alkene.
Previously, it has been shown that cationic PdII-hydride species,
which are not stable, can be trapped by reacting with conjugated
dienes.37 Based upon this report, we dissolved the PdII[(ꢀ)-spar-
teine](OTf)2 complex (20) in an isopropanol solution that contained
the reductive coupling product 10a as well as the percent of 5a
remaining were measured over time. At 6 h or about 50% conver-
sion of 5a, the GC yield of 10a and 22 is similar, which indicates that
oxidation of one alcohol yields one product. These data suggest that
the PdII-hydride species undergoes faster alkene insertion than
reductive elimination.38 However, as more of the alkene substrate
is consumed, reductive elimination or other processes become
competitive.
During the optimization studies conducted on the reductive
coupling of organoboronic esters, it was found that 3 equiv of the
arylboronic ester derivative was required to achieve acceptable
yields. This observation led to another question we wanted to in-
vestigate, which is why are multiple equivalents of the trans-
metalating agent required for organoboronic esters, but not for
organostannanes? In both cases, the transmetalation agent can
undergo oxidative homocoupling. However, arylboronic esters can
be oxidized to the respective phenol derivatives by H2O2 generated
in situ.12d We initially hypothesized that the excess boronic ester
may be oxidized under the catalytic conditions. Therefore, as the
reaction progressed, the fate of the boronic ester was investigated.
At 6 h, approximately 2 equiv of 15a was consumed (Table 4). In-
terestingly, at 14 h, a 139% GC yield of phenol (23) was measured,
which supports our hypothesis that the excess 15a required is ox-
idized by H2O2. Additionally, oxidative homocoupling of 15a con-
verts approximately 0.28 equiv of 15a to biphenyl (13). The time
course highlights the undesired side reactions that lead to the re-
quirement of multiple equivalents of organoboronic esters. Typi-
cally organostannanes are more oxidatively stable to H2O2, which
allows for lower quantities to be employed. However, the excess
boronic ester scavenges H2O2, which potentially prevents oxidation
10 equiv of styrene (Fig. 11B). The desired [(ꢀ)-sparteine]PdII-h3
-p-
benzyl(OTf) complex (21) was generated and characterized by ESI-
HRMS. Unfortunately, attempts to isolate the complex led to the
formation of a black precipitate and 1H and 13C NMR analysis of the
complex generated in situ reveals the presence of multiple un-
identifiable species.
The generation of complex 21 supports our mechanistic hy-
pothesis and suggests that the unstable PdII-hydride intermediate
B, which is generated during the catalysis, undergoes competitive
alkene insertion instead of reductive elimination of HX. This pro-
posal led to the question of how efficient is the alcohol oxidation
compared to alkene functionalization? To investigate this question,
a time course analysis of the reductive coupling of styrene 5a and
organoboronic ester 15a was conducted with sec-butanol as the
solvent (Table 4).33 The higher molecular weight alcohol allows for
quantification of the amount of ketone product being formed by GC.
The GC yields of the oxidized alcohol product butan-2-one (22) and
Diene Reductive Coupling via Possible π-allyl Intermediate
3.5 mol% Pd[(−)-sparteine]Cl2
O
40 mol% (−)-sparteine
17
tBu
75 mol% MnO2
+
Deuterium Labeling Experiments
tBu
IPA, 25 psi O2, 60 °C, 18h
Bu3Sn
O
18, 40%
2.5 mol% Pd[(−)-sparteine]Cl2
40 mol% (−)-sparteine
Ph
No Deuterium
Possible -allyl Intermediate
75 mol% MnO2
+
PhSnBu3
1.5 equiv. (9f)
OTf
(CH3)2CHOD
25 psi O2, 60 °C, 20 h
5a
1.5 equiv (9a)
Incorporation
N
PdII
N
CH2D
D
Instead
(CH3)2CDOH
19
Ph
+
Ph
+
10a, 8%
tBu
16a, 70%
16b, 22%
Figure 9. Deuterium labeling experiments on the reductive coupling of 5a and
PhSnBu3.
