Iodonium Salts Preparation, Chemoselectivity and Metal- Catalyzed Applications

Iodonium Salts
Preparation, Chemoselectivity and MetalCatalyzed Applications
Joel Malmgren
© Joel Malmgren, Stockholm University 2014
Cover picture: Malmgrens bokbinderi. Photo taken by Marie Malmgren,
edited by Anuja Nagendiran
ISBN: 978-91-7447-999-7
Printed in Sweden by US-AB, Stockholm 2014
Distributor: Department of Organic Chemistry, Stockholm University
ii
“The richest people are the ones that are
happy with what they already have”
[José Mujica, President of Uruguay]
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Abstract
This thesis concerns the preparation and use of diaryliodonium salts. In
Project I various unsymmetrical diaryliodonium salts were reacted with three
different nucleophiles in order to study the chemoselectivity of the reactions
of the salts. The main focus of this project was to gain a deeper understanding of the underlying factors that affect the chemoselectivity in transition
metal-free arylation reactions. They were found to be very nucleophiledependent. Some nucleophiles were very sensitive to electronic effects,
whereas others were sensitive to steric factors. Ultimately, some arenes are
never transferred. A very interesting scrambling reaction was also observed
under the reaction conditions, where unsymmetrical diaryliodonium salts
form symmetrical salts in situ.
Project II details the preparation of N-heteroaryliodonium salts via a onepot procedure. The salts were designed so that the N-heteroaryl moiety was
selectively transferred in applications both with and without transition metals. The chemoselectivity was demonstrated by selective transfer of the
pyridyl group onto two different nucleophiles.
The third project in the thesis discusses the synthesis of alkynyl(aryl)iodonium salts and alkynylbenziodoxolones from arylsilanes. This
protocol could potentially be a very useful complement to the existing procedures, in which boronic acids are used.
The last part of the thesis (Project IV) describes a C-2 selective arylation
of indoles where diaryliodonium salts were used in combination with heterogeneous palladium catalysis. This transformation was performed in water at
ambient temperature to 50 °C, and tolerated variations of both the indole and
the diaryliodonium salt. Importantly, several N-H indoles could be arylated.
The MCF-supported Pd-catalyst showed very little leaching and it was
demonstrated that the main part of the reaction occurred via heterogeneous
catalysis.
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List of Publications
This thesis is based on the following projects, referred to in the text by their
Roman numerals I-IV. All published material is open access and the contribution by the author to each publication is clarified in Appendix A.
I.
Arylation with Unsymmetrical Diaryliodonium Salts A Chemoselectivity Study
Joel Malmgren, Stefano Santoro, Nazli Jalalian, Fahmi Himo*
and Berit Olofsson*
Chem. Eur. J. 2013, 19, 10334-10342.
II.
One-Pot Synthesis and Applications of N-Heteroaryl
Iodonium Salts
Marcin Bielawski, Joel Malmgren, Leticia Pardo, Ylva Wikmark
and Berit Olofsson*
ChemistryOpen 2014, 3, 19-22.
III.
Synthesis of Alkynyl(aryl)iodonium Salts from TMS-alkynes
Joel Malmgren, Marinus Bouma and Berit Olofsson*
Ongoing project
IV.
C-2 Selective Arylation of Indoles with Heterogeneous
Nanopalladium and Diaryliodonium Salts
Joel Malmgren, Anuja Nagendiran, Cheuk-Wai Tai, Jan-E.
Bäckvall* and Berit Olofsson*
Chem. Eur. J. 2014, 20, DOI: 10.1002/chem.201404017.
Publication not included in this thesis:
Synthesis of Diaryliodonium Triflates using Environmentally Benign
Oxidizing Agents
Eleanor A. Merritt, Joel Malmgren, Felix J. Klinke and Berit Olofsson*
Synlett 2009, 2277-2280.
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Table of Contents
Abstract…...……………………………………………….…………..................…..v
List of publications……………………………………………....………..…..….....vii
Abbreviations.............................................................................................................. xi
1
Introduction .......................................................................................................... 1
1.1 Hypervalent iodine compounds .................................................................... 1
1.1.1 Diaryliodonium salts – properties and preparation ............................... 2
1.1.2 Mechanistic overview ........................................................................... 5
1.1.3 Chemoselectivity overview ................................................................... 7
1.2 Catalysis with hypervalent iodine ................................................................. 9
1.2.1 Homogeneous versus heterogeneous catalysis ................................... 10
1.2.2 Metal nanoparticles ............................................................................. 10
1.2.3 Palladium catalysis .............................................................................. 11
1.2.4 Mesocellular foam............................................................................... 11
1.3 Applications of diaryliodonium salts .......................................................... 12
1.3.1 α-Arylation of carbonyl compounds ................................................... 12
1.3.2 Arylation of heteroatom nucleophiles ................................................. 15
1.3.3 Ar−Ar couplings ................................................................................. 17
1.3.4 Other applications ............................................................................... 19
1.4 Alkynyl(aryl)iodonium salts ....................................................................... 19
1.5 Aim of the thesis ......................................................................................... 20
2
Arylation with Diaryliodonium Salts: A Chemoselectivity Study (Project I) .... 23
2.1 Preparation of diaryliodonium salts ............................................................ 23
2.2 Arylation study............................................................................................ 25
2.2.1 Aryl exchange ..................................................................................... 29
2.2.2 Summary of the DFT calculations ...................................................... 32
2.3 Conclusion .................................................................................................. 33
3
N-Heteroaryliodonium Salts: Synthesis and Applications (Project II) ............... 35
3.1 Optimization ............................................................................................... 36
3.1.1 Modified procedure for electron-rich substrates ................................. 37
3.1.2 Analysis and deprotonation of the heteroaryliodonium bistriflates .... 38
3.2 Substrate scope............................................................................................ 39
3.3 Application studies...................................................................................... 41
ix
3.4
Conclusion .................................................................................................. 43
4
Synthesis of alkynyl(aryl)iodonium salts from TMS-alkynes (Project III) ........ 45
4.1 Results and discussion ................................................................................ 46
4.1.1 Optimization ....................................................................................... 46
4.1.2 Substrate scope .................................................................................... 47
4.2 Conclusion .................................................................................................. 49
5
C-2 Selective Arylation of Indoles using Heterogeneous Nanopalladium
Catalysis and Hypervalent Iodine (Project IV) .................................................. 51
5.1 Optimization ............................................................................................... 52
5.2 Substrate scope............................................................................................ 54
5.3 Recycling and leaching studies ................................................................... 58
5.4 Mechanism .................................................................................................. 59
5.5 Conclusion .................................................................................................. 60
Concluding remarks ................................................................................................... 61
Appendix A ............................................................................................................... 63
Appendix B ................................................................................................................ 65
Acknowledgements ................................................................................................... 67
References ................................................................................................................. 69
x
Abbreviations
Abbreviations and acronyms are used in agreement with the standard of the subject.1
Only nonstandard and unconventional abbreviations that appear in the thesis are
listed here.
DMP
EAS
EDG
EWG
HFIP
HTIB
IBX
ICP-OES
mCBA
MCF
mCPBA
NHC
nr
PET
SM
TFE
TIPS
Dess-Martin periodinane
Electrophilic aromatic substitution
Electron donating group
Electron withdrawing group
1,1,1,3,3,3-Hexafluoroisopropanol
[Hydroxy(tosyloxy)iodo]benzene
2-Iodoxybenzoic acid
Inductively coupled plasma optical emission spectrometry
meta-Chlorobenzoic acid
Mesocellular foam
meta-Chloroperbenzoic acid
N-Heterocyclic carbene
No reaction
Positron emission tomography
Starting material
2,2,2-Trifluoroethanol
Triisopropylsilyl
xi
1 Introduction
1.1 Hypervalent iodine compounds
Chemical elements that belong to groups 15-18 can be regarded as hypervalent if they possess more than 8 electrons in their valence shell.2 The
German chemist Conrad Willgerodt pioneered the field in 1886 by preparing
(dichloroiodo)benzene as the first hypervalent iodine compound,3 but it was
not until approximately 60 years later that interest in this research area
increased significantly.2, 4 The oxidation of an iodine atom from its +I state
to two of its possible hypervalent states, +III and +V is depicted in Scheme
1. A classification system of these types of compounds, devised by Kochi
and coworkers,5 is shown below each structure. The number to the left of the
iodine atom is the number of electrons situated in the valence shell, and to
the right the number of ligands surrounding the iodine atom is shown. An
8-I-1 annotation hence denotes that the iodine atom has 8 electrons in its
valence shell with one ligand.
L
Oxidation state
Classification
I
L
L
I
L
L
L
I
L
L
L
I
L
L
L
L I
L
L
L
L
+I
+III
+III
+V
+V
8-I-1
8-I-2
10-I-3
10-I-4
12-I-5
Non-hypervalent
L
L
Hypervalent
Scheme 1. Oxidation of a general iodide to its hypervalent states +III and +V.
Hypervalent compounds have a non-standard number of bonds. Therefore, they are given a λ-notation according to IUPAC nomenclature. Iodine
compounds with three or five ligands are hence denoted as λ3- and λ5iodanes respectively.6 A λ3-iodane forms a trigonal bipyramid with its 10
valence electrons whereas a λ5-compound has 12 valence electrons and
adopts a distorted octahedral structure (Scheme 1). Iodine(III) compounds
have one 3-center-4-electron bond (3c-4e bond) and iodine(V) compounds
have two. These types of bonds are also called hypervalent bonds and are
comprised of a doubly occupied 5p-orbital from the iodine atom and one porbital from each of the two ligands arranged linearly (Figure 1). The two
1
ligands that are part of the hypervalent bond are referred to as apical, the
others as equatorial.
a)
Lδ
Ar
antibonding orbital
b)
non-bonding orbital
δ
I
bonding orbital
Lδ
L
I
L
Figure 1. a) Structure of a general λ3-iodane. b) Orbital diagram of a hypervalent
bond.
The electron distribution in the filled non-bonding orbital gives the iodine
atom a partial positive charge and the two apical ligands a partial negative
charge. Therefore, the stability of the bond increases with the electronegativity of the apical ligands. The positive charge on the iodine makes it
susceptible to nucleophilic attack.2, 4a
The discovery of Dess-Martin periodinane (DMP) in the 1980s lead to a
breakthrough in hypervalent iodine applications.7 Nicolaou has reported use
of the related λ5-iodane, iodoxybenzoic acid (IBX), in various oxidation
reactions8 contributing to the growing popularity of hypervalent iodine.
These compounds can now be utilized in a variety of transformations
including C−C9 and C−heteroatom10 bond formations as well as in rearrangement reactions11 and in total syntheses.12 The main focus of this
thesis is on diaryliodonium salts, which IUPAC have termed diaryl-λ3iodanes. The preparation and application of this type of reagent will be
discussed in the following chapters.
1.1.1 Diaryliodonium salts – properties and preparation
Diaryliodonium salts are air and moisture stable compounds that were first
reported by Hartmann and Meyer in 1894.13 They adopt a trigonal bipyramidal structure with one aromatic moiety occupying the equatorial
position and the other aryl group in the apical position together with a
heteroatom ligand (Figure 2a). Structural studies have shown that the
Ar1−I−Ar2 bond angle is about 90° in the solid state, supporting the hypervalent model described in Figure 1.4b However, insufficient understanding of
the hypervalent structure in solution makes depiction of unsymmetrical diaryliodonium salts (Ar1 ≠ Ar2) as T-shaped trigonal bipyramids problematic.
The difficulty is in knowing which aryl group should reside in the equatorial
position and which in the apical position. Instead, these salts are often illustrated as a positively charged iodine atom with two aryl ligands and an
associated anion (Figure 2b). The heteroatomic anion influences both the
solubility and the reactivity of the salts.
2
a)
b)
X
Ar1
I
I
X
R2
R1
Ar2
X = Cl, Br, I, OTf, OTs, BF 4, PF 6 ...
Figure 2. General structure of diaryliodonium salts. a) T-shaped form. b) Salt form.
Anions that coordinate strongly render the salts less soluble in organic
solvents, whereas weakly coordinating anions tend to increase the solubility
since they are more prone to undergo exchange with the solvent. As a consequence, it is desirable to use weakly coordinative anions such as triflate,
tosylate, tetrafluoroborate or hexafluorophosphate in synthetic applications
rather than halides. Halide anions are also problematic due to their
nucleophilic nature.
Unsymmetrical salts (Ar1 ≠ Ar2) are often preferred over symmetrical
ones (Ar1 = Ar2) for a variety of reasons, one being that the former are easier
to prepare. The loss of an expensive aryl iodide may also be avoided by
choosing an unsymmetrical salt (Scheme 2). However, the possibility of
transferring one of two different aryl groups to a given nucleophile gives rise
to a chemoselectivity problem. This is avoided either by using a symmetrical
salt, or by using an unsymmetrical salt where the transfer of one of the
arenes is selective. The chemoselectivity of unsymmetrical salts is discussed
in Chapter 2 (Project I) of this thesis.
X
Ar1
I
Nu
Ar1 Nu
Ar2
I
Ar2
Scheme 2. General arylation of a nucleophile.
Previous preparation protocols for diaryliodonium salts involve multistep
syntheses,4c, 4d e.g. by reacting pre-made iodine(III) compounds with
arenes,14 aryl-silanes,15 stannanes or borates16.
Our group has developed efficient one-pot syntheses of both symmetrical
and unsymmetrical salts (Scheme 3).17 In the first one-pot procedure,
mCPBA is used to oxidize iodoarenes together with triflic acid (TfOH)
(Scheme 3a).17a, 17b
3
a)
I
R2
R1
CH 2Cl 2, rt, 10 min - 21 h
OTf
I
mCPBA, TfOH
R1
R2
up to 94%
b)
R
I2
mCPBA, TfOH
OTf
I
R
R
CH 2Cl 2, rt, 10 min - 21 h
up to 93%
c)
I
R2
R1
CH 2Cl 2, rt, 10 min - 14 h
OTs
I
mCPBA, TsOH
R1
R2
up to 100%
d)
mCPBA, TsOH
R
I2
CH 2Cl 2, rt, 10 min - 14 h
I
OTs
R
R
up to 89%
e)
I
R2
R1
I
Urea-H 2O 2, Tf2O
CH 2Cl 2:TFE (2:1)
40 °C, 3 h
OTf
R2
R1
up to 86%
Scheme 3. One-pot preparation of diaryliodonium salts by our group.
Symmetrical versions of the salts can be readily obtained directly from
molecular iodine and arenes (Scheme 3b and d). Addition of Et2O followed
by filtration/trituration furnishes the pure product in a simple fashion since
the remaining reagents and byproducts in the crude reaction mixture are
soluble in Et2O. This protocol is, however, limited by the fact that electronrich arenes such as anisole react violently with TfOH without product
formation. These substrates are instead accessible by exchanging the TfOH
for the weaker para-toluenesulfonic acid (Scheme 3c and d).17c Both unsymmetrical and symmetrical electron-rich diaryliodonium tosylates can be
prepared using this method and if the triflate anion is desired, it can be
obtained via a simple in situ anion exchange. A more environmentally benign way of preparing the salts was also developed, replacing the potentially
explosive mCPBA with urea-hydrogen peroxide as the oxidant (Scheme
3e).17d
The salts formed in these reactions have a substitution pattern that originates from the electrophilic aromatic substitution (EAS) reaction between
the in situ formed iodine(III) intermediate and the arene (Scheme 4).
