Preparation, Chemoselectivity and Metal- Catalyzed Applications …749581/... · 2014-09-25 ·...

Iodonium Salts Preparation, Chemoselectivity and Metal-Catalyzed Applications

Joel Malmgren

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© 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

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“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 understand-ing of the underlying factors that affect the chemoselectivity in transition metal-free arylation reactions. They were found to be very nucleophile-dependent. 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 one-pot procedure. The salts were designed so that the N-heteroaryl moiety was selectively transferred in applications both with and without transition met-als. 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 pro-cedures, 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 hetero-geneous 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 contri-bution 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

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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

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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 Dess-Martin periodinane EAS Electrophilic aromatic substitution EDG Electron donating group EWG Electron withdrawing group HFIP 1,1,1,3,3,3-Hexafluoroisopropanol HTIB [Hydroxy(tosyloxy)iodo]benzene IBX 2-Iodoxybenzoic acid ICP-OES Inductively coupled plasma optical emission spectrometry mCBA meta-Chlorobenzoic acid MCF Mesocellular foam mCPBA meta-Chloroperbenzoic acid NHC N-Heterocyclic carbene nr No reaction PET Positron emission tomography SM Starting material TFE 2,2,2-Trifluoroethanol TIPS Triisopropylsilyl

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1 Introduction

1.1 Hypervalent iodine compounds Chemical elements that belong to groups 15-18 can be regarded as hyper-valent 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.

Hypervalent compounds have a non-standard number of bonds. There-

fore, they are given a λ-notation according to IUPAC nomenclature. Iodine compounds with three or five ligands are hence denoted as λ3- and λ5-iodanes 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 p-orbital from each of the two ligands arranged linearly (Figure 1). The two

Scheme 1. Oxidation of a general iodide to its hypervalent states +III and +V.

L IL

L I L I I L IL L L

L L

L L

LL

LL

LL

L

+I

8-I-1

+III

8-I-2

+III

10-I-3

+V

10-I-4

+V

12-I-5

Oxidation state

Non-hypervalent Hypervalent

Classification

2

ligands that are part of the hypervalent bond are referred to as apical, the others as equatorial.

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 electro-negativity 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 re-arrangement reactions11 and in total syntheses.12 The main focus of this thesis is on diaryliodonium salts, which IUPAC have termed diaryl-λ3-iodanes. 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 bi-pyramidal 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 hyper-valent model described in Figure 1.4b However, insufficient understanding of the hypervalent structure in solution makes depiction of unsymmetrical dia-ryliodonium 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 illus-trated 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.

Figure 1. a) Structure of a general λ3-iodane. b) Orbital diagram of a hypervalent bond.

L

IAr

L

δ

δ

δ

L I L

bonding orbital

non-bonding orbital

antibonding orbitala) b)

3

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 conse-quence, 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.

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

Figure 2. General structure of diaryliodonium salts. a) T-shaped form. b) Salt form.

Scheme 2. General arylation of a nucleophile.

Nu Ar1 Nu Ar2 I

X

IAr1

Ar2

X

IAr1

Ar2

IX

R2R1 X = Cl, Br, I, OTf, OTs, BF4, PF6 ...

a) b)

4

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 electron-rich 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 un-symmetrical 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 be-nign 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 origi-nates from the electrophilic aromatic substitution (EAS) reaction between the in situ formed iodine(III) intermediate and the arene (Scheme 4).

Scheme 3. One-pot preparation of diaryliodonium salts by our group.

I

up to 94%

mCPBA, TfOH

CH2Cl2, rt, 10 min - 21 h

I

up to 100%

mCPBA, TsOH


a)

b)

c)

Urea-H2O2, Tf2O

CH2Cl2:TFE (2:1)

I

40 °C, 3 h

I

OTf

I2

R2R1

R2R1

R1 R1

up to 86%

R2

OTs

OTf

IR2R1

R

I2

IR2R1

R

R2

mCPBA, TfOH


I

up to 93%

OTf

RR

d)

mCPBA, TsOH


I

up to 89%

RR

OTs

e)

5

Activated arenes are ortho and para directing. Mostly para-substituted products are observed, probably due to the steric hindrance in the ortho-position of the arene. Deactivated arenes are meta directing but these are generally too unreactive and often result in decomposition of the iodine(III) intermediate.

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 symmet-rical and unsymmetrical salts can readily be made using this method.

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

Scheme 4. EAS of a general ArIL2 compound.

