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University of Southern California Dissertations and Theses
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Applications of oxidative boron Heck-type reactions and the development of novel tridentate NHC-amidate-alkoxide containing palladium(II) catalysts
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Applications of oxidative boron Heck-type reactions and the development of novel tridentate NHC-amidate-alkoxide containing palladium(II) catalysts
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Content
APPLICATIONS OF OXIDATIVE BORON HECK-TYPE REACTIONS AND THE
DEVELOPMENT OF NOVEL TRIDENTATE NHC-AMIDATE-ALKOXIDE
CONTAINING PALLADIUM(II) CATALYSTS
by
Justin Michael O’Neill
A Dissertation Presented to the
FACULTY OF THE USC GRADUATE SCHOOL
UNIVERSITY OF SOUTHERN CALIFORNIA
In Partial Fulfillment of the
Requirements for the Degree
DOCTOR OF PHILOSOPHY
(CHEMISTRY)
December 2010
Copyright 2010 Justin Michael O’Neill
ii
In memory of
Bradford James O’Neill
and
Dr. Kyung Soo Yoo
iii
ACKNOWLEDGEMENTS
I would like to acknowledge and thank all of those who have helped me
along the road in my academic growth, especially Sean Regan, Paul Groves,
Casey Shotwell, Gregory Ring, and Paul Boyd from South Pasadena High
School, Dr. David Soulsby, Dr. David Schrum, Dr. Ben Aronson, and Tony
Mueller from the University of Redlands, Dr. Travis Williams, Dr. Kyung Soo Yoo,
and my advisor Dr. Kyung Woon Jung from the University of Southern California.
I would also like to thank all of those who have helped in my personal growth and
been with me all along the way, especially Keyes, Chas, Clayton, Devon, Pete,
Arthur, Dr. Anthony Ribera, Dr. David Young, and the rest of the men of Chi Rho
Psi, Andre, Teddy, Ben, Randy, Jimmy, Troy, the Mackey-Mason brothers,
Earnest, Boz, Pete, Derek, Phil, and the rest of the South Pasadena guys. A
special thanks is in order to Leslie O’Dell and my entire family, especially Aunt
Chris, Cousin Ben, Uncle Rick, Grammi, Paca, the Teter family, my brother
Kevin, my mom Leanne, and dad Michael for all of their love and support.
iv
Table of Contents
Dedication
Acknowledgements
List of Tables
List of Figures
Abstract
Chapter 1: General Introduction
1.1 Palladium in Organic Chemistry
1.2 Palladium in Catalytic C-C Bond Formation
1.3 The Heck Reaction
1.4 Development of the “Oxidative Boron Heck-Type Reaction
1.5 Mechanism of the “Oxidative Boron Heck-Type Reaction”
1.6 Chapter 1 References
Chapter 2: Tandem Oxidative Born Heck-Type and Suzuki Reactions
2.1 Introduction and Dual Palladium Catalyzed Reaction
Concept
2.2 Results and Discussion
2.3 Conclusion and Future Possibilities
2.4 Chapter 2 References
Chapter 3: Asymmetric Oxidative Boron Heck–Type Reactions of
Acyclic Alkenes Using Bidentate Nitrogenous Ligands
3.1 Introduction
3.2 Results and Discussion
3.3 Conclusion and Further Direction
3.4 Chapter 3 References
Chapter 4: The Development of Novel Tridentate NHC–Amidate–
Alkoxide Containing Palladium Catalysts
4.1 Introduction and Catalyst Design
4.2 Results and Discussion for Hydroxyl Containing Ligands and
Corresponding Palladium Complexes
ii
iii
vi
vii
ix
1
1
3
7
12
18
21
24
24
28
38
39
40
40
43
47
49
50
50
53
v
4.3 Results and Discussion for Methoxy Containing Ligands and
Corresponding Palladium Complexes
4.4 Conclusion and Applications
4.5 Chapter 4 References
Chapter 5: Asymmetric Oxidative Boron Heck–Type Reactions of
Alkenes Using Novel Tridentate NHC–Amidate–Alkoxide Containing
Palladium(II) Catalysts
5.1 Introduction
5.2 Results and Discussion
5.3 Conclusion and Future Aims
5.4 Chapter 5 References
Bibliography
Appendices
Appendix 1: Supporting Information for chapter 2
Appendix 2: Supporting Information for chapter 3
Appendix 3: Supporting Information for chapter 4
Appendix 4: Supporting Information for chapter 5
61
63
64
65
65
66
76
78
79
84
84
130
166
191
vi
List of Tables
Table 2.1: Optimization of the Oxidative Boron Heck-Type Reactio
Using t-Butyl Acrylate.
Table 2.2: Initial attempts at the Tandem Oxidative Boron–Heck and
Suzuki Reaction.
Table 2.3: Optimization of the Oxidative Boron Heck-Type Reaction
Using Cyclohexenone.
Table 3.1: Effect of Various Bidentate Ligands on the Formation of 1.
Table 3.2: Asymmetric Oxidative Boron Heck–Type Reactions Using
Catalyst 8.
Table 5.1: Screening of Representative Oxidants in the Formation of 1.
Table 5.2: Asymmetric Oxidative Boron Heck–Type Reactions of
Linear Olefins and Arylboronic Acids Using 3.
Table 5.3: Optimization of Conditions for the Oxidative Boron Heck–
Type Reactions of Cyclic Olefins and Arylboronic Acids Using 3a.
Table 5.4: Asymmetric Oxidative Boron Heck–Type Reactions of Cyclic
Olefins and Arylboronic Acids Using 3
30
32
33
44
47
68
71
73
75
vii
List of Figures
Figure 1.1: Examples of commonly used palladium catalyzed C-C
bond formation
Figure 1.2: Mechanism of the Mizoroki-Heck reaction.
Figure 1.3: Generation of a stereogenic center in asymmetric Heck
reactions.
Figure 1.4: Oxidative boron Heck-type reactions by Jung.
Figure 1.5: Oxidative boron-Heck type reactions by Larhed.
Figure 1.6: Optimized oxidative boron Heck-type reactions by Jung.
Figure 1.7: Mechanism of the “oxidative boron Heck-type reaction.”
Figure 2.1: Basic concept for sequential one pot palladium catalysis.
Figure 2.2: Competition reactions among Suzuki, Heck, and boron
Heck-type substrates under different conditions.
Figure 2.3: Tandem oxidative boron Heck–type and Suzuki reaction
using 7, 13, and phenylboronic acid.
Figure 2.4: Products generated via oxidative boron Heck–type and
Suzuki tandem reactions (Suzuki component variation).
Figure 2.5: Products generated via oxidative boron Heck–type and
Suzuki tandem reactions (center component variation).
Figure 3.1: Previous asymmetric oxidative boron Heck-type reactions
by Mikami and Gelman.
Figure 3.2: Synthesis of catalyst 8 for asymmetric boron-Heck type
reactions.
Figure 4.1: Examples of previously developed organometallic
complexes with NHC ligands.
4
8
11
16
17
18
19
25
27
35
36
37
41
45
52
viii
Figure 4.2: Design for novel tridentate NHC -amidate - alkoxide
containing palladium(II) catalyst
Figure 4.3: General scheme for the construction of novel tridentate
ligands to be used for new palladium(II) catalysts.
Figure 4.4: Reduction of amino acids and coupling of resulting amino
alcohols with haloacetyl halides to give chiral amide-alcohols.
Compound 3 prepared by Satoshi Sakaguchi, compounds 4 and 5
prepared by Justin O’Neill.
Figure 4.5: Alkylation of benzimdazole with 3,4,5 and N-methylation
of resulting compounds. Compounds 6 and 8 prepared by Satoshi
Sakaguchi (from 3), compounds 6, 7, 8, and 9 prepared by Justin
O’Neill (from 4 and 5).
Figure 4.6: Formation of palladium complexes by silver–NHC
complexation and palladium transmetallation. Complex 10 synthesized
by Satoshi Sakaguchi, complex 11 synthesized by Justin O’Neill.
Figure 4.7: Dimerization of new palladium catalysts to give unique
oxygen bridged structures. Complex 12 synthesized by Satoshi
Sakaguchi, complex 13 synthesized by Justin O’Neill.
Figure 4.8: X-ray structures (hydrogen omitted) of 10 (top) and 12
(bottom). Crystal analysis and structure determination by Timothy
Stewart.
Figure 4.9: Synthesis of novel palladium complex 17. Complex 17
synthesized by Joo Ho Lee and Justin O’Neill.
Figure 5.1: Earlier work for the enantioselective boron Heck-type
reaction.
Figure 5.2: Asymmetric boron Heck–type reactions using 2 and 3.
53
54
55
56
58
58
60
61
65
67
ix
Abstract
Several applications of the “oxidative boron Heck-type” reaction have
been successfully explored. These include the development of tandem oxidative
boron Heck-type and Suzuki reactions where biaryls were generated
expeditiously in a one pot procedure by properly utilizing different mechanisms in
each step. In addition, the asymmetric coupling between trisubstituted linear
olefins and arylboronic acids via oxidative Heck-type chemistry and utilizing chiral
bidentate nitrogenous ligands resulted in yields and enantioselectivities superior
to previously known studies.
Novel tridentate NHC-amidate-alkoxide containing ligands and their
corresponding novel palladium complexes were developed. These complexes
can be synthesized starting from chiral amino acids and provide strong binding
between ligand and palladium. These complexes can be produced in monomeric
or dimeric forms. Consequently, these new palladium complexes acted
successfully as catalysts in asymmetric oxidative boron Heck-type reactions as
well, producing excellent chiral induction when using both cyclic and acyclic
olefins.
1
Chapter 1: General Introduction
1.1 Palladium in Organic Chemistry
The utilization of transition metals in organometallic chemistry as an
important method for carbon-carbon bond formation and carbon-heteroatom
bond formation has developed significantly over the last fifty years.
1
The
increasing complexity of target organic scaffolds and consequent need to
perform difficult bond formations has resulted in the exploration and development
of modern organometallic chemistry. Classical carbon-carbon, and carbon-
heteroatom bond forming reactions such as the Aldol condensation, Henry
reaction, Williamson ether synthesis, and Mannich reaction to name just a few,
have always been relevant and are still very useful in synthetic organic
chemistry. However, these classical reactions often suffer from problems such as
cross-coupling limitations, functional group tolerance, and practical difficulties in
the laboratory. Many of these problems are now overcome by the more
developed use of transition metals in organic chemistry. At the forefront of this
field are organometallic transformations catalyzed by palladium.
1,2
Palladium itself is a group 10 transition metal situated below nickel and
above platinum. Common oxidation states of palladium with regards to its use in
organometallic chemistry are 0 and +2. However, more recent research has
demonstrated that higher valent Pd species are not only possible, but relevant in
organometallic palladium chemistry.
3
Oxidation states of palladium become very
2
important when considering the mechanistic pathways involved in palladium
catalyzed transformations, as is the case with organometallic chemistry in
general. The ability to move between oxidation states, or conversely, stay in a
single oxidation state, often determines the efficiency and applicability of the
catalytic cycle employed by a particular reaction.
In the early 1900’s palladium was already being used on an industrial
scale for high pressure hydrogenation of unsaturated carbon compounds.
In the
mid 1950’s, the Wacker oxidation (Eq. 1.1) was developed as an industrial
process where a palladium catalyst is used to oxidize olefins to ketones and
aldehydes in the presence of oxygen and water.
4
H
O
PdCl
2
(cat), CuCl
2
(cat)
H
2
O, O
2
(1.1)
Here, palladium starts to become more noticeable as a weapon of choice
for synthetic organic chemists when forming bonds to carbon. By the late 60’s,
modern organopalladium chemistry starts to take shape, and by the mid 90’s,
Palladium has become one of the more widely used transition metals in synthetic
organic chemistry. Today, palladium has continued to be an exceptional
transition metal for the pure organometallic, synthetic organometallic, and purely
synthetic organic chemist. Palladium is used to facilitate the formation of not only
3
common C-C, C-O, and C-N bonds, but also C-B,
5
C-S,
6
C-Si,
7
and C-F
8
bonds.
With regard to carbon–carbon bond forming reactions, palladium has
become so widely used because it promotes and facilitates all needed steps
found in C-C coupling mechanistic pathways. This pheonomenon is best stated
by Elschenbroich in his text “Organometallics”, He states, “The preponderance of
palladium in the homogeneous catalysis of C-C coupling reactions rests in its
ability to promote all mechanistically essential elementary reactions (ligand
dissociation, oxidative addition, insertion, reductive elimination, β – H elimination)
.
9
In addition, palladium, palladium salts, and organopalladium adducts have
been found to be relatively easy to handle, tolerant of multiple functional group
and relatively insensitive to air and water.
9
Paramount to much of the reactive
properties of palladium is the excellent ability of palladium to coordinate to
carbon-carbon multiple bonds and the relatively non-polar carbon-palladium
bond.
9
1.2 Palladium in Catalytic C-C Bond Formation
In 1967, Ichiro Moritani and Yuzo Fujiwara reported their initial account
that they had coupled benzene to the terminal end of the vinyl group of styrene to
yield stilbene.
10
Reported in this initial finding, a styrene–palladium chloride
complex was used. Thus, this reaction was not catalytic, but it showed that
palladium could be used to form carbon–carbon bonds at the terminal ends of
vinyl groups. Later, in 1969, they extended this chemistry to include substituted
4
aromatics, substituted vinyl arenes, and a few olefins not conjugated to arenes,
including ethylene. More importantly, in this later study, several examples were
successfully carried out catalytically.
11
One might even consider this reaction to
be an early version of the Mizoroki-Heck reaction.
Eventually, early organometallic palladium chemistry would develop into
the many useful palladium catalyzed C-C bond forming reactions such as the
Stille, Sonogashia, Suzuki, Hiyama, Kumada, and Negishi coupling reactions that
have become common in everyday organic synthesis (Figure 1.1).
12
Figure 1.1: Examples of commonly used palladium catalyzed C-C bond
formations.
An obvious feature of these reactions is the use of an organic halide and a
metal containing organic compound as coupling partners. Consequently, the
5
mechanisms of the reactions in figure 1.1 typically involve both an oxidative
addition where an alkyl, vinyl or aryl halide (dependant on reaction) adds to a
Pd(0) catalyst, usually followed by a transmetallation step where an aryl, vinyl, or
alkynyl metal transfers the organic group to the palladium center. The following
rearrangement and subsequent reductive elimination results in the desired cross-
coupling product and regeneration of a palladium zero catalyst that can
immediately re-enter the catalytic cycle. It is common for Pd(II) sources to be
employed as pre-catalysts in these reactions. Often, ligand exchange with
phosphine, nitrogen, or oxygen based ligands will yield the Pd(0) catalyst
necessary for these reactions in-situ.
13
The diversity of these reactions allow them to all have their place in
organic synthesis. Where at a particular stage in a synthesis it may be necessary
to use a silicon reagent rather than a Grignard, one could employ a Hiyama
coupling, rather than a Kumada reaction, for example. These reactions are not
limited to the use of Sp
2
and Sp carbons either; one could use an alkyl 9-BBN
compound in a Suzuki coupling or an alkyl halide compound in a Negishi reaction
to afford the installment of an alkyl group in a synthesis. Whether the reason may
be substrate compatibility, the type of group to be introduced, need for mild
conditions, or the multitude of complications that can arise in complex molecule,
small molecule, or materials synthesis, one of these reactions may very well
meet the needed criterion.
2,12
It is worth mentioning further development of these reactions using
6
Nickel catalysts. Most notable, is the excellent work done by the Fu and Hu
groups, where they have increased substrate scopes and improved conditions for
Suzuki, Hiyama, Sonogashira, and Negishi couplings using nickel catalysts.
14
Despite the versatility of these reactions, it is important to note some of
the shortcomings that encompass most of them. As mentioned before, all of
these reactions employ the use of a metal containing organic compound and an
organic halide. This can be limiting in that both coupling partners may need to be
altered or independently synthesized before they can be used in a particular
reaction. Some are still more limited in that the carbons to be joined have to be at
least sp
2
hybridized, with some exceptions. Thus, the type of coupling partners
that can be used is often limited. While most of these reactions have had lots of
development aimed towards their optimization, most do require at least elevated,
often high temperatures, and/or the aid of a base or additional reagent to help
generate higher valent metal species that can more easily undergo
transmetallation. Thus, it would be advantageous to have a reaction where only
one coupling partner needed to posses a halide, pseudohalide, or metal, and the
other could simply be hydrocarbon based. Presumably this could be achieved via
C-H activation or by using unsaturated C-C bonds that can easily coordinate to
palladium. It would also be desired for reaction conditions to avoid high
temperatures and/or the use of bases and additives. The former of these
conditions can be met by the Mizoroki-Heck reaction (Heck reaction)
7
1.3 The Heck Reaction
An important development in organometallic chemistry was reported
independently by both Mizoroki (1971)
15
and Heck (1972).
16
Both of their initial
findings demonstrated the ability of a palladium catalyst to cross couple aryl and
vinyl halides with terminal olefins in the presence of a base to generate styrene
and diene type products. A general representation of the Mizoroki-Heck reaction
is shown in equation 1.2.
R"
R'
R"
R' X
R' = alkenyl, aryl
+
Pd
0
, base, heat
(1.2)
More specifically, Heck and Nolley used only 1 mole % of palladium
acetate to cross couple an array of organic halides and terminal olefins to acquire
desired styrenyl and diene products in moderate to high yields. In the almost 40
years since, the Heck reaction has evolved to become one of the most versatile
and useful organometallic reactions in synthetic organic chemistry. Of paramount
importance to this trend is the ability of the Heck reaction to evolve. Common
with classical organic reactions and numerous organometallic reactions is
extreme sensitivity to solvent, temperature, atmosphere, moisture, pH, etc. In
addition, problems regarding substrate compatibility and scope are common.
However, for the Mizoroki-Heck reaction, none of this appears to hold true. Over
and over, new protocols are found that show the Mizoroki-Heck reaction to be
8
compatible with conditions and substrates that allow it to be used in innumerous
situations in organic synthesis. This phenomena has caused for the Heck
reaction to be the reaction against which all other palladium catalyzed organic
transformations are measured.
17
The traditional Heck reaction is a Pd(0) catalyzed reaction and has been
studied at great lengths, leading to an established and accepted mechanism
(Figure 1.2).
17
Prior to the catalytic cycle beginning, a Pd(0) catalyst is generated
in situ. Usually this is done using a Pd(II) precatalyst, such as Pd(OAc)
2
or PdCl
2
.
The precatalyst is usually mixed with a ligand to generate a Pd(0) species in the
form of PdL
2
.
R"
R' X
R' = aryl, alkenyl
X= I, Br, Cl,OTf
Ligand (L)
Base
Pd(II)
Pd
L
X
R'
L
PdL
2
Pd
L
X L
R"
H
R'
H
R'
R"
Pd
L
X
H
L
III
Base
[BaseH]
+
X
-
oxidative
addition
olefin
insertion
beta-hydride
elimination
Pd(0)
regeneration
I
II
Figure 1.2: Mechanism of the Mizoroki-Heck reaction.
9
Of all the ligands that have been used, phosphines have proven to be the most
versatile and useful in the Heck reaction.
12,17
Once generation of the Pd(0)
catalyst is achieved, the first step in the catalytic cycle occurs through the
oxidative addition of an aryl or alkenyl halide to the Pd catalyst to generate the
intermediate I. Following oxidative addition, olefin coordination followed by
insertion gives the alkenyl or aryl containing organo palladium species II.
Subsequent beta–hydride elimination results in the formation of a new alkenyl
product and the palladium hydride species III. The final step of the Heck catalytic
cycle is the regeneration of the Pd(0) species that can now re-enter and
participate in the catalytic cycle.
Electronic requirements for these reactions range from catalytic system to
catalytic system. Most of the more traditional Mizoroki-Heck systems work well
with the olefin coupling partner possessing an ester type or other electron
withdrawing group. However, systems have been developed to be tolerant of
electronic variation in both coupling partners. When considering the alkenyl and
aryl halides used in the Heck reaction, traditionally, iodides and bromides are the
best for couplings, with chlorides often proving to be difficult to use.
Pseudohalides such as triflates have been found to be suitable as well. In their
infancy, Mizoroki-Heck reactions needed high temperatures, often exceeding 100
degrees, with reactions times ranging from a few hours to days. Amine,
carbonate, and acetate bases are commonly used in the Heck reaction.
17
One of the versatile features of the Heck reaction is the ability of it to be
10
used in both intermolecular and intramolecular reactions. Often, intramolecular
versions of the reaction can be found in synthesis as a means of cyclization.
