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Development and Applications of Hypervalent Iodine Compounds Powerful Arylation and Oxidation Reagents

Nazli Jalalian

ii

© Nazli Jalalian, Stockholm 2012 Cover Picture: Round-bottomed flask containing iodine. ISBN 978-91-7447-505-0 Printed in Sweden by US-AB, Stockholm 2012 Distributor: Department of Organic Chemistry, Stockholm University

iii

Det löser sig, det gör det alltid. [Toran Aghili a.k.a min mamma]

v

Abstract

The first part of this thesis describes the efficient synthesis of several hypervalent iodine(III) compounds. Electron-rich diaryliodonium salts have been synthesized in a one-pot procedure, employing mCPBA as the oxidant. Both symmetric and unsymmetric diaryliodonium tosylates can be isolated in high yields. An in situ anion exchange also enables the synthesis of previously unobtainable diaryliodonium triflates. A large-scale protocol for the synthesis of a derivative of Koser’s reagent, that is an isolable intermediate in the diaryliodonium tosylate synthesis, is furthermore described. The large-scale synthesis is performed in neat TFE, which can be recovered and recycled. This is very desirable from an environmental point of view. One of the few described syntheses of enantiopure diaryliodonium salts is discussed. Three different enantiopure diaryliodonium salts bearing electron-rich substituents are synthesized in moderate to high yields. The synthesis of these three salts shows the challenge in the preparation of electron-rich substituted unsymmetric salts. The second part of the thesis describes the application of both symmetric and unsymmetric diaryliodonium salts in organic synthesis. A metal-free efficient and fast method for the synthesis of diaryl ethers from diaryliodonium salts has been developed. The substrate scope is wide as both the phenol and the diaryliodonium salt can be varied. Products such as halogenated ethers, ortho-substituted ethers and bulky ethers, that are difficult to obtain with metal-catalyzed procedures, are readily prepared. The mild protocol allows arylation of racemization-prone α-amino acid derivatives without loss of enantiomeric excess. A chemoselectivity investigation was conducted, in which unsymmetric diaryliodonium salts were employed in the arylation of three different nucleophiles in order to understand the different factors that influence which aryl moiety that is transferred to the nucleophile.

vii

List of Publications

This thesis is based on the following papers, referred to in the text by their Roman numerals I-VI. Reprints were made with the kind permission of the publisher. The contribution by the author to each publication is clarified in Appendix A. I. One-Pot Synthesis of Diaryliodonium Salts using

Toluenesulfonic Acid: A Fast Entry to Electron-Rich Diaryliodonium Tosylates and Triflates Zhu, M.; Jalalian, N.; Olofsson, B. Synlett, 2008, 592-596.

II. Synthesis of Koser's Reagent and Derivatives

Jalalian, N.; Olofsson, B. Accepted for publication in Org. Synth.

III. Design and Asymmetric Synthesis of Chiral Diaryliodonium

Salts Jalalian, N.; Olofsson, B. Tetrahedron, 2010, 66, 5793-5800.

IV. Room Temperature, Metal-Free Synthesis of Diaryl Ethers with

Use of Diaryliodonium Salts Jalalian, N.: Ishikawa, E. E.: Silva, L. F.: Olofsson, B. Org. Lett., 2011, 13, 1552-1555.

V. Metal-Free Arylation of Oxygen Nucleophiles with

Diaryliodonium Salts Jalalian, N.: Petersen, T. B.; Olofsson, B. Submitted for Publication

VI. Arylation with Unsymmetric Diaryliodonium Salts – a

Chemoselectivity Study Jalalian, N.: Malmgren, J.; Olofsson, B. Manuscript

ix

Table of Contents

Abstract ........................................................................................................................ v

List of Publications ................................................................................................... vii

Abbreviations .............................................................................................................. xi

1. Introduction ............................................................................................................. 1 1.1 Hypervalent Iodine Compounds ........................................................................ 1 1.2 Diaryl-λ3-Iodanes ............................................................................................. 3