Scheme 5. Regiospecific preparation of diaryliodonium tetrafluoroborates.

mCPBABF3•OEt2

30 - 60 min, rt15 min, rt

I

up to 88%

R2R1

BF4IR1

IL2R1

B(OH)2R2

CH2Cl2

L

I

L

R

I

R

I

RL L

I L RR = EWG

R = EDG

Deactivated

Activated

generally not observed

6

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 conduct-ed.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 equato-rial 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

Scheme 6. Formation of a T-shaped PhLINu complex via a dissociative or associa-tive pathway.

L

IPh

L

L:

I

L

8-I-2

Nu

IPh

L

L

IPh

L :Nu

LIPh

L

Nu

12-I-4 (trans)

Associative pathway

Dissociative pathway

Nu:

NuIPh

L

L

12-I-4 (cis) L

Nu

IPh

L

Ph

10-I-310-I-3

10-I-3 10-I-3

7

reflects the initial hypervalent character as well as the extraordinary leaving group ability of the molecule.

1.1.3 Chemoselectivity overview As mentioned earlier, chemoselectivity problems arise when un-

symmetrical 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 trans-ferred.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.

Upon ligand exchange between a nucleophile and the counterion in an un-

symmetrical 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 equa-torial 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 electron-donating groups can best stabilize this developing positive charge and contribute to a lower transition state energy by residing in the apical position

Scheme 7. Ligand coupling of a general nucleophile and an aryl group.

Scheme 8. Decomposition study by Beringer.

Ar1 Nu

Ar2I

Nu

IAr1

Ar2

ligand coupling

I

O2N

I

MeO

SO32-

SO32-

O2N

SO3- I

MeO

I SO3-

H2O, reflux

H2O, reflux

8

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).

In addition to the electronic factors discussed above, there are also steric factors influencing the selectivity. The equatorial positions in the hyper-valent 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.

The electronic effect dictates that the most electron-poor aryl group occupies the equatorial position in the TS. Electron-donating groups situated

Scheme 9. Two T-shapes in equilibrium leads to two different reaction pathways.

I

Nu

Me

Nu

Me

I

Scheme 10. Increased steric bulk in the ortho-position of the arene forces it to oc-cupy the equatorial position, resulting in its transfer.

Berry pseudorotation

Minor

Major

EDG EWG

Nu I

EWG EDG

Nu I

I

Nu

EDG

EWG

I

Nu

EWG

EDG

IEWG

EDG

Nuδ

δ

IEDG

EWG

Nuδ

δ

C

D

A

B

9

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.

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.

Figure 3. An uncatalyzed reaction (blue) compared to a catalyzed reaction (red).

10

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 Nano-particles are soluble in organic solvents, making them suitable as homo-geneous catalysts34 and they can be characterized by conventional spectro-scopic 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.

11

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 nano-particles 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

12

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 metal-catalyzed 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.

Figure 4. Schematic picture of a MCF pore, (a) without functionalization, (b) with Pd0-aminopropyl-functionalization and (c) with PdII-aminopropyl-functionalization.

NH2NH2

NH2

NH2

H2N

NH2

H2NH2NH2N

H2N

H2NH2N

H2N

NH2

NH2

NH2

NH2H2N Pd0

NH2NH2

NH2

NH2

H2N

NH2

H2NH2NH2N

H2N

H2NH2N

H2N

NH2

NH2

NH2

NH2H2N PdII

OHOH

OH

OH

OH

OHOH

OH

OH HO

HOHO

HOHO

HOHO

HOHO

a) b) c)

13

Later, Gao and Portoghese successfully achieved diastereoselective α-arylation 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

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.

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.

Scheme 11. Early arylation of a diketone.

Scheme 12. Diastereoselective α-arylation of morphan-6-ones.

Scheme 13. α-Arylation of substituted malonates by Oh.

O

O

Ph2ICltBuONa

OH

O

Ph

O

O

22% 23%

Ph

PhtBuOHreflux, 4 h

O

O

OMe

MeN

i) LHMDSii) Ph2II

O

O

OMe

MeNPh

THF:DMF (1:3)-78 °C → rt

EtO OEt

O

R

O i) NaHii) Ar2IOTf

EtO OEt

O

Ar

O

RDMF, rt, 2 h

Up to 95%

14

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

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.

Scheme 14. Ochiai’s asymmetric arylation of a β-ketoester.

Scheme 15. The key step in the preparation of (−)-epibatidine.