Again, the versatility of the Heck reaction allows for such types of cyclizations to
be performed in the middle or closer to the end of complex syntheses. The
intermolecular version of the Heck reaction is demonstrated in small and complex
molecule synthesis. Thus, it can be used as a means of installing small molecule
fragments, or as a method for joining to larger molecule portions. There are some
excellent reviews dedicated to and highlighting the role of Mizoroki-Heck
reactions in synthesis.
12,17
In the case of the traditional Heck reactions, asymmetric reactions have
been primarily limited to either intramolecular cyclizations or intermolecular
couplings using cyclic olefins.
12,17
The use of linear olefins in the asymmetric
intramolecular Heck reaction is largely underdeveloped, leaving very few
examples of such transformations.
18
Asymmetry in Heck coupling reactions
arises from the situation where competing beta hydride eliminations from multiple
carbons is possible, and can result in multiple isomers of products. Selective
asymmetry can be achieved if there is a discrepancy between the numbers of
hydrogens that can participate in beta hydride elimination on the competing
centers (figure 1.3).
11
R
1
Pd
R
2
after olefin insertion
R
3
H
H
H
R
1
R
2
R
3
H
H
new stereogenic center
*
more hydrogens avaible
for beta hydride elimination
possible chiral center
after beta-hydride elimination
beta hydride elimination
Figure 1.3: Generation of a stereogenic center in asymmetric Heck reactions.
When this condition is met, the carbon at which more hydrogens are
available for elimination will often prevail as the carbon at which beta hydride
elimination occurs, thus resulting in the generation of an sp
3
center at the other
beta position. Such criteria can only really be met with internal olefins, either
cyclic or linear.
Having met one of the desirable criteria for more efficient coupling
reactions mentioned in section 1.2 in that the Heck reaction uses an olefin rather
than a metal containing organic compound as a coupling partner (this criteria
could also be met by replacing the organic halide with an olefin as well), it is
needed to address the need for mild conditions. Additionally, the Heck reaction
has traditionally experienced difficulty when using poly substituted linear olefins.
Often, these substrates are unable to be used or very long reaction times are
required at high temperatures even to afford modest yields. Even in these
12
cases, multiple regioisomers are often formed. Some methodologies have been
developed to overcome these problems and have allowed traditional Mizoroki-
Heck reactions to occur at room temperature and even employ trisubstituted
olefins.
19
1.4 Development of the “Oxidative Boron Heck-Type Reaction”
In his 1975 work, Heck was able to use boronic acids in place of a vinyl
halide in a cross coupling of methyl acrylate (reacting solvent) and 1-hexenyl-1-
boronic acid to give the desired diene products in good yields (70% using the Z
isomer and 82% using E) in the presence of triethylamine (Eq. 1.3).
20
1 equiv Pd(OAc)
2
,
Et
3
N, 0
o
C
O
O
R O
O
(1.3)
(HO)
2
B
R
R = n-butyl R = n-butyl
However, this reaction only proceeded in the presence of stoichiometric amounts
of palladium. Regardless, this particular example showed that groups other than
halides could be used in this reaction. In addition, the reaction was performed at
0
o
C, denoting that boronic acids may be used to perform such couplings using
mild conditions. Also of interest was that the use of the Z boronic acid gave
predominately the E, Z diene, while use of the E boronic acid yielded
predominately the E, E diene product. Such stereoregulation was not observed
13
when using the E and Z iodides in the analogous catalytic reaction.
The use of boronic acids in “Heck-type” reactions has become more
prevalent in the last 15 years. More recent work by several groups to be
discussed below have highlighted the ability of boronic acid and boronic ester
compounds as excellent surrogates for vinyl and arylhalides in Heck-type
reactions. The advantages of boronic acids and esters over halides may not be
apparent at first, but they are present. First, there is an abundance of
commercially available boronic acids and they are often easy to handle. In
addition, their preparation from other organic starting materials is often facile.
21
But more important than these seemingly small improvements over halides is the
versatility bestowed by using boronic acids when considering practical
advantages in the laboratory. As will be discussed in more detail, the use of
boronic acids and esters in Heck-type reactions leads more specifically to the
use of “oxidative boron Heck-type reaction” chemistry. The very nature of this
chemistry allows for mild conditions, improved substrate scope, and increased
regio and stereoselectivity. Since Heck’s initial finding using a boronic acid, other
surrogates for halides in Heck-type reaction have been studied as well. These
have included the use of antimony chlorides,
22
silanols,
23
and organotin
compounds.
23,24
to name a few. However, boronic acids offer advantages over
these compounds from availability, ease of preparation, and lower toxicity
standpoints.
The mechanistic consequences for the use of a boronic acid are that a
14
transmetallation step occurs rather than the oxidative addition step found when
using an aryl or vinyl halide used in Mizoroki-Heck coupling. For the reactions
involving a transmetallation step that were discussed in section 1.2,
transmetallation occurs while palladium is in the +2 oxidation state. It would seem
reasonable that when Heck performed this particular reaction using a boronic
acid in the 1970’s, that the boronic acid compounds transmetallated with the
Pd(II) precatalyst (Pd(OAc)
2
) before it could be reduced to the Pd(0) catalyst
used in the traditional Mizoroki-Heck reaction. After the ensuing olefin insertion
and the following beta hydride elimination, a Pd(0) species is generated. Without
an oxidant available, as is the case with traditional Heck systems,
transmetallation could not occur again, accounting for the need of a
stoichiometric amount of palladium in Heck’s original use of a vinyl boronic acid.
Thus, in order for Heck-type reactions using boronic acids to be catalytic, it would
be required that palladium be in the +2 oxidation state for this first step prior to
olefin insertion. This is advantageous in that now a Pd(II) catalyst can be used
directly instead of having to generate the Pd(0) catalyst for the normal Heck
cycle. However, an oxidant must now be provided in order to regenerate a Pd(II)
complex that can re-enter the catalytic cycle after beta-hydride elimination ejects
the product from the palladium center.
In the case of palladium, successful oxidants range from metal acetates,
to organic oxidants like benzoquinone, and molecular oxygen.
25
With regard to
oxidative Heck-type reactions in particular, metal acetates and molecular
15
oxygen have shown to be the most successful so far. An excellent example using
copper(II) acetate was demonstrated by Du and Mori, where boronic acids were
coupled with olefins in the presence of a catalytic amount of Pd(OAc)
2
and
stoichiometric Cu(OAc)
2
at 100
o
C without the use of a base.
26
Similarly, Parrish
and Jung employed Cu(OAc)
2
and CuCl
2
as oxidants to couple organotin
compounds with an array of olefins by using catalytic Pd(OAc)
2
and sodium
acetate in Heck-type reactions.
24
The yields and olefin geometry for both the
Jung and Mori studies were excellent. However, the more interesting part of the
work by Parrish and Jung was that the reactions were also carried out using
molecular oxygen as the sole oxidant and compared to those using Cu(II) salts.
In all cases, yields were similar or better when using molecular oxygen (1 atm) as
the oxidant, and in several cases, the reactions were only facilitated when
oxygen was used and not with the copper(II) salts. The use of molecular oxygen
at atmospheric pressure as an oxidant is beneficial in that the separation
required when employing metal and organic oxidants is no longer necessary. In
addition, the delivery of oxygen to the reaction can usually be accomplished by
simply leaving reactions open to air or affixing an oxygen balloon to the reaction
vessel.
As we begin to move towards the use of molecular oxygen as an oxidant,
the use boronic acids in Heck-type reactions becomes dominant. Jung and co-
workers reported the expeditious (3 hours) coupling of arylboronic acids and
esters with an array of olefins using mild conditions (50
o
C, DMF) with catalytic
16
Pd(OAc)
2
and sodium carbonate as a base, under an O
2
atmosphere.
27
Whereas
the majority of the previously reported reactions of this type employed terminal
mono-substituted olefins, this particular report showed the efficient coupling of
several internal di-substituted acrylates. Shortly thereafter, the Jung group also
reported similar findings using vinylboronic acids and esters with an array of
olefins to generate dienes, using similar conditions.
28
Additional in this report was
the successful coupling of 1-hexenylpinocolboronic ester with 2-cyclohexenone
(figure 1.4).
Figure 1.4: Oxidative boron Heck-type reactions by Jung.
Similarly, Larhead used molecular oxygen for the regioselective coupling of
arylboronic acids with both electron rich (enamides)
29
and electron poor
(acrylates)
30
olefins with the aid of a base and bidentate nitrogen-based
phenanthroline ligands. In both cases, good yields, excellent regiochemistry, and
excellent olefin geometry were observed (figure 1.5).
17
Pd(OAc)
2
, dmphen
NMM, O
2
, MeCN, 50
o
C
ArB(OH)
2
+
EWG
EWG
Ar
Pd(OAc)
2
, dmphen, NMM
O
2
, 1,4-dioxane, 50
o
C
ArB(OH)
2
+
N
R'
R"
N
R'
R"
Ar
8 examples, 31-96%
12 examples, 43-95%
N
N
dmphen
Figure 1.5: Oxidative boron-Heck type reactions by Larhed.
The convergence of both the Jung and Larhed methods resulted in the
seminal work by Jung, in which it was found that the reactivity both groups
experienced could be achieved simply by using conditions previously determined
by Jung, but without the use of a base. Excellent yields were observed when
various vinylpinocolboronic esters were coupled with multiple differentiated
olefins to afford dienes when catalytic Pd(OAc)
2
was used. In addition,
Arylboronic acids coupled very well with various olefins to yield vinyl arenas
using similar conditions and the employment of a phenanthroline ligand such as
Larhed used. The use of such ligands in the reactions using vinylboronic esters
was not necessary, but the reaction rate was accelerated from 6 hours to 2 hours
(figure 1.6).
31
Since this work, there have been several other contributions to
these types of reactions.
32
18
Figure 1.6: Optimized oxidative boron Heck-type reactions by Jung.
1.5 Mechanism of the “Oxidative Boron-Heck Type Reaction”
Several reports have proposed a mechanism for this oxidative boron-Heck
type catalysis (Figure 1.7).
31,32e,32f
There are also several studies and reviews
devoted to the role of oxygen as an oxidant in Pd catalysis.
33
19
R"
R' B(OR)
2
R' = aryl, alkenyl
R'
R"
olefin
insertion
beta-hydride
elimination
[B(OH)
2
]
+
L
-
transmetallation
R'
R"
Pd
II
-L
H- Pd
II
-L
L - Pd(II)-L
L=OAc
I
II
III
R'- Pd
II
-L
Pd
0
LH
HOO-B(OR)
2
O
O
Pd
II
R'- Pd
II
-OO-B(OR)
2
IV
V
VI
R' B(OR)
2
Figure 1.7: Mechanism of the “oxidative boron Heck-type reaction.”
As demonstrated in figure 1.7, catalysis for the “oxidative boron Heck
reaction begins with the transmetallation of a Pd(II) catalyst to generate the
organopalladium adduct I. The following olefin coordination and insertion in to the
carbon–palladium bond results in the formation of the Pd(II) species II. Beta
hydride elimination dispels the product in the form of a diene or vinyl arene to
give the Pd(II) hydride species III. Ligand hydride dissociation gives the short
lived Pd(0) species IV, and rapid reoxidation by molecular oxygen yields the
palladium peroxo complex V. At this point, another boronic acid transmetallates
with the Pd(II) peroxo species to give VI. The ligand hydride that had earlier
20
disscociated now re-enters the cycle and the hydride intercepts and eliminates
the peroxoboronic acid ligand from the palladium center, while the ligand affixes
to palladium to regenerate the organopalladium adduct I.
The most striking feature of this mechanism is the very short lived
existence of Pd(0). The use of an effective oxidant assures that Pd remains at
the +2 oxidation state, allowing for transmetallation and preventing the Pd(0)
pathway present in traditional Heck reactions. This condition allows for the
oxidative boron Heck-type reaction to be compatible with halides in that they are
not consumed, as shown by Jung (Eq. 1.4).
31
I
B(OH)
2
O-tBu
O
I
O-tBu
O
Pd(OAc)
2
(5 mol%)
dmphen (5 mol%)
O
2
,DMF,rt,12 hr
81%
+ (1.4)
21
1.6 Chapter 1 References
1. (a) Elschenbroich, C. Organometallics. 3
rd
ed. Wiley-VCH: Weinheim, 2006;
(b) Metal Catalyzed Cross – Coupling reactions (eds. deMeijere, A; Diederic, F.).
Wiley–VCH; Weinheim, 2004
2. (a) Heck, R. F. Palladium Reagents in Organic Synthesis. Academic: New
York, 1995; (b) Handbook of Organopalladium Synthesis for Organic Synthesis
(eds. Negishi, E.). Wiley interscience; New York, 2002
3. (a) Muniz, K. Angew. Chem. Int. Ed. 2009, 48, 9412; (b) Khusnutdinova, J. R.;
Rath, N. P.; Mirica, L. M. J. Am. Chem. Soc .2010, 132, 7307.
4. Elschenbroich, C. Organometallics. 3
rd
ed. Wiley-VCH: Weinheim, 2006; pp.
660-664.
5. Elschenbroich, C. Organometallics. 3
rd
ed. Wiley-VCH: Weinheim, 2006; p.
658.
6. (a) Fernández-Rodríguez, M. A.; Shen, Q.; Hartwig, J. F. J. Am. Chem. Soc.,
2006, 128, 218; (b) Lee, J-Y.; Lee, P.H. J. Org. Chem., 2008, 73, 7413; (c)
Murata, M.; Buchwald, S. L. Tetrahedron, 2004, 60, 7397.
7. (a) Elschenbroich, C. Organometallics. 3
rd
ed. Wiley-VCH: Weinheim, 2006; p.
659; (b) McNeill, E.; Barder, T.E.;Buchwald, S. L. Org. Lett., 2007, 9, 3785; (c)
Murata,M.; Ota,K.; Yamasaki, H.;Watanabe, S.; Masuda, Y. Synlett, 2007, 1387;
(d) Chang, K-J.; Rayabarapu, D. K.; Yang, F-Y.; Cheng, C-H. J. Am. Chem. Soc.,
2005,127, 126.
8. (a) Furuya, T.; Kaiser, H. M.; Ritter, T. Angew. Chem. Int. Ed. 2008, 47, 5993;
(b) Ball, N. D.; Sanford, M. S. J. Am. Chem. Soc. 2009, 131, 3796.
9. Elschenbroich, C. Organometallics. 3rd ed. Wiley-VCH: Weinheim, 2006; p.
637.
10. Moritani, I.; Fujiwara, Y. Tet. Lett. 1967, 12, 1119.
11. Fujiwara, Y.; Morutani, I.; danno, S.; Asano, R.; teranishi, S. J. Am. Chem.
Soc. 1969, 91, 7166.
12. (a) Nicolau, K. C.; Bulger, P. G.; sarlah, D. Angew. Chem. Int. Ed. 2005,
22
44, 4442; (b) Tietze, L. F. Ila, H.; Bell, H. P. Chem. Rev. 2004, 104, 3453; (c)
Tenaglia, A.; Heumann, A. Angew. Chem. Int. Ed. 1999, 38, 2180.
13. Elschenbroich, C. Organometallics. 3rd ed. Wiley-VCH: Weinheim, 2006;
pp.637-652.
14. (a) Saito, B.; Fu, G. C. J. Am. Chem. Soc. 2007. 129, 9602; (b) Saito, B.; Fu,
G. C. J. Am. Chem. Soc. 2008. 130, 6694; (c) Smith, S. W.; Fu, G. C. J. Am.
Chem. Soc. 2008. 130, 12645; (d) Vechorkin, O.; Hu, X. Angw. Chem. Int. Ed.
2009, 48, 1.
15. Mizoroki, T.; Mori, K.; Ozaki, A. Bull. Chem. Soc. Jap. 1971, 44, 581.
16. Heck, R. F.; Nolley, J. P. Jr. J. Org. Chem. 1972, 37(14), 2320.
17. (a)Elschenbroich, C. Organometallics. 3rd ed. Wiley-VCH: Weinheim, 2006;
pp. 642-645; (b) belatskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100, 3009;
(c) DeMeijere, A.; Meyer, F. E. Angew. Chem. Int. Ed. 1994, 33, 2379.
18. Yonehara, K.; Mori, K.; Hashizume, T.; Chung, K-G.; Ohe, K.; Uemura, S. J.
Organomet. Chem. 2000, 603, 40.
19. (a) Littke, A. F.; Fu, G. C. J. Am. Chem. Soc. 2001, 123, 6989; (b) Stambuli,
J. P.; Stauffer, S. R.; Shaughnessy, K. H.; hartwig, J. F. J. Am. Chem. Soc. 2001,
123, 2677.
20. Dieck, H. A.; Heck, R. F. J. Org. Chem. 1975, 40(8), 1083.
21. Hydroboration of alkynes and alkenes and Miyaura reactions are common
methods for organoboron synthesis.
22. Cho, C. S.; Uemure, S. J. Organomet. Chem. 1994, 465, 85.
23. Hirabayashi, K.; Ando, J-i.; Kawashima, J.; Nishihara, Y.; Mori, A.; Hiyama, T.
Bull. Chem. Soc. Jpn. 2000, 73, 1409.
24. Parrish, J. P.; jung, Y. C.; Shin, I. S.; Jung, K. W. J. Org. Chem. 2002, 67,
7127.
25. Becalli, E. M.; Broggini, G.; Martinelli, M.; Sottocornola, S. Chem. Rev. 2007,
107, 5318.
23
26. Du and Mori Du, X.; Suguro, M.; Hirabayashi, K.; Mori, A. Org. Lett. 2001, 3
(21), 3313.
27. Jung, Y. C.; Mishra, R. K.; Yoon, C. H.; Jung, K. W. Org. Lett. 2003, 5(13),
2231.
28. Yoon, C. H.; Yoo, K. S.; Yi, S. W.; Mishra, R. K.; Jung, K. W. Org. Lett. 2004,
6(22), 4037.
29. Andappan, M. M. S.; Nilsson, P.; von Schenk, H.; Larhed, H. J. Org. Chem.
2004, 69, 1133.
30. Andappan, M. M. S.; Nilsson, P.; Larhed, H. Chem. Comm. 2004, 69, 218.
31. Yoo, K. S.; Yoon, C. H.; Jung, K. W. J. Am. Chem. Soc. 2006, 128, 16384.
32. (a) Su, Y.; Jiao, N. Org .Lett. 2009, 11(14), 2980; (b) Ruan, J.; Li, X.; Saidi,
O.; Xiao, J. J. Am. Chem. Soc. 2008, 130, 2424; (c) Delcamp, J. H.; Brucks, A.
P.; White, M. C. J. Am. Chem. Soc. 2008, 130, 11270; (d) Lindh, J.; Enquist, P-
A.; Pilotti, A.; Nilsson, P.; Larhed, M. J. Org. Chem. 2007, 72, 7957; (e) Likhar, P.
R.; Roy, M.; Roy, S.; Subhas, M. S.; Kantam, M. L.; Sreedhar, B. Adv. Syn.
Catal. 2008, 350, 1968; (f) Lindh, J.; savmarker, J.; Nilsson, P.; Sjoberg, P. J. R.;
Larhed, M. Chem. Eur. J. 2009, 15, 4630.
33. (a) Adamo, C.; Amatore, C.; Ciofini, I.; Jutand, A.; Lakmini, H. J. Am. Chem.
Soc. 2006, 128, 6829; (b) Stahl, S. S. Angew. Chem. Int. ed. 2004, 43, 3400.
24
Chapter 2: Tandem Oxidative Boron Heck-Type and
Suzuki Reactions
-Work presented in this chapter is demonstrated in the publication below.
O’Neill, J.; Yoo, K. S.; Jung, K. W. Tet. Lett. 2008, 49, 7307.
-All work and analysis presented in this chapter was done by Justin O’Neill
2.1 Introduction and Dual Palladium Catalyzed Tandem Reaction Concept
It was our goal to demonstrate some possible applications of these
oxidatvie boron Heck–type reactions. One of the applications we sought was the
development of dual palladium catalyzed reactions that could take place
sequentially, preferably in a one pot fashion. Being that oxidative boron–Heck
type reactions take place via a Pd(II) mechanism, it seemed reasonable that the
palladium catalyst used in these reactions could then again be used again
directly in a Pd(0)/Pd(II) cycle reaction. Thus, we chose the Suzuki coupling as a
possible candidate for a second reaction. One of the excellent features of the
Suzuki reactions is its remarkable ability to give biaryls in high yields.
1
The biaryl
moiety itself has been prevalent as a key structure of the fuctional molecules in
raw materials for LCD (liquid crystal display) and OLED (organic light emitting
diode) scaffolds, as well as biologically active compounds.
2
Many of the reactions
that were metioned in section 1.2 have been employed as powerful and versatile
methods for biaryl synthesis and have offered increased utility because of their
mild conditions compared to traditional biaryl synthetic methods such as the
25
Scholl,
3
Gomberg-Bachmann,
4
or Ullmann-type reactions.