4
Activated arenes are ortho and para directing. Mostly para-substituted
products are observed, probably due to the steric hindrance in the orthoposition of the arene. Deactivated arenes are meta directing but these are
generally too unreactive and often result in decomposition of the iodine(III)
intermediate.
R
I
L
I
L
Activated
R
R = EDG
L
generally not observed
R
I
L
R = EWG
I
Deactivated
L
R
Scheme 4. EAS of a general ArIL2 compound.
To circumvent this limitation, a regiospecific protocol for the salts was
developed (Scheme 5). The utilization of arylboronic acids makes both meta
and ortho substituted salts readily available as the desired C−I bond is
formed via an ipso-substitution on the boron-bearing carbon. Both symmetrical and unsymmetrical salts can readily be made using this method.
B(OH) 2
I
R1
mCPBA
BF 3 •OEt 2
CH2Cl2
30 - 60 min, rt
IL 2
R1
R2
I
15 min, rt
BF 4
R1
R2
up to 88%
Scheme 5. Regiospecific preparation of diaryliodonium tetrafluoroborates.
Symmetrical salts where the aryl groups are very bulky, electron-rich or
electron-poor are generally difficult to make using these one-pot methods,
whereas unsymmetrical salts with varying electronic and steric properties are
easily prepared.
1.1.2 Mechanistic overview
When a nucleophile reacts with a general iodine(III) compound, it initially
undergoes a ligand exchange with one of the heteroatomic ligands. Two
general mechanistic pathways are proposed for this transformation;
dissociative and associative (Scheme 6).2, 18
5
Dissociative pathway
L:
L
Ph
Nu:
I
Ph
I
Nu
Ph
L
L
10-I-3
I
L
8-I-2
10-I-3
Associative pathway
Ph
I
L
10-I-3
:Nu
I
Nu
Nu
L
L
Ph
Nu
L
12-I-4 (trans)
Ph
I
Ph
L
L
12-I-4 (cis)
I
L
L
10-I-3
Scheme 6. Formation of a T-shaped PhLINu complex via a dissociative or associative pathway.
Studies on the behavior of diaryliodonium salts in solution have been
lacking, but investigations on [hydroxy(tosyloxy)iodo]benzene (i.e. Koser’s
reagent), as well as on its mesyloxy derivative, in water have been conducted.19 The results showed that the OTs/OMs counterion indeed is dissociated
from the iodine complex, creating a positively charged center. However, the
empty coordination site is quickly filled by a nearby water molecule,
keeping the T-shape intact. Ochiai and coworkers investigated the hydrated
and protonated form of iodosylbenzene in water [PhI(H2O)OH]+ using X-ray
diffraction analysis, confirming that the water molecule was ligated with the
iodine at one of the apical sites. Together with the hydroxyl group, a near
linear O−I−O bond angle of 174° was observed, which is in agreement with
a λ3-iodane structure.20 These studies indicate that even though the cationic
8-I-2 species (see Scheme 1) in the dissociative pathway has been observed
in mass spectrometry for most diaryliodonium salts known, it is not present
in its free form. Even if the counterion is dissociated the vacant position will
be taken by a solvent molecule, retaining the hypervalent bond and the 90°
Ar1−I−Ar2 bond angle.
The associative pathway starts with the formation of a trans 12-I-4
complex by addition of a nucleophile to the iodine atom. After isomerization
to a cis 12-I-4 complex the T-shaped intermediate forms by elimination of a
ligand L-. This mechanism was validated by X-ray analysis of stable square
planar 12-I-4 complexes, like the [ICl4]- [SCl3]+ salt.21
In arylations with diaryliodonium salts, under transition metal-free
conditions, it is widely accepted that the aryl group is transferred to the
nucleophile via a T-shaped complex. A ligand coupling between the equatorial aryl group and the nucleophile in a cis fashion forms the product with
the concomitant elimination of an iodoarene as the driving force of the
reaction (Scheme 7). 2, 22 Iodobenzene is a 106 times better leaving group
than a triflate anion23 and Ochiai termed it a “hypernucleofuge”.2 This term
6
reflects the initial hypervalent character as well as the extraordinary leaving
group ability of the molecule.
Nu
Ar1
I
ligand coupling
Ar2
Ar1
Nu
Ar2I
Scheme 7. Ligand coupling of a general nucleophile and an aryl group.
1.1.3 Chemoselectivity overview
As mentioned earlier, chemoselectivity problems arise when unsymmetrical diaryliodonium salts are used, since two different aryl groups
can be transferred from the salt to a nucleophile. The observed selectivity is
the outcome of several factors. In transition metal-catalyzed reactions, the
most electron-rich arene or the least hindered will preferentially be transferred.4c, 24 Under transition metal-free conditions, the chemoselectivity is
different. Beringer performed a decomposition study of two diaryliodonium
salts, which showed that the most electron-deficient aryl group is transferred
to the nucleophile (Scheme 8).25 The nucleophile, in this case the sulfite
anion of the salt, exclusively ended up on the least electron-rich arene.
SO32I
H 2O, reflux
O 2N
I
MeO
SO3-
I
I
SO3-
O 2N
SO32-
H 2O, reflux
MeO
Scheme 8. Decomposition study by Beringer.
Upon ligand exchange between a nucleophile and the counterion in an unsymmetrical salt, there are two possible outcomes. The two formed T-shape
complexes are in rapid equilibrium via Berry pseudorotations (Scheme 9).2,
4g
In the reductive elimination step, a negative charge develops on the equatorial arene approached by the nucleophile (transition states C and D). Thus,
transition state (TS) D, which has the electron-withdrawing aryl group in the
equatorial position, will be lower in energy. At the same time, there is a
partial positive charge developing on the iodine. An arene with electrondonating groups can best stabilize this developing positive charge and
contribute to a lower transition state energy by residing in the apical position
7
and is not transferred. As shown in Scheme 9, the electron-withdrawing
arene is preferentially transferred over the electron-donating one via TS D.
The lowest energy intermediate (A or B) does not necessarily lead to the
lowest energy TS (C or D). Electronically, intermediate A is the more stable
one due to the stabilization of the small negative charge (see Figure 1) by the
electron-withdrawing group. However, the lowest energy TS D, leading to
the coupling reaction, stems from the less stable intermediate B. This is why
unsymmetrical salts are usually depicted in salt form (Figure 2).
Nu
EDG
I
EDG
Nu
δ
I
δ
A
I
EDG
EWG
Minor
C
EWG
Nu
EWG
Berry pseudorotation
Nu
EWG
I
EWG
Nu
δ
I
δ
Nu
I
EWG
EDG
Major
B
D
EDG
EDG
Scheme 9. Two T-shapes in equilibrium leads to two different reaction pathways.
In addition to the electronic factors discussed above, there are also steric
factors influencing the selectivity. The equatorial positions in the hypervalent model are considered to be less hindered compared to the apical ones.
Therefore, steric bulk in the ortho-position of the arene will increase its
tendency to occupy the equatorial position, despite the fact that it might be
more electron-rich.22b-22d The transfer of aryl groups with ortho-substituents
is commonly referred to as the ortho-effect. Scheme 10 shows a coupling
between a nucleophile and an ortho-methyl substituted arene. The methyl
group makes the arene more electron-rich, hence it should occupy the apical
position, but due to the increased bulk in ortho-position it resides in the
equatorial position and it is thus transferred to the nucleophile.
Nu
I
Nu
I
Me
Me
Scheme 10. Increased steric bulk in the ortho-position of the arene forces it to occupy the equatorial position, resulting in its transfer.
The electronic effect dictates that the most electron-poor aryl group
occupies the equatorial position in the TS. Electron-donating groups situated
8
in the ortho-position counteract this effect. With many nucleophiles, the
ortho-effect dominates the electronic effect. However, there are reports
where aryl groups were not transferred despite containing steric bulk in the
ortho-position, especially with carbon nucleophiles.22e, 26
1.2 Catalysis with hypervalent iodine
The Swedish chemist J. J. Berzelius coined the term catalysis in his 1835
annual report to the Swedish Academy of Sciences.27 He described it as
when a substance solely by its presence had the ability to make reactions
proceed under otherwise inert conditions.28 A more modern definition of a
catalyst is when a substance increases the rate of a reaction without being
consumed or changing the overall standard Gibbs free energy of the reaction
(Figure 3). In modern society catalysis plays a major role in, for instance,
today’s fuel29 and chemical industries30.
Figure 3. An uncatalyzed reaction (blue) compared to a catalyzed reaction (red).
Transition metals are of great use in the field of catalysis. Upon the
discovery of the properties of these elements during the 20th century, a
revolution occurred in the field of organic chemistry. New routes were
developed in order to create more complex molecules and industrial scale
atom-economical processes emerged.31 Commonly this impact is attributed
to the ability to form complexes with different oxidation states, as transition
metals have both electron-donating and electron-accepting capabilities.
9
1.2.1 Homogeneous versus heterogeneous catalysis
A catalyst can be either homogeneous or heterogeneous, both having distinct
advantages and disadvantages. In homogeneous catalysis the catalyst and the
reagents reside in the same phase. This makes the probability of an
encounter between the catalyst and a substrate molecule very high, making
homogeneous catalysts generally more effective than their heterogeneous
counterparts. However, drawbacks including the need for additional
purification steps in order to keep the trace metal amounts below threshold
values in products, and difficulty recycling the catalyst, are associated with
homogeneous catalysis.
In heterogeneous catalysis the substrate and catalyst are in separate
phases, the most common being a liquid−solid combination but gas−solid or
immiscible liquids can also constitute heterogeneous catalytic systems.32
Heterogeneous catalysts can be easily separated from the reaction mixture,
often by simple filtration procedures. This allows for easier catalyst
recycling, making these types of systems preferable from an environmental
point of view.
1.2.2 Metal nanoparticles
Nanoparticles have a high surface area to volume ratio with sizes ranging
from 1 to 100 nm in diameter. Smaller nanoparticles are considered to be
more catalytically active and their reactivity is determined by their size,
shape and morphology. The surface atoms are considered to be responsible
for substrate interactions since they are exposed to the reaction medium,
whereas interior atoms contribute to the reactivity more indirectly.33 Nanoparticles are soluble in organic solvents, making them suitable as homogeneous catalysts34 and they can be characterized by conventional spectroscopic methods. Metal nanoparticles are made by reducing metal ions either
chemically or electrochemically in the presence of some kind of stabilizer to
avoid uncontrolled aggregation. Heterogeneous metal nanoparticles can be
readily obtained by using a solid support such as silica, alumina, metal
oxides or carbon as the stabilizer.35
Nanoparticles are utilized in different ways in fields such as energy
technology and material chemistry.36 Transition metal nanoparticles have
been realized as efficient alternatives to traditional catalysts, promoting
reactions under mild conditions. In particular supported metal nanoparticles
have recently received increased attention.37 These types of catalysts have
large surface areas,38 making them attractive from a synthetic organic
chemistry point of view.
10
1.2.3 Palladium catalysis
Among all the transition metals, palladium is the most studied.39 After the
discovery of the Wacker process in the 1950s,40 the research interest
involving palladium skyrocketed with an untold number of applications. The
most common oxidation states of palladium are 0 and +II, with electron
configurations of d10 and d8, respectively. The two oxidation states give the
palladium different characteristics; in the 0 state a nucleophilic character is
seen whereas in the +II state the Pd becomes more electrophilic. PdII can in
turn be further oxidized to PdIV upon treatment with a suitable two-electron
oxidant. Even though diaryliodonium salts had been used together with
palladium in early applications,4c Canty and coworkers were first to report
the transfer of a Ph+ species to a PdII compound using diphenyliodonium
triflate, effectively producing a stable triorganyl PdIV complex.41 Arylation
reactions employing diaryliodonium salts for the utilization of a supposed
PdII/IV cycle have been reported by the groups of Sanford and Daugulis.42
One obvious advantage of utilizing a PdII/IV over a Pd0/II redox cycle is to
avoid Pd0 intermediates, which are often unstable and readily form inactive
Pd0 species. This allows for lower catalytic loadings. Furthermore, milder
reaction conditions can be used when employing PdII/IV cycles, allowing
substrates containing aryl and allyl halides to be tolerated, which under Pd0
arylation conditions would not survive due to oxidative addition to
palladium.43 Other benefits include facile reductive eliminations from PdIV to
PdII as well as easy transmetallations of organometallics to PdIV species.42c, 44
1.2.4 Mesocellular foam
Porous materials are divided into three different classes depending on their
respective pore sizes; microporous (<2 nm), mesoporous (2-50 nm) and
macroporous (>50 nm).45 In organic chemistry, microporous materials are
less suitable as the pores are too small to allow efficient mass transfer of
larger molecules. On the other hand, the size distribution of mesoporous
materials fit very well with the needs of organic synthesis, as the whole pore
system is accessible by bulky molecules without formation of larger inactive
metal particles, which is a problem associated with macroporous materials.46
Siliceous mesocellular foam (MCF) has been shown to be a capable
support for chemical catalysts.46-47 Its three-dimensional structure creates a
high surface area of 500−800 m2/g and 10−20 nm windows connect pores
with sizes of 20−40 nm (Figure 4a).45-46
The Bäckvall group has recently reported a catalyst where Pd nanoparticles were supported in amino-functionalized MCF forming Pd0- and
PdII-AmP-MCF respectively (Figure 4b and c).48 These catalysts have
proved useful in a variety of organic transformations, including oxidation of
alcohols and cycloisomerizations.49
11
a)
b)
OH
OH
OH
OH
OH
HO
HO
HO
HO
HO
NH2
NH2
NH2
NH2
NH2
H2 N
H2 N
H2 N
H2 N
H2 N
NH2
NH2
NH2
NH2
NH2
H2 N
H2 N
H2 N
H2 N
H2 N
HO
HO
HO
NH2
NH2
NH2
NH2
H2 N
H2 N
H2 N
H2 N
NH2
NH2
NH2
NH2
H2 N
H2 N
H2 N
H2 N
OH
OH
OH
OH
c)
HO
Pd0
PdII
Figure 4. Schematic picture of a MCF pore, (a) without functionalization, (b) with
Pd0-aminopropyl-functionalization and (c) with PdII-aminopropyl-functionalization.