R

I PhBF4

O

CO2Me

O

CO2Me

Ph

tBuOKtBuOH, rt, 20 h

R = HR = MeR = BnR = +IPh BF4

-

38% ee, 69% yield34% ee, 68% yield53% ee, 30% yield37% ee, 51% yield

O

N(Boc)2

i) Ph NLi

Ph

2 equiv, THF, -118 °C

ii)N

I

N

Cl

ClCl

1 equiv, DMF, -45 °C

O

N(Boc)2

N

Cl

six steps

HN

N

Cl

(−)-epibatidine 31% overall yield

>20:1 dr, 94% ee,41% yield

15

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.

Scheme 16. Enantioselective α-arylation of aldehydes.

Scheme 17. Arylation of oxygen nucleophiles by Olofsson.

R

O

OH

R

O

OAr

X

I

R2

R1

RO

OR

N

O

O

OH

NaOH, H2O,rt or 50 °C, 3 h

ROH

Ar

Ar

N

O

O

OAr

tBuOKDMF, 60 °Cup to 2 h

R3 OH

R4 R5

R3 O

R4 R5

ArtBuONaPhMe, rtup to 1.5 h

OR

Ar

tBuOKPhMe, reflux, 1 h

EtO NOH

tBuONaMeCN, rt30 min

EtO NO

Ar

R3

OR4

OR1 R3

R4

HCl aq.MeCN, 70 °C2 h

9 examplesup to 92% yield

over 20 examplesup to 98% yield


OHR tBuOK

THF, rt or 40 °C30 min

a) c)

d)

e)

f)

b)





H

O

R

cat. (10 mol%) CuBr (10 mol%)PhMe:Et2O (2:1)NaHCO3

H

O

Ar1

RAr1

IAr2OTf

22 examplesup to 95% yield and 94% ee

N

NH

Me O

tBu Ph

cat.TCA

TCA = Trichloroacetic acid

16

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 un-activated 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 metal-free 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-hydroxy-succinimide 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.

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

Scheme 18. Metal-free arylation of anilines.

NH2

RDMF, 130 °C

24 h

HN

RAr 9 examples

up to 92% yieldAr2IX

17

can also be prepared under metal-free conditions albeit in lower yields and with a narrower substrate scope.66

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

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

Sanford and co-workers achieved selective C-2 arylation of indoles with diaryliodonium salts together with homogeneous palladium catalysis under

Scheme 19. Formation of 18F-arenes by Sanford.

Scheme 20. Arylation of thiols and thioethers by Sanford.

Scheme 21. a) Cu-catalyzed meta-selective arylation. b) Pd-catalyzed ortho-selective arylation.

X

I

R2

R1 K18F

12 examplesup to 79% radiochemical yield

DMF, 85 °C, 20 min

(CH3CN)4CuOTf

R1

18F

CF3COOH1,4-dioxane110 °C, 15 h

R1S

R2

R1 = alkyl or arylR2 = H or alkyl 16 examples

up to 90% yield

OCOCF3

I

R3

R3 R1S

R3

NHPh2IOTfCu(OTf)2

NH

Ph

Ph2IPF6Pd(OAc)2

NH

Ph

R = 4-Me R1 = OtBu

a) b)O

R1

O

R1

O

R1


RR R

Ph

79%

18

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

Diaryliodonium salts can also be used in the pursuit of more environmen-

tally 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.

Scheme 23. Kita’s metal-free cross-coupling reaction of thiophenes.

Scheme 22. Sanford’s C-2 arylation of indoles.

S

R1 R2PhI(OH)OTs

HFIP

IPhTMS-Br

Ar-H

S

R1 R2

Ar42-98% yield

OTs

SR1

R2

IPh

Br

SR1

R2

NH

R1NR1

IMesPd(OAc)2 (5 mol%)

AcOH, rt, 18 h

CN N

1,3-bis(2,4,6-trimethylphenyl)imidazol-2-ylidene (IMes)

R3R2 R2

16 examplesYields 62% - 90%>20:1 C-2 selectivity

IR3

R3

BF4

R1 = H, alkyl

19

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.

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, elimi-nating the chemoselectivity issues seen with diaryliodonium salts.

Waser and coworkers have successfully developed the use of the reagents

trimethylsilylethynyl-1,2-benziodoxol-3(1H)-one (TMS-EBX) and the corre-sponding triisopropyl version (TIPS-EBX),74 introducing an alkynyl

IPh

TMS

Bu4NF

OTf O

O

O

R

O

RR

O


Scheme 24. Diaryliodonium salt used as an aryne precursor.

Figure 5. General alkynyl(aryl)iodonium salt with an external (a) or internal (b) ani-on.

IX R2

R1 X = OTf, OTs, etc...