5
Thus, this new
tandem aproach compliments these reactions as an efficient means of
generating differentiated biaryls and conjugated compounds.
As demonstrated in equation 1.4, the optimized oxidative born Heck-type
reaction developed by Jung is compatable with halogens. Consequently, this
should lend these reactions as excellent candidates for tandem or sequential
“one pot” reactions. The halogen remaining intact after after an initial oxidative
boron Heck-type Reaction can now be exploited for an array of other reactions
that recquire halogens. More specifically, if palladium were still present in the
reaction media, another Pd catalyzed coupling requiring a halogen could take
place at that site (Figure 2.1).
B(OH)
2
OR
O
OR
O
Pd(OAc)
2
(5 mol%)
dmphen (5 mol%)
O
2
,DMF,rt,12hr
+
X
X
R'O
O
X
Heck
Suzuki
Sonogashira
Stille
Kumada
Negishi
Hiyama
R'O
O
R"
X= I, Br,Cl,OTf R" =aryl,alkenyl
Step 1: Oxidative boron Heck-type reaction
Step 2: Other Pd catalyzed C-C bond forming reaction
Figure 2.1: Basic concept for sequential one pot Pd catalysis.
26
With this basic concept in mind, we undertook several competition
reactions to ultimately test the feasability of the first step of these tandem
reactions. To do so, 4-iodoanisole (1), 4-dimethylaminophenylboronic acid (2),
and t-butylacrylate (3) were used together in several coupling reactions.
Dependant on conditions, it should be possible to generate Suzuki, and/or Heck,
and/or oxidative boron Heck-type products in the presence of all three of these
substrates.
27
B(OH)
2
O
t
Bu
O
N
I
H
3
CO
N
O
N
O
O
t
Bu
O
O
O
t
Bu
45 6
(Heck) (boron-Heck) (Suzuki)
++
12 3
conditions
conditions products formed
45 6
Pd(OAc)
2
, dmphen, O
2
, DMF, r.t. 0% 91% 0%
Pd(OAc)
2
, dmphen, N
2
,DMF, 100
o
C. Na
2
CO
3
92% 0% trace
-1,2, and 3 were present in equimolar ratios, 5 mole% of Pd(OAc)
2
and dmphen were
used,reactions allowed to proceed for 16 hours, yields shown are isolated yields.
Figure 2.2: Competition reactions among Suzuki, Heck, and boron Heck-type
substrates under different conditions.
As shown in Figure 2.2, we found that under oxidative conditions, the
boron-Heck compound (5) was formed exclusively. These results implied that
under these oxidative coupling conditions, the formation of Heck (4) and Suzuki
(6) coupling products was suppressed due to the absence of bases, relatively low
temperature, and the presence of an oxygen atmosphere. For the same
competition reaction under nitrogen with sodium carbonate (base) at 100
28
degrees, there was almost completely selective formation of the Heck product 4,
and no trace of the boron-Heck coupling product. This suggested that we could
simply use different atmospheres to sequentially employ different palladium
catalyzed cross-coupling reactions in a three component coupling tandem
reaction.
Mechanistically, we essentially aimed to use a Pd(II) mechanism followed
by a Pd(0) mechanism. Therefore, we examined the oxidative palladium
catalyzed cross-coupling reactions of 4-iodophenylboronic acid with olefins such
as t-butyl acrylate (Eq. 2.1) and cyclohexenone (Eq. 2.2) because the resulting
products would become suitable substrates for ensuing Suzuki couplings. As
expected, boron Heck-type products were exclusively generated, and no other
coupling products were obtained.
I
B(OH)
2
O-
t
Bu
O
I
O-
t
Bu
O
Pd(OAc)
2
(10 mol%)
dmphen (11 mol%)
O
2
,DMF, rt,16 hr
92%
+
I
B(OH)
2
Pd(OAc)
2
(10 mol%)
dmphen (11 mol%)
O
2
,DMF,50
o
C, 6 hr
85%
+
O
I
O
(2.1)
(2.2)
2.2 Results and Discussion
On the basis of these results, we endeavored to develop a one-pot
regioselective method for the preparation of biaryl compounds via a tandem
29
oxidative palladium catalyzed boron Heck-type and Suzuki coupling approach.
Initial studies focused on optimization of the boron-Heck type coupling of 4-
iodophenylboronic acid (7) and olefins such as t-butyl acrylate (acyclic example)
and cyclohexenone (cyclic example).
Table 2.1 shows results from the screening of various temperatures, mole
ratios, and catalyst/ligand loading amounts for this Heck–type coupling of t-butyl
acrylate and 7. At first, we examined the use of only 5 mole % of Pd(OAc)
2
with a
slight excess of 3 at room temperature. After a 16 hour period, the desired
product (8) was formed exclusively at a yield of 81% (entry 1). While also at room
temperature, the amount of Pd(OAc)
2
was increased to 10 mole%, slightly
increasing the yield of 8 (entry 2). In the presence of the same amount of
catalyst, but using two equivalents of t-butyl acrylate, the reaction proceeded to
give an excellent yield of 92% (entry 3). Despite acceleration of the reaction rate,
elevating the temperature to 50
o
C diminished the yield of the desired product,
presemably due to generation of 4-iodophenol as a side product (entry 4).
6
As
the conditions determined prior by our group (Jung) were found to be excellent
for such reactions, and the results in table 2.1 were consistant with these
findings, there was no reason to further investigate optimal conditions. Also of
note is the excellent solubility of all the reagents involved in these reactions in
DMF.
30
Table 2.1: Optimization of the Oxidative Boron Heck-Type Reaction Using t-Butyl
Acrylate
I
B(OH)
2
O-
t
Bu
O
I
O-
t
Bu
O
Pd(OAc)
2
dmphen
O
2
,DMF
+
73 8
-Yields shown are isolated yields, mole percent dmphen used is the same as that for Pd(OAc)
2
Entry Mole ratio (7/3) Pd(OAc)
2
Temp Time Yield(8)
11/1.1 5mol%23
o
C16hr 81%
21/1.1 10mol%23
o
C16hr 85%
31/2 10mol%23
o
C16hr 92%
41/2 10mol%50
o
C 6 hr 87%
Next, experiments directed toward the development of a tandem oxidative
boron-Heck/Suzuki reaction were carried out using 4-iodophenylboronic acid,
various olefins, and phenylboronic acid as coupling partners. In general, these
reactions will have three coupling partners. A halo-arylboronic acid will be used
as the central coupling partner, an olefin will partake in the oxidative boron-Heck
type reaction, and another arylboronic acid that will act in the Suzuki reaction. In
order to have these tandem reactions give selective products, the reagents for
the Suzuki step (2
nd
) of the tandem reaction will need to be added seqeuntially to
the crude reaction mixture after the first reaction is complete. Since it will be
possible to have variation at all three coupling partners, it was decided to fix the
central halo-arylboronic acid and the arylboronic acid used in the Suzuki
31
coupling while examining olefins to be used in the oxidative boron Heck–type
step.
As shown in Table 2.2, the variable oxidative boron-Heck reaction
intermediate product (brackets) was prepared at room temperature, and then
further reacted with phenylboronic acid in a Suzuki coupling in the presence of
NaOH under a N
2
atmosphere at 50
o
C. Under these conditions, a tandem
oxidative boron-Heck/Suzuki reaction using two equivalents of t-butyl acrylate as
alkene formed biaryl product (9) and disubstituted acryl product (10) in a 2 : 1
ratio (entry 1). The product 10 results from excess acrylate participating in a
traditional Heck reaction during the second reaction, as such olefins are very
suceptable to this. Therefore, in order to avoid the issue of lingering excess
acrylate, we changed the ratio of t-butyl acrylate to a molar equivalent, and
obtained more of the oxidative boron-Heck/Suzuki reaction product (entry 2).
However, in the coupling reaction of disubstituted olefins such as ethyl crotonate
and trans β-methyl styrene (entries 3 and 4), only desired tandem oxidative
boron-Heck/Suzuki reaction products (11) and (12) were obtained in good yields.
32
Table 2.2: Initial attempts at the Tandem Oxidative Boron–Heck and Suzuki
Reaction.
These initial tandem attempts showed the use of disubstituted olefins in the first
step to be preferable by not participating readily in Heck reactions later in the
reaction sequence. Therefore, cyclohexenone was chosen to fully investigate the
substrate scope of this reaction with regards to boronic acids that could be
introduced in the Suzuki step.
33
Using cyclohexenone (13) as an olefin, a similar screening process was carried
out as with t-butyl acrylate, the results of which are summarized in Table 2.3.
Table 2.3: Optimization of the Oxidative Boron Heck-Type Reaction Using
Cyclohexenone
B(OH)
2
I
I
O
O
Pd(OAc)
2
,O
2
,dmphen
DMF, time, temp
+
-Yields shown are isolated yields, mole percent dmphen used is the same as that for Pd(OAc)
2
713 14
Entry Mole ratio (7/13) Pd(OAc)
2
Temp Time Yield(14)
11/1.2 5mol%23
o
C 16 hr 61%
2 1/1.2 10 mol% 23
o
C 16 hr 78%
3 1/2 10 mol% 23
o
C 16 hr 80%
4 1/2 10 mol% 50
o
C 6 hr 85%
5 1/1.2 10 mol% 50
o
C 6 hr 65%
At room temperature in the presence of 5 mole percent of Pd(OAc)
2
and
dmphen, 7 and 13 coupled to give the desired cyclohexenyl aryl product (14) in
61% yield (entry1). An increase in the amount of Pd(II) complex from 5 mole
percent to 10 mole percent provided an appreciable rise in yield of 14 (entry 2).
Increasing the molar ratio of cyclohexenone to that of 4-iodophenylboronic acid
increased the yield slightly (entry 3). Elevation of the temperature to 50
o
C
further
increased the yield, while also accelerating the reaction rate from 16 hours down
34
to 6 hours (entry 4). However, lowering the ratio of cyclohexenone to 4-
iodophenylboronic acid at this higher temperature resulted in significant decrease
in the yield of 14 (entry 5). Thus, we determined that optimal conditions for the
cross-coupling reaction were to use two equivalents of cyclohexenone compared
to 4–iodophenylboronic acid at 50
o
C in the presence of 10 mol % of Pd(OAc)
2
and ligand.
Now that we had determined optimal conditions for the use of
cyclohexenone in the initial oxidative boron Heck-type step of this tandem
reaction, we examined the Suzuki reaction of intermediate compound 14 with
phenylboronic acid. Thus, intermediate compound 14 was generated from 7 and
13 using optimal conditions so it could be further reacted. Then, to the crude
reaction mixture containing 14, phenylboronic acid and NaOH were added and
the reaction was stirred at 50
o
C under N
2
. After six hours, the cross-coupling
reaction proceeded to give a 45% yield of the desired biaryl product (15). This
yield was in fact the overall yield for the two step one pot tandem reaction. This
conversion was noticebly lower and not satisfactory compared to the Suzuki
reaction of the intermediates generated in table 2.2 under the same conditions.
Therefore, we sought optimal conditions by screening various bases and
temperatures to increase the Suzuki, and consequently, the overall reaction
yield. The use of carbonate and phosphate bases such as Na
2
CO
3
, K
2
CO
3
and
K
3
PO
4
at 50
o
C in the Suzuki step provided the biaryl coupling product 15 in low
yields of 29%, 24%, and 37%, respectively. Also, the use of the organic base
35
Et
3
N reduced the yield to only 25%. However, at the elevated temperature of 90
o
C, and again using NaOH, the reaction proceeded well to afford the coupling
compound 15 in an increased yield of 67% for the two step tandem reaction
(Figure 2.3).
I
O
PhB(OH)
2
NaOH
N
2
, 6hr, 90
o
C
O
7+ 13
table 3, entry 4
14 15 (67%)
Figure 2.3: Tandem oxidative boron Heck–type and Suzuki reaction using 7, 13,
and phenylboronic acid.
Utilizing these optimized Suzuki reaction conditions, we examined tandem
palladium catalyzed oxidative boron-Heck and Suzuki reactions with 4-
iodophenylboronic acid, cyclohexenone, and various arylboronic acids to explore
the substrate scope of the Suzuki reaction portion of these tandem couplings
(Figure 2.4). Reactions with electron donating substituted aryl boronic acids such
as 4-methoxyphenylboronic acid, 3,4-dimethoxyphenylboronic acid, and 4-N,N-
dimethylaminophenylboronic acid took place smoothly to provide the desired
compounds (16), (17), and (18) in 60%, 51%, and 59% yields, respectively.
Additionally, reactions with 4-cyanophenylboronic acid, 4-nitrophenylboronic acid,
and 4-acetylphenylboronic acid, all possessing highly electron withdrawing
groups, afforded the biaryl products (19), (20), and (21) in 59%, 77%, and 78%
yields, respectively. The coupling reaction using 2,6-dimethyl phenylboronic
36
acid gave a 30 % yield of the desired product (22), presumably due to steric
hinderance. In addition, we examined the Suzuki coupling reaction of the
alkenylboronic acid, trans-styrenyl boronic acid, producing the corresponding
cross-coupling compound (23) in 48% yield.
Figure 2.4: Products generated via oxidative boron Heck–type and Suzuki
tandem reactions (Suzuki component variation).
37
To further investingate the scope and limitation of the final coupling
partner, we sought to use different halo-arylboronic acids as the centerpiece
component for the tandem reaction. Several different halo-arylboronic acids were
used in conjunction with cyclohexenone and phenylboronic acid as coupling
partners using the established optimal reaction conditions. The results of these
reactions are summarized in figure 2.5.
1.Pd(OAc)
2
,O
2
, dmphen, DMF, 16 hr, rt
2.PhB(OH)
2,
NaOH, N
2
,8 hr,90
o
C
Halo Aryl Boronic Acid +
O
O
O
24 (52%)
15 (45%), from 4-Bromophenylboronic Acid
-Yields shown are isolated yields. 10 mole % Pd(OAc)
2
and dmphen was used in all cases.
O
R
Figure 2.5: Products generated via oxidative boron Heck–type and Suzuki
tandem reactions (center component variation).
A tandem reaction using 4-iodophenylboronic acid was converted
efficiently to biaryl product 15 in 67% yield as shown earlier, while 4-chloro and
4-bromophenylboronic acid, afforded the desired product 15 in 5% and 45%
yields, respectively. This is consistant with typical Suzuki coupling reactions
38
where aryl bromides and iodides easily react with arylboronic acids, but chlorides
tend not to participate in coupling readily.
1
Furthermore, 3-iodophenylboronic
acid reacted with cyclohexenone, and then phenylboronic acid to give a 52%
yield of (24). In the case of di-substituted halo-arylboronic acids, the use of both
2-fluoro-3-iodophenylboronic acid and 2-fluoro-4-iodophenyl-boronic acid as the
central coupling partner resulted in the formation of no desired product.
2.3 Conclusion and Future Possibilities
A tandem oxidative boron-Heck and Suzuki coupling reaction was
successfully developed for the preparation of biaryls in good to moderate yields.
The reaction can be performed with variability at all three coupling partners. In
addition, the biaryls formed in this study were done so without the use of long
laborious purification or the addition of more palladium catalyst in between
coupling reactions. Furthermore, the use of different atmospheric conditions and
consequently, different mechanisms, allows for the longevity of palladium
catalysts. The possibilities for the development of other tandem oxidative
palladium reactions are quite forseeable. It should be possible to couple oxidative
boron Heck-type chemistry with other palladium catalyzed reactions such as
Heck, Sonogoshira, or Hiyama couplings. If developed, these methods would
result in more expeditious and facile means of synthesizing differentiated biaryls
and conjugated compounds.
39
2.4 Chapter 2 References
1. (a) Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457; (b) Suzuki, A. J.
Organomet. Chem. 1999, 576, 147; (c) Kotha, S.; Lahiri, K.; Kashinath, D.
Tetrahedron. 2002, 58, 9633; (d) Persichini, P. J. Curr. Org. Chem. 2003, 7,
1725; (e) Bellina, F.; Carpita, A.; Rossi, R. Synthesis. 2004, 2419.; (f) Nicolau, K.
C.; Bulger, P. G.; sarlah, D. Angew. Chem. Int. Ed. 2005, 44, 4442;
(g) Elschenbroich, C. Organometallics. 3
rd
ed. Wiley-VCH: Weinheim, 2006;
p.645-649.
2. (a) Poetsch, E. Kontakte 1988, 2, 15; (b)Bemis, G. W.; Murcko, M.A. J. Med.
Chem. 1996, 39, 2887; (c) Pu, L. Chem. Rev. 1998, 98, 2405; (d) Hajduck, P.J.;
Bures, M.; Praestgaard, J.; Fesick, S. W. J. Med. Chem. 2000, 43, 3443; (e)
Horton, D. A.; Bourne, G.T.; Smythe, M. L. Chem. Rev. 2003, 103, 893; (f)
Croom, K. F.; Keating, G. M. Am. J. Cardiovasc. Drugs. 2004, 395.
3. (a) Kovacic, P.; Jones, M. B. Chem. Rev. 1987, 87, 357; (b) March, J.
Advanced organic Chemistry, 4
th
ed. Wiley: New York, 1992; p 539.
4. (a) Gomberg, M.; Bachmann, W. E. J. Am. Chem. Soc. 1924, 46, 2339; (b)
March, J. Advanced organic Chemistry, 4
th
ed. Wiley: New York, 1992; p 715.
5. (a) Ullman, F.; Bielecki, J. Chem. Ber. 1901, 34, 2174; (b) Hassan, J.;
Sevignon, M.; Gozzi, C.; Shulz, E.; Lemaire, M. Chem. Rev. 2002, 102, 1359.
6. Moreno-Manas, M.; Perez, M.; Pleixats, R. J. Org. Chem. 1996, 61, 2346.
40
Chapter 3: Asymmetric Oxidative Boron Heck – Type
Reactions of Acyclic Alkenes Using Bidentate
Nitrogenous Ligands
-Work presented in this chapter is demonstrated in the publication below.
Yoo, K. S.; Park, C. P.; Yoon, C. H.; Sakaguchi, S.; O’Neill, J.; Jung, K. W. Org.
Lett. 2007, 9, 3933.
-Work and analysis presented in this chapter was done by multiple individuals
whose contributions are accordingly noted in each table.
3.1 Introduction
One of the more attractive features of oxidative boron-Heck type reactions
is the prospect of asymmetric catalysis. The mild conditions often used in these
reactions should be more amenable to enantioselective transformations
compared to conditions used in traditional Heck chemistry. In addition, the
relative ease of these reactions in employing cyclic and poly-substituted olefins
compared to traditional Heck couplings, allows for more couplings using prochiral
substrates. Asymmetry can arise from these reactions in same manner it would
from traditional Heck reactions (figure 1.3). The first report of an attempt at
asymmetric boron Heck – type reactions was reported by Mikami’s group in 2005
(Figure 3.1).
1
Using conditions similar to those reported by Jung,
several chiral
ligands were used in conjunction with Pd(OAc)
2
to induce chirality in the coupling
of arylboronic acids and cyclic olefins. The best enantiomeric excess that they
were able to observe was 59% when using (S, S)-chiraphos, a bidentate
41
phosphine based ligand. While the enantioselectivity and yields for these
reactions were modest, it demonstrated that enantioselective couplings were
possible using oxidative boron Heck–type chemistry. More recently, Gelman and
co-workers coupled aryl boronic acids with dihydrofuran using (R)–MeBiphep as
a ligand on Pd(OAc)
2
to afford enantioselectivities up to 86% enantiomeric
excess (figure 3.1).
2
F
3
C
B(OH)
2
CO
2
R
F
3
C
CO
2
R
Pd(OAc)
2
, (S,S) - chiraphos
O2,DMF, 50
o
C, 4 hr
+
5examples, 31-73%
(22 - 49 % ee)
B(OH)
2
O
Pd(OAc)
2
, (R) - MeOBiphep
Cu(OAc)
2
,THF,RT
+
10 examples, 33-78 %
(1- 86 % ee)
R
O
R
Mikami
Gelman
PPh
2
Ph
2
P
(S,S) - chiraphos
MeO
MeO
PPh
2
PPh
2
(R) - MeOBiphep
Ligands
Figure 3.1: Previous asymmetric oxidative boron Heck-type reactions by Mikami
and Gelman.
This previous work towards the goal of using oxidative boron Heck-type
chemistry for asymmetric catalysis focused on cyclic alkenes as substrates.
42
However, attempts for the asymmetric coupling of linear olefins have only been
done using traditional Heck reactions.
3
Unfortunately, in this study; only modest
enantioselectivities (17% ee) were observed. In these earlier attempts at
asymmetric Heck and Heck–type couplings, primarily bidentate ligands with
coordinating N, P, or O atoms had been used.