Figure 10. Reductive coupling of a diene and 9f, which proceeds via the possible PdII-
-p
h3
-allyl intermediate 19.

K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
5081
[PdII(SiPr)Cl2]2 and free (ꢀ)-sparteine were obtained. This suggests
that complex 24 is in equilibrium with the dimer and (ꢀ)-sparteine.
Under these conditions, PdII[(ꢀ)-sparteine]Cl2 was not detected by
ESI-MS. These data suggest the possibility of the role of (ꢀ)-spar-
teine is to break up the dimer or the free nitrogen of complex 24
may act as an intramolecular base.13
A Attempted PdII-Hydride via Alcohol Oxidation
OH
N
N
Black Precipitate
PdII
TfO OTf
20
rt
4. Conclusion
B Synthesis of the PdII- -Benzyl Complex
OTf
Based upon mechanistic insight garnered from the study of the
hydroalkoxylation reaction of vinyl phenols, we were able to design
and develop a fundamentally new reductive cross-coupling re-
action of styrenes and organometallic reagents. This transformation
is proposed to proceed by initial oxidation of the alcoholic solvent
followed by alkene insertion to yield a PdII-alkyl species, which
subsequently undergoes transmetalation with either an organo-
stannane or an organoboronic ester to ultimately generate a new
carbon–carbon bond. Overall, this process rapidly yields a valuable
diarylmethine core structure via an sp3–sp2 cross-coupling in high
regioselectivity, which is proposed to arise from stabilization via
OH
N
PdII
N
N
PdII
N
+
rt
5g
21
TfO OTf
HRMS [M]+ calc. = 445.1835
obs. = 445.1841
Figure 11. (A) Attempted synthesis of a PdII-hydride complex via alcohol oxidation.
(B) Synthesis of PdII-h3
-benzyl complex 21.
-
p
a PdII-h3
-p-benzyl complex. One interesting aspect of this trans-
formation is the use of O2 as a terminal oxidant in an overall formal
reduction of the alkene. This unique mode of catalysis is currently
being investigated in our laboratories in the development of new
hydrofunctionalization reactions as well as applications to asym-
metric catalysis.
of the exogenous (ꢀ)-sparteine that would inhibit the catalysis as
observed with the use of organostannanes.
Possible Role of (−)-sparteine
N
N
5. Experimental section
[Pd(SiPr)Cl2]2
DCE, reflux
24
Cl Pd Cl
+
(3)
2 (−)-sparteine
iPr
iPr
5.1. General considerations
N
N
Isopropanol was dried by refluxing over calcium oxide for 12 h
iPr
iPr
followed by fractional distillation. Pd[(ꢀ)-sparteine]Cl2 was syn-
m/z calc. [M+H]+ = 801.36
thesized according to
a
previously reported procedure.40
(ꢀ)-Sparteine was prepared from (ꢀ)-sparteine sulfate pentahy-
drate according to a previously reported procedure.41 HRMS were
obtained with either an ESI or APCI source with a Waters TOF. GC
separations were performed with an HP6890 GC with a flame
ionization detector equipped with a DB-5 column using a 50:1 split.
While our laboratory has not encountered any problems, great caution
should be taken when heating flammable solvents and adding solid
metals to a flammable solution in the presence of O2.