1.2.1 Structural Features ..................................................................................... 3 1.2.2 Synthesis .................................................................................................... 4

1.3 Applications of Diaryliodonium Salts ............................................................... 7 1.3.1 α-Arylation of Carbonyl Compounds ........................................................ 7 1.3.2 Cross-Coupling Reactions ......................................................................... 8 1.3.3 Arylation of Heteroatom Nucleophiles ...................................................... 9 1.3.4 Other Applications ................................................................................... 10

1.4 Mechanistic Considerations ............................................................................ 10 1.4.1 Chemoselectivity ..................................................................................... 12

1.5 Objective ......................................................................................................... 13

2. One-pot Synthesis of Electron-Rich Diaryliodonium Salts (Paper I) .................... 15 2.1 Results and Discussion .................................................................................... 15

2.1.1 Optimization ............................................................................................ 15 2.1.2 Symmetric Salts ....................................................................................... 16 2.1.3 In Situ Anion Exchange ........................................................................... 18 2.1.4 Unsymmetric Salts ................................................................................... 18 2.1.5 Mechanism ............................................................................................... 20

2.2 Conclusion ....................................................................................................... 21

3. Large Scale Synthesis of Koser’s Reagent and Derivatives (Paper II) ................. 23 3.1 Synthetic Strategy ............................................................................................ 24 3.2 Optimization .................................................................................................... 24 3.3 Conclusion ....................................................................................................... 26

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4. Asymmetric Synthesis of Chiral Diaryliodonium Salts (Paper III) ....................... 27 4.1 Synthetic Strategy ............................................................................................ 28 4.2 Results and Discussion .................................................................................... 29

4.2.1 Synthesis of Monosubstituted Chiral Salt I ............................................. 29 4.2.2 Synthesis of Disubstituted Chiral Salt II ................................................. 30 4.2.3 Synthesis of Trisubstituted Chiral Salt III ............................................... 32 4.2.4 Structural Investigations .......................................................................... 33 4.2.5 Arylation of 2-(Ethoxycarbonyl)cyclohexanone ..................................... 35

4.3 Conclusion ....................................................................................................... 35

5. Synthesis of Diaryl Ethers (Paper IV and V) ........................................................ 37 5.1 Results and Discussion .................................................................................... 38

5.1.1 Optimization ............................................................................................ 38 5.1.2 Phenylation of Functionalized Phenols ................................................... 40 5.1.3 Arylation of Phenols with Symmetric Diaryliodonium Salts .................. 42 5.1.4 Arylation of Amino Acid Derivatives ..................................................... 45 5.1.5 Arylation of Phenols with Unsymmetric Diaryliodonium Salts .............. 46

5.2 Conclusion ....................................................................................................... 48

6. Chemoselectivity Investigation in Arylations of O, N and C Nucleophiles (Paper VI) .............................................................................................................................. 49

6.1 Results and Discussions .................................................................................. 49 6.2 Conclusion ....................................................................................................... 53

Concluding Remarks ................................................................................................. 55

Appendix A ............................................................................................................... 57

Appendix B ................................................................................................................ 58

Acknowledgements ................................................................................................... 65

References ................................................................................................................. 67

xi

Abbreviations

Abbreviations are used in agreement with the standard of the subject.1 Only nonstandard and unconventional abbreviations that appear in this thesis are listed here. CALB Candida Antarctica lipase B DIB (diacetoxy)iodobenzene DMP Dess-Martin periodinane DPE 1,1-diphenylethylene EAS electrophilic aromatic substitution ee enantiomeric excess HFIP 1,1,1,3,3,3-hexafluoro-2-propanol HTIB [hydroxy(tosyloxy)iodo]benzene IBX 2-iodoxybenzoic acid mCPBA 3-chloroperbenzoic acid Tf2O trifluoromethanesulfonic anhydride TFE 2,2,2-trifluoroethanol TfOH trifluoromethanesulfonic acid TsOH p-toluenesulfonic acid