For asymmetric oxidative boron Heck-type catalysis, the use of
trisubstituted olefins such as a tiglates should provide circumstances for the
generation of new chiral sp
3
centers (Eq. 3.1).
To test the feasability of oxidative boron Heck-type reactions with
trisubstituted olefins, we attempted the coupling of phenylboronic acid with trans–
2–methyl–butenal using the previously established Jung conditions for coupling
arylboronic acids and olefins.
43
After 16 hours at room temperature, the desired coupling product (1) was
generated in 85% yield, accompanied with the formation of a new sp
3
center (Eq.
3.2). The corresponding Mizoroki-Heck reaction using Iodobenzene only
delivered 5% of 1, even after 24 hours at high temperature (Eq. 3.3), further
demonstrating the difficulty of using highly substituted linear olefins in traditional
Heck couplings. Thus, our group set out to examine the enantioselective coupling
of trisubstituted linear olefins and aryl boronic acids via oxidative palladium
catalysis.
3.2 Results and Discussion
Being that the use of the 2,9–dimethylphenanthroline worked extremely
well in the racemic coupling reaction shown above (Eq. 3.2), chiral N-N ligands
were targeted as possible candidates for use in asymmetric coupling reactions.
44
Table 3.1: Effect of Various Bidentate Ligands on the Formation of 1.
Pd(OAc)
2
[Pd-ligand complex] 1
PhB(OH)
2
+
O
2
,DMF,rt, 16hr.
O
Ligand, DMF
rt, 20 min
N
O
N
O
N
O
N
O
N
N
O
R
23
4 (R = i-Pr)
5 (R = Ph)
6 (R = t-Bu)
Entry ligand yield(1) ee
1 2 71% 16%
2 3 66% 9%
3 4 71% 25%
4 5 69% 21%
5 6 76% 42%
- Yields shown are isolated yields, 5 mole% Pd(OAc)
2
and ligand used, ee's
determined using chiral HPLC (see supporting information). Work by Kyung Soo Yoo,
Cheol Hwan Yoon, and Chan Pil Park.
Various bidentate N-N ligands possessing chiral elements were premixed with
Pd(OAc)
2
to generate Pd – ligand complexes in situ. After 20 minutes,
phenylboronic acid and olefin were added to the reaction mixture and subjected
to oxidative conditions to promote the formation of 1 (Table 3.1). In all cases,
yields of the desired product were good, ranging from 66 to 76 percent. However,
analysis of the enatioselectivity produced by each coupling reaction showed that
bis-oxazoline ligands (2) and (3) afforded low enantiomeric excess (entries 1 and
2). Poor, but slightly higher enantioselectivities were acheived through the use
45
of pyridinal oxazoline ligands (4) and (5) (entries 3 and 4). Only the pyridinal t-
butyl oxazoline ligand (6) drastically increased asymmetric induction to 42%ee
(entry 5). While the use of the t-butyl pyridinal oxazoline ligand provided a
marked improvement for the enantioselctive coupling of linear olefins in Heck and
Heck-type couplings, there seemed to be much room for improvement.
It had occurred to us that while generation of the Pd-ligand complex in-situ
provided complexes capable of asymmetric catalysis, there was still the
possibility for uncomplexed Pd(OAc)
2
to facilitate racemic couplings as a
background reaction. This hypothesis was further supported when the same
reaction was done without pre-mixing the ligand 6 and Pd(OAc)
2
and even lower
ee was observed (31%). To mitigate this shortcoming, a preformed Pd(II) catalyst
was synthesized to minimize the amount of free Pd catalyst that could participate
in undesired racemic reactions (figure 3.2). The ligand 6 was was mixed at room
temperature in dichloromethane with palladium(II) bis(acetonitrile) dichloride to
yield (7). Subsequent ligand exchange using silver acetate gave the desired
chiral palladium(II) complex (8). Both steps of the catalyst synthesis proceeded in
high yield.
N
N
O
N
N
O
Pd
Cl
Cl
N
N
O
Pd
OAc
AcO
67 8
Pd(CH
3
CN)
2
Cl
2
DCM, rt
96%
AgOAc, DCM, rt
94%
Figure 3.2: Synthesis of catalyst for asymmetric boron-Heck type reactions.
46
With the pre-formed catalyst 8 in hand, asymmetric coupling of various
arylboronic acids with trisubstituted olefins were attempted again (Table 3.2).
When using complex 8 in the coupling reaction to give 1, good yield was
observed, but more impressive was the drastic increase in enantioselectivity to
75% ee (entry 1). In addition, when using trans–2–methyl–butenal, coupling with
electron donating para-methoxy and para-dimethylamino phenylboronic acid
gave the products (9) and (10) in good yields with ee’s similar to that of 1 (entries
2 and 3). Napthyl based boronic acids also coupled with trans–2–methyl–butenal
to give the desired products (11) and (12) in good yield and similar ee’s (entries 4
and 5). However, the use of 6-methoxy-2-napthylboronic acid, resulted in a
slightly lower ee at 68%. Methyl tiglate coupled well with phenylboronic acid and
para-methoxyphenylboronic acid to yield compounds (13) and (14), respectively
(entries 6 and 7). The yield and enantiomeric excess of 13 and 14 were similar to
that of the corresponding reactions using trans–2–methyl–butenal.
47
Table 3.2: Asymmetric Oxidative Boron Heck–Type Reactions Using Catalyst 8
Entry ArB(OH)
2
alkene product (yield) ee
1Ar=Ph 1 (74%) 75%
2p-MeOPh 9 (67%) 73%
3p-Me
2
NPh 10 (79%) 75%
42-Napthyl 11 (73%) 72%
5 6-MeO-2-Naptyl 12 (68%) 68%
6Ar=Ph 13 (67%) 69%
7p-MeOPh 14 (76%) 75%
-All yields shown are isolated yields, 5 mole% of Pd(OAc)
2
and ligand used in all cases, chiral
analysis perform by HPLC. Work by Kyung Soo Yoo, Chan Pil Park, and Justin O'Neill
O
CO
2
CH
3
R
ArB(OH)
2
+
Ar
R
8,O
2
,DMF,rt,16hr
3.3 Conclusion and Further Direction
The use of the bidentate pyridinal oxazoline ligand 6 successfully helped
promote chiral induction for the oxidative boron Heck–type reaction of
trisubstituted olefins and several arylboronic acids. More importantly, it was
determined that unligated palladium(II) participated in deleterious racemic
coupling reactions. Thus, it was neccesary make a pre-formed chiral Pd catalyst
to use in these asymmetric reactions. Even though the enantiomeric excesses
demonstrated in this study were the highest to date, there was still a strong
desire to generate catalysts that can induce ee’s above 90% for these oxidative
48
boron Heck–type reactions. More strongly bound and sterically demanding ligand
systems are most likely needed to reach such goals.
49
3.4 Chapter 3 References
1. Akiyama, K.; Wakabayashi, K.; Mikami, K. Adv. Syn. Catal. 2005, 347, 1569.
2. Penn, L.; Shpruhman, A.; Gelman, D. J. Org. Chem. 2007, 72, 3875.
3. Yonehara, K.; Mori, K.; Hashizume, T.; Chung, K-G.; Ohe, K.; Uemura, S. J.
Organomet. Chem. 2000, 603, 40.
50
Chapter 4: The Development of Novel Tridentate NHC –
Amidate – Alkoxide Containing Palladium Catalysts
-Work presented in this chapter is demonstrated in the publications below.
Sakaguchi, S.; Yoo, K. S.; O’Neill, J.; Lee, J. H.; Jung, K. W. Angew. Chem. Int.
Ed. 2008, 47, 9326.
Sakaguchi, S.; Kawakami, M.; O’Neill, J.; Yoo, K. S.; Jung, K. W. J. Organomet.
Chem. 2009, 695(2), 195.
-Work and analysis presented in this chapter was done by multiple individuals
whose contributions concerning original synthesis of compounds are accordingly
noted in approprite schemes.
4.1 Introduction and Catalyst Design
As discussed in chapter 3, it was the desire of our group to achieve
excellent enantioselectivities for the oxidative boron Heck–type reaction,
preferably above 90%. Thus, we set out to develop novel palladium complexes
that would be able to induce these high measures of enantioselectivity in said
reactions. Additionally, we not only aimed for these complexes to be novel, but to
have further applications and be able to act in other palladium catalyzed
reactions. These reactions may be novel and underdeveloped themselves, or be
enantioselective versions of known ones. To meet this goal and to address what
was learned from previous attempts at asymmetric Heck-type reactions, it was
felt that at least three criteria should be met in developing new catalysts:
51
1. The novel catalysts must have a very strong association between
ligand and palladium.
2. The novel catalysts should possess cumbersome stereo-directing
elements.
3. The novel catalysts should be Pd(II) complexes.
Common to asymmetric Mizoroki–Heck reactions is the use of phosphines
as ligands.
1
There is an abundance of commercially available phosphines that
can be used in asymmetric catalysis. Also, phosphines are good σ–donor / π-
acceptor ligands. Thus, they are strongly coordinating to, and activate palladium
centers in catalysis. However, in order to develop more stable and robust
catalysts that meet our needs, an even more highly σ–donating ligand should be
employed.
More recently, N-heterocyclic carbenes (NHC’s) have been used as
ligands in asymmetric transition metal catalysis.
2
NHC’s have the ability to
engage in very strong σ–bonding in palladium complexes. This property
enhances the stability and activity of such complexes, and the synthesis of NHC
containing ligands can be achieved by using common imidazole based
compounds. In addition, the nitrogens in NHCs provide atoms at which stereo-
directing pendants can be installed. Some of these complexes and their
applications are shown in figure 4.1.
3
52
N
N
O
N
Ir
B(Ar)
4
N
N N
N
Pd
Br Br
alpha arylation of ketones
3a
Heck coupling
3b
asymmetric hydrogenation
3c
Me
2
N Pd
Cl
N
N
R'
R"
Nolan Herrmann Pflatz
Figure 4.1: Examples of previously developed organometallic complexes with
NHC ligands.
To this point, NHC ligands that have been employed in asymmetric
palladium(II) catalysis are either mondentate or bidentate. In the case of
monodentate NHC ligands, only moderate enantioselectivities have been
observed, as stereo-directing elements are not locked in place and free to
rotate.
4
Dissociation of the monodentate NHC ligands is also common, especially
in the presence of harsh conditions. Bidentate NHC ligands have shown to
perform better in asymmetric catalysis, as chiral arms of the complexes are often
locked in place and the complexes themselves as a whole tend to be more
stable.
5
A novel tridentate NHC containing palladium(II) catalyst would have the
potential to enhance enatioselectivities in coupling reactions, and offer potential
for use in underdeveloped reactions. Combining an NHC, Amidate, and alkoxide
ligand in one catalyst design could accomplish this goal and allow for a stereo-
regulating group to be easily incorporated, while providing a stable and robust
catalyst (figure 4.2).
53
N
N
N R'
Pd
L O
R
strong sigma donation
strong chelation
steric bulk (chiral)
chelation
Figure 4.2: Design for Novel tridentate NHC – amidate - alkoxide containing
palladium(II) catalysts.
This catalyst design allows for all of the criteria mentioned above to be
met. A strong σ–donating NHC, strongly chelating nitrogen and chelating oxygen
allow for increased stability of the complex and the introduction of steric bulk
between the nitrogen and oxygen. In addition, the majority of the ligand skeleton
can be constructed through basic nitrogen alkylation methods.
4.2 Results and Discussion for Hydroxyl Containing Ligands and
Corresponding Palladium Complexes.
With the catalyst design shown in figure 4.2 in mind, a new ligand that
would be able to bind in a tridenatate manner to a palladium center had to be
synthesized. It was noticed that that a chiral amino alcohol could be used as a
means of introducing a chiral, stereo-directing group into this new class of
ligands. Conveniently, chiral amino alcohols themselves can easily be
synthesized via the reduction of commercially available chiral amino acids.
54
Once in hand, alkylation of the amino alcohol nitrogen with a halo-acetylhalide
should provide an alkoxide–amidate-halogen containing “arm” that could be
coupled to an imidazole based compound. Subsequent alkylation of an imidazole
compound with this arm, and alkylation of the opposite nitrogen with methyl
iodide should yield a ligand that is capable of forming a tridentated complex with
palladium (figure 4.3).
X
X
O
N
H
X
O
OH
R
H
2
N
OH
R
H
2
N
OH
R
O
N
N
H
N
O
N
H
N
R
OH
N
N
H
N
O
R
OH
I
CH
3
I
reduction
Figure 4.3: General scheme for the construction of novel tridentate ligands to be
used for new palladium(II) catalysts.
The reduction of L-valinol and L-alpha-phenylglycine using NaBH
4
with
Iodine in THF at reflux provided the desired chiral amino alcohols (S)–valinol (1)
and (S)–alpha-phenylglycinol (2) in high yields of 92% and 91%, respectively
after 24 hours. With the possibility of undesired alkylation of the amino alcohol
oxygen, it was felt that TBAF protection would be necessary. The entire synthetic
scheme outlined in figure 4.3 was attempted after TBAF protection of the alcohol
in 2. However, removal of the TBAF after methylation proved to be low yielding at
55
best (11%), and often proceeded with no deprotection of the alcohol. Thus, a
method of alkylation of 1 and 2 with no protection of the alcohol had to be
investigated. The slow addition (1 ml/15 min) of bromoacetylbromide or
chloroacetylchloride to a dilute solution of amino alcohol and triethylamine at
negative 15
o
C in DCM provided the desired products (3), (4), and (5) exclusively
in moderate yields (figure 4.4).
X
X
O
N
H
X
O
OH
R
H
2
N
OH
R
DCM, Et
3
N,
-15
o
C, 30 min
H
2
N
OH
R
O
NaBH
4
,I
2
,THF
reflux
3, X= Br, R = i-Pr (62%)
4, X= Cl, R = i-Pr (81%)
5, X= Br, R = Ph (51%)
1,R = i-Pr (92%)
2,R=Ph (91%)
(L)-amino acids
Figure 4.4: Reduction of amino acids and coupling of resulting amino alcohols
with haloacetyl halides to give chiral amide-alcohols. Compound 3 prepared by
Satoshi Sakaguchi, compounds 4 and 5 prepared by Justin O’Neill.
The omission of either low temperature, slow addition, or dilute conditions
resulted in lower yields of the desired products and a mixture of desired product,
O-alkylated product, and O, N–double alkylated products. These alkylation
reactions were usually complete after a few hours and stirring for extended
periods of time (overnight) was not detrimental to reaction yield. The use of
chloroacetyl chloride to give 4 did result in a higher yield than the corresponding
reaction with bromoacetyl bromide. This can be accounted for by the higher
reactivity of bromoacetyl bromide relative to its chloride counterpart, and
56
resulting tendency to decompose and react with moisture readily. However, the
presence of the chloride will have consequence in the next step of the ligand
synthesis.
Once the compounds 3, 4, and 5 were produced, they were coupled with
benzimidazole in the presence of KOH in DMF. These benzimidazole alkylations
were complete after 24 hours at room temperature, producing single products.
When the bromide compounds 3 and 5 were used, the reaction proceeded to
give (6) and (7) in good yield. However, coupling using the chloride compound 4
resulted in a moderate yield of 6 due to the lower reactivity of the chloride (figure
4.5).
Figure 4.5: Alkylation of benzimidazole with 3,4,5 and N-methylation of resulting
compounds. Compounds 6 and 8 prepared by Satoshi Sakaguchi (from 3),
compounds 6, 7, 8, and 9 prepared by Justin O’Neill (from 4 and 5).
After the coupling of 3, 4, and 5 to benzimidazole to yield 6 and 7, these
compounds were then subjected to methylation conditions. To a suspension of
either 6 or 7 in THF, iodomethane was added and the mixture refluxed for up to
24 hours. The resulting benzimidazolium iodide salts (8) and (9) were produced
as a suspension in excellent yields (figure 4.5). These salts were easy to
57
separate and after drying in vacuo, were stable to air and light, even for extended
periods of at least 4 days. The structure of all synthesized compounds was
confirmed by NMR, and no dimethylated compounds were observed.
The palladation of 8 and 9 and synchronized bonding/chelation of the
NHC, amide, and alkoxide to the palladium center was the next challenge.
Attempts to palladate 8 by addition of Pd(OAc)
2
, PdCl
2
, or Pd(CH
3
CN)
2
Cl
2
in
dichloromethane or acetonitrile proved to be fruitless as no or very little
complexation was observed. It was decided to try transfer of the ligand to
palladium via a silver NHC complex.
6
Stirring of 8 and 9 in the presence of Ag
2
O
in DCM, resulted in formation light gray solids that were easily separable by
filtration. These reactions were sensitive to light and drastic decreases in yield
were experienced if reaction vessels were not covered to exclude light. Excess
ligand was washed away by rinsing with methanol as the silver complexes were
insoluble in any solvent we tested at room temperature. Unfortunately, the
insolubility of these compounds made NMR analysis of them impossible, and IR
gave little insight as to if the silver complex even formed. Acting in good faith that
the desired NHC silver complexes were what lay in front of us, palladation by
transmetallation of the silver complex was attempted. To our surprise, mixing of
the silver complexes with Pd(CH
3
CN)
2
Cl
2
in acetonitrile at room temperature
gave the desired palladium complexes (10) and (11) in good yield, as determined
from the amount of 8 and 9 used in silver complexation (figure 4.6). Attempts at
transmetallation using Pd(OAc)
2
resulted in complicated mixtures of products.
58
Figure 4.6: Formation of palladium complexes by silver – NHC complexation and
palladium transmetallation. Complex 10 synthesized by Satoshi Sakaguchi,
complex 11 synthesized by Justin O’Neill.
The presence of the Pd-chloride and O-H in 10 and 11 appealed as
features that could be used to promote dimerization of the palladium complexes
by dehydrohalogenation. If accomplished, this would give access to unique
oxygen bridged palladium dimer structures. When placed in a water and DCM bi-
layer system in the presence of K
2
CO
3.
, the dimeric structures (12) and (13) were
formed in good yield. These dimers dissolved in the organic phase and can also
be formed by using just water and potassium carbonate, followed by extraction
with DCM (figure 4.7).
Figure 4.7: Dimerization of new palladium catalysts to unique oxygen bridged
structures. Complex 12 synthesized by Satoshi Sakaguchi, complex 13
synthesized by Justin O’Neill.
N
N
H
N
O
R
OH
I
1. Ag
2
O, DCM, rt
2. Pd(MeCN)
2
Cl
2
MeCN, rt
10,R=i-Pr(73%)
11, R = Ph (85%)
N
N
Pd
N
O
O
R
Cl
H
Pd
O
N
N
N
O
R
12,R=i-Pr (76%)
13, R = Ph (81%)
K
2
CO
3
H
2
O/DCM
N
N
Pd
N
O
O
R
Cl
Pd
O
N
N
N
O
R
H
59
The dimerization of the monomers 10 and 11 in good yield in water;
demonstrated the tolerance of these new catalysts to moisture. This property is
advantageous in that moisture and water stable organometallic complexes for
catalysis are always of need and can be attributed to the stable and robust
nature of the novel complexes.
Despite confirmation of these structures by NMR, it was desirable to
obtain the crystal structures of these new catalysts in order to fully examine their
spatial arrangement and for absolute confirmation of their structures.
Crystallization of 10 and 12 through layering of diethyl ether and DCM, resulted
in the final determination of their structures by single-crystal X-ray diffraction
(figure 4.8). Slow evaporation of DCM from a DCM solution of 12 and 13 also
resulted in crystals that were suitable for analysis.
60
Figure 4.8: X-ray structures (hydrogen omitted) of 10 (top) and 12 (bottom).
Crystal analysis and structure determination by Timothy Stewart.
61
Of note in these X-ray structures are the relatively short Pd-N bond as
compared to other Pd-N bonds.
7
The shorter length of this bond indicates an
anionic coordination between Pd and nitrogen. Also, the Pd-O bond is found to
be shorter in 12 than in 10. This denotes the participation of the Oxygen in the
Pd-O bond in the Pd
2
O
2
via electron delocalization. The Pd
2
O
2
bridging structure
is not planar itself, but bent at an angle of 145.5
o
using the Pd-Pd axis.
4.3 Results and Discussion for Methoxy Containing Ligands and
Corresponding Palladium Complexes.
The alkoxide pendant of the novel palladium complexes above were
hydroxyl based, leading to the ability of the monomers 10 and 11 to dimerize. In
order to generate monomers that would be resistant to dimerization and that
could eventually have sterically bulky groups on the alkoxide group introduced,
the synthesis of a methoxy possessing ligand system was explored (figures 4.9,
4.10, 4.11).