The last mechanistic question we wanted to address originated
from the optimization studies. Specifically, why is (ꢀ)-sparteine
required to achieve catalysis considering other amines such as 2,20-
bibyridine, TMEDA, and TEA are not viable? One of our initial hy-
potheses was that (ꢀ)-sparteine was responsible for breaking up
the dimeric [PdII(SiPr)Cl2]2 catalyst. To investigate the plausibility of
our proposal, we dissolved [PdII(SiPr)Cl2]2 and 2 equiv of
(ꢀ)-sparteine in 1,2-dichloroethane (DCE) and heated the mixture
to reflux (Eq. 3). After 2 h, the solution was analyzed by ESI-MS and
one major Pd species was observed [m/z (MþH)þ¼801.3]. The
molecular weight corresponds to the PdII[(ꢀ)-sparteine](SiPr)Cl2
complex (24). We propose that the NHC ligand is trans to the
monodentate (ꢀ)-sparteine ligand based upon the trans geometry
of previously reported PdII(NHC)(pyridine)Cl2 complexes.39 How-
ever, attempts to isolate complex 24 were unsuccessful, but instead
5.2. General reductive coupling procedure of alkenes and
organostannanes
The procedure and characterization data for the synthesis of
compounds 10a–j have been previously reported.9 The following
general procedure was used to synthesize compounds 10a–j:
a three-way joint was fitted to the side arm of an oven dried 100 mL
thick-wall glass pressure vessel equipped with a stir bar. An O2 tank
was connected to the three-way joint and O2 was flowed through
the vessel. To the vessel, were added 65.2 mg of MnO2 (0.750 mmol,
Table 4
Time course analysis of the reductive coupling of 5a and 15a
0.75 mol% [Pd(SiPr)Cl2]2
0.750 equiv), 4.30 mL of isopropanol, 200 mL of a 2.00 M solution of
6 mol% (−)-sparteine
6 mol% tBuOK
O
O
+
Ph
B
(ꢀ)-sparteine (0.400 mmol, 0.400 equiv) in isopropanol, 1.00 mmol
of the alkene (1.00 equiv), and 1.50 mmol of the organostannane
(1.50 equiv). The vessel was sealed, pressurized to 25 psi, evacuated
via water aspiration, and re-pressurized to 25 psi O2. This pro-
cedure was repeated three times. The vessel was sealed and the
mixture was stirred vigorously for ca. 20 min at room temperature
at 25 psi O2. The vessel was opened and O2 was flowed through the
vessel. To the stirred mixture, was added 10.3 mg of Pd[(ꢀ)-spar-
teine]Cl2 (0.0250 mmol, 0.0250 equiv). The vessel was immediately
pressurized to 25 psi O2 and was sealed. The three-way joint was
removed and the reaction mixture was stirred vigorously for 5 min
at room temperature. The mixture was then heated to 60 ꢁC in an
5a
sec-BuOH, O2, 55 °C
3 equiv, 15a
O
+
+
+
Ph Ph
Ph OH
Ph
10a
22
13
23
Time (h)
5aa (%)
15aa (%)
10ab (%)
22b (%)
13b (%)
23b (%)
6
14
47
3
98
<1
46
78
47
112
12
14
86
139
a
Percent remaining measured by GC using an internal standard.
GC yield measured using an internal standard.
b

5082
K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
oil bath and was stirred vigorously for 18 h. The vessel was re-
moved from the oil bath, cooled to room temperature, and the
pressure released. To the reaction mixture, was added 5.00 mL of
a 1.00 M solution of aqueous NaOH and was stirred for 1 h.42 The
mixture was filtered through Whatman filter paper, rinsed with ca.
10.0 mL of Et2O, and was transferred to a separatory funnel. The
aqueous layer was extracted three times with 20.0 mL of Et2O, all of
the organic extracts were combined, washed with 40.0 mL of brine,
and dried over MgSO4. The mixture was filtered and the solvent
was removed in vacuo. The product was purified via flash
chromatography.
precipitate began to form. The mixture was diluted by adding 1 mL
to 1 mL of isopropanol. The solution was infused into an ESI-MS
instrument and no identifiable Pd complexes were observed.
5.6. Synthesis of the PdII-h3
-p-benzyl complex from Pd[(L)-
sparteine](OTf)2 (21)
To a flame dried 5 mL round bottom flask equipped with a stir
bar under a nitrogen atmosphere, were added 5.2 mg of styrene
(0.050 mmol, 10 equiv) and 500 mL of isopropanol. Next, 3.2 mg of
Pd[(ꢀ)-sparteine](OTf)2 (0.0050 mmol, 1.0 equiv) was added and
the orange mixture was stirred for 10 min. The mixture was diluted
5.3. General reductive coupling procedure of alkenes and
organoboronic esters
by adding 0.5 mL to 1 mL of isopropanol. The solution was infused
into the (APCI/ESI)-HRMS instrument. HRMS (ESI/APCI) m/z (M)þ
for 106Pd calcd: 445.1835 obsd: 445.1841. Unfortunately, attempts to
isolate the complex result in the formation of black precipitate.