1

1. Introduction

The first polyvalent iodine compound was reported in 1886 by the German chemist Conrad Willgerodt, who synthesized (dichloroiodo)benzene from iodobenzene and chlorine gas.2 Iodine is the largest, most electropositive and most polarizable element in group 17 of the periodic table.3 As a result of these properties, iodine can form stable multivalent compounds. Even though more than a century has passed since hypervalent iodine compounds were first discovered, they have only recently begun to receive attention as mild, non-toxic and selective reagents in organic synthesis.4

1.1 Hypervalent Iodine Compounds A hypervalent state is defined as when an atom expands its valence shell beyond the limits of the Lewis octet rule. Hypervalent compounds are common in elements in group 15-18 of the periodic table.5 The oxidation process of an iodine compound is described in Scheme 1.

Scheme 1. Oxidation process for iodine compounds.

According to IUPAC nomenclature guidelines, iodine(III) and iodine(V) compounds are called λ3- and λ5-iodanes respectively. The most common type of λ3-iodanes are ArIL2, where L is a heteroatom.5 Figure 1a shows the pseudotrigonal bipyramid T-shaped geometry of λ3-iodanes with two heteroatom ligands and two free electron pairs. The least electronegative group, generally the aryl moiety, and the lone pairs of electrons on the iodine occupy the equatorial positions, while the two most electronegative ligands occupy the apical positions.5 The linear hypervalent bond in ArIL2 (L-I-L), which is weaker than normal covalent bonds, is a three-center four-electron

L L L

+I +III +V+III +V

Oxidation LigandAssociation

LigandAssociationOxidation

8-I-1 10-I-3 12-I-5

L

8-I-2 10-I-4

IL IL

L IL

LL IL

L

L

L IL

L

L

LL

2

(3c-4e) bond formed from the doubly occupied iodine 5pz orbital and one orbital from each of the apical ligands. As a result of the filled nonbonding orbital, which is located on the apical ligands, iodine(III) compounds are electrophilic at the iodine center (Figure 1b).5-6 The highest electron density is localized at the ends of the 3c-4e-bond axis. Electronegative ligands therefore have a stabilizing effect on the molecule by withdrawing the electron density from the bond. X-ray studies have confirmed that in the solid phase, diaryliodonium salts exhibit T-shaped geometry, whereas the geometry of the salts in solution differs, depending on both the anion and the solvent.6

Figure 1a. Pseudotrigonal bipyramid geometry of ArIL2. b. Molecular orbitals in the hypervalent bond.

Hypervalent iodine compounds are widely used in organic synthesis.4c, 5, 7 Examples of well-known iodine(III) compounds with two heteroatom ligands are shown in Figure 2. The use of iodosylbenzene, (diacetoxyiodo)benzene (DIB) and [hydroxy(tosyloxy)iodo]benzene (HTIB) has become increasingly widespread in recent years. These reagents can be employed not only in oxidations,4a, 4b but also applied in areas such as functionalization of carbonyl compounds,8 rearrangements9 and diaryliodonium salt formation.4d, 10

Figure 2. Well-known iodine(III) compounds.

Dess-Martin periodinane (DMP) and 2-iodoxybenzoic acid (IBX) are well-known hypervalent iodine(V) compounds that are frequently used in mild and selective oxidative transformations in total synthesis of natural products (Figure 3).7, 11 Recently Wirth and coworkers developed a tetrafluoro-IBX derivative (FIBX) that showed greater solubility in organic

I LL

bonding orbital

nonbonding orbital

antibonding orbital

I

L

L

δ+

δ−

δ−

a. b.

Iodosylbenzene (Diacetoxyiodo)benzene [Hydroxy(tosyloxy)iodo]benzeneHTIB

I OTsHOI OAcAcO

DIB

I O( )n

3

solvents, and hence improved reactivity compared to the nonfluorinated IBX.12

Figure 3. Widely used iodine(V) compounds.