Figure 4.9: Synthesis of novel palladium complex 17. Complex 17 synthesized
by Joo Ho Lee and Justin O’Neill.
O
NH
2
Br
Br
O
Et
3
N, DCM, rt, 1hr.
O
N
H
Br O
Benzimidazole
KOH, DMF, rt
N
N
H
N
O
O
14 (89%) 15 (76%)
15
CH
3
I, THF
reflux N
N
H
N
O
O
I
16 (85%) 17 (73%)
Pd
O
N
N
N
O
CH
3
Cl
1. Ag
2
O, DCM, 2hr, rt
2. Pd(MeCN)
2
Cl
2
,
MeCN, 8hr, rt
62
As shown in figure 4.9, the use of 2-methoxy ethylamine allows for a
complex having a methyl ether moiety to be generated following a similar
reaction sequence as used to generate monomers 10 and 11. This will be
considered an “achiral catalyst” as it will possess no cumbersome chiral alkyl
group between the alkoxide and amidate. The N-alkylation of 2-methoxy
ethylamine with bromoacetyl bromide occurs in high yield at room temperature in
one hour to give (14) exclusively in good yield. This is accomplished by the slow
addition of a solution of the 2-methoxy ethylamine and triethylamine to
bromoacetyl bromide. Lower temperatures are not required in this reaction as in
the synthesis of 3,4, and 5, as O-alkylation should not take place. Alkylation of
benzimidazole with 14 gave the compound (15) in moderate yield. The following
methylation of 15 proceeded well to give the iodine salt (16). The desired
palladium complex 17 was prepared in the same manner as 10 and 11 by
formation of an NHC silver complex and subsequent palladation via
transmetallation of the silver complex in an overall 73% yield for the two steps.
63
4.4 Conclusion and Applications
Novel tridentate NHC–amidate–alkoxide containing palladium(II)
complexes were successfully synthesized and their structures confirmed. These
complexes can be prepared with variability at the group found between the
amidate and alkoxide (isopropyl, phenyl, hydrogen) and at the substituent of
alkoxide (hydroxyl, methoxy). Reactions for the synthesis of the ligands used in
these complexes occurred in good yields and chiral elements were introduced
through the use of commercially available chrial amino acids. Monomeric
palladium complexes can be generated from the transmetallation of palladium to
silver-NHC compounds. In addition, oxygen bridged dimeric versions of these
complexes can be accessed through dehydrohalogenation. These new
complexes are water and air stable.
These catalysts can now be tested in their ability to induce high
enantioselectivities in asymmetric boron-Heck type reactions as they possess
desired features for such transformations. The novel structure of these catalysts
may also allow for their employment in difficult or underdeveloped reactions.
64
4.5 Chapter 4 References
1. (a)Elschenbroich, C. Organometallics. 3rd ed. Wiley-VCH: Weinheim, 2006;
pp.642-645; (b) belatskaya, I. P.; Cheprakov, A. V. Chem. Rev. 2000, 100,.3009;
(c) DeMeijere, A.; Meyer, F. E. Angew. Chem. Int. Ed. 1994, 33, 2379; (d)
Dounay, A. B.; Overman, L. E. Chem. Rev. 2004, 104, 3453.
2. (a) M. C. Perry, K. Burgess, Tetrahedron: Asymmetry 2003, 14, 951; (b) V.
César, S. Bellemin-Laponnaz, L. H. Gade, Chem. Soc. Rev. 2004, 33, 619; (c)
E. A. B. Kantchev, C. J. O'Brien, M. G. Organ, Angew. Chem. 2007, 119, 2824.
3. (a) Viciu, M.S.; Kelley III, R.A.; Stevens, E. D.; Naud, F.; Studer, M.; Nolan, S.
P. Org. Lett. 2003. 5(9), 1479; (b) Schreg, T.; Schneider, S. B.; Frey, G. D.;
Schwartz, J.; Herdtweck, E.; Herrmann, W. A. Synlett, 2006, 18, 2894; (c)
Nanchen, S.; Platz, A. Chem. Eur. J. 2006, 12, 4550.
4. (a) S. Lee, J. F. Hartwig, J. Org. Chem. 2001, 66, 3402; (b) Y. Sato, T.
Yoshino, M. Mori, Org. Lett. 2003, 5, 31.
5. (a) L. G. Bonnet, R. E. Douthwaite, Organometallics 2003, 22, 4187; (b) R.
Hodgson, R. E. Douthwaite, J. Organomet. Chem. 2005, 690.
6. (a) H. M. J. Wang, I. J. B. Lin, Organometallics 1998, 17, 972 (b)I. J. B. Lin,
C. S. Vasam, Coord. Chem. Rev. 2007, 251, 642.
7. (a) K. I. Gasanov, A. S. Antsyshkina, G. G. Sadikov, N. A. Ivanova, D. I. Mirzai,
I. A. Efimenko, V. S. Sergienko, Crystallogr. Rep. 2002, 47, 603; (b) W. Beck,
W. P. Fehlhammer, K. Feldl, T. M. Klapotke, G. Kramer, P. Mayer, H. Piotrowski,
P. Pollmann, W. Ponikwar, T. Schutt, E. Schuierer, M. Vogt, Z. Anorg. Allg.
Chem. 2001, 627; (c) A. Fernández, E. Pereira, J. J. Fernandez, M. Lopez-
Torres, A. Suarez, R. Mosteiro, J. M. Vila, Polyhedron 2002, 21, 39.
65
Chapter 5: Asymmetric Oxidative Boron Heck – Type
Reactions of Acyclic and Cyclic Alkenes Using Novel
Tridentate NHC – Amidate – Alkoxide Containing
Palladium (II) Catalysts
-Work presented in this chapter is demonstrated in the publication below.
Yoo, K. S.; O’Neill, J.; Sakaguchi, S.; Giles, R.; Lee, J. H.; Jung, K. W. J. Org.
Chem. 2010, 75, 95.
5.1 Introduction
The highly enantioselective coupling of boronic acids and olefins via
oxidative boron Heck-Type reactions has long been a goal of the Jung research
group.
1
Using bidentate pyridinal – oxazoline ligands, we were able to afford
enantioselectivities for such reactions up to 75% enantiomeric excess (figure
5.1).
Figure 5.1: Earlier work for the enantioselective boron Heck-type reaction.
R
O
+ArB(OH)
2
Ar
R
O
Pd cat, O
2
DMF, rt, 16hr
(67-79% yield)
(62-75% ee)
Pd cat =
N
N
O
Pd
OAc
AcO
66
Though this was the best enantioselectivity reported for the asymmetric
Heck or Heck–type coupling of linear olefins, higher ee values were sought. It
was felt that robust palladium(II) complexes with stereo-directiong elements and
strongly bound ligand systems, could afford theses higher ee values. Therefore,
novel tridentate palladium(II) complexes bearing NHC, amidate, and alkoxide
containing ligands were developed.
1b
Chiral groups found in these complexes
were incorporated from chiral amino acids. Both monomeric and dimeric versions
of these novel complexes were developed for use in asymmetric catalysis. More
specifically, these catalysts were immediately examined for their ability to
generate high measures of chiral induction in oxidative boron Heck–type
reactions.
5.2 Results and Discussion
Using the novel catalysts whose development was highlighted in the
previous chapter, oxidative boron Heck-type coupling between 4-methoxy
phenylboronic acid and methyl tiglate to produce (1) were carried out using
catalysts (2a) and (3) (figure 5.2). The yields in both cases were moderate at 52
and 65%, with the majority of remaining arylboronic acid undergoing
deboronylation. However, the ee afforded by catalyst 3a (91%) was much higher
than that afforded by catalyst 2 (7%).
67
Figure 5.2: Asymmetric boron Heck–type reactions using 2 and 3.
After identification of 3a as a superior catalyst for chiral induction
compared to 2, we screened some representative oxidants to examine the
possibility of oxidants that work in conjunction with 3a better than molecular
oxygen. As shown in Table 5.1, the reaction under an air atmosphere resulted in
low yield of 1 (11%) (entry 2), and almost no reaction occurred by employing
CuCl
2
, Cu(OAc)
2
, and benzoquinone as oxidants (entries 3 - 5). Formation of the
cross-coupled product was also not improved under high pressure (6 atm) of O
2
(entry 6).
O
O
O
B(OH)
2
O
O
O
Pd cat, O
2
DMF, rt, 16 hr
N
N
O
N
Pd
Cl O
H
Pd
O
Pd
O
N
N
N
N
N
N
O
O
R
Pd Cat =
3a (R= i-Pr)
3b (R= Ph)
Pd Cat =
2
+
1
65% yield, 7% ee 52% yield, 91% ee
R
68
Table 5.1: Screening of Representative Oxidants in the Formation of 1
O
B(OH)
2
OMe
O
O
OMe
O
3a (5 mole%)
oxidant
DMF, rt, 16 hr
+
entry oxidant yield(%) ee(%)
1O
2
52 91
2Air 11 -
3CuCl
2
<1 -
4Cu(OAc)
2
<1 -
5BQ 0 -
6O
2
(6 atm) 50 -
1
The extreme difference in the enantiomeric excess values of 1 between
using 3a and 2, prompted the exploration of the fate of the dimmer structure
during catalysis. Since the first elementary step in oxidative boron Heck-type
reactions is transmetallation, 3a was mixed with phenylboronic acid to search for
any observable differences in structure (Eq. 5.1). The transfer of phenyl to
palladium from phenylboronic acid should result in the severing of the dimeric
structure in 3a.
69
Pd
O
N
N
N
O
PhB(OH)
2
DMF
3a 4
Pd
Ph
B(OH)
2
O
N
N
N
O
3.42
4.74, 4.11
PhB(OH)
2
DMF
Pd
Ph
H
O
N
N
N
O
Pd
Cl
H
O
N
N
N
O
25
(5.1)
(5.2)
As depicted in equation 5.1, the dimer structure is severed and there is a
transfer of the borate group from phenylboronic acid to the alkoxide portion of the
ligand. This is not observed in the case of the monomer 2 (Eq. 5.2). From these
results, we suspected that higher enantioselectivities exhibited by use of the
dimer catalyst were due to dual steric effect of the transferred borate and the
isopropyl group of transmetallation compound 4. Both of these groups must be
present to induce high ee values. Although the reaction was very slow in DMF
solution and it was not isolated as a product, the transmetalation of
phenylboronic acid was observed to give phenyl-palladium complex 4 comprising
the borate moiety by
1
H NMR spectra analysis, exhibiting a distinct pattern
compared to other complexes such as 3a and 2.
In this process, chemical shifts
70
of methylene protons (CH
2
O) in 4 were further downfield than the corresponding
protons in 3a and 2, implying the formation of boric esters.
Having established optimized conditions, the representative asymmetric
coupling reactions of arylboronic acids and tri-substituted olefins were examined
to evaluate the feasibility of the methodology as shown in Table 5.2. Cross-
coupling reactions of phenylboronic acid and 2-naphthyl boronic acid with methyl
tiglate took place smoothly to provide the desired rearrangement product 6 in
61% yield with excellent enantioselectivities (entry 1). Also, the coupling reaction
of 4-methoxyphenylboronic acid and N,N-dimethylphenylboronic acid, substituted
with electron-donating groups, and 4-acetylboronic acid possessing an electron-
withdrawing group reacted with methyl tiglate to give the desired products 1, 7,
and 8 in 51, 52, and 42% yields, respectively (entries 2 to 4) with excellent
enantioselectivity. The coupling reaction of sterically hindered 2-
methylphenylboronic acid with methyl tiglate afforded 29% yield of the desired
product 9 (entry 5). In addition, the coupling reaction of 2-naphthylboronic acid
and 2-methyl-2-pentenoic methyl ester afforded the desired product 10 in 41%
yield with 88% ee (entry 6). To our knowledge, the existing method for the
enantioselective intermolecular arylation of acyclic alkenes has provided
enantiomeric excess as high as only 17%.
Meanwhile, our improved catalytic
conditions by chiral tridentate NHC-amidate-Pd(II) complexes, yield
enantioselectivities higher than 90% enantiomeric excess.
71
Table 5.2: Asymmetric Oxidative Boron Heck–Type Reactions of Linear Olefins
and Arylboronic Acids Using 3.
catalyst
ArB(OH)
2
+alkene
O
2
,DMF,rt, 16h
Entry ArB(OH)
2
Alkene Cat. Product
13a 6 (61%, 92% ee)
23a 1 (61%, 92% ee)
33a 7 (61%, 92% ee)
43a 8 (61%, 92% ee)
53a 9 (61%, 92% ee)
63a 10 (61%, 92% ee)
-5 mole % of catalyst used in all cases. Yields are isolated. Work by Justin
O'Neill and Kyung Soo Yoo.
R R'
O Ar
B(OH)
2
B(OH)
2
B(OH)
2
B(OH)
2
B(OH)
2
O
N
O
B(OH)
2
OMe
O
OMe
O
72
Next, we sought to examine the use of cyclic olefins in these oxidative
asymmetric boron-Heck reactions using our new catalysts. At first we screened
various solvents, temperatures, and catalyst loadings for the asymmetric cross-
coupling reaction between phenyl boronic acid and 1-acetyl-1-cyclopetene in the
presence of palladium(II) complex 3a to determine the optimal conditions, as we
had primarily focused on the coupling of linear olefins (table 5.3). In the case of
acetonitrile and DMF as solvents, these reactions provided good yields at 61%
and 70%, respectively (entries 1 and 2) when using 5 mol% of palladium(II)
complex 3a at room temperature for 16 hours. However, in THF, MeOH, toluene,
or DMA as a solvent, only poor yields were obtained (entries 5 - 8). At higher
temperature, 50
o
C, and 10 mol% of palladium(II) catalyst loading, the yields of
cross-coupling compound were slightly decreased due to the increase of homo-
coupled compound and deboronylation product. In addition, when we examined
the coupling reaction with palladium(II) monomeric complex 2, enantioselectivity
was lower (21% ee) than that observed in the reaction with complex 3a (entry 9).
Consequently, we determined that the conditions in entry 2 were optimal and
thus we checked to confirm that these conditions would translate efficiently when
using the chiral tridentate NHC-amidate-Pd(II) complexes in the reaction.
73
Table 5.3: Optimization of Conditions for the Oxidative Boron Heck–Type
Reactions of Cyclic Olefins and Arylboronic Acids Using 3a.
PhB(OH)
2
+
3a,O
2
solvent
temp, 16 hr
O
O
Ph
*
Entry Solvent Temp. Pd (mol%) Yield
1
2
3
4
5
6
7
8
9
Acetonitrile
DMF
DMF
DMF
THF
Methanol
Toluene
DMA
DMF
r.t.
r.t.
50
o
C
50
o
C
r.t.
r.t.
r.t.
r.t.
r.t.
5
5
5
10
5
5
5
5
5
61%
70% (88% ee)
67%
71%
28%
29%
24%
21%
62% (21% ee)
With the determined optimized conditions for the asymmetric boron-Heck
reaction using cyclic olefins in hand, we examined the substrate scope of the
reaction (table 5.4). When employing 1-acetyl-1-cyclopentene as the cyclic olefin,
the use of phenylboronic acid gave coupling compound 11 in 70% yield and 85%
ee (entry 1). The use of slightly sterically hindered o-tolylphenylboronic acid
resulted in a 44% yield and 87%ee of the product 12 (entry 2). Electron donating
4-methoxy phenylboronic acid and 4-dimethylamino phenylboronic acid yielded
74
the desired products 13 and 14 in 54% and 51%, respectively with enantiomeric
excess of 81% and 82 % (entries 3 and 4). In addition, electron withdrawing 4-
chlorophenylboronic acid gave a desired compound 15 in a 57% yield and 91%
ee (entry 5).
75
Table 5.4: Asymmetric Oxidative Boron Heck–Type Reactions of Cyclic Olefins
and Arylboronic Acids Using 3.
catalyst
ArB(OH)
2
+alkene
O
2
,DMF,rt,16h
Entry ArB(OH)
2
Alkene Cat. Product
13a 11 (70%, 85% ee)
23a 12 (44%, 87% ee)
33a 13 (54%, 81% ee)
43a 14 (51%, 82% ee)
53a 15 (57%, 91% ee)
63a 16 (56%, 85% ee)
73a 17 (48%, 82% ee)
-5 mole % of catalyst used in all cases. Yields are isolated. Work by Justin
O'Neill and Kyung Soo Yoo.
B(OH)
2
B(OH)
2
B(OH)
2
B(OH)
2
B(OH)
2
O
N
Cl
R
O
Ar
O
O
O
B(OH)
2
Cl
B(OH)
2
O
76
Furthermore, we examined the reaction with methyl 1-cyclopentene-1-
carboxylate and several arylboronic acids. The asymmetric reactions of 4-
methoxy phenylboronic acid and 4-chloro phenylboroic acid with methyl 1-
cyclopentene-1-carboxylate afforded the desired products 16 and 17 with
modest conversion yields and good enantioselectivities (entries 6 and 7). Overall,
this oxidative asymmetric Pd(II) catalysis offered an efficient enantioselective
protocol for intermolcular cross-coupling reactions between arylboronic acids and
acyclic/cyclic olefins under mild conditions.
5.3 Conclusion and Future Aims
In conclusion, new chiral tridentate amidate/alkoxy/carbene palladium(II)
complexes 3a and 3b were successful in the catalytic oxidative asymmetric
Heck-type reactions of arylboronic acids with acyclic and cyclic alkenes. The
desired rearrangement products exhibited high enantioselectivities
unprecedented in intermolecular Heck-type couplings. The high degree of
asymmetric induction during catalysis was presumably due to the biased facial
selection of the alkenes, which was caused by counter axial groups (isopropyl
and borate groups) embedded in the transition state. These ligand architectures
can be readily altered by using different chiral substrates such as amino alcohols
77
and can then be expanded for use with various palladium catalyzed coupling
reactions. Further studies on various palladium catalyzed asymmetric cross-
coupling reaction using various substrates should be explored with these novel
catalysts.
78
5.4 Chapter 5 References
1. (a) Yoo, K. S.; Park, C. P.; Yoon, C. H.; Sakaguchi, S. O’Neill, J.; Jung, K.W.
Org. Lett, 2007, 9, 2993; (b) Sakaguchi, S.; Yoo, K. S.; O’Neill, J.; Lee, J. H.;
Jung, K. W. Angew. Chem. Int. Ed. 2008, 47, 9326.
79
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84
Appendices
Appendix 1: Supporting Information for Chapter 2
A. General information
All commercially available reagents and solvents were used as received from
Aldrich and Acros chemical without further purification. Anhydrous DMF from a
Sigma-Aldrich sure sealed bottle was used in all reactions.
1
H and
13
C NMR
spectra were recorded on 250 MHz Bruker and 400 MHz Varian Mercury
instrument. Thin-layer chromatography (TLC) was performed using commercially
prepared 60 mesh silica gel plates visualized with short-wavelength UV light (254
nm). Silica gel 60 (9385, 230-400 mesh) was used for column chromatography.
The reported yields are isolated yields and are the average of two runs.
Elemental analysis were performed by Atlantic Microlab, Inc. (Norcross, GA). MS
analysis was performed using a Thermo Scientific DSQ II GC-MS (ESI)
instrument (He gas, 25 minute run time, the first 5 minutes at 40 degrees Celsius,
an increase of 15 degrees/min for the next 15 minutes, and the final 5 minutes at
250 degrees Celsius, with a constant flow of 1.5 mL per minute).
B. Typical tandem procedure for biphenyl acrylate analog
compounds
To an oven dried 10 mL round bottomed flask equipped with a stir bar was added
Pd(OAc)
2
(0.1 mmol), and 2,9-dimethyl phenanthroline (0.11 mmol) in DMF (2.5
mL). The reaction mixture was stirred at room temperature for 30 minutes, at
which time acrylate (2.0 mmol) was added, followed by 4-iodophenylboronic acid
(1.0 mmol). The reaction flask was then fitted with an oxygen balloon and was
stirred at room temperature for 16 hours, or at 50
o
C for 6 hours. Following
confirmation of consumption of starting material by TLC, the oxygen balloon was
removed and N
2
bubbled through the solution for at least 1 minute. Phenyl
boronic acid (1.2 mmol) and NaOH (2.0 mmol) in DMF (2 mL) was then added to
the solution and the solution was stirred for up to 8 hours under N
2
atmosphere
at 90
o
C. The reaction mixture was then diluted in Ethyl Acetate (50 mL) and
washed twice with water (2 x 50 mL), and then once with brine (50 mL). The
separated organic layer was dried over anhydrous sodium sulfate and filtered.
The filtrate was concentrated in vacuo and the residue was subjected to column
chromatography on silica gel to give a tandem coupled product.