Additional attempts to employ (CD3)2CD(OD) as the solvent to
characterize the complex by 1H and 13C NMR indicated the pres-
ence of multiple species, which could not be identified.
The procedure and characterization data for the synthesis of
compounds 10k–r have been previously reported.33 The following
general procedure was used to synthesize compounds 10k–r: to an
oven dried 100 mL Schlenk flask equipped with a stir bar, were
added 4.3 mg of [Pd(SiPr)Cl2]2 (0.0038 mmol, 0.0076 equiv), 300 mL
of a 100 mM solution of (ꢀ)-sparteine (0.030 mmol, 0.060 equiv) in
isopropanol, and 7.4 mL of isopropanol. A dried water condenser
and a three-way joint fitted with a balloon of O2 were installed on
the flask. The flask was evacuated via water aspiration and refilled
with oxygen three times and the mixture was stirred vigorously for
ca. 20 min at room temperature under an O2 atmosphere. To the
mixture, was added 1.0 mL of a 500 mM solution of the alkene
(0.50 mmol, 1.0 equiv) in isopropanol, 1.0 mL of a 1.5 M solution of
the organoboronic ester (1.5 mmol, 3.0 equiv) in isopropanol, and
Acknowledgements
This work was supported by the National Institutes of Health
(Grant NIGMS RO1 GM3540). M.S.S. thanks the Dreyfus Foundation
(Teacher-Scholar) and Pfizer for their support. K.M.G. thanks
Sanofi-Aventis for a graduate research fellowship. Y.I. thanks Kyorin
Co., Ltd for financial support. We would like to thank Dr. Jim Muller
for assistance with the ESI-MS experiments. We are grateful to
Johnson Matthey for the gift of various Pd salts.
300 mL of a 100 mM solution of potassium tert-butoxide
(0.030 mmol, 0.060 equiv) in isopropanol. The mixture was then
heated to 55 ꢁC and was stirred vigorously for 24 h. The reaction
mixture was cooled to room temperature. The mixture was con-
centrated under reduced pressure. To the residue, was added 10 mL
of water and was extracted two times with 10 mL of hexanes. To the
combined organic extracts, were added 1.0 g of magnesium sulfate
and 1.00 g of silica. The mixture was stirred at room temperature
for 10 min, filtered, washed with hexanes, and concentrated under
reduced pressure to yield a colorless oil. The product was purified
via flash chromatography.
References and notes
1. Beller, M.; Seayad, J.; Tillack, A.; Jiao, H. Angew. Chem., Int. Ed. 2004, 43,
3368–3398.
2. (a) Tsuji, J. Palladium Reagents and Catalysts; John Wiley & Sons: Hoboken, NJ,
2004; (b) Stahl, S. S. Angew. Chem., Int. Ed. 2004, 43, 3400–3420; (c) Cornell, C.
N.; Sigman, M. S. Inorg. Chem. 2007, 46, 1903–1909.
3. (a) Cornell, C. N.; Sigman, M. S. J. Am. Chem. Soc. 2005, 127, 2796–2797; (b)
Cornell, C. N.; Sigman, M. S. Org. Lett. 2006, 8, 4117–4120.
4. (a) Gligorich, K. M.; Schultz, M. J.; Sigman, M. S. J. Am. Chem. Soc. 2006, 128,
2794–2795; (b) Zhang, Y.; Sigman, M. S. Org. Lett. 2006, 8, 5557–5560; (c) For an
example of a PdII-catalyzed coupled alcohol oxidation/alkene hydrogenation,
see: Tsuchiya, Y.; Hamashima, Y.; Sodeoka, M. Org. Lett. 2006, 8, 4851–4854.
5. For examples of metal catalyzed alkene hydroalkoxylation reactions, see: (a)
Qian, H.; Han, X.; Widenhoefer, R. A. J. Am. Chem. Soc. 2004, 126, 9536–9537; (b)
Yang, C.-G.; Reich, N. W.; Shi, Z.; He, C. Org. Lett. 2005, 7, 4553–4556; (c)
Coulombel, L.; Favier, I.; Dunach, E. Chem. Commun. 2005, 2286–2288; (d) Yang,
C.-G.; He, C. J. Am. Chem. Soc. 2005, 127, 6966–6967.