The focus of this thesis is on iodine(III) compounds and their applications, iodine(V) compounds will therefore not be discussed further.

1.2 Diaryl-λ3-Iodanes

1.2.1 Structural Features Diaryliodonium salts are air- and moisture-stable compounds,4c which were first synthesized by Hartmann and Meyer in 1894.13 As shown in Figure 4, the salts consist of an iodine atom, two aryl moieties and an anion, which not only influences the solubility, but also the reactivity of the salt. Salts with halide anions are generally less soluble in organic solvents, while salts with anions such as tosylate, triflate and tetrafluoroborate exhibit better solubility. These non-nucleophilic anions are generally also preferred over the halides in applications. Symmetric salts (R1=R2) are often preferred over unsymmetric salts (R1≠R2) as issues of chemoselectivity in reactions do not arise.4c, 14 The chemistry of iodine(III) compounds bearing two carbon ligands is comparable to that of heavy metal reagents such as HgII, TlIII and PbIV, as they can undergo reductive elimination. Iodine(III) compounds can therefore be employed in organic reactions as mild, inexpensive and non-toxic replacements of heavy metals.15

Figure 4. General structure of diaryliodonium salts.

OI OAcOAcAcO

O

OI

O

O OH

Dess-Martin periodinaneDMP

2-Iodoxybenzoic acidIBX

OI

O

O OH

FIBX

FF

FF

IX

R1 R2

X = Cl, Br, I, OTf, OTs, BF4, etc

4

1.2.2 Synthesis The synthesis of diaryliodonium salts has developed considerably in the last decade. The most common synthetic strategies are shown in Scheme 2. The synthesis usually requires two or three steps, where the aryl iodide is initially oxidized to an iodine(III) compound which is isolated, and the diaryliodonium salts is subsequent obtained by a ligand exchange reaction.4c, 4d Typically an anion exchange is required to obtain a suitable anion. Pre-oxidized iodine compounds can also be employed as starting materials, and are further reacted with silanes16 or boron reagents17 to yield diaryliodonium salts, circumventing the electrophilic aromatic substitution (EAS) step and its inherent regioselectivity restrictions (vide infra).

Scheme 2. General strategies for synthesis of diaryliodonium salts.

Basic conditions can be used to generate both symmetric and unsymmetric diaryliodonium salts, both with organic and inorganic iodine(III) starting materials. Scheme 3a describes a synthesis that involves a very unstable intermediate, trans-chlorovinyliodoso dichloride,18 which is reacted with a lithiated arene to afford symmetric salts in low to good yields.18 Alkynes can be reacted with (diacetoxyiodo)benzene and trifluoromethanesulfonic acid (triflic acid, TfOH) to give a more stable aryl(vinyl)iodonium triflate intermediate,19 which also is treated with a lithiated arene.20 This method provides unsymmetric salts in moderate to high yields (Scheme 3b).

Ar1 I

IL3

Ar1 IL2oxidant

acid acidAr2 H Ar2 Mor

I Ar2Ar1X

acid/baseAr H Ar Mor

Ar2IY

M = B(OH)2, SiMe3, SnBu3

anion exchangefrom X to Y

a.

b.

c.

d. I ArArX

Ar1 I

I2

oxidantacid

+

+ Ar2 H

Ar H4 2

I Ar2Ar1X

I ArAroxidant

acidX

X

5

Scheme 3. Synthesis of diaryliodonium salts under basic conditions.

Beringer and co-workers developed methods whereby iodosyl sulfate, together with an acid and an arene, was used to prepare symmetric salts in moderate yields (Scheme 4a).21 More recently, Zhdankin and coworkers demonstrated the use of inorganic compounds such as (dicyano)iodonium triflate and iodosyl triflate in the synthesis of diaryliodonium salts.22 The preformed iodine(III) compound reacts with activated TMS-substituted arenes to deliver diaryliodonium salts in moderate to high yields (Scheme 4b). The major drawback associated with preparation of diaryliodonium salts from inorganic iodine(III) compounds is that such precursors are often very unstable.