I

O

O

R1

R2

R2 = TMS, TIPS, Ph, tBu, nBu, etc...

a) b)

20

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

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 reac-tion proceeded at rt and was complete within five minutes.

1.5 Aim of the thesis The objective of this thesis is the preparation and application of diaryl-iodonium 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.

Scheme 25. C-2 selective alkynylation of indoles by Waser.

Scheme 26. Alkynylation of thiols by Waser.

I

O

O SiiPr3

THF, rt, <5 minS SiiPr3

Over 30 examplesup to >99% yield

R-SH Me2N NMe2

NHR

I

O

O SiiPr3

NR'

R Pd(MeCN)4(BF4)2 (2 mol%)

CH2Cl2:H2O (50:1), rt NR'

R SiiPr3


21

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.

23

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 stoichio-metric 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 diaryl-iodonium 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 chemo-selectivity, a study was conducted where three different nucleophiles were arylated under previously reported conditions.54, 57, 78 The salts were system-atically 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

24

possessed the corresponding methoxy-substituents (1h−m), to allow investi-gation 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.

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 (equiv)

Temp Time Yielda (%)

1

Scheme

3a

2

0 °Crt

25 min

90

2

Scheme

3a

2

rt

30 min

52

3

Scheme

3a

2

0 °C

2 h

95

4

Scheme 3a

2

rt

5 h

69

5b

Scheme

5

2.5

rt

30 min

+ 30 min

76

Figure 6. Diaryliodonium salts 1b−m used in this study.

IPh

IPh

IPh

IPh

IPh

IPh

IPh

OMe

IPh

MeO

IPh

MeO OMe

IPh

MeO

OMe IPh

MeO

OMeI

Ph

MeO

OMe

OMe

OTf

OTf

OTf OTfOTf

OTf OTf OTf OTf OTf

OTfOTf

1e 1f 1g

1b 1c 1d 1h 1i 1j

1k 1l 1m

25

6

Scheme

3a

2

rt

1 h

79

7 Scheme 3c

1

rt

6 h

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 pre-pared 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).

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 di-

phenyliodonium 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 nucleo-philes were selected so that a conclusion could be drawn regarding the difference in reactivity between O, N and C nucleophiles. The methoxy-substituent on the phenol and aniline was used to simplify the 1H NMR interpretation of the results.

Scheme 27. Preparation of electron-rich unsymmetrical diaryliodonium salts.

IOTs

R

TMSR

MeCN, reflux, 4 h

OTsI

OH

Bu3SnR

IOTs

RCH2Cl2, 0 °C, 30 min

1l: R = 2,6-dimethoxy 47%1m: R = 2,4,6-trimethoxy 94%

1i: R = 2-methoxy 56%1j: R = 2,4-dimethoxy 96%1k: R = 2,5-dimethoxy 68%

26

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 electron-donating 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).

Scheme 28. Arylation conditions for a) m-methoxyphenol (2), b) m-anisidine (5) and c) diethyl methylmalonate (8).

EtO OEt

O O

NaH, DMF

OHMeO

tBuOK, THF

EtO OEt

O

Ph

O

MeO OPh

NH2MeO

DMF

rt, 18 h

130 °C, 24 h

40 °C, ≤2 h

MeO OAr

MeOHN

PhMeO

HN

Ar

EtO OEt

O

Ar

O

a)

b)

c)

78-99%

30-75%

26-95%

Ph(Ar)IOTf

Ph(Ar)IOTf

Ph(Ar)IOTf

2 3 4

5 6 7

8 9 10

27

IPh

OTf

1g

Diethyl methylmalonate (8) also gave preferential transfer of the phenyl group with all methyl-substituted salts. The electronic effect from the p-methyl 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

3:4 Yielda 6:7 Yielda 9:10 Yielda

1

2.9:1

78%

1.4:1

53%

3.3:1

54%

2

1:2.4 98% 1.4:1 40% 11:1 64%

3

1.3:1 98% 4.5:1 75% 5.0:1 52%

4

1:1.6 >99% 2.5:1 60% 2.0:1 95%

5

1:9.0 98% 6.5:1 53% Only 9 26%

6

1:1.9 84% 15:1 50% Only 9 55%

a Combined yields of the isolated products.

IPh

OTf

1b

IPh

OTf

1c

IPh

OTf

1d

IPh

OTf

1e

IPh

OTf

1f

MeO OPh/Ar

MeOHN

Ph/ArEtO OEt

O

Ph/Ar

O

28

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 mono-substituted 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 trimethoxy-substituted 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 σ-withdrawing m-methoxy substituent.80 Table 3. Phenylation versus arylation of 2, 5 and 8 using methoxy substituted salts 1h−m.