6. For an example of a Pd(0)-catalyzed hydroalkoxylation, see: Matsukawa, Y.;
Mizukado, J.; Quan, H.; Tamura, M.; Sekiya, A. Angew. Chem., Int. Ed. 2005, 44,
1128–1130.
7. (a) For a review of quinone methides in synthesis, see: Van De Water, R. W.;
Pettus, T. R. R. Tetrahedron 2002, 58, 5367–5405; (b) For the use of stoichio-
metric Pd(II)/Cu(II) to generate a quinone methide in the elegant synthesis of
carpanone, see: Chapman, O. L.; Engel, M. R.; Springer, J. P.; Clardy, J. C. J. Am.
Chem. Soc. 1971, 93, 6696–6698.
5.4. Synthesis of Pd[(L)-sparteine](OTf)2 (20)
To a flame dried 100 mL round bottom flask equipped with a stir
bar under a nitrogen atmosphere, were added 618 mg of Pd[(ꢀ)-
sparteine]Cl2 (1.50 mmol, 1.00 equiv) and 60.0 mL of CH2Cl2. The
orange solution was stirred for 5 min and 771 mg of silver triflate
(3.00 mmol, 2.00 equiv) was added. The cloudy orange solution was
stirred for 1 h and the precipitate was removed by filtering the
solution through Celite rinsing with CH2Cl2. The solution was
concentrated in vacuo to approximately 10 mL and ca. 10 mL of
hexanes was added until the solution turned cloudy. The solvent
was removed in vacuo to yield an orange solid, which was rinsed
with hexanes and the residual solvent was removed by applying
a vacuum to the solid. Yield: 76% (730 mg); orange solid, mp: 120–
123 ꢁC (decomposition); IR 3140, 2941, 2870, 1453, 1271, 1224, 1161,
1025, 982, 625, 576; HRMS (ESI/APCI) m/z (MꢀOTf)þ calcd:
489.0646, obsd: 489.1531.
8. (a) Stahl, S. S. Science 2005, 309, 1824–1826; (b) Gligorich, K. M.; Sigman, M. S.
Angew. Chem., Int. Ed. 2006, 45, 6612–6615.
9. Gligorich, K. M.; Cummings, S. A.; Sigman, M. S. J. Am. Chem. Soc. 2007, 129,
14193–14195.
10. Netherton, M. R.; Fu, G. C. Palladium-Catalyzed Cross-Coupling Reactions of
Unactivated Alkyl Electrophiles with Organometallic Compounds. In Topics in
Organometallic Chemistry; Springer: Berlin, 2005; Vol. 14, pp 85–108.
11. For selected examples of the oxidative Heck reaction, see: (a) Hirabayashi, K.;
Ando, J.-I.; Nishihara, Y.; Mori, A.; Hiyama, T. Synlett 1999, 99–101; (b) An-
dappan, M. M. S.; Nilsson, P.; Larhed, M. Chem. Commun. 2004, 218–219; (c)
Delcamp, J. H.; Brucks, A. P.; White, M. C. J. Am. Chem. Soc. 2008, 130, 11270–
11271; For a mechanistic study of the oxidative Heck reaction, see: (d) Enquist,
P. A.; Nilsson, P.; Sjoberg, P.; Larhed, M. J. Org. Chem. 2006, 71, 8779–8786.
12. For selected examples of PdII-catalyzed homocoupling of organometallic re-
agents, see: (a) Alcaraz, L.; Taylor, R. J. K. Synlett 1997, 791–792; (b) Smith, K. A.;
Campi, E. M.; Jackson, W. R.; Marcuccio, S.; Naeslund, C. G. M.; Deacon, G. B.