Scheme 4. Preparation of diaryliodonium salts from inorganic iodine(III) compounds.

One of the main limitations of many of the general methods outlined above arises from the electrophilic aromatic substitution mechanism operating in the addition of the arene to the iodine(III) intermediate. Conventional substitution pattern rules apply, i.e. activated arenes show ortho- and para-selectivity, and in reactions with iodine(III) species a high para-selectivity is observed (Scheme 5). Deactivated arenes are generally not reactive enough and result in byproduct formation and decomposition.

H HICl3HCl Cl

ICl2 Ar-LiAr I Ar

Cl

highly unstable 32-100%

R HPhI(OAc)2

TfOH TfO I Ar-LiPh I ArTfO

67-93%

R

Ph

a.

b.

-78 °C

TfO

(IO)2SO4 + 4 ArH H2SO4 2 Ar I Ar

HSO4

anion exchange2 Ar I Ar

X

39-62%

O I OTfTMS

2+I

R R

TfO

57-93%

a.

b. R

6

Scheme 5. Electrophilic aromatic substitution of ArIL2.

Several efficient one-pot protocols for the synthesis of diaryliodonium salts have been developed in our group over recent years (Scheme 6).23 The synthesis of diaryliodonium salts, from either aryl iodides and arenes or by in situ iodination of an arene using molecular iodine, is illustrated in Scheme 6a.23a-c 3-Chloroperbenzoic acid (mCPBA) is employed as the oxidizing agent and TfOH is used both to activate the oxidant and to provide the anion in the salt. This method proved to be very general and simple as the salts were prepared in only 10 minutes at room temperature and purified by precipitation with ether from the crude reaction mixture. A more environmentally benign version of the protocol was subsequently developed where urea-hydrogen peroxide was used as the oxidant instead of mCPBA, and Tf2O was used as the activator (Scheme 6b).23d A regiospecific one-pot reaction, employing mCPBA and boron trifluoride etherate was developed in order to overcome regiochemistry limitations imposed by the EAS reaction (Scheme 6c).23e Using an arylboronic acid in place of the arene, diaryliodonium salts with alternative substitution patterns could be prepared as an ipso attack of the boron-bearing carbon provides the desired C-C bond. Symmetric and unsymmetric tetrafluoroborate and triflate salts could be synthesized in high yields.

IIII

Deactivating

ActivatingI I

R

byproduct formation

Major Regioisomer

L

LR

+

R = EDG

R = EWG

X X

R+

IX R

7

Scheme 6. One-pot protocols for the synthesis of diaryliodonium salts.

1.3 Applications of Diaryliodonium Salts

1.3.1 α-Arylation of Carbonyl Compounds α-Arylated carbonyl compounds occur widely in natural products and pharmaceutically active compounds. Standard procedures for synthesis of α-arylated carbonyl compounds often require toxic reagents and/or harsh reaction conditions.24 The introduction of diaryliodonium salts into this field enabled the use of milder reaction conditions and eliminated the need for toxic reagents. In 1960 Beringer and co-workers reported the first α-arylation procedure using diphenyliodonium chloride, albeit in low yields and with diphenylated byproducts (Scheme 7).25

Scheme 7. The first reported α-arylation reaction with diaryliodonium salts.

Many α-arylation protocols using diaryliodonium salts have since been reported. Oh and co-workers demonstrated the arylation of substituted malonates with various para-substituted diaryliodonium salts in high yields.26 They observed a transfer of the most electron-deficient aryl group to the nucleophile in arylations with unsymmetric diaryliodonium salts.