85
C. Typical tandem procedure for biphenyl cyclohexenone analog
compounds
To an oven dried 10 mL round bottomed flask equipped with a stir bar was
charged Pd(OAc)2 (0.1 mmol), and 2,9-dimethyl phenanthroline (0.11 mmol) in
DMF (2.5 mL). The reaction was stirred at room temperature for 30 minutes, at
which time 2-cyclohexen-1-one (2.0 mmol) was added, followed by halo-
arylboronic acid (1.0 mmol). The reaction flask was then fitted with an oxygen
balloon and was stirred at room temperature for 16 hours. Following confirmation
of consumption of starting material by TLC, the oxygen balloon was removed and
N
2
bubbled through the solution for at least 1 minute. Arylboronic acid (1.2 mmol)
and NaOH (2.0 mmol) were then added to the solution and the solution was
stirred for up to 6 hours under N
2
atmosphere at 90
o
C. The reaction mixture was
then diluted with ethyl acetate (50 mL) and washed twice with water (50 mL), and
then once with brine (50 mL). The separated organic layer was dried over
anhydrous sodium sulfate and filtered. The filtrate was concentrated in vacuo and
the residue was subjected to column chromatography on silica gel to give a
tandem coupled product.
86
D. Spectroscopic data
Compound 8
3-(4-Iodophenyl)acrylic acid tert-butyl ester (8), (Table 2.2, entry 3):
To a premixed solution of palladium acetate (0.1 mmol) and 2,9-dimethyl
phenanthroline (0.11 mmol) in DMF (2.5 mL) for 30 minutes, was added tert-butyl
acrylate (2 mmol) and 4-iodophenylboronic acid (1.0 mmol). The reaction flask
was fitted with an oxygen balloon and the reaction mixture was stirred at room
temperature for 16 hours, then diluted with ethyl acetate (20 mL), and washed
with water and brine (2 X 10 mL). The separated organic layer was dried over
anhydrous Na2SO4 and filtered.The filtrate was concentrated in vacuo and the
residue was chromatographed on silica gel to give a cross-coupled product 8 (92
%) as a white solid.
1
H-NMR (CDCl3): δ 7.67 (d, J = 8.0 Hz, 2H), 7.45 (d, J = 16.2 Hz, 1H), 7.20 (d, J
= 8.0 Hz, 2H),6.32 (d, J = 16.0 Hz, 1H), 1.52 (s, 9H);
13
C-NMR (CDCl3): δ 166.0,
142.4, 136.0,132.5, 128.2, 121.0, 96.0, 80.6, 28.1
87
88
89
Compound 14
3-(4-Iodophenyl)cyclohex-2-enone (14) (Table 2.3, entry 4):
To a premixed solution of palladium acetate (0.1 mmol) and 2,9-dimethyl
phenanthroline (0.11 mmol) in DMF (2.5 mL) for 30 minutes, was added 2-
cyclohexenone (2.0 mmol) and 4-iodophenylboronic acid (1.0 mmol). The
reaction flask was fitted with an oxygen balloon and the reaction mixture was
stirred at 50
o
C for 6 hours, then diluted with ethyl acetate (20 mL), and washed
with water and brine (2 X 10 mL). The separated organic layer was dried over
anhydrous Na2SO4 and filtered. The filtrate was concentrated in vacuo and the
residue was chromatographed on silica gel to give a cross-coupled product 14
(85%) as a white solid.
1
HNMR (CDCl3): δ 7.74 (dd, J = 6.5 Hz, 1.7 Hz, 2H), 7.25 (dd, J = 6.7 Hz, 1.7 Hz,
2H), 6.38 (t, J = 1.5 Hz, 1H), 2.72 (t, J = 6.0 Hz, 2H), 2.48 (t, J = 6.5 Hz, 2H),
2.16 (m, 2H);
13
C-NMR (CDCl3): δ 199.4, 158.3, 138.1, 137.8, 127.5, 125.5, 96.1,
37.0, 27.7, 22.6: Anal calcd for C12H11IO: C 48.35, H 3.72, found: C 48.32, H
3.73; MS-ESI (m/z) calcd [M
+
]: 297.99, found: 297.76
90
91
92
Compound 9
(E)-3-(biphenyl-4-yl)acrylic acid tert-butyl ester (9) (Table 2.2, entry 2):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of 4-
iodophenylboronic acid (297 mg, 1.2 mmol) with tert-butyl acrylate (146 L, 1.0
mmol) then added phenylboronic acid (146 mg, 1.2mmol) to afford desired
product 9 (63%) as a white solid.
1
H-NMR (400 MHz, CDCl3): δ 7.62 (d, J = 16 Hz, 1H), 7.60 (m, 6H), 7.36-7.48 (m,
3H), 6.40 (d, J = 16 Hz, 1H), 1.51 (s, 9H);
13
C-NMR (CDCl3): δ 166.0, 143.0,
141.0, 130.1, 128.8, 128.4, 127.7, 127.4, 127.0, 121.9, 120.0, 80.5, 28.2.
93
94
95
Compound 11
(E)-3-(biphenyl-4-yl)but-2-enoic acid ethyl ester (11) (Table 2.2, entry 3):
Following the general tandem procedure withPd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of 4-
iodophenyl-boronic acid (297 mg, 1.2 mmol) with ethyl crotonate (124 L, 1.0
mmol) and then added phenylboronic acid (146 mg, 1.2 mmol) to afford desired
product 11 (81%) as a white solid.
1
H-NMR (CDCl3): δ 7.36-7.63 (m, 9H), 6.21 (s, 1H), 4.23 (q, J = 7.2 Hz, 2H), 2.62
(s, 3H), 1.33 (t, J = 7.2 Hz, 3H);
13
C NMR (CDCl3): δ 166.8, 141.8, 128.8, 127.5,
126.4, 127.2, 59.8, 17.7, 14.3
96
97
98
Compound 12
4-(1-Methyl-2-phenyl-vinyl)-biphenyl (12) (Table 2.2, entry 4):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of 4-
iodophenylboronic acid (297 mg, 1.2 mmol) with trans- -methylstyrene (130 L,
1.0 mmol) and then added phenylboronic acid (146 mg, 1.2 mmol) to afford
desired product 14 (80%) as awhite solid.
1
H-NMR (CDCl3): δ 6.88 - 7.29 (m, 14H), 6.56 (s, 1H), 1.96 (s, 3H);
13
C-NMR
(CDCl3): δ 140.7, 139.9, 138.3, 129.1, 128.7, 128.1, 127.7, 127.2, 127.0, 126.9,
126.4, 126.3, 114.6, 17.4; Anal. calcd for C21H18: C 93.29, H 6.71, found: C 93.31,
H 6.69; ESI-MS (m/z) calcd: 270.14 [M
+
], found: 269.86
99
100
101
Compound 15
3-Biphenyl-4-yl-cyclohex-2-enone (15) ( Figure 2.3):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg,0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol),the coupling reaction of 4-
iodophenylboronic acid (248 mg, 1.0 mmol) with 2-cyclohexen-1-one (194 L, 2.0
mmol) then added phenylboronic acid (146 mg, 1.2 mmol) to afford desired
product 15 (67%) as a white solid.
1
H NMR (250 MHz, CDCl3): δ 7.60-7.67 (m, 6H), 7.42 (m, 3H), 6.49 (s, 1H), 2.81
(t, J = 6.0 Hz, 2H), 2.51 (t, J = 6.5 Hz, 2H), 2.17 (m, 2H);
13
C NMR
(CDCl3): δ 199.8, 137.4, 128.9, 127.8, 127.4, 127.3, 127.0, 126.5, 125.1,
97.1,37.2, 27.9, 22.7; Anal. calcd for C18H16O: C 87.06, H 6.49, found: C 87.03, H
6.51; ESI-MS (m/z)calcd: 248.12 [M
+
], found: 247.86
102
103
104
Compound 16
3-(4’-Methoxy-biphenyl-4-yl)-cyclohex-2-enone (16) (Figure 2.4): Following
the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and 2,9-
dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of 4-
iodophenylboronic acid (248 mg, 1.0 mmol) with 2- cyclohexen-1-one (194 L,
2.0 mmol) and then added 4-methoxyphenylboronic acid (182 mg, 1.2 mmol) to
afford desired product 16 (60%) as a white solid.
1
H-NMR (CDCl3): δ 7.60 (s, 4H), 7.56 (d, J = 6.5 Hz, 2H), 7.01 (d, J = 6.5 Hz,
2H), 6.47 (s, 1H), 3.85 (s, 3H), 2.80 (t, J = 6.0 Hz, 2H), 2.50 (t, J = 6.0 Hz, 2H),
2.17 (m, 2H);
13
C-NMR (CDCl3): δ 199.8, 159.6, 159.1, 142.3, 136.7, 132.3,
128.0, 126.7, 126.5, 124.8, 114.3, 55.3, 37.2, 27.8, 22.7 Anal. calcd for C19H18O2:
C 81.99, H 6.52, found: C 82.01, H 6.52; ESI-MS (m/z) calcd: 278.13 [M
+
], found:
277.92
105
106
107
Compound 17
3-(3’,4’-Dimethoxy-biphenyl-4-yl)-cyclohex-2-enone (17) (Figure 2.4):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of
4-iodophenylboronic acid (248 mg, 1.0 mmol) with 2- cyclohexen-1-one (194 L,
2.0 mmol) then added 3,4- dimethoxyphenylboronic acid (218 mg, 1.2 mmol) to
afford desired product 17 (51%) as a pale light green solid.
1
H-NMR (CDCl3): δ 7.57 (s, 3H), 7.21 (d, J = 9.0 Hz, 2H), 6.99 (d, J = 9.0 Hz,
2H), 6.47 (s, 1H), 3.86 (s, 3H), 3.95 (s, 3H), 2.79 (t, J = 6.0 Hz, 2H), 2.50 (t, J =
5.25 Hz, 2H), 2.17 (m, 2H);
13
C-NMR (CDCl3): δ 200.2, 149.1, 142.7, 136.8,
132.9, 127.9, 127.7, 126.9, 126.5, 124.8, 119.4, 115.6, 111.5, 110.1, 55.9, 37.1,
27.8, 22.7 Anal. calcd for C20H20O3: C 77.90, H 6.54, found: C 77.89, H 6.55; ESI-
MS (m/z) calcd: 278.09 [M
+
], found: 278.95
108
109
110
Compound 18
O
N
3-(4’-Dimethylamino-biphenyl-4-yl)-cyclohex-2-enone (18) (Figure 2.4):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of
4-iodophenylboronic acid (248 mg, 1.0 mmol) with 2-cyclohexen-1-one (194 L,
2.0 mmol) then added 4-(dimethylamino)phenylboronic acid (198 mg, 1.2 mmol)
to afford desired product 18 (59%) as a green solid.
1
H-NMR (CDCl3): δ 7.59 (s, 4H), 7.53 (d, J = 9.0 Hz, 2H), 6.80 (d, J = 9.0 Hz,
2H), 6.48 (s, 1H), 3.01 (s, 6H), 2.80 (t, J = 6.25 Hz, 2H), 2.50 (t, J = 5.75 Hz, 2H),
2.16 (m, 2H);
13
C-NMR (CDCl3): δ 200.0, 159.5, 150.4, 142.9,135.9, 127.6,
126.5, 126.1, 124.4, 112.6, 111.7, 40.4, 37.2, 27.8, 22.8; Anal. calcd for
C20H21NO: C 82.44, H 7.26, N 4.81, found: C 82.51, H 7.23, N 4.79; ESI-MS
(m/z): 291.16 [M
+
], found: 291.13
111
112
113
Compound 19
4’-(3-Oxo-cyclohex-1-enyl)-biphenyl-4-carbonitrile (19) (Figure 2.4):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of 4-
iodophenylboronic acid (248 mg, 1.0 mmol) with 2-cyclohexen-1-one (194 L, 2.0
mmol) then added 4-cyanophenylboronic acid (176 mg, 1.2 mmol) to afford
desired product 21 (63%) as a pale yellow solid.
1H-NMR (CDCl3): δ7.72 (m, 4H), 7.65 (s, 4H), 6.47 (s, 1H), 2.81 (t, J = 5.25 Hz,
2H), 2.51 (t, J = 6.5 Hz, 2H), 2.18 (m, 2H); 13C-NMR (CDCl3): δ 199.9, 158.6,
144.3, 140.4, 138.9, 134.4, 132.6, 127.5, 126.8, 118.6, 115.7, 111.3, 37.1, 27.9,
22.7; Anal. calcd for C19H15NO: C 83.49, H 5.53, N 5.12 found: C 83.45, H 5.54,
N 5.18; ESI-MS (m/z) calcd: 273.12 [M
+
], found: 272.87
114
115
116
Compound 20
3-(4’-Nitro-biphenyl-4-yl)-cyclohex-2-enone (20) (Figure 2.4):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of 4-
iodophenylboronic acid (248 mg, 1.0 mmol) with 2-cyclohexen-1-one (194 L, 2.0
mmol) then added 4-nitrophenylboronic acid (200 mg, 1.2 mmol) to afford desired
product 20 (77%) as a light green solid.
1
H-NMR (CDCl3): δ 8.32 (d, J = 9.25 Hz, 2H), 7.76 (d, J = 8.7 Hz, 2H), 7.68 (s,
4H), 6.49 (s, 1H), 2.82 (t, J =.0 Hz, 2H), 2.52 (t, J = 6.25 Hz, 2H), 2.19 (m, 2H);
13
C-NMR (CDCl3): δ 199.6, 158.4, 147.4, 146.4, 140.1, 139.3, 127.7, 127.6,
126.8, 125.9, 124.2, 37.2, 28.0, 22.7; Anal. Calcd for C18H15NO3: C 73.71, H 5.15,
N 4.78 found: C 73.79, H 5.12, N 4.69; ESI-MS (m/z): 293.11 [M
+
], found: 292.92
117
118
119
Compound 21
O
O
3-(4’-Acetyl-biphenyl-4-yl)-cyclohex-2-enone (21) (Figure 2.4):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9 dimethyl phenanthroline (22.9 mg, 0.11 mmol), the coupling reaction of
4iodophenylboronic acid (248 mg, 1.0 mmol) with 2-cyclohexen-1-one (194 L,
2.0 mmol) then added 4-acetylphenylboronic acid (197 mg,1.2 mmol) to afford
desired product 21 (78%) as a white solid.
1H-NMR (CDCl3): δ 8.05 (d, J = 9.0 Hz, 2H), 7.72 (d, J = 8.75 Hz, 2H), 7.66 (m,
4H), 6.49 (s, 1H), 2.82 (t, J = 6.25 Hz, 2H), 2.65 (s, 3H), 2.50 (t, J = 6.25 Hz, 2H),
2.19 (m, 2H); 13C-NMR (CDCl3): δ 199.8, 197.6, 158.8, 144.5, 141.3, 138.5,
136.3, 129.0, 127.5, 127.1, 126.7, 125.6, 37.2, 28.0, 26.6, 22.8; Anal. calcd for
C20H18O2: C 82.73, H 6.25, found: C 82.81, H 6.19; ESI-MS (m/z) calcd:
290.13 [M
+
], found: 290.12
120
121
122
Compound 22
3-(2’,6’-Dimethyl-biphenyl-4-yl)-cyclohex-2-enone (22) (Figure 2.4):
Following the general tandem procedure with Pd(OAc)2 (22.4mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11mmol), the coupling reaction of 4-
iodophenylboronic acid (148 mg,1.0 mmol) with 2-cyclohexen-1-one (194 L, 2.0
mmol) then added 2,6-dimethylphenylboronic acid (180 mg, 1.2 mmol) to afford
desiredproduct 22 (30%) as a white solid.
1H-NMR (CDCl3): δ 7.62 (d, J = 8.5 Hz, 2H), 7.54 (m,1H), 7.41 (d, J = 4.0 Hz,
2H), 7.21 (d, J = 8.5 Hz, 2H), 6.42 (s, 1H), 2.79 (t, J = 6.0 Hz, 2H), 2.49 (t, J =
5.25 Hz, 2H), 2.18 (m, 2H), 2.03 (s, 6H); ESI-MS (m/z) calcd: 276.15 [M
+
], found:
275.86
123
124
Compound 23
3-(4-Styryl-phenyl)-cyclohex-2-enone (23) (Figure 2.4):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg, 0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11mmol), the coupling reaction of 4-
iodophenylboronic acid (248 mg, 1.0 mmol) with 2-cyclohexen-1-one (194 L, 2.0
mmol)then added trans-2-phenylvinylboronic acid (177 mg, 1.2 mmol)
to afford desired product 23 (48%) as a pale green solid.
1
H-NMR (CDCl3): δ 7.26 - 7.55 (m, 9H), 7.11 (d, J = 6.75 Hz, 2H), 6.45 (s, 1H),
2.76 (t, J = 5.75 Hz, 2H), 2.47 (t, J = 6.0 Hz,2H), 2.13 (m, 2H);
13
C-NMR (CDCl3):
δ 200.2, 159.1, 139.1, 137.4, 136.8, 130.1, 128.7,128.5, 128.0, 127.8, 127.5,
126.7, 126.6, 126.4, 124.8, 115.7, 37.2, 27.8, 22.7; Anal. calcd for C20H18O: C
87.56, H 6.61, found: C 87.51, H 6.65; ESI (m/z) calcd: 274.14 [M
+
], found:
273.91
125
126
127
Compound 24
3-Biphenyl-3-yl-cyclohex-2-enone (24) (Figure 2.5):
Following the general tandem procedure with Pd(OAc)2 (22.4 mg,0.1 mmol) and
2,9-dimethyl phenanthroline (22.9 mg, 0.11 mmol), thecoupling reaction of 3 -
iodophenylboronic acid (248 mg, 1.0 mmol) with 2-cyclohexen-1-one (194 L, 2.0
mmol) then added phenylboronic acid (146 mg, 1.2 mmol) to afford desired
product 24 (52%) as a white solid.
1
H-NMR (CDCl3): δ 7.73 (s, 1H),7.26-7.62 (m, 8H), 6.49 (s, 1H), 2.83 (t, J = 6.0
Hz, 2H), 2.51 (t, J = 6.5 Hz, 2H), 2.18 (m, 2H);
13
C-NMR (CDCl3): δ 199.2, 158.3,
129.2, 128.9, 128.7, 127.7, 127.1, 125.7, 124.9,119.4, 37.2, 28.2, 22.7; Anal.
calcd for C18H16O: C 87.06, H 6.49, found: C 87.02, H 6.50;ESI-MS (m/z) calcd:
248.12 [M
+
], found: 247.85
128
129
130
Appendix 2: Supporting Information for Chapter 3
A. General Information
All commercially available reagents and solvents were used as received by
Aldrich or Acros chemical without further purification.
1
H and
13
C NMR spectra
were recorded on a 250 and 63 MHz Bruker instrument. Thin-layer
chromatography (TLC) was performed using commercially prepared 60 mesh
silica gel plates visualized with short-wavelength UV light (254 nm). Silica gel 60
(9385, 230-400 mesh) was used for column chromatography. The reported yields
are isolated yields and are the average of two runs. Elemental analysis were
performed by Atlantic Microlab, Inc. (Norcross, GA). HRMS analysis was
performed by the Analytical Chemistry Instrumentation Facility at University of
California Riverside. The enantiomertric excess was determinded by HPLC and
NMR analyses. HPLC analyses were conducted on a HP 1096 series II
instrument equipped with an UV detector and a Chiralcel OD-H column, and
NMR analyses were determined by using of Europium tris[3- (heptafluoro-
propylhydroxymethylene)-(+)-camphorate].
B. General Procedure for the Asymmetric Intermolecular Heck-
type Reaction of Arylboronic acid and Olefins
1. Pre-mixed condition with Pd(OAc)
2
and ligand (Table 3.1)
To a premixed solution of palladium acetate (0.05 mole) and ligand (0.06 mmol)
such as 1,10-phenanthroline, ligand 2, 3, 4, 5, and 6 in DMF (2.5 mL) for 20
minutes, was added olefin (1.0 mmol) and boronic acid (1.1 mmol). The reaction
flask was fitted with an oxygen balloon and the reaction mixture was stirred at
room temperature for 16 hours, then diluted with ethyl acetate (20 mL), and
washed with water and brine (2 X 10 mL). The separated organic layer was dried
over anhydrous Na
2
SO
4
and filtered. The filtrate was concentrated in vacuo and
the residue was chromatographed on silica gel to give a cross-coupled product.