Synlett 1997, 131–132; (c) Yoshida, H.; Yamaryo, Y.; Ohshita, J.; Kunai, A. Tet-
rahedron Lett. 2003, 44, 1541–1544; For a mechanistic study of PdII-catalyzed
homocoupling of organoboronic acids, see: (d) Adamo, C.; Amatore, C.; Ciofini,
I.; Jutand, A.; Lakmini, H. J. Am. Chem. Soc. 2006, 128, 6829–6836.
5.5. Attempted hydride synthesis via isopropanol and Pd[(L)-
sparteine](OTf)2
To a flame dried 5 mL round bottom flask equipped with a stir
bar under a nitrogen atmosphere, were added 3.2 mg of Pd[(ꢀ)-
sparteine](OTf)2 (0.0050 mmol, 1.0 equiv) and 500 mL of iso-
propanol. The orange mixture was stirred for 10 min and a black

K.M. Gligorich et al. / Tetrahedron 65 (2009) 5074–5083
5083
13. (a) Mueller, J. A.; Sigman, M. S. J. Am. Chem. Soc. 2003, 125, 7005–7013; (b)
Mueller, J. A.; Goller, C. P.; Sigman, M. S. J. Am. Chem. Soc. 2004, 126, 9724–9734;
(c) Mueller, J. A.; Cowell, A.; Chandler, B. D.; Sigman, M. S. J. Am. Chem. Soc.
2005, 127, 14817–14824; (d) Sigman, M. S.; Jensen, D. R. Acc. Chem. Res. 2006,
39, 221–229.
14. Balija, A. M.; Stowers, K. J.; Schultz, M. J.; Sigman, M. S. Org. Lett. 2006, 8,
1121–1124.
15. Podhajsky, S. M.; Sigman, M. S. Organometallics 2007, 26, 5680–5686.
16. Nishimura, T.; Kakiuchi, N.; Onoue, T.; Ohe, K.; Uemura, S. J. Chem. Soc., Perkin
Trans. 1 2000, 1915–1918.
A.; Coniglio, S.; Colagioia, S.; Beccari, A. R.; Bizzarri, C.; Cavicchia, M. R.; Locati,
M.; Galliera, E.; Di Benedetto, P.; Vigilante, P.; Bertini, R.; Allegretti, M. J. Med.
Chem. 2007, 50, 3984–4002; (c) Liang, H.; Wu, X.; Yalowich, J. C.; Hasinoff, B. B.
Mol. Pharmacol. 2008, 73, 686–696.
29. For selected examples of alkene hydroarylation reactions, see: (a) Youn So, W.;
Pastine Stefan, J.; Sames, D. Org. Lett. 2004, 6, 581–584; (b) Nevado, C.; Echa-
varren, A. M. Synthesis 2005, 167–182; (c) Anderson, L. L.; Arnold, J.; Bergman,
R. G. J. Am. Chem. Soc. 2005, 127, 14542–14543; (d) Han, X.; Widenhoefer, R. A.
Org. Lett. 2006, 8, 3801–3804; (e) Lapis, A. A. M.; Da Silveira Neto, B. A.;
Scholten, J. D.; Nachtigall, F. M.; Eberlin, M. N.; Dupont, J. Tetrahedron Lett. 2006,
47, 6775–6779; (f) Rueping, M.; Nachtsheim, B. J.; Scheidt, T. Org. Lett. 2006, 8,
3717–3719; (g) Sun, G.; Sun, H.; Wang, Z.; Zhou, M. M. Synlett 2008, 1096–1100.
30. For a review of the hydrovinylation reaction, see: RajanBabu, T. V. Chem. Rev.
2003, 103, 2845–2860.
17. Sen, A.; Lai, T. W. Inorg. Chem. 1984, 23, 3257–3258.
18. (a) For a review of the Stille reaction, see: Espinet, P.; Echavarren, A. M. Angew.
Chem., Int. Ed. 2004, 43, 4704–4734; (b) Shirakawa, E.; Nakao, Y.; Murota, Y.;
Hiyama, T. J. Organomet. Chem. 2003, 670, 132–136.