+or

I2 +

mCPBA, TfOH IR1 R2

TfO

up to 94%CH2Cl2, rt, 10 min - 21 h

Ar1 I Ar2 H

Ar H

a.

H2O2⋅urea, Tf2OCH2Cl2/TFE, 40 °C, 3 h

IR2

TfOI

R2+

up to 86%R1 R1

b.

rt, 15 min

IR1

mCPBA, BF3⋅OEt2CH2Cl2, rt, 30 min

B(OH)2R2 I

R1 R2

BF4

up to 88%

c.

O

O

OH

O

O

OH

PhO

O

PhPh

Ph2IClt-BuONa

+

22% 23%

8

There are only a few reports on asymmetric α-arylation of carbonyl compounds with diaryliodonium salts. Ochiai and co-workers reported the first asymmetric α-arylation of carbonyl compounds with enantiopure diaryliodonium salts in 1999. 1,1’-Binaphthyl-2-yl(phenyl)iodonium tetrafluoroborates were used to arylate β-keto esters in moderate yields and enantiomeric excesses (Scheme 8).10

Scheme 8. Asymmetric phenylation with chiral diaryliodonium salt.

Aggarwal and Olofsson reported a total synthesis of (–)-epibatidine, where the key step was an asymmetric α-arylation of a substituted cyclic ketone. Employing the chiral Simpkins’ base enabled the reaction to proceed in an asymmetric fashion with high diastereoselectivity and enantioselectivity, albeit in moderate yields (Scheme 9).27

Scheme 9. Asymmetric synthesis of (–)-epibatidine.

1.3.2 Cross-Coupling Reactions The outstanding leaving-group ability of iodobenzene makes iodonium salts more reactive than aryl halides, and the salts are therefore commonly used in metal-catalyzed cross-coupling reactions. The use of diaryliodonium salts in C-H bond arylation is an excellent example of how versatile the salts are. Zaitsev and Daugulis reported selective ortho-arylation of anilides employing PdII catalysis in high yields (Scheme 10a).28 Phipps and Gaunt reported a remarkable protocol in 2009, in which anilides where selectively meta-arylated (Scheme 10b).14c The use of 10 mol% Cu(OTf)2 with diaryliodonium triflates or tetrafluoroborates resulted in a highly electrophilic Cu(III)-aryl species, which selectively adds to the arene meta to the amino substituent, enabling meta-arylated products to be obtained in

I Ph

BF4R

O

CO2Met-BuOK

O

t-BuOH, rt, 20 hCO2MePh

37% yield, 53% ee

O

N(Boc)2

1. 2 equiv , THF, -118 oCPh NLi

Ph

2. DMF, -45 oC

O

N(Boc)241%, d.r. >20:1, 94% ee

HN N

Cl

(−)-epibatidine6 steps31% overall yield

N

Cl

N N

I

Cl Cl

Cl

9

moderate to good yields. In metal-catalyzed reactions the more electron-rich or the least sterically hindered aryl group is generally transferred to the nucleophile.14c, 29

Scheme 10. Ortho- and meta-selective C-H arylation.

There are only a few metal-free C-C cross-coupling reactions reported with diaryliodonium salts, even though the demand for more environmentally benign reaction conditions is increasing. The first cross-coupling of unfunctionalized aromatic compounds was reported by Kita.30 The reaction proceeds via an α-thienyliodonium tosylate, and sequential addition of TMSBr and an arene afforded the biaryl product in high yield (Scheme 11).

Scheme 11. Metal-free cross-coupling reaction.

1.3.3 Arylation of Heteroatom Nucleophiles The synthesis of diaryl ethers from diaryliodonium salts and phenols was first reported by Beringer in 1953 (Scheme 12).31 Several protocols have since been published but the reactions still required prolonged reaction times and high temperatures.32 Protic solvents such as water are often used, which is detrimental to the reactivity, as the oxygen nucleophile can hydrogen bond to the solvent and therefore become less reactive.33

Scheme 12. Original phenylation protocol by Beringer.