1.3 Applications of diaryliodonium salts
Diaryliodonium salts can be used in a variety of different applications. They
possess a higher reactivity towards metals compared to aryl iodides,
allowing for milder conditions. This originates from the much better leaving
group that results from an oxidative addition. Many transition metalcatalyzed transformations have emerged in combination with diaryliodonium
salts.50 In many situations however, they may be used as environmentally
benign alternatives in order to avoid metals such as lead, mercury and
thallium.4e
1.3.1 α-Arylation of carbonyl compounds
The introduction of an aryl group in the α-position of a carbonyl compound
is an ongoing challenge in the field of organic synthesis. Beringer showed in
the 1960s that diaryliodonium salts could be used towards this end.51 The
phenylation of 5,5-dimethylcyclohexane-1,3-dione furnished the desired
product in 22% together with 23% of the di-phenylated byproduct (Scheme
11). This report showed that this type of transformation could be achieved
without the aid of transition metals, even if the yields were not optimal.
12
O
OH
O
Ph 2ICl
tBuONa
Ph
tBuOH
O
Ph
Ph
O
O
reflux, 4 h
22%
23%
Scheme 11. Early arylation of a diketone.
Later, Gao and Portoghese successfully achieved diastereoselective αarylation of ketones using lithium hexamethyldisilazane (LHMDS) as the
base (Scheme 12).52 Stang also contributed to this field by utilizing CuCN in
the arylation of lithium enolates with diaryliodonium salts in order to form
α-arylated cyclic ketones in up to 50% yield.53
MeN
MeN
Ph
O
O
i) LHMDS
ii) Ph 2II
O
THF:DMF (1:3)
-78 °C → rt
O
OMe
OMe
Scheme 12. Diastereoselective α-arylation of morphan-6-ones.
Oh and coworkers showed in 1999 that α-substituted malonates can be
arylated simply by stirring the deprotonated malonate and a diaryliodonium
salt in DMF at rt (Scheme 13).54 In the same study a small chemoselectivity
investigation revealed that some unsymmetrical salts preferably react by
transferring the most electron-deficient aryl group. It was shown that
palladium could not catalyze the reaction and it was also established that
simple iodoarenes could not be used instead of the diaryliodonium salt.
Products formed from possible radical reactions were not encountered either.
O
i) NaH
ii) Ar2IOTf
O
EtO
OEt
DMF, rt, 2 h
O
O
EtO
OEt
R
R
Ar
Up to 95%
Scheme 13. α-Arylation of substituted malonates by Oh.
At the same time, Ochiai and coworkers demonstrated the use of chiral
diaryliodonium salts in asymmetric α-arylation.26a The chiral binaphthyl
diaryliodonium salt was able to provide the α-arylated β-ketoester in varying
yields (20-69%) and up to 53% ee (Scheme 14). Asymmetric arylations with
diaryliodonium salts was not previously reported and this is so far the only
reported example of asymmetric induction obtained with chiral salts.
13
O
I
CO 2Me
BF 4
Ph
R
O
tBuOK
tBuOH,
CO 2Me
Ph
rt, 20 h
R
R
R
R
38% ee,
34% ee,
53% ee,
37% ee,
=H
= Me
= Bn
= +IPh BF 4-
69%
68%
30%
51%
yield
yield
yield
yield
Scheme 14. Ochiai’s asymmetric arylation of a β-ketoester.
Another way of inducing chirality in α-arylations is to employ a chiral
base. So far, the sole example of this is by Aggarwal and Olofsson. They
employed Simpkin’s base to desymmetrize a ketone and subsequently
reacted it with a diaryliodonium salt to form the α-arylated product in
excellent dr and ee. This methodology was employed as the key step in a
short synthesis of the analgesic agent (−)-epibatidine with an overall yield of
31% (Scheme 15).12a
O
i)
Ph
N
Ph
Li
2 equiv, THF, -118 °C
Cl
O
H
N
N
six steps
I
N(Boc) 2
ii)
Cl
N
Cl
N
Cl
N(Boc) 2
N
Cl
>20:1 dr, 94% ee,
41% yield
(−)-epibatidine
31% overall yield
1 equiv, DMF, -45 °C
Scheme 15. The key step in the preparation of (−)-epibatidine.
Diaryliodonium salts are also used to enantioselectively α-arylate
aldehydes, demonstrated by MacMillan and Allen (Scheme 16).55 The
aldehyde reacts with the imidazolidinone organocatalyst, forming a chiral
enamine that subsequently reacts with an electron-deficient CuIII species
formed by oxidative addition between the CuBr and the diaryliodonium salt.
Reductive elimination furnishes the optically enriched α-arylated aldehyde in
excellent yields and ee. This report also shows that aryl(mesityl)iodonium
salts can selectively transfer a variety of arenes to the aldehyde, using the
mesityl group as a dummy.
14
O
H
Ar1
O
N
R
H
PhMe:Et 2O (2:1)
NaHCO 3
R
Me
O
cat. (10 mol%)
CuBr (10 mol%)
OTf
I
Ar2
tBu
Ar1
Ph
N
H
22 examples
up to 95% yield and 94% ee
TCA
cat.
TCA = Trichloroacetic acid
Scheme 16. Enantioselective α-arylation of aldehydes.
1.3.2 Arylation of heteroatom nucleophiles
This field was initiated in the early 1950s by Beringer, who arylated various
heteroatomic nucleophiles including alkoxides, phenoxides and amines.56
Since then, this area has experienced many advances.
Our group has in the recent years contributed greatly with numerous
protocols for oxygen arylations (Scheme 17). In 2011, a facile protocol for
the arylation of phenols was developed (Scheme 17a).57 Over 20 phenols
were shown to form diarylethers in excellent yields by stirring the
deprotonated phenol together with the diaryliodonium salt in THF at either rt
or 40 °C.
a)
c)
O
R
Ar
over 20 examples
up to 98% yield
b)
R
OH
R
O
R
O
Ar
tBuOK
THF, rt or 40 °C
30 min
tBuOK
over 20 examples
up to 97% yield
O
R
PhMe,
reflux, 1 h
R3
R1
PhMe, rt
up to 1.5 h
O
EtO
N
Ar
EtO
R5
R3
O
N
d)
Ar
over 20 examples
up to 98% yield
e)
O
R3
HCl aq.
O
N O
R4
OH
N OH MeCN, rt
30 min
O
O
OH
tBuONa
R2
f)
R5
R4
tBuONa
8 examples
up to 79% yield
Ar
O
NaOH, H 2O,
rt or 50 °C, 3 h
I
tBuOK
DMF, 60 °C
up to 2 h
Ar 9 examples
up to 92% yield
ROH
X
OH
O
R
O
Ar
MeCN, 70 °C
2h
15 examples
up to 98% yield
R4
R4
R3
R1
O
11 examples
up to 82% yield
Scheme 17. Arylation of oxygen nucleophiles by Olofsson.
15
In a continuation of this study it was shown that carboxylic acids could be
arylated in a similar fashion (Scheme 17b).58 Simply by refluxing the
reagents in toluene for 1 hour, aryl esters were obtained in excellent yields.
This protocol is tolerant towards various functional groups including
carbonyls, heteroatoms and alkenes.
Various activated alcohols can be readily arylated under mild conditions
in water (Scheme 17c).59 Allylic and benzylic alcohols as well as phenols
could be arylated using this procedure.
Diaryliodonium salts have also proved useful in the arylation of unactivated aliphatic alcohols (Scheme 17d).60 The mild transition metal-free
conditions furnished alkylaryl ethers in high yields without employing
excess reagents or long reaction times.
Ethyl acetohydroxamate was efficiently arylated under transition metalfree conditions giving the O-arylated products in up to 89% yield (Scheme
17e).61 The O-arylated substrates could then readily be made into the
corresponding substituted benzofurans via a Fisher-indole type
transformation employing a suitable ketone. The utility of the protocol was
further demonstrated by preparing benzofurans in a one-pot procedure
directly from ethyl acetohydroxamate.
O-aryloxyamines were prepared through the arylation of N-hydroxysuccinimide or N-hydroxyphthalimide (Scheme 17f).62 The formation of the
O-aryloxyamines was achieved by aminolysis of the imide using NH3 or
NH2OH in a methanol−chloroform mixture. This method avoids the use of
hydrazine, which is an otherwise common reagent to obtain these
substrates.63
Heteroatoms other than oxygen have also been arylated with the aid of
diaryliodonium salts. Carroll and Wood were able to arylate anilines,
forming diarylamines in good to excellent yields, by stirring the two
components in DMF at 130 °C for 24 h (Scheme 18).64 Steric hindrance or
high electron density in the aniline did not affect the outcome of the reaction.
This report also included a small chemoselectivity study.
NH 2
R
Ar2IX
DMF, 130 °C
24 h
H
N
R
Ar 9 examples
up to 92% yield
Scheme 18. Metal-free arylation of anilines.
Another important application of diaryliodonium salts is the preparation
of radiolabeled 18F-arenes. Sanford has shown that nucleophilic 18F ions
react with diaryliodonium salts in the presence of a Cu catalyst to form the
radiolabeled arenes (Scheme 19),65 which are used as tracers in positron
emission tomography (PET). This preparation method eliminates the need
for hazardous reagents such as [18F] fluorine gas. These types of products
16
can also be prepared under metal-free conditions albeit in lower yields and
with a narrower substrate scope.66
X
(CH 3CN) 4CuOTf
I
18F
K18F
R1
R1
DMF, 85 °C, 20 min
R2
12 examples
up to 79% radiochemical yield
Scheme 19. Formation of 18F-arenes by Sanford.
Sanford and Wagner have also shown that diaryliodonium salts can be
utilized in the preparation of aryl sulfides from thiols or thioethers (Scheme
20).67
OCOCF3
S
R1
I
R2
R1
CF 3COOH
R3
R3
1,4-dioxane
110 °C, 15 h
R3
R1 = alkyl or aryl
R 2 = H or alkyl
S
16 examples
up to 90% yield
Scheme 20. Arylation of thiols and thioethers by Sanford.
1.3.3 Ar−Ar couplings
One of the more significant examples of diaryliodonium salt-mediated
Ar−Ar couplings is the meta-selective arylation of anilides reported by
Gaunt (Scheme 21a), where various meta-substituted biaryls were obtained
using Cu(OTf)2 as the catalyst.24a When a palladium catalyst was used, the
corresponding ortho-substituted product was formed instead (Scheme
21b).42e
a)
O
R1
b)
O
NH
Ph 2IOTf
Cu(OTf) 2
R
R1
R
O
NH
Ph 2IPF 6
Pd(OAc) 2
R1
NH
Ph
Ph
R = 4-Me
R1 = OtBu
R
Ph
over 20 examples
up to 93% yield
79%
Scheme 21. a) Cu-catalyzed meta-selective arylation. b) Pd-catalyzed orthoselective arylation.
Sanford and co-workers achieved selective C-2 arylation of indoles with
diaryliodonium salts together with homogeneous palladium catalysis under
17
mild conditions using the IMes ligand (Scheme 22).42b This work formed the
basis of the project described in Chapter 5. Gaunt and coworkers later
showed that diaryliodonium salts can be used in a similar fashion together
with Cu catalysts. Both C-2 and C-3 arylated indoles could be synthesized
depending on the conditions used.68 Transition metal-free preparations of
both C-2 and C-3 arylated indoles using diaryliodonium salts was reported
by Ackermann and co-workers.69
BF 4
I
R2
R3
H
IMesPd(OAc) 2 (5 mol%)
R2
R3
AcOH, rt, 18 h
N
R1
N
R1
R3
R1 = H, alkyl
N
16 examples
Yields 62% - 90%
>20:1 C-2 selectivity
N
C
1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene
(IMes)
Scheme 22. Sanford’s C-2 arylation of indoles.
Diaryliodonium salts can also be used in the pursuit of more environmentally benign arylation protocols, as demonstrated by Kita and coworkers with
a transition metal-free cross-coupling reaction of thiophene derivatives
(Scheme 23).9c In this reaction, the salt is formed in situ from [hydroxyl(tosyloxy)iodo]benzene (HTIB or Koser’s reagent), which after activation by
TMS−Br undergoes an EAS with an arene to form the cross-coupled product
in high yields.
OTs
R1
R2
S
PhI(OH)OTs
Ph
Br
I
Ph
TMS-Br
R1
S
HFIP
R2
R1
R2
Ar-H
42-98% yield
S
Ar
Scheme 23. Kita’s metal-free cross-coupling reaction of thiophenes.
18
R1
I
S
R2
1.3.4 Other applications
Kitamura and coworkers demonstrated that the salts can be used as benzyne
precursors for cycloadditions (Scheme 24).70 The presence of a TMS group
next to the iodine makes it a potent aryne precursor due to the excellent
leaving group ability of iodobenzene. The salt forms the aryne in situ by
reacting with Bu4NF, which then undergoes a cycloaddition reaction with
furan.
I
R
OTf
Ph
O
Bu 4NF
O
R
R
TMS
O
O
O
4 examples
up to 98% yield
Scheme 24. Diaryliodonium salt used as an aryne precursor.
Diaryliodonium salts can also be used for dearomatization of phenols,22a
polymerization of epoxides71 and synthesis of macrocycles72.
1.4 Alkynyl(aryl)iodonium salts
Another important group of hypervalent iodine reagents are the alkynyl(aryl)iodonium salts.2, 4d-4g, 73 The structure of alkynyl salts is similar to that
of diaryliodonium salts except that one of the aryl groups is replaced by an
alkynyl functionality. The associated anion can be of external or internal
nature (Figure 5). When the anion of hypervalent iodine compounds is
internal, the term benziodoxolone is used. This structural feature increases
the stability of the reagent. These electrophilic alkynylation agents can be
used under mild conditions. The alkynyl group is always transferred, eliminating the chemoselectivity issues seen with diaryliodonium salts.
a)
b)
X
R1
I
R2
X = OTf, OTs, etc...
O
O
R1
I
R2
R 2 = TMS, TIPS, Ph, tBu, nBu, etc...
Figure 5. General alkynyl(aryl)iodonium salt with an external (a) or internal (b) anion.
Waser and coworkers have successfully developed the use of the reagents
trimethylsilylethynyl-1,2-benziodoxol-3(1H)-one (TMS-EBX) and the corresponding triisopropyl version (TIPS-EBX),74 introducing an alkynyl
19
functionality equipped with a silyl group as a synthetic handle. For example,
they reported a C-2 selective alkynylation of indoles using a PdII catalyst and
TIPS-EBX (Scheme 25).75
O
I
SiiPr 3
Pd(MeCN) 4(BF 4)2 (2 mol%)
R
O
N
SiiPr 3
R
N
CH2Cl2:H 2O (50:1), rt
R'
17 examples
up to 72% yield
R'
Scheme 25. C-2 selective alkynylation of indoles by Waser.
The alkynylation of thiols was also demonstrated under mild
conditions.74b Aliphatic thiols, thiophenols and heterocyclic phenols were
successfully alkynylated under metal-free conditions (Scheme 26). The reaction proceeded at rt and was complete within five minutes.