Entry

Iodonium salt

3:4 Yielda 6:7 Yielda 9:10 Yielda

1

Only 3 94% 5.4:1 74% 13:1 36%

2

Only 3 93% 3.0:1 62% 2.6:1 61%

3

Only 3 82% Only 6 50% Only 9 53%

4

Only 3 90% 2.3:1 30% Only 9 57%

5

Only 3 >99% Only 6 70% Only 9 38%

6

Only 3 85% Only 6 45% Only 9 44%

a Combined yields of the isolated products.

IPh

OMe

OTf

1h

IPh

MeO

OTf

1i

IPh

MeO OMe

OTf

1j

IPh

MeO

OMeOTf

1k

IPh

MeO

OMeOTf

1l

IPh

MeO

OMe

OMe

OTf

1m

MeO OPh/Ar

MeOHN

Ph/ArEtO OEt

O

Ph/Ar

O

29

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 methoxy-substituted 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 diaryl-iodonium 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 un-symmetrical salt.

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 inter-mediate that can undergo scrambling. The salt is then reformed with a differ-ent aryl group (Scheme 30).

Scheme 29. Aryl exchange reported by DiMagno.

Scheme 30. Hypothesized aryl ligand exchange mechanism by Cuifolini.

Ar2I

Ar1X

Ar1I

Ar1X

Ar2I

Ar2

XFMeCN, rt

OTfIAr1

Ar2Δ

IAr1

Ar2

I Ar3IIAr1

Ar2

Ar3 I

IAr1

Ar2

Ar3 Ar3

IAr1 Ar2 I

OTf

OTf

30

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 diaryl-iodonium 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.

The methyl-substituted salt 1e exhibited scrambling together with malo-

nate 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.

Figure 7. Iodonium cations detected by HRMS in the arylation of m-methoxyphenol (2) with salt 1k.

31

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 spe-cies is very similar or that the aryl exchange is in rapid equilibrium. A con-trol 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(p-tolyl)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.

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.

Scheme 31. a) Arylation of 8 with two different symmetrical salts present. Scram-bling was detected. b) Arylation of 8 in the presence of an aryl iodide. No scrambling was detected.

EtO OEt

O O

DMF, rt, <5, min

IOTf

I

NaH (1.3 equiv)

1.3 equiv

8 1q

I

I

EtO OEt

O O

8

IOTf

I

MeO OMe

OTf

1o

1p

DMF, rt, <5 min

NaH (1.3 equiv)

I

I

MeO OMe

I

MeO

b)

a)

EtO OEt

O O

1 equiv

1.3 equiv

1.3 equiv

EtO OEt

O O

not isolated1 equiv 1.3 equiv

EtO OEt

O O

OMenot isolated

32

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.

INT8-1f-Ar0.0

INT8-1f-Ph+1.9

TS8-1f-Ar+15.3

+13.3TS8-1f-Ph

10 + PhI-55.8

9 + ArI-66.0

TS8-1f-Ph+13.3

TS8-1f-Ar+15.3

2.132.48

2.582.93

2.142.44

2.562.72

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.

33

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 methyl-substituted 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 observa-tion 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 di- or 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).

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.

Figure 9. Suitable dummy groups for diaryliodonium salts in chemoselective arylations.

35

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-chloro-3-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.

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

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

Scheme 32. Acidic preparation of a heteroaryl iodonium salt.

Scheme 33. Four-step procedure to a pyridyl iodonium salt.

N

ICl2

N

ICl2NaOH

N

IOAc2O/AcOH

N

I(OAc)2

R

TFA

N

IOCOCF3

R

overall yield 11%

N

I

Cl

mCPBA, TfOH

CH2Cl2, 80 °C, 2 h N

I

60%

OTf

Cl

36

case achieved using a salt prepared with this method (Scheme 15).12a Zefirov also reported a similar procedure to prepare unsymmetrical salts.85

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 N-heteroaryliodonium 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

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

Scheme 34. Strongly basic route to symmetrical heteroaryliodonium chlorides.

N

I mCPBATfOH

N

IOTf

N

IOTf

and/or

HOTf

11a 12a 13a 13a'

Scheme 35. Model reaction for the preparation of N-heteroaryliodonium salts.

HHICl3HCl

H

Cl H

ICl2 H

Cl H

IAr2Ar2ICl

6 examples up to 71% yieldvery unstable

Li

R

37

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 chemo-selectivity, we subsequently focused on more useful dummy groups than the phenyl moiety.