HN O

R

HN O

R

HN O

R

Ph

PhCu(II) catalysis

Ph2IBF4

Pd(II) catalysis

Ph2IPF6

meta-arylationortho-arylation

a. b.

42-98%

I

Ph

XS

R2

1,3-dimethoxybenzeneTMSBr, HFIP, rt

S

R2

MeO

OMeR1 R1

PhOHI

Br

MeOH, reflux, 24 h+

1 equiv5 equiv

OPh

76%

NaOMe (5 equiv)

10

Nitrogen nucleophiles can be arylated with diaryliodonium salts, as shown by Carroll and Wood in 2007 (Scheme 13).34 In their arylations with unsymmetric salts, they observed the transfer of the most electron-deficient arene in the salt, which also had been observed with other nucleophiles.35

Scheme 13. Arylation of anilines.

The usage of diaryliodonium salts in the field of fluorine-18 labeling has increased intensively.36 [18F]fluoride ions can be introduced onto both electron-rich and electron-deficient arenes by a reaction with diaryliodonium salts. The need for reagents such as [18F]F2 is therefore avoided.

1.3.4 Other Applications Diaryliodonium salts are mostly used in arylation reactions but they nevertheless find applications outside this field. Kitamura and co-workers reported generation of benzynes through diaryliodonium salts in 1999 (Scheme 14).37 The benzyne intermediate could be trapped with various dienes to give cycloaddition products in high yields. Diaryliodonium salts have also been employed in photochemistry,38 polymerizations39 and macromolecular chemistry.40

Scheme 14. Benzyne generation with hypervalent iodine.

1.4 Mechanistic Considerations Chen and Koser proposed a mechanism for the formation of α-phenyl ketones from silyl enol ethers, in which they postulate that an enolate performs a nucleophilic attack on the iodine with either the oxygen or the carbon, giving intermediate A or B respectively (Scheme 15).41 The α-arylated product is then obtained through either a reductive elimination or a radical reaction.

ArNH2 +DMF, 130 °C, 24 h

IX H

NAr

50-92%

I Ph

TMS

TfO

Bu4NF O

O

11

Scheme 15. Suggested mechanism for α-arylation of carbonyl compounds.

Ochiai and coworkers performed a mechanistic study on the phenylation of β-keto ester enolates with diaryliodonium salts. An aryl radical trap was added to the reaction without affecting the outcome, which indicates that radical pathways are unlikely.42 More recently, computational studies have indicated that an enolate reacts either with a neutral iodine(III) molecule A or a cationic compound B, which would lead to an O-I intermediate (C) or a C-I intermediate (D) respectively (Scheme 16). However, the isomerization barrier between the two different pathways is small and thus a fast equilibrium between C and D is likely. The product is formed via a [2,3] rearrangement from the O-I intermediate and a [1,2] rearrangement from the C-I intermediate, with the first pathway being favored.

Scheme 16. Calculated reaction pathways in the arylation of enolates.

Ozanne-Beaudenon and Quideau reported a thorough investigation on dearomatization of phenols with diaryliodonium salts, where they discounted the radical mechanism.43 Addition of a radical scavenger

R1R2

OLiX

R1R2

O IPh

Ph and/or R1

OLiI Ph

Ph

R1

OPh

I+R1

R2

O

PhI Ph

A BA

BR3 R3

R2 R3

R3

R2 R3

Ph I Ph

Ar IAr

L

Ar IAr

L R

O+

R

O I Ar

Ar

R

OI Ar

Ar

R ArO

O-I bondforms

C-I bondforms

[2,3]

[1,2]

A

B

C

D

fast

12

(1,1-diphenylethylene, DPE) to their system did not affect the outcome of the reaction and therefore a radical mechanism is unlikely.