131
2. One pot reaction with pre-made Pd-ligand complex 8 (Table 3.2)
To a solution of Pd-ligand complex 8 (0.05 mmol) in DMF (2.5 mL) was added
olefin (1.0 mmol) and boronic acid (1.1 mmol). The reaction flask was fitted with
an oxygen balloon and the reaction mixture was stirred at room temperature for
16 hours, then diluted with ethyl acetate (20 mL) and washed with water and
brine (2 X 10 mL). The separated organic layer was dried over anhydrous
Na
2
SO
4
and filtered. The filtrate was concentrated in vacuo and the residue was
chromatographed on silica gel to give a cross-coupled product.
132
C. Spectroscopic Data
PdL(OAc)
2
adduct 8
N
N
O
Pd
OAc
AcO
The mixture solution of pyridinyl-oxazoline compound 6 (500 mg, 2.45 mmol) and
PdCl
2
(CH
3
CN)
2
(635 mg, 2.45 mmol) in dichloromethane (20 mL) was stirred for
5 hours with exclusion of light at room temperature. The mixture was filtered
through a celite pad and the solution was concentrated to ca. 1 mL in vacuo. The
crude substrate was precipitated with hexane (20 mL). The resulting solid was
filtered and washed with diethyl ether to give product 7 (899 mg, 96% yield) as
an orange solid. To a suspension of PdLCl
2
complex 7 ( 800 mg, 2.1 mmol) in
dichloromethane (50 mL) was added silver acetate (699 mg, 4.2 mmol) at
room temperature. The suspension quickly became yellow in color. Then, the
resulting suspension was stirred for 15 min in the absence of light and filtered
through a plug of glass fiber filter paper. The filtrate was evaporated to dryness in
vacuo to afford product 7 (845 mg, 94% yield) as yellow solid.
1H NMR (250 MHz, CDCl3) δ 8.31 (d, J = 4.0 Hz, 1H), 8.13 (t, J = 7.7 Hz, 1H),
7.70 (d, J = 7.0 Hz, 1H), 7.64 (t, J = 7.0 Hz, 1H), 4.81 (dd, J = 3.7 Hz, 9.2Hz, 1H),
4.71 (t, J = 9.2 Hz, 1H), 4.06 (dd, 4.2 Hz, 9.2 Hz, 1H), 2.09 (s, 3H), 2.01 (s, 3H),
1.01 (s, 9H); 13C NMR (250 MHz, CDCl3): δ 178.6, 178.5, 168.7, 150.8, 144.2,
140.3, 129.0,124.8, 73.9, 72.3, 34.6, 25.6, 22.9.
133
134
135
Compound 1
H
O
3-Phenyl-2-methylene-butyraldehyde (1): Following the one pot reaction with
Pd-ligand complex 8 (21.5 mg, 0.05 mmol), the coupling reaction of
phenylboronic acid (146 mg, 1.2 mmol) with trans-2-methyl butenal (97 μL, 1.0
mmol) afforded desired product 1 (74%) as a colorless oil.
1
H NMR (250 MHz, CDCl3) δ 9.52 (s, 1H, CHO), 7.16-7.29 (m, 5H, Ph), 6.22 (s,
1H), 6.06 (s, 1H), 4.01 (q, J = 7.2 Hz, 1H), 1.42 (d, J = 7.2 Hz, 3 H);
13
C NMR (63
MHz, CDCl3): δ 194.4, 154.4, 141.8, 130.5, 128.7, 127.9, 125.5, 36.5, 20.7 ;
Anal. calcd for C
11
H
13
O: C 82.46, H 7.55, found: C 82.41, H 7.54; HRMS-ESI
(m/z) [M+H
1
] calcd for C
11
H
13
O: 161.0921, found: 161.0926; HPLC (Daicel
CHIRALCEL OD-H; 95:5hexanes/isopropanol, detection wavelength = 280 nm,
flow rate = 1.0 mL/min) Tr = 5.84 min (major) and 6.16 (minor).
136
137
138
139
Compound 9
H
O
O
3-(p-Methoxyphenyl)-2-methylene-butyraldehyde (Table 3.2, entry 2):
Following the one pot reaction with Pd-ligand complex 8 (21.5 mg, 0.05
mmol), the coupling reaction of p-methoxyphenylboronic acid (182 mg, 1.2
mmol) with trans-2-methyl butenal (97 μL, 1.0 mmol) afforded desired
product 9 (67%) as a colorless oil:
1
H NMR (250 MHz, CDCl3) δ= 9.53 (s,1H, CHO), 7.13 (d, J = 8.2 Hz, 2H), 6.82
(d, J = 8.2 Hz, 2H), 6.22 (s, 1H), 6.05 (s, 1H), 3.99 (q, J = 7.2 Hz, 1H), 3.78 (s,
3H), 1.40 (d, J = 7.2 Hz, 3 H);
13
C NMR (63 MHz, CDCl3): δ=194.0, 158.1, 154.6,
135.7, 133.5, 128.6, 113.8, 55.2, 36.4, 20.1; Anal. calcd for C
12
H
14
O
2
: C 75.76, H
7.42, found: C 75.75, H 7.42; HRMS-ESI (m/z) [M+NH
4
+
] calcd for C
12
H
18
NO
2
:
208.1338, found: 208.1334; HPLC (Daicel CHIRALCEL
OD-H; 95:5 hexanes/isopropanol, detection wavelength = 250 nm, flow rate = 1.0
mL/min)Tr = 5.20 min (major) and 6.57 (minor).
140
141
142
143
Compound 10
H
O
N
3-(p-Dimethylaminophenyl)-2-methylene-butyraldehyde (Table 3.2, entry
3): Following the one pot reaction with Pd-ligand complex 8 (21.5 mg, 0.05
mmol), the coupling reaction of p-(dimethylamino)phenylboronic acid (198
mg, 1.2 mmol) with trans-2-methyl butenal (97 μL, 1.0 mmol) afforded desired
product 10 (79%) as a colorless oil:
1
H NMR (250 MHz, CDCl3) δ= 9.54 (s, 1H, CHO), 7.09 (d, J = 8.7 Hz, 2H), 6.69
(d, J = 8.2 Hz, 2H), 6.21 (s, 1H), 6.02 (s, 1H), 3.95 (q, J = 7.2 Hz, 1H), 2.91 (s,
6H), 1.39 (d, J = 7.2 Hz, 3 H);
13
C NMR (63 MHz, CDCl3): δ= 194.0, 154.5, 141.9,
132.3, 129.9, 127.5, 113.8, 43.7, 36.9, 21.1; Anal. calcd for C
13
H
17
NO: C 76.81,
H 8.43, N 6.89, found: C 76.77, H 8.46, N 6.82; HRMS-ESI (m/z) [M+H
+
] calcd for
C
13
H
18
NO: 204.1244, found: 204.1348; HPLC (DaicelCHIRALCEL OD-H; 95:5
hexanes/isopropanol, detection wavelength = 250 nm, flow rate =
1.0 mL/min) Tr = 4.17 min (major) and 4.54 (minor).
144
145
146
147
Compound 11
H
O
3-(2-Naphthyl)-2-methylene-butyraldehyde (Table 3.2, entry 4):
Following the one pot reaction with Pd-ligand complex 8 (21.5 mg, 0.05
mmol), the coupling reaction of 2-naphthalenyl phenylboronic acid (206
mg, 1.2 mmol) with trans-2-methyl butenal (97 μL, 1.0 mmol) afforded
desired product 11 (73%) as a colorless oil:
1
H NMR (250 MHz, CDCl3) δ= 9.61 (s, 1H, CHO), 7.85 (m, 3H), 7.71 (s, 1H), 7.48
(m, 2H), 7.35 (d, J = Hz, 1H), 6.31 (s,1H), 6.17 (s, 1H), 4.23 (q, J = 7.2 Hz, 1H),
1.58 (d, J = 7.2 Hz, 3 H);
13
C NMR (63 MHz,CDCl3): δ= 193.2, 154.3, 141.1,
134.0, 133.5, 132.3, 128.1, 127.7, 127.6, 126.3, 126.0,125.6, 125.2, 37.3, 19.9;
Anal. calcd for C
15
H
14
O: C 85.68, H 6.71, found: C 85.59, H 6.72; HRMS-ESI
(m/z) [M+NH
4
+
] calcd for C
15
H
14
NO: 228.1388, found: 228.1387; HPLC (Daicel
CHIRALCEL OD-H; 99:1 hexanes/isopropanol, detection wavelength = 254 nm,
flow rate = 1.0 mL/min) Tr = 5.63 min (major) and 6.99 (minor).
148
149
150
151
Compound 12
H
O
O
3-(6-Methoxy-naphthalen-2-yl)-2-methylene butyraldehyde (Table 3.2,
entry 5): Following the one pot reaction with Pd-ligand complex 8 (21.5
mg, 0.05 mmol), the coupling reaction of 6-methoxy-2-naphthylboronic acid (242
mg, 1.2 mmol) with trans-2-methylbutenal (97 μL, 1.0 mmol) afforded desired
product 12 (68%) as a colorless oil.:
1
H NMR (250 MHz, CDCl3) δ = 9.57 (s, 1H), 7.71 – 7.66 (m, 2H), 7.59 (d, J = 1.8
Hz, 1H), 7.30 (dd, J = 8.5 Hz, 1.8 Hz, 1H), 7.16 -7.11 (m, 2H), 6.27 (s, 1H), 6.11
(s, 1H), 4.18 (q, J = 7.5 Hz, 1H), 3.91 (s, 3H),1.51 (d, J = 7.5 Hz, 3 H);
13
C NMR
(63 MHz, CDCl3): δ= 193.9, 157.4, 154.4, 138.7, 133.8, 133.3, 129.1, 128.9,
126.9, 126.8, 125.5, 118.8, 105.6, 55.3, 37.1, 19.9; Anal. calcd for
C
16
H
16
O
2
: C 79.97, H 6.71, found: C 79.95, H 6.69; HRMS-ESI (m/z) [M+H
+
]
calcd for C
16
H
17
O
2
: 241.1184, found: 214.1198; HPLC (Daicel CHIRALCEL OD-
H; 99:1 hexanes/isopropanol, detection wavelength = 260 nm, flow rate =1.0
mL/min) Tr = 5.77 min (major) and 6.80 (minor).
152
153
154
155
Compound 13
O
O
3-Phenyl-2-methylene butyric acid methyl ester (Table 3.2, entry 6):
Following the one pot reaction with Pd-ligand complex 8 (21.5 mg, 0.05 mmol),
the coupling reaction of phenylboronic acid (146 mg, 1.2 mmol) with methyl
tiglate (120 µL, 1.0 mmol) afforded desired product 13 (67%) as a colorless oil:
1
H NMR (250 MHz, CDCl3) δ = 7.15-7.29 (m,5H), 6.28 (s, 1H), 5.62 (s, 1H), 4.02
(q, J = 7.7 Hz, 1H), 3.67 (s, 3H), 1.42 (d, J = 7.2 Hz, 3 H);
13
C NMR (63 MHz,
CDCl3): δ = 167.3, 144.8, 144.2, 128.3, 127.3, 126.2, 123.8, 51.7, 40.4, 20.7;
Anal. calcd for C
12
H
14
O
2
: C 75.76, H 7.42, found: C 75.69, H 7.39; HRMS-ESI
(m/z) [M+NH
4
+
] calcd for C
12
H
18
NO
2
: 208.1324, found: 208.1327; HPLC (Daicel
CHIRALCEL OD-H; 99:1 hexanes/isopropanol, detectionwavelength = 230 nm,
flow rate = 1.0 mL/min) Tr = 4.30 min (minor) and 4.69 (major).
156
157
158
159
Compound 14
O
O
O
3-(p-Methoxyphenyl)-2-methylene butyric acid methyl ester (Table 3.2, entry
7): Following the one pot reaction with Pd-ligand complex 8 (21.5 mg, 0.05
mmol), the coupling reaction of p-methoxyphenylboronic acid (182 mg, 1.2 mmol)
with methyl tiglate (120 µL, 1.0 mmol) afforded desired product 14 (76%) as a
colorless oil.:
1
H NMR (250 MHz, CDCl3) δ= 7.12 (d, J = 8.2 Hz, 2H), 6.85 (d, J = 8.2 Hz, 2H),
6.21 (s, 1H), 5.52 (s,1H), 3.97 (q, J = 7.2 Hz, 1H), 3.77 (s, 3H), 3.61 (s, 3H), 1.33
(d, J = 7.2 Hz, 3 H);
13
C NMR(63 MHz, CDCl3): δ = 167.4, 155.5, 144.9, 139.2,
128.6, 123.7, 118.7, 56.2, 51.8, 39.8, 20.3; Anal. calcd for C
13
H
14
O
3
: C 75.76, H
7.42, found: C 75.69, H 7.39; HRMS-ESI (m/z) [M+NH
4
+
] calcd for C
13
H
18
NO
3
:
238.1443, found: 238.1442; HPLC (Daicel CHIRALCEL OD-H; 99:1
hexanes/isopropanol, detection wavelength = 250nm, flow rate = 0.5 mL/min) Tr
= 6.74 min (minor) and 7.69 (major).
160
161
162
163
Compound 15
O
O
O
3-(6-Methoxy-naphthalen-2-yl)-2-methylene butyric acid methylester (Table
2, entry 8): Following the one pot reaction with Pd-ligand complex 8 (21.5 mg,
0.05 mmol), the coupling reaction of 6-methoxy-2-naphthylboronic acid (242 mg,
1.2 mmol) with methyl tiglate(120 µL, 1.0 mmol) afforded desired product 15
(75%) as a colorlessoil.:
1
H NMR (250 MHz, CDCl3) δ = 7.74 – 7.69 (m, 2H), 7.62 (s, 1H),7.35 (d, J = 8.5
Hz, 1H), 7.18 -7.13 (m, 2H), 6.36 (s, 1H), 5.69 (s, 1H), 4.22 (q, J = 7.5 Hz,
1H), 3.91 (s, 3H), 3.69 (s, 3H), 1.53 (d, J = 7.5 Hz, 3 H);
13
C NMR (63 MHz,
CDCl3): δ =167.4, 157.2, 144.9, 139.4, 133.2, 129.1, 128.9, 126.7, 125.3, 118.6,
105.5, 55.2, 51.7, 40.3,20.7; Anal. calcd for C
17
H
18
O
3
: C 75.53, H 6.71, found: C
75.59, H 6.69; HRMS-ESI (m/z) [M+H
+
] calcd for C
17
H
19
O
3
: 271.1289, found:
271.1293
164
165
166
Appenedix 3: Supporting Information for Chapter 4
A. General Information
All commercially available reagents and solvents were used as received from
Aldrich and Acros chemical without further purification.
1
H and
13
C NMR spectra
were recorded on a 250 Bruker and 400 MHz Varian Mercury instrument.
Chemical shifts were reported in ppm relative to TMS for
1
H and
13
C NMR
spectra where CD
3
OD or CDCl
3
was used as NMR solvent. Thin-layer
chromatography (TLC) was performed using commercially prepared 60 mesh
silica gel plates visualized with short-wavelength UV light (254 nm). Silica gel 60
(9385, 230-400 mesh) was used for column chromatography. The reported yields
are isolated yields and are the average of two runs. Elemental analysis was
performed by Atlantic Microlab, Inc. (Norcross, GA). HRMS analyses were
performed by the Analytical Chemistry Instrumentation Facility at University of
California Riverside.
167
B. Preparation of Ligand and Pd-Complexes and Corresponding
Spectroscopic Information
Compound 6
N
N
H
N
O
OH
2-Benzimidazol-1-yl-N-[(1S)-hydroxymethyl-2-methyl-propyl]acetamide (6)
To a solution of benzimidazole (500 mg, 4.23 mmol) in DMF (10 mL) was added
2-bromo-N-(1S)-hydroxyl-methyl-2-methyl-propyl)acetamide 3 (948 mg, 4.23
mmol) followed by KOH (356 mg, 6.35 mmol). After stirring the reaction mixture
for 16 h at room temperature, EtOAc (50 mL) was added. Subsequently, a
precipitated solid was removed by filtration. The filtrated organic layers were
washed with brine twice, dried over anhydrous Na
2
SO
4
and then concentrated
under reduced pressure to give a crude oil, which was purified by column
chromatography on silica gel using EtOAc followed by MeOH as an eluent to
afford 6 as a white solid (940 mg, 85% yield).
1
H-NMR (CD
3
OD): δ 8.16 (s, 1H), 7.68-7.65 (m, 1H), 7.51-7.47 (m, 1H), 7.34-
7.23 (m, 2H), 5.05(d, J = 16.3 Hz, 1H), 4.98 (d, J = 16.3 Hz, 1H), 3.75-3.67 (m,
1H), 3.67-3.52 (m, 2H),1.94-1.80 (m, 1H), 0.93 (d, J = 4.7 Hz, 3H), 0.90 (d, J =
4.7 Hz, 3H);
13
C-NMR (CD
3
OD): δ 169.1, 145.7, 124.4, 123.7, 120.0, 111.3, 63.0,
58.4, 48.2, 30.0, 20.0, 18.8; Anal. calcd. for C
14
H
19
N
3
O
2
: C 64.35, H 7.33, N
16.08, found: C 64.32, H 7.34, N,16.07; HRMS-ESI (m/z) [M+H
+
] calcd for
C
14
H
19
N
3
O
2
: 262.1550, found: 262.1557
168
169
170
Compound 7
N
N
H
N
O
OH
2-Benzimidazol-1-yl-N-[2-hydroxy-(1S)-phenyl-ethyl]acetamide (7) Following
the above procedure with benzimidazole (500 mg, 4.23 mmol), 2-bromo-N-(2-
hydroxyl-1-phenyl-ethyl) acetamide 5 (1.12 g, 4.23 mmol), and KOH (356 mg,
6.35 mmol) the desired product 7 was formed as a white solid (1.14g, 91% yield).
1
H-NMR (CD
3
OD): δ 8.15 (s, 1H), 7.65 (m, 1H), 7.47 (m, 1H), 7.25-7.34 (m, 7H),
5.07 (s, 2H), 5.01 (dd, J = 5.25, 7.5 Hz, 1H), 3.78 (m, 2H);
13
C-NMR (CD
3
OD): δ
169.7, 141.5, 130.4, 130.3, 129.3,128.8, 125.2, 124.4, 120.8, 112.1, 66.7, 58.1,
49.0; HRMS-ESI (m/z) [M+H
+
] calcd. forC
17
H
17
N
3
O
2
: 296.1394, found: 296.1398
171
172
173
Compound 8
N
N
H
N
O
OH
I
3-[(1-Hydroxymethyl-(2S)-methyl-propylcarbamoyl)methyl]-1-methyl-3H-
benzimidazol-1-ium iodide (8) To a 300 mL round-bottom flask 6 (1.82 g, 6.9
mmol), iodomethane (3.94 g, 20.7 mmol), and THF (100 mL) were added. The
reaction mixture was stirred under reflux for 16 hours. After cooling the solution
to room temperature, a white solid, which is the desired product 8, was filtrated
and then washed with THF (2.64 g, 94% yield).
1
H-NMR (CD
3
OD): δ 9.55 (s, 1H), 8.01-7.95 (m, 1H), 7.93-7.86 (m, 1H), 7.75-
7.67 (m, 2H), 5.43 (d, J = 16.3 Hz, 2H), 4.18 (s, 3H), 3.78-3.69 (m, 1H), 3.69-3.55
(m, 2H), 1.97-1.83 (m, 1H), 0.95 (d, J = 6.8 Hz, 6H);
13
C-NMR (CD
3
OD): δ 167.2,
144.7, 128.3, 128.2, 114.4, 114.2, 63.0, 58.9, 49.7, 34.0, 30.0, 20.0, 18.9;
HRMS-ESI (m/z) [M+H
+
] calcd for C
15
H
22
IN
3
O
2
: 404.0830, found:404.0836
174
175
176
Compound 9
N
N
H
N
O
OH
3-[(2-hydroxyl-(1S)-phenyl-ethylcarbamoyl)methyl]-1-methyl-3
benzimidazol-1-ium iodide (9) Following the above procedure with 7 (1.0 g,
3.39 mmol) and iodomethane (1.44 g, 10.2 mmol) in THF to afford desired
product 9 (1.26 g, 85%yield) as white solid.