Table 4. Summary of the optimization.

Entry mCPBA (equiv)

TfOH (equiv)

T (°C) Time (h) Yielda (%)

1 1.1 3.0 80 3 54 2 1.5 3.0 80 3 60 3 2.0 3.0 80 3 52 4 1.5 4.0 80 3 68 5 1.5 4.0 80 10 min 48 6 1.5 4.0 80 0.5 60 7 1.5 4.0 60 0.5 69 8 1.5 4.0 40 0.5 0 9 1.5 4.0 rt 0.5 0

a Isolated yield after evaporation in vacuo and precipitation by addition of Et2O.

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).

N

I i) PhH (12a, 1.1 equiv)ii) mCPBA

T, time N

IOTf

N

ITfOH

CH2Cl2, rt, 5 min

H OTfH OTf11a

13a'

38

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 precipita-tion 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).

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 concentration-dependent. 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)

Scheme 36. Modified procedure for the preparation of electron-rich heteroaryl salts.

Scheme 37. Deprotonation of 13’ to 13.

N

IOTf

HOTf13'

R ?

N

IOTf

13'

R

N

I

N

I

N

IL2

HCH2Cl2, 60 °C, 30 min

i) H2O (2 equiv)ii) PhOMe (12b, 1.1 equiv) in CH2Cl2

0 °C, 10 min

i) TfOH (4 equiv)

H

OTf

OTf OTf11a 13b'

81%

ii) mCPBA (1.75 equiv)

OMe

39

together with 1 equiv of fluorobenzene (12c) indeed showed a 6:1 ratio between the two detected peaks, indicating the presence of two triflates.

Various attempts were made to find suitable conditions for the de-

protonation 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).

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-heteroaryl-iodonium salts, it is important to have control over the chemoselectivity in

Figure 10. Fluorine containing N-heteroaryl salt 13c’

Scheme 38. Optimized deprotonation procedure.

N

I

H

OTf

OTf

13b'

N

IOTf

13b97%

Al2O3

CH2Cl2:MeOH (20:1) OMeOMe

40

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.

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 3-iodopyridine (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.

Scheme 39. Difference in chemoselectivity between a) transition metal-catalyzed and b) transition metal-free arylations.

I

[M], Nu-

Nu-Nu

Nu

OTf

IOTf

OMe

R

RR

R

a)

b)

41

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.

Scheme 40. Synthesized N-heteroaryliodonium triflates. The optimized procedure was used unless otherwise noted. The yields of 13 are from isolated 13’. a The modi-fied procedure was used.

N

I

N

I

OMe N

I

F

N

I

N

I

iPr

iPr

iPr

OTf

N

I

Cl

N

I

N

I

iPr

iPr

iPr

IHN

N

I

iPr

iPr

iPr

HNN

I

iPr

iPr

iPr

HNN N

I

OMe

I

OMe

HNN N N

NI

O

OMe

Me

OTf OTf OTf

OTf

OTf

13a', 69% 13b', 81%a

13b, 97%13c', 84%13c, 85%

13f', 70%13f, 92%

13e', 59%13d, 73%

13g', 77% 13h', 82% 13i', 67%13i, 92%

13j', 70%13j, 97%

IHN

N

13k', 75%13k, 72%

13l', 75%13l, 90%

13m', 90%a

13m, 87%

13n', 83%a

13n, 78%13o', 86%a

13o, 81%

OTf OTf OTf

OTf OTf OTf OTf

OTfOTf

CH2Cl2, rt, 5 min

i) Ar (12, 1.1 equiv)ii) mCPBA

60 °C, 30 min

TfOH

1113' 13

N I N I

HOTf

NI

OTf

HOTfN

IOTf

R RAl2O3

CH2Cl2:MeOH (20:1)

42

Bulky salts 13f and 13f’ were reacted with malonate 8 in order to demon-strate that this type of dummy group is also useful without employing transi-tion 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.

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.

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.

Scheme 41. Chemoselective arylation of malonate 8.

Scheme 42. Chemoselective arylation of phenols 15.

OH

15a R = H15b R = 2,4-dimethyl

R

O

THF, 40 °C, ≤2 h N16a

88%59%

O

N16b

65%52%

N

I

OMe

OTf

13b13b' = 13f•TfOH

tBuOK

EtO OEt

O O

DMF, rt, 18 h

EtO OEt

O O

8 14 N

NaH

72%26%

N

IOTf

13f13f' = 13f•TfOH

43

3.4 Conclusion N-heteroaryliodonium triflates can now be prepared using an efficient one-pot 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 hetero-aryliodonium 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.