O
R-SH
I
NH
SiiPr 3
O
Me 2N
NMe 2
THF, rt, <5 min
R
S
SiiPr 3
Over 30 examples
up to >99% yield
Scheme 26. Alkynylation of thiols by Waser.
1.5 Aim of the thesis
The objective of this thesis is the preparation and application of diaryliodonium salts as well as the preparation of alkynyl(aryl)iodonium salts. A
large part of the thesis is devoted to finding a convenient way of preparing
iodonium salts, in particular heteroaryliodonium salts. These salts can then
be used to transfer a heteroaryl group onto a nucleophile. We demonstrated
the utility of the salts by selectively introducing a pyridyl moiety on two
different nucleophiles. The preparation of alkynyl(aryl)iodonium salts using
alkynylsilanes were briefly looked into. The protocol aimed to be a useful
complement to the current procedure where boronic acids are utilized, and in
that way increase the amount of available salts.
The other main focus of the thesis is to achieve a greater understanding of
the chemoselectivity in arylation reactions of unsymmetrical diaryliodonium
salts. A thorough chemoselectivity study was conducted, and it is hoped that
this knowledge will contribute to the development of catalytic arylation
protocols as well as to research into polymer supported diaryliodonium salts.
20
Another feature of diaryliodonium salts, that we aim to demonstrate in the
last part of the thesis, is their ability to facilitate metal-catalyzed reactions.
Our salts were combined with a potent heterogeneous palladium catalyst,
leading to a very mild protocol for the selective C-2 arylation of indoles in
water. This protocol compares well to others previously reported as the
catalyst is heterogeneous in nature and the conditions are mild.
21
22
2 Arylation with Diaryliodonium Salts: A
Chemoselectivity Study (Project I)
Diaryliodonium salts are versatile arylation agents, as illustrated in Chapter
1.4c The main drawback with these reagents is the formation of a stoichiometric amount of aryl iodide, which is undesirable both from isolation and
atom efficiency points of view.
One way to circumvent this problem would be to attach the salt to a solid
support, in order to facilitate recovery of the aryl iodide.76 Alternatively one
could employ the aryl iodide catalytically and form the diaryliodonium salt
in situ using a terminal oxidant (still unknown). The realization of these
goals requires the use of unsymmetrical diaryliodonium salts (Figure 2b,
when R1 ≠ R2) where the two aryl groups are differentiated either by sterics
or electronics.22b If one of the aryl groups acts as a dummy and is never
transferred, the aryl iodide can be used catalytically, forming the diaryliodonium salt in situ in an arylation reaction. Conveniently, unsymmetrical
salts are often easier to prepare compared to their symmetrical equivalents.4c,
17a-17c, 77
Additionally, if an expensive aryl moiety needs to be transferred, the
use of unsymmetrical salts avoids the waste of an expensive aryl iodide.
However, in order to benefit from the use of unsymmetrical salts, the factors
influencing the chemoselectivity have to be well understood and a thorough
investigation under transition metal-free conditions has up to this point been
lacking.54, 64
To gain a deeper understanding of the factors affecting the chemoselectivity, a study was conducted where three different nucleophiles were
arylated under previously reported conditions.54, 57, 78 The salts were systematically varied with respect to the electronic and steric properties, in order to
achieve a comprehensive overview of the observed selectivities. The results
of the study are presented in this chapter.
2.1 Preparation of diaryliodonium salts
Diphenyliodonium triflate (1a) was used to verify the arylation protocols
used in the study. Twelve different aryl(phenyl)iodonium triflates 1 were
prepared (Figure 6), six of which had one to three methyl substituents on the
aryl group (1b−g), mainly providing a steric effect, and the other six
23
possessed the corresponding methoxy-substituents (1h−m), to allow investigation of the electronic effect. The phenyl group was the most electron-poor
aryl group in all salts and was expected to be preferentially transferred in all
cases in the absence of steric effects.
I
Ph
OTf
I
Ph
OTf
Ph
I
OTf
Ph
OTf
I
OMe
1c
1b
Ph
I
OTf
1e
Ph
I
1d
OTf
1f
Ph
I
Ph
I
OTf
OMe
Ph
MeO
1k
1g
OTf
Ph
I
OTf
I
OTf
MeO
1j
MeO
1i
1h
OTf
I
Ph
OMe
Ph
I
OMe
OTf
MeO
1m
MeO
1l
OMe
OMe
Figure 6. Diaryliodonium salts 1b−m used in this study.
The diaryliodonium salts with methyl substituents 1b−g as well as the
methoxy substituted salt 1h were synthesized according to the one-pot
protocols shown in Chapter 1, as detailed in Table 1.
Table 1. One-pot procedures for preparation of salts 1b−h.
Entry
Salt
Method
Acid
Temp
(equiv)
Yielda
(%)
1
Scheme
3a
2
0 °Crt
25 min
90
2
Scheme
3a
2
rt
30 min
52
3
Scheme
3a
2
0 °C
2h
95
2
rt
5h
69
2.5
rt
30 min
+ 30
min
76
4
5b
24
Time
Scheme
3a
Scheme
5
6
Scheme
3a
7
Scheme
3c
2
rt
1h
79
1
rt
6h
99
a
Isolated yields. b after reaction completion, an anion exchange was performed in
situ with 1 equiv of TfOH.
The remaining five methoxy-substituted salts (1i−m) could not be prepared by the conventional one-pot methods due to difficulties in preparation
of the aryl iodides. These salts were therefore prepared by reacting Koser’s
reagent with an aryl stannane79 or silane15 (Scheme 27).
I
OTs
TMS
R
R
MeCN, reflux, 4 h
1l: R = 2,6-dimethoxy 47%
1m: R = 2,4,6-trimethoxy 94%
OTs
I
OH
Bu 3Sn
R
I
OTs
R
CH2Cl2, 0 °C, 30 min
1i: R = 2-methoxy 56%
1j: R = 2,4-dimethoxy 96%
1k: R = 2,5-dimethoxy 68%
Scheme 27. Preparation of electron-rich unsymmetrical diaryliodonium salts.
Since the salts obtained from these methods originate from Koser’s
reagent, the anion is a tosylate. The triflate salts were obtained by anion
exchange, whereby the tosylate salts were dissolved in CH2Cl2 and washed
with an aq. solution of NaOTf. The procedure was repeated a minimum of
three times to ensure full anion exchange.
2.2 Arylation study
The reproducibility of the three model reactions was verified using diphenyliodonium triflate (1a). The study was conducted using previously
reported protocols to arylate m-methoxyphenol57 (2), forming the phenylated
and the arylated products 3 and 4, m-anisidine78 (5), forming 6 and 7, and
diethyl methylmalonate54 (8), forming 9 and 10 (Scheme 28). The nucleophiles were selected so that a conclusion could be drawn regarding the
difference in reactivity between O, N and C nucleophiles. The methoxysubstituent on the phenol and aniline was used to simplify the 1H NMR
interpretation of the results.
25
a)
MeO
OH
Ph(Ar)IOTf
MeO
O
Ph
MeO
O
Ar
tBuOK,
THF
40 °C, ≤2 h
2
3
4
b)
MeO
NH 2
Ph(Ar)IOTf
78-99%
H
N
MeO
Ph
H
N
MeO
Ar
30-75%
DMF
130 °C, 24 h
6
5
c)
O
O
O
8
O
O
O
Ph(Ar)IOTf
OEt
EtO
7
NaH, DMF
rt, 18 h
EtO
OEt
EtO
OEt
Ph
9
26-95%
Ar
10
Scheme 28. Arylation conditions for a) m-methoxyphenol (2), b) m-anisidine (5)
and c) diethyl methylmalonate (8).
Product ratios were determined from the 1H NMR spectra of the
combined isolated products for compounds 3:4 and from crude mixtures of
compounds 6:7 and 9:10, due to lower yields and difficult separations. The
yields given in tables 2 and 3 are of the combined isolated products. The
yields of arylated products 9 and 10 from malonate 8 were often lower
compared to when diphenyliodonium triflate (1a, 80%) was used.
Table 2 summarizes the results from the methyl-substituted salts 1b−g. In
the arylation of phenol 2 both of the previously described effects could be
observed. Salt 1b gave a 2.9:1 ratio (entry 1) with preference towards phenyl
transfer, which was as expected considering that the phenyl group is the
most electron-poor of the two. The o-tolyl salt 1c, however, preferentially
transferred the aryl moiety, exemplifying the ortho-effect (entry 2). Salts 1d
and 1e gave very poor selectivities (entries 3 and 4), which is explained by
the two effects opposing each other. The selectivity difference between the
two could be attributed to the fact that the p-Me moiety is more electrondonating than the m-Me moiety.80 When two methyl-substituents occupy the
ortho-positions the selectivity towards transferring the arene increases, as
seen in the reaction with salt 1f (entry 5). A combination of the results from
salt 1b and 1f could be seen when the mesityl salt 1g was used resulting in
poor selectivity (entry 6).
All methyl-substituted salts gave preferential transfer of the phenyl group
when reacted with m-anisidine 4. No ortho-effect seemed to be present for
this nucleophile as indicated by the similar results obtained with salt 1b and
1c (entries 1 and 2). An increase in phenyl transfer was observed when the
salts with two methyl groups (1d−f) were employed (entries 3-5). The
mesityl salt 1g gave high selectivity towards the phenylated product 6
(entry 6).
26
Diethyl methylmalonate (8) also gave preferential transfer of the phenyl
group with all methyl-substituted salts. The electronic effect from the pmethyl moiety gave a 3.3:1 selectivity with preference to phenylation (entry
1). However, when an o-Me moiety was present instead, the selectivity
towards phenylation increased to 11:1. This effect had not previously been
reported and we named it the “anti-ortho effect”. The selectivity obtained
with salt 1d was only 5:1 (entry 3), i.e. considerably lower than that of 1c
(11:1, entry 2). It is difficult to explain why the results are not additive, as
seen with the other nucleophiles. Complete selectivity was achieved with
two ortho-substituents (entry 5) as well as with the mesityl salt 1g (entry 6).
Table 2. Phenylation versus arylation of 2, 5 and 8 using diaryliodonium salts with
methyl-substitution 1b−g.
Entry
Iodonium salt
MeO
O
Ph/Ar
MeO
H
N
O
Ph/Ar
EtO
O
OEt
Ph/Ar
1
Yielda
6:7
Yielda
9:10
Yielda
2.9:1
78%
1.4:1
53%
3.3:1
54%
1:2.4
98%
1.4:1
40%
11:1
64%
1.3:1
98%
4.5:1
75%
5.0:1
52%
1:1.6
>99%
2.5:1
60%
2.0:1
95%
1:9.0
98%
6.5:1
53%
Only 9
26%
1:1.9
84%
15:1
50%
Only 9
55%
OTf
I
Ph
3:4
1b
2
OTf
I
Ph
1c
3
OTf
I
Ph
1d
4
I
Ph
OTf
1e
5
I
Ph
OTf
1f
6
Ph
I
OTf
1g
a
Combined yields of the isolated products.
27
Table 3 summarizes the results from the methoxy-substituted salts 1h−m.
Phenol 2 reacted with complete selectivity with all six salts to transfer the
phenyl moiety (entries 1−6). The electronic effect exerted by the methoxy
groups is evidently strong enough to override the steric ortho-effect giving
very selective phenylation reactions.
Aniline 5 gave higher selectivity towards phenyl transfer with the monosubstituted methoxy salts 1h and 1i compared to their methyl substituted
equivalents (entries 1 and 2). This was expected since the methoxy group is
much more electron-donating than the methyl group. Di- and trimethoxysubstituted salts 1j, l−m gave full selectivity towards phenyl transfer (entries
3, 5 and 6) while salt 1k only gave a 2.3:1 ratio towards phenylation. This is
in accordance with exchanging a π-donating p-methoxy substituent to a σwithdrawing m-methoxy substituent.80
Table 3. Phenylation versus arylation of 2, 5 and 8 using methoxy substituted salts
1h−m.
Entry
Iodonium salt
MeO
O
Ph/Ar
MeO
H
N
O
Ph/Ar
EtO
O
OEt
Ph/Ar
1
Ph
3
4
OMe
OTf
I
I
Ph
OTf
6
Ph
OTf
MeO
1m
a
Only 3
94%
5.4:1
74%
13:1
36%
Only 3
93%
3.0:1
62%
2.6:1
61%
Only 3
82%
Only 6
50%
Only
9
53%
Only 3
90%
2.3:1
30%
Only
9
57%
Only 3
>99%
Only 6
70%
Only
9
38%
Only 3
85%
Only 6
45%
Only
9
44%
OMe
MeO
1l
I
Yielda
OMe
MeO
1k
5
9:10
OTf
MeO
1j
Ph
Yielda
OTf
I
MeO
1i
I
6:7
OMe
Ph
Ph
Yielda
OTf
I
1h
2
3:4
OMe
OMe
Combined yields of the isolated products.
28
Malonate 8 gave a better selectivity with the methoxy group in the para
position compared to the ortho position (entry 1 and 2). Considering the
observed anti-ortho effect with the methyl-substituted salts, this result was
unexpected. It is possible that the oxygen of the methoxy group in ortho
position is able to coordinate to the malonate, which could lower the
transition state energy when the aryl group is in equatorial position, thus
facilitating the transfer of the aryl group to the nucleophile. Complete
selectivity towards phenylation was observed for the di- and tri-substituted
methoxy salts (entries 3-6).
In summary, the chemoselectivity observations reveal that methoxysubstituted aryl moieties are able to act as “dummy ligands” in the arylation
of compounds 2, 5 and 8. Mono-substituted salts are enough to obtain full
selectivity with phenol 2, whereas di- or tri-substituted salts are required for
aniline 5 and malonate 8.
2.2.1 Aryl exchange
DiMagno and coworkers reported in 2010 that unsymmetrical diaryliodonium salts make aryl exchanges, in situ forming two symmetrical salts
in the presence of a fluoride anion (Scheme 29).66e When an unsymmetrical
salt was dissolved in MeCN together with a fluoride anion, the authors
discovered the formation of two symmetrical diaryliodonium cations by
HRMS, formed by scrambling of the aryl ligands of the initial unsymmetrical salt.
I
Ar1
X
Ar2
F
MeCN, rt
Ar1
I
X
Ar1
Ar2
I
X
Ar2
Scheme 29. Aryl exchange reported by DiMagno.
Very recently Cuifolini and coworkers investigated this type of ligand
exchange more thoroughly.81 They observed that scrambling occurs when
the diaryliodonium salt is heated to 125 °C in CH2Cl2 in the presence of an
aryliodide. No scrambling was detected in more polar solvents such as DMF
or MeCN. The hypothesized mechanism involves replacement of the triflate
anion of the salt with an aryliodide, forming a positively charged intermediate that can undergo scrambling. The salt is then reformed with a different aryl group (Scheme 30).
I
Ar3
OTf
Ar1
I
Ar2
I
Ar1
Δ
I
Ar2
Ar1
I
Ar2
Ar3
Ar3
I
Ar1
I
Ar2
OTf
Ar3
Ar1
I
Ar2
I
OTf
Scheme 30. Hypothesized aryl ligand exchange mechanism by Cuifolini.