1
H-NMR (CD
3
OD): δ 9.50 (s, 1H), 7.95 (d, J = 4.8 Hz, 1H), 7.86(d, J = 5.8 Hz,
1H), 7.69 (m, 2H), 7.26-7.39 (m, 5H), 5.42 (s, 2H), 5.02 (dd, J = 4.8, 8.4Hz, 1H),
4.15 (s, 3H), 3.81 (m, 2H);
13
C-NMR (CD
3
OD): δ 167.2, 141.2, 134.1,
133.9,130.4, 129.4, 129.1, 129.0, 128.8, 115.1, 66.7, 58.5, 50.5, 34.7; HRMS-
ESI (m/z)[M+H
+
] calcd for C
18
H
20
IN
3
O
2
: 438.0673, found: 438.0671
177
178
179
Compound 10
N
N
Pd
N
O
O
Cl
H
Pd(II)-Ligand Complex 10: The suspension of benzimidazolium salt 8 (500 mg,
1.24 mmol) and silver(I) oxide (144 mg, 0.62 mmol) in CH
2
Cl
2
(40 mL) was stirred
for 2 hours with exclusion of light at room temperature. The reaction mixture was
concentrated under reduced pressure to give a dark-red solid. To a suspension
of the silver complex in CH
3
CN (50 mL) was added PdCl
2
(CH
3
CN)
2
(322 mg,
1.24 mmol) with exclusion of light at room temperature. Then, the resulting
suspension was stirred for 2 hours and filtered through a plug of celite and the
filtrate was evaporated to dryness in vacuo to afford product 10 (378 mg, 73%
yield for two steps) as an orange solid.
1
H-NMR (CD
3
OD): δ 7.61 (d, J = 16.0 Hz, 1H), 7.54 (d, J= 16.4 Hz, 1H) 7.37 (m,
2H), 5.82 (d, J = 16.4 Hz, 1H), 5.49 (d, J = 16.4 Hz, 1H), 4.35 (s, 1H), 3.75 (q,
1H), 3.61-3.51 (ABX, J = 16.4 Hz, 2H), 1.82 (m, 1H), 0.84 (d, J = 6.7 Hz, 3H),
0.77 (d, J = 6.7 Hz, 3H);
13
C-NMR (CD
3
OD): δ 168.9, 136.1, 135.9, 135.8,
135.6, 124.9, 124.7, 111.9, 111.4, 62.9, 58.5, 52.4, 35.1, 29.8, 20.0, 19.0, 18.6,
18.5; HRMS-ESI (m/z) [M+H
+
] calcd for C
15
H
20
ClN
3
O
2
Pd: 416.0357,
found:416.0356
180
181
182
Compound 11
N
N
Pd
N
O
O
Cl
H
Pd(II)-Ligand Complex 11: Following the above procedure with 9 (500 mg, 1.14
mmol) and silver oxide (132mmg, 5.7 mmol) to give the silver complex, then
added PdCl
2
(CH
3
CN)
2
(363 mg, 1.14mmol) to afford Pd-ligand complex 11 (358
mg, 75% yield for two steps) as an orange solid.
1
H-NMR (CD3OD): δ 7.49 (d, J = 8.4 Hz, 1H), 7.40 (d, J = 7.6 Hz, 1H) 7.17-7.30
(m, 7H), 5.74 (d, J = 16.4 Hz, 1H), 5.65 (d, J = 16.4 Hz, 1H), 5.03 (t, 7.2 Hz,1H),
4.30 (s, 3H), 3.73 (m, 2H);
13
C-NMR (CD3OD): δ 169.1, 141.3, 136.8,
136.4,130.0, 129.1, 128.9, 128.8, 125.6, 125.5, 112.7, 112.2, 66.7, 58.1, 53.1,
36.1;HRMS-ESI (m/z) [M+H
+
] calcd for C
18
H
18
ClN
3
O
2
Pd: 450.0201, found:
450.0198
183
184
185
Compound 12
Pd
O
N
N
N
O
Pd
O
N
N
N
O
Pd(II)-Ligand Complex 12: To a stirring suspension of monomer 10 (300
mg,0.72 mmol) in 60 mL HPLC grade water was added K
2
CO
3
(199 mg, 1.44
mmol) in one addition. After the resulting suspension was stirred at room
temperature for 4 hrs open to air, 50 mL of CH
2
Cl
2
was added. The mixture was
stirred vigorously for 30 minutes. The layers were then separated and the
aqueous layer was extracted twice with CH
2
Cl
2
(2 x 50 mL). All organic layers
were combined and then washed once with H
2
O (50 mL), separated, poured over
sodium sulfate, filtered, and concentrated in vacuo to give a pale yellow solid 12
(208 mg, 76%). Crystal for X-ray diffraction was obtained by layering solutions of
12 in dichloromethane with Et
2
O and allowing slow diffusion at room
temperature.
1
H-NMR (CD
3
OD): δ 7.64-7.69 (m, 2H), 7.44-7.46 (m, 2H), 4.99 (d, J = 16.4 Hz,
1H), 4.91 (d, J = 16.4 Hz, 1H), 4.17 (s, 3H), 3.62 (m, 1H), 3.45 (m, 2H), 2.18 (m,
1H), 0.96 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.8 Hz, 3H);
13
C-NMR (CD3OD): δ
166.8, 164.7, 135.4, 134.6, 125.4, 125.2, 112.2, 111.7, 74.4, 70.7, 54.7, 52.4,
33.8, 30.5, 20.4, 19.8; HRMS-ESI (m/z) [M+H
+
] calcd. for C
30
H
38
N
6
O
4
Pd
2
:
759.1102, found: 759.1105
186
187
188
Compound 13
Pd
O
N
N
N
O
Pd
O
N
N
N
O
Pd(II)-Ligand Complex 13: Following the above procedure with 11 (300 mg,
0.66 mmol) and K
2
CO
3
(184 mg, 1.33mmol) to afford Pd-ligand complex 13 (223
mg, 81% yield) as an orange solid.
1
H-NMR (CDCl
3
): δ 7.58 (d, J = 8.0 Hz, 2H), 7.44 (m, 4H), 7.29 (m, 2H), 7.21 (m,
1H),5.21, (d, J = 3.6 Hz, 1H), 5.05, (d, J = 16.4 Hz, 1H), 4.92 (d, J = 16.4 Hz,
1H), 4.09 (dd,J = 4.4, 9.2 Hz, 1H), 4.06 (s, 3H), 3.78 (d, J = 8.8 Hz, 1H);
13
C-
NMR (CDCl
3
): δ 164.5,142.3, 134.1, 133.5, 128.1, 127.3, 126.4, 124.2, 123.9,
110.6, 110.5, 77.6, 65.3, 52.0;HRMS-ESI (m/z) [M+H
+
] calcd. for C
36
H
36
N
6
O
4
Pd
2
:
831.0951, found: 830.9821
189
190
191
Appendix 4: Supporting Information for Chapter 5
A. general Information
All reagents were used as received from either Aldrich or Across without further
purification.
1
H and
13
C NMR spectra were recorded on a 250 MHz Bruker or 400
MHz Varian Mercury instrument. Chemical shifts were reported in ppm relative to
TMS for
1
H- and
13
C-NMR spectra where CD
3
OD or CDCl
3
was used as the NMR
solvent. Thin-layer chromatography (TLC) was performed using commercially
prepared 60 mesh silica gel plates visualized with shortwavelength UV light (254
nm). Silica gel 60 (230-400 mesh) was used for column chromatography. The
reported yields are isolated yields and are the average of two runs. Elemental
analysis and high-resolution mass spectra (HRMS) data were obtained as
specified. The enantiomeric excess was determined by HPLC and NMR
analyses. HPLC analyses were conducted with an UV detector and a Chiralcel
OD-H column, and NMR analyses were determined by using of Europium tris[3-
(heptafluoro propylhydroxy-methylene)-(+)-camphorate].
B. General Procedure for the Asymmetric Intermolecular Heck-
Type Reaction of Arylboronic Acids and Olefins
To an oven-dried round bottom flask equipped with a stir bar was added
palladium catalyst (0.05 mmol) and DMF (3 ml). The resulting solution was
allowed to stir for 10 minutes at room temperature. To the stirring solution was
then added arylboronic acid (1.0 mmol) and cyclic olefin (2.0 mmol) and the
reaction flask was fitted with an oxygen balloon and stirred overnight at room
temperature. After consumption of the starting material (confirmed by TLC), the
reaction solution was diluted with ethyl acetate (40 ml) and washed twice with
water (2 x 20 ml), and once with brine (20 ml). The combined aqueous layers
were then extracted once with dichloromethane (20 ml). All organic layers were
then combined and anhydrous sodium sulfate added. The solution was filtered
and the filtrate concentrated at reduced presssure. The crude product was then
subjected to column chromatography using an eluent gradient (50:1 Hex/EA to
10:1Hex/EA) to give the desired product.
192
C. Spectroscopic Information
Compound 1 (Table 5.2, entry 2)
See compound 14, chapter 3 for NMR and mass data
193
Compound 6
O
OMe
Methyl 2-methylene-3-(2-naphthalenyl)butanoate (Table 5.2, entry 1):
Following the typical procedure outlined above, the title compound was isolated
as a colorless oil.
1
H-NMR (CDCl
3
): δ 7.82-7.76 (m, 3H), 7.67-7.66 (m, 1H), 7.49-7.34 (m, 3H),
6.36-6.35 (m, 1H), 5.68-5.67 (m, 1H), 4.22 (q, J = 7.2 Hz, 1H), 3.67 (s, 3H), 1.52
(d, J = 7.2 Hz, 3H);
13
C-NMR (CDCl
3
): δ 167.4, 144.7, 141.8, 133.5, 132.2, 127.9,
127.6, 127.5, 126.3, 125.8, 125.5, 125.3, 124.1, 51.8, 40.5, 20.7; Anal. calcd for
C
16
H
16
O
2
: C 79.97, H 6.71, found: C 79.95, H 6.69; HRMS-ESI (m/z) [M+H
+
]
calcd for C
16
H
17
O
2
: 241.1184, found: 214.1198; NMR data for ee (after treating
with europium tris[3-(heptafluoro-propyl-hydroxymethylene)-(+)-camphorate]):
δ 3.909 ppm (major) and 3.896 ppm
194
195
196
197
Compound 7
N
O
OMe
Methyl 2-methylene-3-(4-dimethylaminophenyl)butanoate (Table 5.2, entry
3): Following the typical procedure outlined above, the title compound was
isolated as a light brown oil.
1
H-NMR (CDCl
3
): δ 7.08 (d, J= 5.5.Hz, 2H), 6.69 (d, J= 5.5.Hz, 2H), 6.21 (s, 1H),
5.56 (s, 1H), 3.94 (q, J= 5 Hz, 1H), 3.67 (s, 3H), 2.91 (s, 3H), 1.52 (d, J = 8.5 Hz,
3H);
13
C-NMR (CDCl
3
): δ 167.97, 158.86, 145.49, 132.37, 128.16, 123.23,
112.94, 51.80, 40.90, 39.50, 20.84; Anal. calcd for C
16
H
16
O
2
: C 79.97, H 6.71,
found: C 79.95, H 6.69; HRMS-ESI (m/z) [M+H
+
] calcd for C
16
H
17
O
2
: 241.1184,
found: 214.1198.
198
199
200
201
Compound 8
O
OMe
O
202
203
204
205
Compound 9
O
OMe
206
207
208
209
Compound 10
O
OMe
210
211
212
213
Compound 11
1-(5-phenylcyclopent-1-enyl)ethanone (Table 5.4, entry 1). Following the
typical procedure outlined above, the title compound was isolated as a colorless
oil.
1
H NMR 250 MHz (CDCl
3
): 1.85 - 1.97 (m, 1H), 2.24 (s, 3H), 2.43 - 2.64 (m,
2H), 2.67 - 2.84 (m, 1H), 4.14 - 4.22 (m, 1H), 6.92 - 6.95 (s, 1H), 7.11 - 7.19 (m,
3H), 7.22 - 7.29 (m, 2H);
13
C NMR, 250 MHz (CDCl
3
): 27.2, 32.5, 33.9, 49.4,
126.1, 126.9, 128.4, 144.7, 145.0, 148.3, 195.9; Anal. calcd for C
13
H
14
O: C
83.83, H 7.58, found: C 83.59, H 7.71; HRMS-ESI (m/z) [M+H
+
] calcd for
C
13
H
14
O: 187.1117, found: 187.1126; NMR data for ee (after treating with
europium tris[3-(heptafluoropropyl-hydroxyl-methylene)-(+)-camphorate]): 3.04
ppm (major) and 3.08 ppm (minor).
214
215
216
217
Compound 12
1-(5-o-toylcyclopent-1-enyl)ethanone (Table 5.4, entry 2). Following the
typical procedure outlined above, the title compound was isolated as a colorless
oil.
1
H NMR, 400 MHz (CDCl
3
): 1.73 - 1.81 (m, 1H), 2.27 (s, 3H), 2.43 (s, 3H), 2.46
- 2.63 (m, 2H), 2.64 - 2.75 (m, 1H), 4.36 - 4.42 (m, 1H), 6.84 - 6.88 (s, 1H), 6.97 -
6.99 (m, 1H), 7.04 - 7.09 (m, 2H), 7.13 - 7.17 (m, 1H);
13
C NMR, 250 MHz
(CDCl
3
): 19.7, 27.2, 32.2, 32.7, 45.2, 125.0, 125.9, 126.0, 130.3, 135.3, 143.0,
145.1, 148.3, 195.9; Anal. calcd for C
14
H
16
O: C 83.96, H 8.05, found: C 83.81, H
7.97; HRMS-ESI (m/z) [M+H
+
] calcd for C
14
H
16
O: 201.1274, found: 201.1279;
NMR data for ee (after treating with europium tris[3-(heptafluoropropyl-hydroxyl-
methylene)-(+)-camphorate]): 2.97 ppm (major) and 3.04 ppm (minor).
218
219
220
221
Compound 13
1-(5-(4-methoxyphenyl)cyclopent-1-enyl) ethanone (Table 5.4, entry 3).
Following the typical procedure outlined above, the title compound was isolated
as a pale yellow oil.
1
H NMR, 400 MHz (CDCl
3
) 1.83 - 1.92 (m, 1H), 2.24 (s, 3H), 2.41 - 2.49 (m,
1H), 2.51 - 2.61 (m, 1H), 2.67 - 2.78 (m, 1H), 3.76 (s, 3H), 4.11 - 4.17 (m, 1H),
6.80 (d, 2H, J = 10.5 Hz), 6.90 (q, 1H, J = 6 Hz), 7.06 (d, 2H, J = 10.5 Hz);
13
C
NMR, 400 MHz (CDCl
3
) 27.3, 32.4, 33.9, 48.5, 55.1, 113.7, 127.8, 137.1,
144.5, 148.4, 157.8, 196.1; Anal. calcd for C
14
H
16
O
2
: C 77.75, H 7.46, found: C
77.51, H 7.32; HRMS ESI (m/z) [M+H
+
] calcd for C
14
H
16
O
2
: 217.1223, found:
217.1229; NMR data for ee (after treating with europium tris[3-(heptafluoropropyl-
hydroxyl-methylene)-(+)-camphorate]): 3.06 ppm (major) and 3.15 ppm (minor).
222
223
224
225
Compound 14
1-(5-(4-dimethylamino)phenyl)cyclopent-1-enyl)ethanone (table 5.4, entry
4). Following the typical procedure outlined above, the titlecompound was
isolated as a light brown oil.
1
H NMR, 400 MHz (CDCl
3
) 1.82 - 1.95 (m, 1H), 2.21 (s, 3H), 2.38 - 2.63 (m,
2H), 2.64 - 2.76 (m, 1H), 2.89 (s, 6H), 4.08 - 4.15 (m, 1H), 6.66 (d, 2H, J = 17
Hz), 6.86 - 6.90 (m, 1H), 7.02 (d, 2H, J = 18 Hz);
13
C NMR, 400 MHz (CDCl
3
)
27.4, 32.4, 34.0, 40.7, 48.4, 112.8, 127.5, 133.1, 144.0, 148.5, 149.1, 196.3;
Anal. calcd for C
15
H
19
NO: C 78.56, H 8.35, N 6.11 found: C 78.11, H 8.19, N
5.97;
HRMS-ESI (m/z) [M+H
+
] calcd for C
15
H
19
NO: 230.1539, found: 230.1546; NMR
data for ee (after treating with europium tris[3-(heptafluoropropyl-hydroxyl-
methylene)-(+)-camphorate]): 3.07 ppm (major) and 3.14 ppm (minor).
226
227
228
229
Compound 15
Cl
O
1-(5-(4-chlorophenyl)cyclopent-1-enyl-ethanone(table 5.4, entry 5). Following
the typical procedure outlined above, the title compound was isolated as a
colorless oil.
1
H NMR, 400 MHz (CDCl
3
) δ 1.81 - 1.90 (m, 1H), 2.25 (s, 3H), 2.41 - 2.53 (m,
1H), 2.55 - 2.65 (m, 1H), 2.68 - 2.79 (m, 1H), 4.12 - 4.18 (m, 1H), 6.92 - 6.95 (m,
1H), 7.07 (d, 2H, J = 10 Hz), 7.21 (d, 2H, J = 10.5 Hz);
13
C NMR, 400 MHz
(CDCl
3
) δ 27.1, 32.5, 33.7, 48.8, 128.3, 128.5, 131.7, 143.6, 145.1, 148.0, 195.6;
HRMS-ESI (m/z)[M+H
+
] calcd for C
13
H
13
ClO: 221.0728, found: 221.0734; NMR
data for ee (aftertreating with europium tris[3-(heptafluoropropyl-hydroxyl-
methylene)-(+)-camphorate]): δ 3.08 ppm (major) and 3.17 ppm (minor).
230
231
232
233
Compound 16
O
O
O
Methyl 5-(4-methoxyphenyl)cyclopent-1-enecarboxylate (Table 5.4, entry6).
Following the typical procedure outlined above, the title compound was isolated
as a pale yellow oil.
1
H NMR, 400 MHz (CDCl
3
) δ 1.85 - 1.93 (m, 1H), 2.44 - 2.56 (m, 2H), 2.61 - 2.73
(m, 1H), 3.61 (s, 3H), 3.77 (s, 3H), 4.08 - 4.12 (m, 1H), 6.82 (d,2H, J = 11 Hz),
6.95 - 6.97 (m, 1H), 7.09 (d, 2H, J = 11 Hz);
13
C NMR, 400 MHz (CDCl
3
) δ 32.0,
34.0, 49.2, 51.2, 55.1, 113.7, 127.8, 137.2, 139.3, 144.4, 157.9, 165.1; Anal.
calcd for C
14
H
16
O
3
: C 72.39, H 6.94, found: C 72.07, H 6.72; HRMS-ESI (m/z)
[M+H
+
] calcd for C
14
H
16
O
3
: 233.1172, found: 233.1179; HPLC (Daicel
CHIRALCEL OD-H; 99:1 hexanes/isopropanol, detection wavelength = 200 nm,
flow rate = 1.0 mL/min) tr = 11.2 min (major) and 13.1 min (minor).
234
235
236
237
Compound 17
O
O
Methyl 5-o-tolylcyclopent-1-enecarboxylate (table 5.4, entry 7). Following the
typical procedure outlined above, the title compound was isolatedas a colorless
oil.
1
H NMR, 400 MHz (CDCl
3
) δ 1.76 - 1.82 (m, 1H), 2.41 (s, 3H), 2.50 - 2.69 (m,
3H), 3.61 (s, 3H) 4.35 - 4.40 (m, 1H), 6.94 - 6.97 (m, 1H), 7.03 - 7.06 (m, 1H),
7.08 - 7.12 (m, 2H), 7.14 - 7.17 (m, 1H);
13
C NMR, 400 MHz (CDCl
3
) δ 19.7, 31.9,
32.9, 45.7, 51.3, 125.2, 125.9, 126.0, 130.2, 135.3, 139.0, 143.0, 145.1, 165.3;
Anal. calcd for C
14
H
16
O
2
: C 77.75, H 7.46, found: C 77.26, H 7.19; HRMS-ESI
(m/z) [M+H
+
] calcd for C
14
H
16
O
2
: 217.1223, found: 217.1230; HPLC (Daicel
CHIRALCEL OD-H; 99:1 hexanes/isopropanol, detection wavelength = 200 nm,
flow rate = 1.0 mL/min) tr = 5.1min (major) and 5.9 min (minor).
238
239
240
241
NMR Spectra for palladium aryl structure 4
3a 4
242
Predicted orientation of Olefin (F) to palladium aryl complex prior to
insertion
Abstract (if available)
Abstract
Several applications of the “oxidative boron Heck-type” reaction have been successfully explored. These include the development of tandem oxidative boron Heck-type and Suzuki reactions where biaryls were generated expeditiously in a one pot procedure by properly utilizing different mechanisms in each step. In addition, the asymmetric coupling between trisubstituted linear olefins and arylboronic acids via oxidative Heck-type chemistry and utilizing chiral bidentate nitrogenous ligands resulted in yields and enantioselectivities superior to previously known studies.
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Catalytic applications of palladium-NHC complexes towards hydroamination and hydrogen-deuterium exchange and development of acid-catalyzed hydrogen-deuterium exchange methods for preparative deut...
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Applications of oxidative boron Heck-type reactions and the development of novel tridentate NHC-amidate-alkoxide containing palladium(II) catalysts
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