45

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 non-commercial 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).

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 phenyl-ethynyl(phenyl)iodonium trifluoroacetate (Scheme 43a, R1 = H, R2 = phenyl and X = trifluoroacetate) from phenylacetylene.92

Scheme 43. One-pot preparation of alkynyl(aryl)iodonium salts.

B(OR)2R2

IL2

R1

I

R1mCPBA, HX

CH2Cl2:TFE (1:1)rt, 30 min

I

R1

X R2

14 examplesup to >99% yield

a)

B(OR)2RmCPBA, HX


I

HO

O IL2

HO

O IX R

HO

O I

O

O R

NaHCO3 (aq.)

b)


rt, 30 min

rt, 30 min

46

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 iodo-benzene, 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 with-out 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.

47

Table 5. Initial optimization of the model reaction, forming 18a.

Entry Solvent t1 (min)

Acid (equiv)

17a (equiv)

t2 (min)

Yield (%)

1 CH2Cl2 30 TfOH (1) 1.1 60 <20a 2 CH2Cl2 30 TfOH (1) 1.1 7 h <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) 3 h Tf2O (1) 2 3 h 0 11d 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 1H 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 condi-tions were applied.

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 precipita-tion/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, produc-ing 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 3-trifluoromethyliodobenzene. The activated iodoarene was thought to form a

TMSPhI

mCPBA (1.1 equiv)TfOHsolventrt, t1

IL2 ITfO Ph

rt, t2

18a

17a

48

more reactive iodine(III) intermediate. Unfortunately, no product was observed either with TfOH or with TsOH.

The preparation of the cyclic alkynyl benziodoxolone 19a was also

attempted using TMS-phenylacetylene (17a). The initial reactions are sum-marized 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 reac-tion lies in the coupling with silane 17 rather than in the cyclization.

Scheme 44. Substrate scope of alkynyl salts 18 from silanes 17.

ITfO nBu

18b40%

ITfO

18c70%

Br

ITfO

18d0%

Cl

ITfO

18e0%

OH

ITfO

18a85%

TMSR2IL2I

mCPBA (1.1 equiv)TfOH (1 equiv)


ITfO R2

17 (2 equiv)rt, 30 min

18

49

Table 6. Initial optimization for formation of 19a.

Entry Acid Base (equiv) Yield of 19a 1 TfOH Pyridine (2) trace 2 TfOH NaHCO3 (excess) trace 3 TsOH NaHCO3 (excess) 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 stabiliz-ing the salt with an internal anion could be helpful in this regard. Un-fortunately this reaction did not furnish any product. The noncyclic interme-diate was not detected either.

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

Scheme 45. Attempt to form the benziodoxolone 19b.

nBuTMSI i) mCPBA, TfOH


IX nBu I

O

O nBuNaHCO3 (aq.)ii)

HO

O

HO

O

X X

19b

TMSPhI

mCPBA (1.1 equiv) HX (1 equiv)


I

O

O Ph

basic workupHO

O IX Ph

HO

O

rt, 60 min17a (2 equiv)

19a18'

50

boronic acids. Further investigations into the substrate scope are necessary to determine whether this protocol will be useful to the chemical community.

51

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 pre-functionalized 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 sili-ceous 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 PdII-AmP-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.

52

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. 2-Phenyl-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.

The encouraging initial results led to a solvent screen, which is summa-

rized 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 opti-mization. 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 co-ordinate more weakly to electrophilic metal ions than tosylate anions, leading to a more reactive metal intermediate.

Scheme 46. Initial conditions for the C-2 arylation of indole.

NH 2 equiv

AcOH, rt, 15 h

PdII-AmP-MCF (4.5 mol%)

1a: X = OTf 21a: X = BF4

20a 22a

Ph2IXNH

Ph

56% 1H NMR yield79% 1H NMR yield

53

Table 7. Solvent and counterion optimizations.a

Entry Counterion Solvent Time (h) Yield (%)b

1 21a BF4 THF 15 11 2 21a BF4 Toluene 15 0 3 21a BF4 CH2Cl2 15 29 4 21a BF4 EtOAc 15 0 5 21a BF4 AcOH 15 79 6 21a BF4 EtOH 15 0 7 21a BF4 H2O 15 91 8 1a OTf H2O 15 0c 9 23 OTs H2O 15 92

10 21a BF4 H2O 6 88 11 23 OTs H2O 6 26

a Reaction conditions: Indole (20a) (0.2 mmol), Ph2IX (0.4 mmol) and PdII-AmP-MCF (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 1,3,5-trimethoxybenzene 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 di-aryliodonium 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-AmP-MCF. In order to observe any reactivity differences, the reaction time was shortened to 3 h. Quite unexpectedly, it was revealed that the PdII-AmP-MCF 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