29
An investigation was conducted to find out whether such an aryl
scrambling took place in any of the three reactions applied in the present
chemoselectivity study. Salt 1k was selected as the model substrate and a
blank test was done without a nucleophile. As expected, stirring the salt in
DMF at either rt or reflux did not result in formation of new iodonium
species according to HRMS data. The presence of aniline 5 under the
reaction conditions did not initiate any aryl exchange either.
However, in the reaction of phenol 2 with salt 1k, three different diaryliodonium cations 1a’, 1k’ and 1n’ were observed by HRMS within 5 min of
reaction time (Figure 7). Considering that the nucleophile in principle could
be arylated by any of the three iodonium cations, the chemoselectivity and
yield of the reaction could be affected. If the phenyl group is transferred
from 1a’ rather than from 1k’, the theoretical yield of 3 drops, as one phenyl
group that could otherwise have been transferred, is lost as iodobenzene. The
high isolated yield of diarylether 3 suggests that the reaction mainly
proceeds via salt 1k’ and that the aryl exchange is reversible.
Malonate 8 displayed the same behavior as phenol 2 in this respect. The
two symmetrical diaryliodonium cations were both detected by HRMS after
only 5 min of reaction time at rt. The reaction between malonate 8 and salt
1k only gave moderate yield of compound 9, with complete selectivity
(Table 3, entry 4), suggesting that 1n’ is unreactive compared to the other
diaryliodonium species in the reaction. The yields with unsymmetrical salts
were consistently lower than with Ph2IOTf (1a), which gave an 80% yield of
9. This could be explained by the observed aryl exchange, as reaction with
1a’ would lower the theoretical yield of 9.
Figure 7. Iodonium cations detected by HRMS in the arylation of m-methoxyphenol
(2) with salt 1k.
The methyl-substituted salt 1e exhibited scrambling together with malonate 8 equally fast as salt 1k, showing that the scrambling is not limited to
electron-rich salts. This reaction was also was followed by 1H NMR,
revealing that the 2:1 product distribution was acquired early in the reaction.
30
Over the course of three hours the ratio changed from 2.1:1 to 1.9:1. This
small deviation indicates that the reaction rate of the different iodonium species is very similar or that the aryl exchange is in rapid equilibrium. A control experiment was also conducted where di(2,5-dimethylphenyl)iodonium
triflate (1o) and di(p-methoxyphenyl)iodonium triflate (1p) were reacted
simultaneously with malonate 8 (Scheme 31a). The expected unsymmetrical
iodonium cation was detected within five minutes. In order to gain some
insight into the mechanism of the reaction, malonate 8 was reacted with di(ptolyl)iodonium triflate 1q in the presence of 2,6-dimethyliodobenzene
(Scheme 31b). No unsymmetrical cations were detected, indicating that the
formed iodoarene species does not participate in the scrambling.
a)
O
O
OEt
EtO
I
8
1 equiv
I
O
OTf
I
EtO
NaH (1.3 equiv)
DMF, rt, <5 min
MeO
O
EtO
OEt
OMe
I
OTf
O
OEt
MeO
1o
1.3 equiv
I
O
not isolated
MeO
OMe
OMe
1p
1.3 equiv
b)
I
I
O
O
O
EtO
I
OTf
1.3 equiv
EtO
O
OEt
NaH (1.3 equiv)
OEt
DMF, rt, <5, min
8
1 equiv
1q
1.3 equiv
I
not isolated
Scheme 31. a) Arylation of 8 with two different symmetrical salts present. Scrambling was detected. b) Arylation of 8 in the presence of an aryl iodide. No scrambling
was detected.
The main distinguishing difference between these three reaction
conditions is that a base is required for phenol 2 and malonate 8. The neutral
nucleophile aniline 5 might result in less effective coordination to the iodine
center. This could make the aryl exchange less likely since the nucleophile
itself exchanges easily. The mechanism of the scrambling is not understood
despite attempts using DFT calculations.
31
2.2.2 Summary of the DFT calculations
The experimental data were in very good agreement with the DFT
calculations performed by Prof. Himo and Dr. Santoro. The electronic effect
favoring the transfer of the most electron-poor aryl group was confirmed.
The calculations also showed that the electronic effect depends on the
nucleophilic attack on the ipso-carbon in the ligand coupling step rather than
on an influence on the 3c-4e bond.
The origin of the ortho-effect was difficult to elucidate since it depends
on the nucleophile. The anti-ortho-effect was shown to depend on steric
repulsion between bulky nucleophiles and the bulky aryl groups in the TS. It
is noteworthy that the T-shaped intermediate with the lowest energy has the
bulkiest aryl group in the equatorial position, whereas it occupies the apical
position in the favored TS (Figure 8). This illustrates the importance of
basing chemoselectivity predictions on the relative TS-energies rather than
on the relative energies of the T-shaped intermediates.
2.72
2.56
2.58
2.93
2.44
2.48
2.14
2.13
TS8-1f-Ar
+15.3
TS8-1f-Ph
+13.3
TS8-1f-Ar
+15.3
+13.3
TS8-1f-Ph
INT 8-1f-Ph
+1.9
INT 8-1f-Ar
0.0
10 + PhI
-55.8
9 + ArI
-66.0
Figure 8. Energy diagram of the reaction pathway from the T-shaped intermediate
from 8 and 1f to products 9 and 10. Energies are given in kcal/mol.
32
2.3 Conclusion
The chemoselectivity in arylations with unsymmetrical diaryliodonium salts
is largely dependent on the type of nucleophile used. For phenol 2, both
electronic and steric factors affect the outcome when using methylsubstituted salts 1b−g. The steric ortho-effect is overruled by electronic
influence when using methoxy-substituted salts 1h−m, resulting in complete
selectivity for phenylation.
Only electronic factors influence arylation of aniline 5 since increased
preference for phenyl transfer was observed with increasing number of
electron-donating substituents, irrespective of steric hindrance.
Methyl-substituted salts 1b−g give increased preference towards arylation
when the salts contain steric bulk in the ortho-position for phenol 2, whereas
the opposite trend was observed for malonate 8. This newly found observation is described as an anti-ortho effect.
Methoxy-substituted salts 1h−m exerted both steric and electronic effects.
Completely selective phenylation was observed in almost all cases where dior trimethoxy-substituted salts were used (the 2,5-dimethoxy-substituted salt
1k was an exception), suggesting that they are well-suited “dummy” aryl
moieties for many nucleophiles (Figure 9).
Figure 9. Suitable dummy groups for diaryliodonium salts in chemoselective
arylations.
The salts were easily accessible through one-pot procedures for the
mesityl and anisyl salts (1g and 1h), or via two-step procedures for salts 1j,l
and 1m.
33
34
3 N-Heteroaryliodonium Salts: Synthesis and
Applications (Project II)
As described in Chapter 1, the preparation of diaryliodonium salts has
become facile due to the development of simple one-pot procedures. These
protocols work very nicely for the formation of many unsymmetrical and
symmetrical diaryliodonium salts (Scheme 3), but unfortunately they are not
suitable for the general preparation of salts containing N-heteroaryl moieties
due to competing N-oxidation.82 One exception is the formation of (6-chloro3-pyridyl)phenyliodonium triflate, which could be synthesized with our
mCPBA/TfOH protocol (Scheme 32).17b The chloride atom is thought to
deactivate the nitrogen from oxidation, thus allowing product formation.
Without this type of deactivation the synthesis does not work.
I
I
Cl
OTf
mCPBA, TfOH
CH2Cl2, 80 °C, 2 h
N
Cl
N
60%
Scheme 32. Acidic preparation of a heteroaryl iodonium salt.
Heteroaromatic diaryliodonium salts are useful in the preparation of [18F]
compounds for positron emission tomography (PET). Carroll and coworkers
hence developed a four-step procedure towards pyridyliodonium salts
(Scheme 33).66b
R
I
N
ICl 2
Cl 2
N
IO
NaOH
N
I
I(OAc) 2
Ac2O/AcOH
OCOCF3
TFA
N
R
N
overall yield 11%
Scheme 33. Four-step procedure to a pyridyl iodonium salt.
There is also a strongly basic route to symmetrical versions of these salts
reported by Stang and coworkers (Scheme 34).83 The synthesis requires
isolation of the highly unstable vinyliodonium dichloride84 and furnishes the
products in low to moderate yields, which lowers the attractiveness of the
reaction. The preparation of the natural product (−)-epibatidine was in any
35
case achieved using a salt prepared with this method (Scheme 15).12a Zefirov
also reported a similar procedure to prepare unsymmetrical salts.85
Li
H
H
ICl 3
H
HCl
Cl
ICl 2
R
H
IAr 2
Ar2ICl
Cl
H
H
6 examples
up to 71% yield
very unstable
Scheme 34. Strongly basic route to symmetrical heteroaryliodonium chlorides.
An increased availability of N-heteroaryliodonium salts should facilitate
the introduction of N-heteroaryl groups onto a variety of nucleophiles, as
well as simplifying the preparation of [18F] heteroaryl compounds. The aim
of this project was to achieve a general simple preparation of Nheteroaryliodonium salts and to demonstrate their utility by employing them
in suitable applications.
3.1 Optimization
As a model reaction, 3-iodopyridine (11a) was reacted with benzene (12a) to
form pyridyliodonium salt 13a according to Scheme 35. The standard
conditions for making diaryliodonium triflates were initially applied; 1.1
equiv of mCPBA and 3 equiv of TfOH (Scheme 32),17b but unfortunately this
resulted in a mixture of products due to competing N-oxidation of 11a.82
N
11a
I
I
and/or
N
N
12a
OTf
OTf
mCPBA
TfOH
I
13a
H
OTf
13a'
Scheme 35. Model reaction for the preparation of N-heteroaryliodonium salts.
This problem was avoided by treating 3-iodopyridine (11a) with TfOH
prior to the addition of the oxidant. Protonation of the nitrogen atom protects
it from oxidation, and allows oxidation of the iodine with subsequent
formation of iodonium salt. It was, however, discovered that the salt remains
protonated upon isolation delivering 13a’ rather than 13a.
Further optimization studies were then conducted and the results are
summarized in Table 4. First, the amount of oxidant was investigated, and
1.1 equiv of mCPBA gave 54% yield (entry 1), which was slightly improved
to 60% by using 1.5 equiv of mCPBA (entry 2). When more oxidant was
36
added, the yield dropped (entry 3). The reaction could be further improved
by increasing the amounts of TfOH to 4 equiv, giving a yield of 68% (entry
4). Lowering the reaction time decreased the yield (entries 5 and 6) but
combining lower temperature with shorter reaction time surprisingly resulted
in 69% yield (entry 7). No product could be detected when 40 °C or rt were
used (entries 8 and 9). Based on our newly obtained knowledge on chemoselectivity, we subsequently focused on more useful dummy groups than the
phenyl moiety.
Table 4. Summary of the optimization.
I
N
I
TfOH
CH2Cl2, rt,
5 min
11a
N
H
I
i) PhH (12a, 1.1 equiv)
ii) mCPBA
T, time
OTf
OTf
N
H
OTf
13a'
Yielda
(%)
1
80
3
54
2
80
3
60
3
80
3
52
4
80
3
68
5
80
10 min
48
6
80
0.5
60
7
60
0.5
69
8
40
0.5
0
9
rt
0.5
0
a
Isolated yield after evaporation in vacuo and precipitation by addition of Et2O.
Entry
mCPBA
(equiv)
1.1
1.5
2.0
1.5
1.5
1.5
1.5
1.5
1.5
TfOH
(equiv)
3.0
3.0
3.0
4.0
4.0
4.0
4.0
4.0
4.0
T (°C)
Time (h)
3.1.1 Modified procedure for electron-rich substrates
The optimized conditions did not work when methoxy-substituted arenes
were used as the dummy group. The reaction mixture immediately turned
black and no product could be detected.
We have previously noted the incompatibility between electron-rich arenes
and TfOH, and a modified protocol was developed in order to keep the
desired 4 equivalents of TfOH and still be able to utilize electron-rich arenes
(Scheme 36).
37
I
N
IL 2
i) TfOH (4 equiv)
ii) mCPBA (1.75 equiv)
N
CH 2Cl2, 60 °C, 30 min
H
i) H 2O (2 equiv)
ii) PhOMe (12b, 1.1 equiv) in CH2Cl2
0 °C, 10 min
OTf
I
N
OTf
OTf
OMe
H
11a
13b'
81%
Scheme 36. Modified procedure for the preparation of electron-rich heteroaryl salts.
The initial protonation of the nitrogen and the activation of mCPBA for
the oxidation of iodine require two equiv of TfOH. To ensure that these steps
proceeded to completion, the amount of mCPBA was slightly increased from
1.5 to 1.75 equiv and the reaction vessel was capped and submitted to a 60
°C oilbath for 30 min. After cooling of the reaction mixture to 0 °C, 2 equiv
of H2O was added to reduce the proton activity of TfOH. A solution of the
electron-rich arene dissolved in CH2Cl2 was then added dropwise and after
additional stirring for 15 min at 0 °C followed by evaporation and precipitation by addition of Et2O, the product was obtained in excellent yield.
3.1.2 Analysis and deprotonation of the heteroaryliodonium
bistriflates
The excess TfOH employed in both sets of reaction conditions resulted in
the isolation of aryl(3-pyridinium)iodonium bistriflate 13’ rather than the
desired aryl(3-pyridyl)iodonium triflate 13. This was discovered due to
repeated isolation of what was thought to be 13b in >100% yield. While it is
possible that both versions of the salt, protonated and deprotonated, could be
used in applications, it is convenient to be able to distinguish and choose
between the two. A search to find suitable deprotonation conditions was thus
initiated (Scheme 37).
OTf
OTf
I
R
N
H
OTf
13'
I
?
R
N
13'
Scheme 37. Deprotonation of 13’ to 13.
NMR samples with different concentrations in CD3OD were prepared to
study the difference between 13 and 13’. In the protonated form, the shifts of
the protons adjacent to the nitrogen were found to be concentrationdependent. In the deprotonated salt there was no concentration effect, due to
the absence of an interchangeable proton. It was also possible to distinguish
the two salts using 19F NMR together with an internal standard such as
fluorobenzene. The 19F NMR integration of the peaks in salt 13c’ (Figure 10)
38
together with 1 equiv of fluorobenzene (12c) indeed showed a 6:1 ratio
between the two detected peaks, indicating the presence of two triflates.