19. (a) For a Rh-catalyzed hydroarylation reaction of vinyl pyridines, see: Lautens,
M.; Roy, A.; Fukuoka, K.; Fagnou, K.; Martin-Matute, B. J. Am. Chem. Soc. 2001,
123, 5358–5359; (b) For an example of PdII-catalyzed hydroarylation reaction of
Michael acceptors, see: Ohe, T.; Wakita, T.; Motofusa, S.-i.; Cho, C. S.; Ohe, K.;
Uemura, S. Bull. Chem. Soc. Jpn. 2000, 73, 2149–2155.
20. (a) Oda, H.; Morishita, M.; Fugami, K.; Sano, H.; Kosugi, M. Chem. Lett. 1996, 811–
812; (b) Fugami, K.; Hagiwara, S.; Oda, H.; Kosugi, M. Synlett 1998, 477–478.
21. Conley, N. R.; Labios, L. A.; Pearson, D. M.; McCrory, C. C. L.; Waymouth, R. M.
Organometallics 2007, 26, 5447–5453.
31. (a) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442–
4489; (b) Kotha, S.; Lahiri, K.; Kashinath, D. Tetrahedron 2002, 58, 9633–9695.
32. (a) Chemler, S. R.; Trauner, D.; Danishefsky, S. J. Angew. Chem., Int. Ed. 2001, 40,
4544–4568; (b) Miyaura, N. J. Organomet. Chem. 2002, 653, 54–57.
33. Iwai, Y.; Gligorich, K. M.; Sigman, M. S. Angew. Chem., Int. Ed. 2008, 47,
3219–3222.
34. Johns, A. M.; Utsunomiya, M.; Incarvito, C. D.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 1828–1839.
35. Grushin, V. V. Chem. Rev. 1996, 96, 2011–2033.
22. Konnick, M. M.; Stahl, S. S. J. Am. Chem. Soc. 2008, 130, 5753–5762.
23. Boczon, W.; Pieczonka, G.; Wiewiorowski, M. Tetrahedron 1977, 33, 2565–2570.
24. Larson, E. J.; Pecoraro, V. L. J. Am. Chem. Soc. 1991, 113, 7809–7810.
25. Steinhoff, B. A.; Stahl, S. S. J. Am. Chem. Soc. 2006, 128, 4348–4355.
26. Fischer, K.; Wilken, M. J. Chem. Thermodyn. 2001, 33, 1285–1308.
27. Iwasawa, T.; Tokunaga, M.; Obora, Y.; Tsuji, Y. J. Am. Chem. Soc. 2004, 126,
6554–6555.
28. (a) Barda, D. A.; Wang, Z.-Q.; Britton, T. C.; Henry, S. S.; Jagdmann, G. E.; Co-
leman, D. S.; Johnson, M. P.; Andis, S. L.; Schoepp, D. D. Bioorg. Med. Chem. Lett.
2004, 14, 3099–3102; (b) Moriconi, A.; Cesta, M. C.; Cervellera, M. N.; Aramini,
36. (a) Konnick, M. M.; Gandhi, B. A.; Guzei, I. A.; Stahl, S. S. Angew. Chem., Int. Ed.
2006, 45, 2790–2793; (b) Johns, A. M.; Tye, J. W.; Hartwig, J. F. J. Am. Chem. Soc.
2006, 128, 16010–16011.
37. Mabbott, D. J.; Maitlis, P. M. J. Chem. Soc., Dalton Trans. 1976, 2156–2160.
38. Hills, I. D.; Fu, G. C. J. Am. Chem. Soc. 2004, 126, 13178–13179.
39. O’Brien, C. J.; Kantchev, E. A. B.; Valente, C.; Hadei, N.; Chass, G. A.; Lough, A.;
Hopkinson, A. C.; Organ, M. G. Chem.dEur. J. 2006, 12, 4743–4748.
40. Mandal, S. K.; Sigman, M. S. J. Org. Chem. 2003, 68, 7535–7537.
41. Mueller, J. A.; Jensen, D. R.; Sigman, M. S. J. Am. Chem. Soc. 2002, 124, 8202–8203.
42. Renaud, P.; Lacote, E.; Quaranta, L. Tetrahedron Lett. 1998, 39, 2123–2126.