NH

NH

PhI

Solvent, rt, Time

PdII-AmP-MCF (4.5 mol%)

X

1a, 21a or 2320a 22a

54

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

Entry Catalyst Loadingb (mol%)

Time (h) Yield (%)c

1 PdII-AmP-MCF 4.5 3 63 2 Pd0-AmP-MCF 4.5 3 91 3 Pd0-AmP-MCF 2.5 6 91d

4 Pd/C (10 wt%) 2.5 6 0 5 Pd0-AmP-MCF 1 14 79 6e Pd0-AmP-MCF 4.5 3 50 7e Pd0-AmP-MCF 4.5 6 93 8f Pd0-AmP-MCF 2.5 6 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 indi-cated time. b With regard to the Pd content. c Determined by 1H NMR using 1,3,5-trimethoxybenzene 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

NH

NH

PhI

H2O, rt, Timecat. (x mol%)

BF4

20a 21a 22a

55

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.

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.

Scheme 47. Phenylation of different indoles 20.

Figure 11. Indoles that were inert under the reaction conditions.

NH

H2NNO

O

NSi

NH

HO

20g 20h 20i 20j

N

Pd0-AmP-MCF (2.5 mol%)

H2O, rt - 50 °C, 6 - 25 hPh2IBF4R1

NR1

NH

O

N N

NH22art, 6 h91%

22b40 °C, 6 h86%

22c40 °C, 15 h85%

22ert, 6 h80%

22f50 °C, 24 h65%

NH

O2N

22d50 °C, 25 h70%

20 21a 22

NH

Br

R2 R2

56

Subsequently, the use of unsymmetrical diaryliodonium salts to select-ively introduce an aryl group was investigated. Studies of the chemo-selectivity 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.

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 ary-lated 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.

Scheme 48. Selective phenylation of indole (20a) using unsymmetrical diaryl-iodonium salts 21 with bulky dummy groups.

NH


NH

PhH2O, 40 °C, 24 h

IBF4

R

R R

50% 1H NMR yield26% 1H NMR yield

20a 22a

21b: R = Me21c: R = iPr

57

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.

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.

Scheme 50. Arylation attempt of 2-methylindole with diphenyliodonium tetra-fluoroborate (21a).

N


H2O, rt or 40 °C, 6 h or 15 hAr2IBF4

N

NH

40 °C, 6 h76%

NH

40 °C, 6 h83%

NO

40 °C, 6 h72%a

NH

Cl

NH

F

NH

Br

40 °C, 15 h92%

40 °C, 15 h87%

NCF3

40 °C, 15 h99%

40 °C, 6 h84%

NH

40 °C, 15 h67%

R1

R1 = H, MeR1

NH

rt, 15 h84%

20 21 22

22d 22e 22f

22g22h

22i

22j 22k 22l

R2

NH


H2O, rt, 24 hPh2IBF4

NH20k

21a2 equiv

X

58

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%, respective-ly). The catalyst was recovered between the cycles by repeated centrifuga-tion 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%).

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-AmP-MCF.

The catalyst leaching was investigated by performing the reaction under the optimized conditions (Scheme 51). Upon reaction completion, the cata-lyst 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 homo-geneous palladium is not the main species responsible for the catalytic activity.

Scheme 51. Reaction conditions for the catalyst recycling experiments.

NH


H2O, rt, 6 hPh2IBF4

NH20a 21a

2 equiv22a

59

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 elimina-tion produces the C-2 arylated indole and regenerates the PdII species.

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 seem-ingly 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

Figure 12. Hypothesized mechanism for the C-2 arylation of indole.

PdIILn

NH

NH

PdIVLn

BF4

PdIVLn

Ar

BF4

Ar2IBF4

ArI

NH

Ar

Ar

60

arylated indoles with high selectivity, demonstrated by Wang and co-workers.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 recyclabil-ity. 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.

61

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 applica-tions. 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 synthe-sized 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.

63

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 sup-porting 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 investi-gated 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 support-ing information.

65

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 multi-plicity (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

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 alkyn-yl(aryl)iodonium triflate 18.

TMSR2IL2I

mCPBA (1.1 equiv)TfOH (1 equiv)


ITfO R2

17 (2 equiv)rt, 30 min

18

66

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 ac-cordance 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), 7.58-7.51 (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.

67

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.

68

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.

69

References

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