Figure 10. Fluorine containing N-heteroaryl salt 13c’
Various attempts were made to find suitable conditions for the deprotonation of the protonated salt 13b’. The addition of NaHCO3 or NaOAc
as solids or in solution to the crude reaction mixture did not give satisfactory
results, nor did a conventional SiO2 column. When the SiO2 was treated with
NH4OH before applying the crude reaction mixture, deprotonation was
achieved. Unfortunately, NH4OTf and the deprotonated product 13b eluted
from the column simultaneously. A solution of salt 13b’ in CH2Cl2 treated
with Et3N gave the deprotonated product 13b in 67% yield after evaporation
and precipitation with Et2O. The most promising deprotonation procedure
was column chromatography using basic Al2O3. Salt 13b’ was dissolved in a
CH2Cl2:MeOH (20:1) mixture, submitted to an Al2O3 column and eluted
using the same mixture. After evaporation in vacuo the deprotonated salt 13b
was obtained in 97% yield (Scheme 38).
I
N
H
OTf
OTf
I
OMe
OTf
Al2O3
CH 2Cl 2:MeOH (20:1)
13b'
N
OMe
13b
97%
Scheme 38. Optimized deprotonation procedure.
It was unfortunately essential to isolate the protonated salt prior to
running the column, as application of the crude reaction mixture directly to
the column only gave back the protonated material.
3.2 Substrate scope
Since the target molecules in this project are unsymmetrical N-heteroaryliodonium salts, it is important to have control over the chemoselectivity in
39
application reactions. In reactions employing transition metals the more
hindered arene acts as the dummy,24a, 68 whereas in metal-free reactions the
dummy groups should be electron-rich (Scheme 39). This was more
thoroughly discussed in Chapters 1 and 2.
OTf
I
a)
[M], Nu -
R
Nu
R
OTf
b)
I
Nu -
R
OMe
Nu
R
Scheme 39. Difference in chemoselectivity between a) transition metal-catalyzed and
b) transition metal-free arylations.
The targeted iodonium salts were designed so that an N-heteroaryl moiety
can be introduced selectively both with and without a transition metal.
Scheme 40 summarizes the prepared products using the optimized
reaction conditions. Salt 13c’ was obtained in 84% yield using 3iodopyridine (11a) and fluorobenzene (12c). 2-Chloro-4-iodopyridine (11b)
was reacted with mesitylene (12d) to give salt 13d in 73% yield without
requiring a deprotonation step. The nitrogen probably loses the proton
quickly after formation of the salt due to the adjacent electron-withdrawing
chloride. Several other iodoarenes were reacted with mesitylene (12d) and
triisopropyl benzene (12e) to create salts 13e’−l’ in good yields. These bulky
salts are suitable for transition metal-catalyzed arylations. Salts 13b’, 13m’
and 13n’, with electron-rich anisyl groups, suitable for transition metal-free
arylations, were prepared in excellent yields. N,N-Dimethyluracil was used
together with 11a to prepare salt 13o’, containing a more uncommon dummy
group,86 in good yield. The electron-rich salts consistently gave higher
yields, which are hypothesized to arise from the higher EAS reactivity of
anisole (12b) compared to other arenes.
40
N
TfOH
I
N
CH 2Cl 2, rt, 5 min
11
i) Ar (12, 1.1 equiv)
ii) mCPBA
I
I
60 °C, 30 min
HOTf
OTf
N
I
Al2O3
R
R
CH 2Cl 2:MeOH (20:1)
HOTf
13
13'
I
OTf
I
N
OTf
I
OMe
N
13a', 69%
I
13g', 77%
i
OTf Pr
OTf
13j', 70%
13j, 97%
OTf
I
iPr
iPr
N
13i', 67%
13i, 92%
i
OTf Pr
I
OTf
HN
N
iPr
iPr
I
HN
HN
iPr
13e', 59%
13h', 82%
I
I
OTf
iPr
HN
N
13f', 70%
13f, 92%
N
N
13d, 73%
N
N
iPr
Cl
OTf
I
OTf
I
N
F
iPr
I
I
13c', 84%
13c, 85%
13b', 81%a
13b, 97%
OTf
OTf
OTf
N
OTf
N
N
13k', 75%
13k, 72%
iPr
13l', 75%
13l, 90%
iPr
N
OMe
13m', 90%a
13m, 87%
OTf O
I
OTf
I
HN
N
OMe
13n', 83%a
13n, 78%
N
N
N
Me
O
Me
13o', 86%a
13o, 81%
Scheme 40. Synthesized N-heteroaryliodonium triflates. The optimized procedure
was used unless otherwise noted. The yields of 13 are from isolated 13’. a The modified procedure was used.
3.3 Application studies
The use of bulky arenes as dummy groups has been demonstrated to work
well in transition metal-catalyzed arylation reactions.87 Gaunt and coworkers
also showed that the uracil salt 13o can successfully be used in the selective
preparation of heteroaryl ketones with the aid of a NHC catalyst.86 The
utility and chemoselectivity of the salts were demonstrated in a transition
metal-free application study, where the heteroaryl salts were reacted with
two different nucleophiles using two of the three arylation methodologies
discussed in Chapter 2.54, 57 In order to establish whether there was a
reactivity difference between the protonated and deprotonated forms, both
salts 13’ and 13 were used. In the reactions with the protonated salt 13’, one
extra equivalent of base was used.
41
Bulky salts 13f and 13f’ were reacted with malonate 8 in order to demonstrate that this type of dummy group is also useful without employing transition metals (Scheme 41). Treatment with NaH furnished the enolate, which
was subsequently reacted with salt 13f or 13f’. The arylated product 14 was
obtained in 72% yield using the deprotonated salt 13f. When the protonated
salt 13f’ was used the product was isolated in only 26%. As expected, both
reactions proceeded completely chemoselectively.
O
O
OTf
O
I
OEt
DMF, rt, 18 h
N
8
EtO
NaH
OEt
EtO
O
14 N
72%
26%
13f
13f' = 13f•TfOH
Scheme 41. Chemoselective arylation of malonate 8.
Heteroaryl salts with an electron-rich dummy group were reacted with
phenols 15 in order to selectively transfer the heteroaryl moiety. The phenols
15 were deprotonated with tBuOK and reacted with salts 13b or 13b’ to form
heteroaryl ethers 16 in a chemoselective fashion. The best result was
obtained with phenol (15a) and salt 13b, giving 16a in 88% yield. The same
phenol only gave 16a in 59% yield when reacted with the protonated salt
13b’. Bulkier phenols were compatible with the system, as demonstrated by
the reaction between 2,4-dimethylphenol (15b) and salts 13b or 13b’, giving
product 16b in 65% and 52% yield respectively. Complete chemoselectivity
was observed in all cases.
OTf
R
N
15a R = H
15b R = 2,4-dimethyl
O
O
I
OH
tBuOK
OMe
THF, 40 °C, ≤2 h
13b
13b' = 13f•TfOH
16a
88%
59%
N
16b
N
65%
52%
Scheme 42. Chemoselective arylation of phenols 15.
The protonated versions of the salts always afforded lower yields. Since
only one extra equivalent of base was used to compensate for the acid, this
might suggest that there is more than one equivalent of acid present in those
salts. Therefore, a control experiment was set up in which phenol (15a) was
reacted with salt 13b’ in the presence of 2.6 equiv of tBuOK. Product 16a
was however still only isolated in 57% yield, indicating that the lower yields
observed were not related to the presence of extra acid in the protonated
salts.
42
3.4 Conclusion
N-heteroaryliodonium triflates can now be prepared using an efficient onepot procedure. Different dummy groups can be used together with the
chosen heteroaryl iodide in order to selectively introduce a heteroaryl group
onto a variety of nucleophiles. This was demonstrated by reacting heteroaryliodonium salts with diethyl methylmalonate as well as with two different
phenols, giving the arylated products with complete selectivity. The
protonated form of the salts consistently gave lower yields compared to the
deprotonated versions, and addition of excess base did not remedy this.
43
44
4 Synthesis of alkynyl(aryl)iodonium salts
from TMS-alkynes (Project III)
The chemistry of alkynyl(aryl)iodonium salts ranges from Diels-Alder
reactions88 to cross-coupling reactions89. These compounds are commonly
obtained via pre-made iodine(III) compounds, such as PhI(CN)OTf, Koser’s
reagent or (PhIO)2•Tf2O.90 The necessary alkyne sources are often noncommercial stannanes or silanes.
Based on the developed one-pot procedures for diaryliodonium salts
shown in Chapter 1, Olofsson and coworkers reported in 2012 that a similar
system could be employed for the synthesis of alkynyl(aryl)iodonium salts
as well (Scheme 43a).91 The corresponding cyclic benziodoxolone could be
obtained after a basic workup in the cases where a carboxylic acid moiety
was present in the ortho-position of the aryl iodide (Scheme 43b).
a)
I
X
IL 2
R2
mCPBA, HX
R1
CH2Cl2:TFE (1:1)
rt, 30 min
R1
R2
I
B(OR) 2
rt, 30 min
R1
14 examples
up to >99% yield
b)
O
HO
O
I
mCPBA, HX
CH2Cl2:TFE (1:1)
rt, 30 min
HO
IL 2
O X
R
B(OR) 2
HO
I
O
R
NaHCO 3 (aq.)
I
R
O
rt, 30 min
6 examples
up to 90% yield
Scheme 43. One-pot preparation of alkynyl(aryl)iodonium salts.
The inherent limitation of this protocol is that boronic acids are not
always readily available. Therefore, we sought to develop a complementary
one-pot protocol for the synthesis of alkynyl(aryl)iodonium salts with the
use of alkynylsilanes. Carroll recently reported the preparation of phenylethynyl(phenyl)iodonium trifluoroacetate (Scheme 43a, R1 = H, R2 = phenyl
and X = trifluoroacetate) from phenylacetylene.92
45
4.1 Results and discussion
4.1.1 Optimization
The coupling between iodobenzene and TMS-phenylacetylene (17a) to form
phenylethynyl(phenyl)iodonium triflate (18a) was chosen as the model
reaction and the optimization is summarized in Table 5.
The two-step protocol was initiated with the oxidation of iodobenzene,
resulting in an iodine(III) intermediate. 17a was then added and the mixture
was stirred at rt, forming the alkynyl(aryl)iodonium salt 18a, which was
isolated by precipitation in Et2O.
The initial conditions gave less than 20% yield (entry 1) and increasing
the reaction time after the addition of 17a did not improve the yield (entry
2), nor did an increased pre-oxidation time (entry 3).
The reaction conditions reported for the boronic acid protocol (Scheme
43) were then employed,91 by changing the solvent to a 1:1 mixture of
CH2Cl2:TFE as well as increasing the amount of silane 17a to 1.4 equiv
(entry 4). This afforded the desired salt in 61% yield. A slightly higher yield
could be obtained by using two equiv of 17a (entry 5) but further increasing
the amount of 17a did not improve the yield (entry 6). More than 1 equiv of
TfOH resulted in a complicated reaction mixture without product formation
(entry 7). As only one equiv of TfOH is required in the oxidation of iodobenzene, unreacted TfOH was probably still present in the reaction mixture
when 17a was added, which would contribute to rapid decomposition of the
silane. No reaction was observed when TfOH was replaced with TsOH or
BF3·OEt (entries 8 and 9). Since the preparation of diaryliodonium salts
from urea-hydrogen peroxide (UHP) and Tf2O is known (Scheme 3c),17d
these types of conditions were investigated for the formation of alkynyl salts
(entry 10). Unfortunately, the dark green crude reaction mixture did not
contain any product at all. It was also investigated whether the addition of
TBAF could activate the silane, making it more reactive (entry 11). Sadly,
this attempt was unsuccessful, as was the addition of pyridine at the end of
the reaction (entry 12), resulting in a complicated mixture of products without formation of the target compound. Fortunately, performing the reaction
under inert conditions with distilled solvents gave 18a in 85% isolated yield
(entry 13). This was unexpected since inert conditions are not generally
required when preparing diaryliodonium salts.
46
Table 5. Initial optimization of the model reaction, forming 18a.
IL 2
I
mCPBA (1.1 equiv)
TfOH
solvent
rt, t1
TfO
Ph
I
Ph
TMS
17a
rt, t2
18a
t1
Acid
17a
t2
Yield
(min)
(equiv)
(equiv) (min)
(%)
1
CH2Cl2
30
TfOH (1)
1.1
60
<20a
2
CH2Cl2
30
TfOH (1)
1.1
7h
<20a
3
CH2Cl2
60
TfOH (1)
1.1
60
<20a
4
CH2Cl2:TFE (1:1)
30
TfOH (1)
1.4
30
61b
5
CH2Cl2:TFE (1:1)
30
TfOH (1)
2
30
73b
6
CH2Cl2:TFE (1:1)
30
TfOH (1)
3
30
69b
7
CH2Cl2:TFE (1:1)
30
TfOH (2)
2
30
0
8
CH2Cl2:TFE (1:1)
30
TsOH (1)
2
30
0
9
CH2Cl2:TFE (1:1)
30
BF3·Et2O (2)
2
30
0
10c
CH2Cl2:TFE (1:1)
3h
Tf2O (1)
2
3h
0
d
11
CH2Cl2:TFE (1:1)
30
TfOH (1)
2
30
0
12e
CH2Cl2:TFE (1:1)
30
TfOH (1)
2
30
0
13f
CH2Cl2:TFE (1:1)
30
TfOH (1)
2
30
85b
a 1
H NMR yield. b Isolated yield. c The UHP–Tf2O protocol was used. d TBAF (75%
aq.) was added. e Pyridine was added after the reaction was finished. f Inert conditions were applied.
Entry
Solvent
4.1.2 Substrate scope
The optimized conditions were applied using different silanes 17 in order to
investigate the substrate scope. Employing TMS-nbutylacetylene (17b)
afforded 40% of the product 18b (Scheme 44). Similar results were obtained
when the reaction was performed without inert conditions. The precipitation/crystallization of compound 18b was slower compared to 18a. The
aliphatic chain increased the solubility of the product in Et2O, making the
addition of pentane a necessity to achieve successful crystallization.
However, if too much pentane was added, the mCBA byproduct precipitated
together with the product. Furthermore, the low reaction efficiency, producing only 40% yield made the product more difficult to crystallize. The
halide-substituted TMS-alkyne 17c were tolerated as salt 18c was achieved
in 70% yield. Attempts were also made with the chloro- and hydroxy
substituted aliphatic TMS-acetylenes 17d and 17e, but unfortunately no
product was obtained.
TMS-nbutylacetylene (17b) was also employed together with 3trifluoromethyliodobenzene. The activated iodoarene was thought to form a
47
more reactive iodine(III) intermediate. Unfortunately, no product was
observed either with TfOH or with TsOH.
I
TfO
IL 2
I
R2
R2
TMS
17 (2 equiv)
mCPBA (1.1 equiv)
TfOH (1 equiv)
rt, 30 min
CH2Cl2:TFE (1:1)
rt, 30 min
18
TfO
I
TfO
18a
85%
nBu
I
I
TfO
Br
I
Cl
18d
0%
I
18c
70%
18b
40%
TfO
TfO
OH
18e
0%
Scheme 44. Substrate scope of alkynyl salts 18 from silanes 17.
The preparation of the cyclic alkynyl benziodoxolone 19a was also
attempted using TMS-phenylacetylene (17a). The initial reactions are summarized in Table 6. The iodoarene oxidation time was increased to 60 min
due to the electron-withdrawing effect exerted by the carbonyl moiety
adjacent to the iodide. After the coupling reaction was finished, a basic
extraction was conducted in order to cyclize the salt into the benziodoxolone
19a. The two bases that were employed, pyridine and NaHCO3, only
delivered the product in trace amounts (entries 1 and 2). Replacement of the
TfOH with TsOH did not produce the desired salt either (entry 3). Attempts
to isolate intermediate 18’ failed, indicating that the problem with the reaction lies in the coupling with silane 17 rather than in the cyclization.
48
Table 6. Initial optimization for formation of 19a.
O
I
mCPBA (1.1 equiv)
HX (1 equiv)
HO
Ph
TMS
17a (2 equiv)
O X
I
Ph
O
basic workup
HO
I
rt, 60 min
CH2Cl2:TFE (1:1)
rt, 60 min
18'
Entry
1
2
3
Ph
O
Acid
TfOH
TfOH
TsOH
19a
Base (equiv)
Pyridine (2)
NaHCO3 (excess)
NaHCO3 (excess)
Yield of 19a
trace
trace
trace
The two different bases employed to induce the cyclization did not show
any significant difference in reaction outcome. It is possible that the
iodine(III) intermediate stemming from 2-iodobenzoic acid is unreactive
towards the silane and thereby inhibiting formation of non-cyclized product.
Attempts to prepare the cyclic version of 18b were made (Scheme 45), as
the low yield observed for compound 18b could arise from product
instability, leading to an isolation problem. It was hypothesized that stabilizing the salt with an internal anion could be helpful in this regard. Unfortunately this reaction did not furnish any product. The noncyclic intermediate was not detected either.
O
HO
I
O X
i) mCPBA, TfOH
ii) TMS
nBu
X
CH2Cl2:TFE (1:1)
rt, 30 min
HO
I
O
nBu
NaHCO 3 (aq.)
X
I
nBu
O
19b
Scheme 45. Attempt to form the benziodoxolone 19b.
4.2 Conclusion
The preparation of alkynyl(aryl)iodonium salts employing easily accessible
silanes was attempted. The synthesis is, however, not as efficient as when
the corresponding boronic acid is employed. The reaction efficiency did not
improve upon addition of TBAF to activate the silane. The low reaction
efficiency observed when preparing hexynylphenyliodonium triflate resulted
in a more difficult product isolation.
The cyclized form of the salts, ethynylbenziodoxolones, turned out to be
challenging to prepare using silanes as the alkyne source. So far the product
has only been observed in trace amounts. The two different bases employed
in the workup to induce the cyclization did not make a significant difference.
So far, TMS-alkynes have proved capable of furnishing the desired
alkynyl(aryl)iodonium salts, but less efficiently than the corresponding
49
boronic acids. Further investigations into the substrate scope are necessary to
determine whether this protocol will be useful to the chemical community.
50
5 C-2 Selective Arylation of Indoles using
Heterogeneous Nanopalladium Catalysis
and Hypervalent Iodine (Project IV)
2-Aryl indole motifs can be found in a variety of potential drug candidates
and natural products.93 Even though palladium-catalyzed cross-coupling
reactions provide these types of products in high yields, they require prefunctionalized reagents.94 To avoid prefunctionalization, several direct C-2
arylation protocols of indole have recently been reported.
However, these methods are still associated with drawbacks such as high
catalyst loadings (5-10 mol%), elevated temperatures (≥80 °C), poor catalyst
recyclability and the need to use harmful solvents or additives. Employing
diaryliodonium salts can solve some of these problems, as demonstrated by
both Sanford and Gaunt (see Chapter 1.3.3).24a, 42b
Since homogeneous catalysis is associated with metal contamination in
the final product and difficult catalyst recycling, a number of protocols
employing heterogeneous catalysis have emerged. Glorious and coworkers
showed that Pd/C can be used together with diaryliodonium salts to C−H
functionalize heteroaromatic compounds, including indoles.95
The Bäckvall group has reported on the preparation and application of a
Pd0 catalyst supported on aminopropyl-functionalized mesocellular foam
(Pd0-AmP-MCF).49a, 96 The utility of this catalyst has been demonstrated in a
variety of transformations with low leaching and high recyclability.49a, 96-97
The 2−3 nm sized palladium nanoparticles are well dispersed on the siliceous mesocellular material (MCF). The morphology is a three-dimensional
network of windowed pores, creating a high surface area.46 These features
are believed to be accountable for the high efficacy of the catalyst.
Bäckvall has recently also demonstrated that the closely related PdIIAmP-MCF catalyst can be used for cycloisomerization of acetylenic acids to
γ-alkylidene lactones.49b Both Pd0 and PdII catalysts are utilized in the
present study, which aims to selectively prepare C-2 arylated indoles by
combining heterogeneous palladium catalysis with hypervalent iodine
chemistry as a collaborative project between the Olofsson and Bäckvall
groups.
51
5.1 Optimization
The initial reactions were performed using conditions derived from
Sanford’s protocol (Scheme 22)42b using indole (20a), diphenyliodonium
triflate (1a) or tetrafluoroborate (21a) and PdII-AmP-MCF as the catalyst. 2Phenyl-1H-indole (22a) was obtained in 56% or 79% 1H NMR yield,
depending on the anion of the salt (Scheme 46). 1,3,5-Trimethoxybenzene
was used as the internal standard for 1H NMR yield determination.
Ph 2IX
N
H
20a
PdII -AmP-MCF (4.5 mol%)
AcOH, rt, 15 h
2 equiv
1a: X = OTf
21a: X = BF 4
Ph
N
H
22a
56% 1H NMR yield
79% 1H NMR yield
Scheme 46. Initial conditions for the C-2 arylation of indole.
The encouraging initial results led to a solvent screen, which is summarized together with anion and time optimizations in Table 7. It was realized
that the solvent had a major influence on the reaction outcome. The aprotic
solvents THF, toluene, CH2Cl2 and EtOAc turned out to be poor choices for
this transformation, with yields ranging from 0% to 29% (entries 1−4).
Instead, protic solvents were able to dramatically increase the product
formation (entries 5 and 7) with H2O giving the highest yield. Surprisingly,
only starting material was recovered when EtOH was used as the solvent
(entry 6).95 Based on the observed yields, H2O was selected for further optimization. In addition, the environmental impact of this solvent is low.
Next, the anion of the salt was investigated. The three different anions
that are easily obtained through our one-pot procedures (Scheme 3) were
examined. Unexpectedly, the triflate anion turned out to be incompatible
with the system as no product was detected (entry 8). It should be noted,
however, that if AcOH was used as solvent rather than H2O, the C-2
phenylated product 22a could be obtained in 56% yield. When the reaction
time was 15 h, no distinction between the BF4 and OTs anions could be
made, as both salts delivered the product in around 90% yield (entries 7 and
9). Reducing the reaction time to 6 h resulted in a clear difference in reaction
rate, as the BF4 salt 21a still furnished the product in close to 90% yield
while only 26% was obtained with the OTs salt 23 (entries 10 and 11). The
reason for this effect could be the different coordination abilities of the
anions to the metal center. Tetrafluoroborate anions are considered to coordinate more weakly to electrophilic metal ions than tosylate anions,
leading to a more reactive metal intermediate.
52
Table 7. Solvent and counterion optimizations.a
X
I
20a
Ph
Solvent, rt, Time
N
H
Entry
1
2
3
4
5
6
7
8
9
10
11
PdII -AmP-MCF (4.5 mol%)
N
H
22a
1a, 21a or 23
Counterion
21a BF4
21a BF4
21a BF4
21a BF4
21a BF4
21a BF4
21a BF4
1a OTf
23 OTs
21a BF4
23 OTs
Solvent
THF
Toluene
CH2Cl2
EtOAc
AcOH
EtOH
H 2O
H 2O
H 2O
H 2O
H 2O
Time (h)
15
15
15
15
15
15
15
15
15
6
6
Yield (%)b
11
0
29
0
79
0
91
0c
92
88
26
a
Reaction conditions: Indole (20a) (0.2 mmol), Ph2IX (0.4 mmol) and PdII-AmPMCF (0.009 mmol with respect to Pd content) were suspended in solvent (2 mL)
and stirred at rt for the indicated time. b Determined by 1H NMR using 1,3,5trimethoxybenzene as internal standard. c 22a was obtained in 56% yield when the
solvent was AcOH instead of H2O.
When it was established that water should be used as the solvent with diaryliodonium tetrafluoroborates 21, the catalyst was examined with respect
to type and loading. Since it is known that both Pd0 and PdII can catalyze the
C-2 arylation of indoles, the Pd0-AmP-MCF was compared to the PdII-AmPMCF. In order to observe any reactivity differences, the reaction time was
shortened to 3 h. Quite unexpectedly, it was revealed that the PdII-AmPMCF performed worse than its Pd0 counterpart, which gave the product in
excellent yield (Table 8, entries 1 and 2). The product could be obtained in
the same yield with half the catalyst loading when the reaction time was
prolonged to 6 h (entry 3). When the conventional Pd/C (10 wt%) catalyst
was employed, no product was obtained, and the SM was recovered (entry
4). The product yield was reduced to 79% when the catalyst loading was
lowered to 1 mol%, even with 14 h of reaction time (entry 5). It was also
investigated whether a catalyst loading of 4.5 mol% would allow for a
reduced amount of 21a, and indeed 1.1 equiv of 21a with 3 and 6 h of
reaction time resulted in 50% and 93% yield, respectively (entries 6 and 7).
This makes it possible to reduce the quantity of the scarcer reagent, whether
it is the diaryliodonium salt or the Pd0-AmP-MCF, and still obtain excellent
53
yields. A control experiment where the diphenyliodonium salt 21a was
replaced with iodobenzene under otherwise unchanged reaction conditions
was performed. As expected, product formation was not observed (entry 8).
Table 8. Investigation of the catalyst type and reaction stoichiometry.a
BF 4
I
Ph
H 2O, rt, Time
N
H
20a
cat. (x mol%)
N
H
21a
Entry
Catalyst
1
2
3
4
5
6e
7e
8f
PdII-AmP-MCF
Pd0-AmP-MCF
Pd0-AmP-MCF
Pd/C (10 wt%)
Pd0-AmP-MCF
Pd0-AmP-MCF
Pd0-AmP-MCF
Pd0-AmP-MCF
22a
b
Loading
(mol%)
4.5
4.5
2.5
2.5
1
4.5
4.5
2.5
Time (h)
Yield (%)c
3
3
6
6
14
3
6
6
63
91
91d
0
79
50
93
0
a
Reaction conditions: Indole (20a) (0.2 mmol), iodonium salt 21a (0.4 mmol) and
catalyst were suspended in H2O (2 mL) and the mixture was stirred at rt for the indicated time. b With regard to the Pd content. c Determined by 1H NMR using 1,3,5trimethoxybenzene as internal standard. d Isolated yield. e 1.1 equiv of 21a was used.
f
The reaction was run with PhI instead of 21a.
Due to the facile access to the diaryliodonium salts 21, it was decided to
evaluate the substrate scope using 2.5 mol% of catalyst and 2 equiv of salt
with 6 h reaction time at room temperature.
5.2 Substrate scope
In order to evaluate the substrate scope of the reaction, a series of indoles
were initially reacted with diphenyliodonium tetrafluoroborate (21a), as
summarized in Scheme 47. The 5-methoxy-substituted indole 20b was
successfully phenylated to 22b in 86% yield and a similar yield was obtained
with 5-bromoindole (20c). The latter substrate is of particular interest since
the bromide is a good synthetic handle for further functionalization. In
addition, bromides can induce undesired side-reactions in the presence of a
metal catalyst and as a consequence, C-2 arylations with this substrate are
scarcely reported.42b, 98 Highly electron-withdrawing substrates were well
tolerated, and 5-nitroindole (20d) was readily arylated using elevated
54
temperature and prolonged reaction time, giving 22d in good yield.
N-methyl protected indole 20e was phenylated to 22e using the optimized
conditions in 80% yield, whereas benzyl-protected indole 20f required
prolonged reaction time (24 h) and elevated temperature (50 °C) in order to
obtain 22f.
Pd 0-AmP-MCF (2.5 mol%)
Ph 2IBF 4
R1
20
R2
R1
H 2O, rt - 50 °C, 6 - 25 h
N
N
21a
22
Br
O
N
H
22a
rt, 6 h
91%
R2
N
H
N
H
22b
40 °C, 6 h
86%
22c
40 °C, 15 h
85%
O2N
N
N
N
H
22d
50 °C, 25 h
70%
22e
rt, 6 h
80%
22f
50 °C, 24 h
65%
Scheme 47. Phenylation of different indoles 20.
The use of protecting groups with large steric bulk were a limitation to the
substrate scope since Boc and TBDMS protected indoles 20g−h were inert
under the reaction conditions (Figure 11). The reactivity of the indole may
also be reduced due to electronic deactivation. This could also be the case
for 3-carbaldehyde-1H-indole (20i) since no reaction was observed with this
substrate. In the case of the Boc-protected indole both steric and electronic
factors probably caused the negative outcome. Additionally, the reaction
between 21a and 5-aminoindole (20j) only returned the starting material.
The amino-functionality is thought to deactivate the catalyst by coordination
to the Pd center.
O
N
O
H 2N
Si
N
H
N
H
O
20g
H
N
20h
20i
20j
Figure 11. Indoles that were inert under the reaction conditions.
55
Subsequently, the use of unsymmetrical diaryliodonium salts to selectively introduce an aryl group was investigated. Studies of the chemoselectivity of the salts have been discussed in Chapter 2. Both Sanford and
Gaunt have demonstrated that mesityl or triisopropyl (TRIP) groups can be
used as “dummies” in metal-catalyzed arylations.68, 99 Therefore, bulky salts
21b and 21c were employed in an attempt to chemoselectively C-2 phenylate
indole (Scheme 48). Even though both of the salts gave excellent selectivity
for phenyl transfer the yields were severely affected. The bulky salts 21b and
21c gave 22a in 50% and 26% yield, respectively, which is significantly
lower than the 91% yield obtained with the symmetrical diphenyliodonium
salt 21a.
BF 4 R
I
N
H
R
Pd 0-AmP-MCF (2.5 mol%)
R
Ph
H 2O, 40 °C, 24 h
22a
20a
21b: R = Me
21c: R = iPr
N
H
1H
50%
NMR yield
26% 1H NMR yield
Scheme 48. Selective phenylation of indole (20a) using unsymmetrical diaryliodonium salts 21 with bulky dummy groups.
Due to the reduced yield observed with unsymmetrical salts, symmetrical
ones were used in the scope study. When necessary, the reaction temperature
and time were increased from the optimized conditions to 40 °C and 15 h,
respectively, and various C-2 arylated indoles were prepared in high yields
(Scheme 49). 4-Alkyl-substituted salts 21d−e gave the corresponding
arylated products 22d−e in 83% and 84% yield, respectively. The o-tolyl moiety
was successfully transferred to give product 22f in 76% yield, indicating that
steric hindrance in the ortho-position can be tolerated to some extent. This
was further demonstrated by the preparation of naphthyl product 22g in 67%
yield. Arenes containing a halide in the 2- or 4-position were successfully
transferred at elevated temperature to form products 22h−j in excellent
yields.
CF3-substituted indole 22k was obtained in 99% yield. It should be noted
that N-protection of the indole was required, as only starting material was
recovered when the N−H indole 20a was employed under the same reaction
conditions. When a 10% AcOH:H2O mixture was used as the solvent, the
free indole product could be detected in 14% 1H NMR yield. Reaction with
the more electron-rich (4-anisyl)2IBF4 (21f) delivered the corresponding
electron-rich indole 22l in 72% yield, unfortunately in an inseparable
mixture of 22l and 7% of the byproduct 4,4’-dimethoxy-1,1’-biphenyl. In
this case, arylation attempts of the N−H indole 20a resulted in a very messy
reaction mixture without product formation.
56
Ar2IBF 4
H 2O, rt or 40 °C, 6 h or 15 h
N
20
R1
Pd 0-AmP-MCF (2.5 mol%)
21
R2
N
22
R1
R1 = H, Me
N
22d H
N
22e H
40 °C, 6 h
83%
rt, 15 h
84%
N
22f H
40 °C, 6 h
76%
F
Cl
22g
N
H
22h
40 °C, 15 h
67%
N
H
22i
40 °C, 15 h
87%
N
H
40 °C, 6 h
84%
Br
O
CF 3
N
22j H
40 °C, 15 h
92%
N
N
22k
22l
40 °C, 15 h
99%
40 °C, 6 h
72%a
Scheme 49. Scope using substituted symmetrical diaryliodonium salts. a The isolated
product (79%) was contaminated with 7% of homocoupled anisole, which gives 72%
yield of 22l.
The C-3 regioisomer was not detected in the 1H NMR spectra of any of
the reactions. A control experiment was set up in which diphenyliodonium
tetrafluoroborate (21a) was reacted with 2-methylindole (20k) (Scheme 50).
No arylation was seen with this substrate, further indicating that the reaction
is highly regioselective.
Ph 2IBF 4
N
20k H
21a
2 equiv
Pd 0-AmP-MCF (2.5 mol%)
X
H 2O, rt, 24 h
N
H
Scheme 50. Arylation attempt of 2-methylindole with diphenyliodonium tetrafluoroborate (21a).
57
5.3 Recycling and leaching studies
Heterogeneous catalysis offers the possibility of facile catalyst recycling.
Hence, the recyclability of the employed Pd0-AmP-MCF was investigated
using the conditions of the model reaction (Scheme 51). Three subsequent
cycles were run and the catalyst showed activity throughout all the cycles,
however a gradual decrease in the conversion from starting material 20a to
product 22a was observed with each cycle (100%, 80% and 67%, respectively). The catalyst was recovered between the cycles by repeated centrifugation and washing. Attempts to improve the recycling was also made by
submitting the recovered catalyst to an atmosphere of H2 (g), in order to
reform Pd0 species from possible higher oxidation states of palladium, but
this did not result in any improvement. As the transformation was
compatible with PdII-AmP-MCF albeit in lower yields, the recyclability was
also examined for the PdII-AmP-MCF catalyst. Unfortunately, the results
were not better than for the Pd0-AmP-MCF (100%, 67%).
Ph 2IBF 4
N
20a H
21a
2 equiv
Pd 0-AmP-MCF (2.5 mol%)
H 2O, rt, 6 h
N
22a H
Scheme 51. Reaction conditions for the catalyst recycling experiments.
It is possible that the Pd species disperses from the nano-clusters during
the reaction to instead coordinate to the aminopropyl groups on the MCF,
which could lower the reactivity and negatively affect the recycling if the
nano-clusters are not reformed upon reaction completion. If this is the case it
might also be the reason for the lower activity observed with the PdII-AmPMCF.
The catalyst leaching was investigated by performing the reaction under
the optimized conditions (Scheme 51). Upon reaction completion, the catalyst was removed from the crude mixture and sent for elemental analysis
(ICP-OES); only 0.6 ppm of leaching was detected. Nevertheless, an
experiment was set up under the optimized conditions (Scheme 51) in order
to evaluate whether the leached palladium was the source of the observed
catalytic activity. After 1 h reaction time the yield was 32%, at which point
the heterogeneous catalyst was removed by filtration, and the reaction
mixture was stirred for an additional 9 h. The yield after 9 h had only
marginally increased to 35%, which is a strong indication that the homogeneous palladium is not the main species responsible for the catalytic
activity.
58
5.4 Mechanism
The hypothesized PdII/IV mechanism (Figure 12) is based on literature
precedence regarding Pd species in combination with diaryliodonium salts,42
as no mechanistic investigations were performed in this study. The PdII
species undergoes an oxidative addition to the diaryliodonium salt with the
concomitant loss of an aryliodide. The resulting PdIV complex then makes a
ligand exchange to coordinate to the indole. A subsequent reductive elimination produces the C-2 arylated indole and regenerates the PdII species.
PdIIL n
Ar
Ar2IBF 4
N
H
ArI
BF 4
PdIVL n
N
H
PdIVL n
Ar
Ar
BF 4
N
H
Figure 12. Hypothesized mechanism for the C-2 arylation of indole.
Our reaction works both with PdII and Pd0 species, which either implies
initial oxidation of Pd0 to PdII, or different catalytic cycles with the two
catalysts. If a diaryliodonium salt oxidizes the catalyst from Pd0 to PdII, the
resulting ligand on the palladium would be an aryl group, leading to a seemingly unstable PdIV species after the ligand exchange.
The mechanism does also not explain the complete C-2 selectivity
observed in the reaction. If the ligand exchange is solely driven by the
nucleophilicity of indole, the aryl group would be expected to couple to the
C-3 position. Similar selectivity was observed by Sanford, although they
arylated the C-3 position when the C-2 carbon was blocked.42b It was
hypothesized that initial electrophilic palladation occurs at the C-3 position
before migration of the palladium to the C-2 carbon where the coupling
takes place. Arylboronic acids with heterogeneous PdII also furnished C-2
59
arylated indoles with high selectivity, demonstrated by Wang and coworkers.37b More investigations are needed to elucidate the mechanism.
5.5 Conclusion
A highly C-2 selective arylation of indoles using heterogeneous palladium
MCF and diaryliodonium salts in water under mild conditions has been
developed. The catalyst exhibits very low leaching and moderate recyclability. Moreover, the system is compatible with both protected and unprotected
indoles and a variety of diaryliodonium salts, giving ortho-substituted,
electron-rich, electron-deficient and halide-substituted products in good to
excellent yields.
60
Concluding remarks
In this thesis it has been shown that complete chemoselectivity can be
obtained with unsymmetrical diaryliodonium salts using an appropriate
dummy ligand. It was demonstrated that electronic factors have a stronger
influence on the chemoselectivity than steric factors in metal-free applications. Different dummy groups should be used depending on the type of
nucleophile. Unsymmetrical salts undergo scrambling of the ligands under
certain conditions, possibly affecting the outcome of the reaction. Conditions
where deprotonation of the nucleophile takes place seem to promote
scrambling more readily than with a neutral nucleophile.
Unsymmetrical N-heteroaryliodonium triflates can now be readily synthesized using a one-pot protocol. The salts can be prepared with different
dummy aryl groups, allowing for selective transfer of the N-heteroaryl
moiety to various nucleophiles. The utility of the salts were demonstrated by
transferring a pyridyl group to diethyl methylmalonate as well as to two
different phenols in a chemoselective fashion.
Alkynyl(aryl)iodonium triflates can be prepared in a one-pot procedure
using silanes as the alkynyl source. The reaction could eventually be a
valuable complement to procedures where the corresponding arylboronic
acids are used.
Using the heterogeneous Pd0-AmP-MCF together with diaryliodonium
salts it was shown that indoles could be arylated selectively in the C-2
position. The protocol showed tolerance towards changes in the indole as
well as in the salt. The heterogeneous nature of the catalyst, as well as the
water-based mild conditions contributes to a low environmental impact of
the reaction. In addition, the catalyst exhibits very low leaching and
moderate recyclability.
61
62
Appendix A
The author’s contribution to projects I-IV:
I.
Prepared some of the diaryliodonium salts. Performed the
chemoselectivity studies on the aniline and the malonate.
Performed the studies regarding the scrambling. Wrote the supporting information.
II.
Joined the project at a late stage after Dr. Marcin Bielawski.
Prepared some of the N-heteroaryliodonium salts. Performed the
arylation studies. Wrote parts of the supporting information.
III.
Initial observations by Dr. Marinus Bouma. Joined the project at
an early stage. Performed the optimization studies and investigated the substrate scope.
IV.
Initiated the project together with Anuja Nagendiran. Performed
the major part of the experimental work. Contributed to the
writing of the manuscript. Wrote the major part of the supporting information.
63
64
Appendix B
Experimental details of project III
General experimental conditions
Precautions to exclude air or moisture were not taken except when
mentioned. Commercial mCPBA was dried under vacuum at rt for 3 h and
subsequently the percentage of active oxidizing reagent was determined by
iodometric titration.100 All other commercially available chemicals were used
as supplied. For TLC analyses precoated silica gel 60 F254 plates were used.
NMR spectra were recorded at 298 K using CDCl3 as solvent. Chemical
shifts are given in ppm relative to the residual solvent peak (1H NMR:
CDCl3 δ 7.26; 13C NMR (proton decoupled): CDCl3 δ 77.16) with multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, app =
apparent), coupling constants (in Hz) and integration. HRMS data were
recorded using TOF ESI detection. Melting points were measured using a
STUART SMP3 and are reported uncorrected.
General experimental procedure for the synthesis of 18
I
IL 2
mCPBA (1.1 equiv)
TfOH (1 equiv)
CH2Cl2:TFE (1:1)
rt, 30 min
TfO
I
R2
R2
TMS
17 (2 equiv)
rt, 30 min
18
Iodoarene (1.0 equiv, 0.25 mmol), mCPBA (1.1 equiv, 0.28 mmol) was
dissolved in a CH2Cl2:TFE mixture (1:1, 1 mL). TfOH (1.0 equiv, 0.25
mmol) was added dropwise and the resulting mixture was stirred at rt for 30
min before addition of TMS-alkyne 17 (2 equiv, 0.5 mmol). The reaction
mixture was then stirred for an additional 30 min. The solvents were then
evaporated in vacuo, followed by the addition of an Et2O:pentane mixture.
The product was allowed to crystallize in the freezer. The formed solid was
washed with an Et2O:pentane mixture and dried in vacuo to give pure alkynyl(aryl)iodonium triflate 18.
65
Phenyl(phenylethynyl)iodonium triflate (18a):
Isolated as colorless crystals in 85% yield. 1H NMR (400 MHz, CDCl3) δ
8.13 (d, J = 8.0, 2H), 7.66 (app t, J = 8.0, 1H), 7.57-7.51 (m, 4H), 7.50-7.44
(m, 1H), 7.42-7.36 (m, 2H). Analytical data were in accordance with those
reported.91
Hex-1-ynyl(phenyl)iodonium triflate (18b):
Isolated as a white solid in 50% yield. mp: 68-69 °C (lit. 66-67 °C).91 1H
NMR (400 MHz, CDCl3) δ 8.06 (d, J = 8.1, 2H), 7.65 (app t, J = 7.4,
1H), 7.56-7.50 (m, 2H), 2.59 (t, J = 7.1 Hz, 2H), 1.59-1.51 (m, 2H),
1.43-1.33 (m, 2H), 0.90 (t, J = 7.3 Hz, 3H). Analytical data were in accordance with those reported.91
((4-Bromophenyl)(ethynyl)(phenyl)iodonium triflate (18c):
Isolated as a light brown solid in 70% yield. mp: 97 °C (decomposed). 1H
NMR (400 MHz, CDCl3) δ 8.12 (d, J = 8.6, 2H), 7.68 (t, J = 7.4, 1H), 7.587.51 (m, 4H), 7.38 (d, J = 8.4, 2H). 13C NMR (101 MHz, CDCl3) δ 134.6,
134.18, 132.9, 132.8, 132.3, 126.7, 120.0 (q, JC-F = 319.2), 118.5,
117.6, 106.7, 34.1. HRMS (ESI) m/z calcd for C14H9IBr+ ([M-OTf]+)
382.8927, found 382.8945.
66
Acknowledgements
This thesis would not have been possible to complete without significant
contribution from the following people:
Berit Olofsson för att du antog mig som doktorand. Tack för all kunskap jag
erhållit från dig! Du har aldrig tvekat till att hjälpa till när det behövs och det
har varit mycket motiverande att jobba i din grupp tack vare roliga och
givande kemi-diskussioner.
Jan-Erling Bäckvall att du visat intresse för min forskning och för ett mycket
gott samarbete. Tack också för de fina gympassen!
Ellie Merritt for being an excellent supervisor, collaborator and friend.
The proofreaders of this thesis – Berit Olofsson, Anuja Nagendiran, Ellie
Merritt, Elin Stridfeldt, Erik Lindstedt, Chandan Dey and Markus Reitti.
Tack till K&A Wallenberg, Ångpanneföreningens forskningsstiftelse,
Svenska kemistsamfundet, Kungliga vetenskapsakademien och Helge
AX:sons stiftelse för finansiellt stöd.
Nazli Jalalian, Marinus Bouma, Marcin Bielawski, Anuja Nagendiran,
Leticia Pardo, Sebastian Biel and Ylva Wikmark for fun and productive
collaborations!
Elias Pershagen – För riktigt många roligheter. Du livar upp tillvaron.
Past and present members of the BO group! You all made this time so much
more enjoyable!
All the involved people in the Cardiff research collaboration! Thank you
Thomas Wirth for being an excellent supervisor. Thank you Mike Brown for
your sharing of knowledge and for bringing lots of fun!
TA-personalen, särskilt Britt Eriksson för stor hjälp vid många olika
tillfällen.
67
Anuja Nagendiran för hjälpen med med framsidan!
All the people at the department of organic chemistry!
Fåröfamiljen – för kompromisslöst stöd.
Eric och Ilze Johnston – Tack för allt roligt häng! Gympassen speciellt. Det
var tider det.
Kristina, Carin, Ola och Martin for all the help throughout the years!
Gymet har alltid varit ett fint ställe att gå till tack vare er - Kalle, Mange,
Ollson, Matti, Birger, Eric, Janne, Madde och Peter!
Farmor Maj och farbror Håkan för att ni är en extremt stabil klippa i all
stockholmstumult.
Min älskade Anuja – Tack för att du stöttat mig under alla tunga perioder.
Du finns alltid vid min sida även när jag är som mest otrevlig. Jag älskar dig.
68
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