1.4.1 Chemoselectivity When using unsymmetric salts it has been shown that the most electron-deficient aryl group is transferred to the nucleophile with varying selectivities (Scheme 17). A fast pseudorotation occurs between intermediates A and B, which provides two different transition states C and D.10 A partial negative charge will develop as the nucleophile interacts with the ipso carbon of the aryl group that is to be transferred. The more electron-deficient aryl group will be more able to stabilize this negative charge than the more electron-rich aryl group, which makes transition state D more favorable. The electron-rich aryl group can also stabilize the positive charge on the iodine(III) more effectively than an electron-deficient aryl group.42

Scheme 17. Chemoselectivity of the reductive elimination.

The so-called ortho-effect can sometimes be seen in reactions between a nucleophile and a diaryliodonium salt where one aryl ligand is ortho-substituted. In such reactions the ortho-substituted arene is often transferred, even if it is more electron-rich.44 This can be rationalized by the most bulky aryl ligand and the two lone pairs occupying the equatorial position for steric reasons in the Nu-I intermediate (Scheme 18). This will lead to a reductive elimination and transfer of the aryl group situated in the equatorial position, with a substituent in ortho position, even though it is the more electron-rich.

I

Nu

EDG

EWG

I

Nu

EWG

EDG

Ψ

INu

EDG

EWG

δ+

INu

EWG

EDG

δ+

Minor path

Major path

Nu

EDG

I

EWD

Nu

EWG

I

EDG

+

+

δ−

δ−

Favored

A

B

C

D

13

Scheme 18. T-shaped model of the iodine(III) intermediate.

1.5 Objective The objective of this thesis has been to develop a wide range of synthetic procedures for the preparation of hypervalent iodine(III) compounds. We envisaged a facile one-pot synthesis of electron-rich diaryliodonium salts as a further development of the previous one-pot procedures. The developed protocols were assumed to aid the synthesis of novel hypervalent iodine compounds that had previously been difficult to synthesize. The chemistry of hypervalent iodine(III) compounds in organic synthesis was thought to be broadened by employing products from the developed protocols in applications such as arylation reactions.

NuI+

Me

I

Nu

Me

15

2. One-pot Synthesis of Electron-Rich Diaryliodonium Salts (Paper I)

The TfOH-mediated protocol previously developed within the group was not without limitations.23a, 23b The synthesis of diaryliodonium salts from electron-rich precursors proved problematic due to over-oxidation of the arenes under the highly acidic conditions (see Scheme 6a). We therefore aimed at finding conditions that would enable the one-pot synthesis of electron-rich diaryliodonium salts. It was hypothesized that use of a weaker acid would prevent over-oxidation of electron-rich arenes, enabling the synthesis of electron-rich salts.

2.1 Results and Discussion

2.1.1 Optimization A number of acids were screened together with molecular iodine, anisole (1a) and mCPBA, in hope of finding a suitable acid for the synthesis of electron-rich diaryliodonium salt 2a (Table 1). TfOH and perchloric acid were too reactive as expected, while both p-toluenesulfonic acid (TsOH) and trifluoroacetic acid (TFA) gave promising yields at elevated temperatures (entries 1-4). Further optimization was carried out using TsOH (entries 6-9). The yield was improved from 73% to 89% by carrying out the reaction at room temperature for 14 h (entry 6). The stoichiometry of acid was also optimized and it was found that 3 equivalents of acid were sufficient for obtaining obtain the desired salt in good yields (entries 7-9). Slow decomposition of the product was observed upon prolonged heating (cf. entries 8 and 9).

16

Table 1. Screening of acids and optimization.a

Entry Acid (equiv) Temp (°C) Time Anion (X) Yieldb (%)

1 TfOH (4) 0 10 min OTf 0c

2 HClO4 (4) rt 30 min ClO4 0c

3 TsOH (4) 80 10 min OTs 73

4 TFA (6) 60 30 min O2CCF3 64

5 AcOH (6) 60 1 h OAc 0

6 TsOH (4) rt 14 h OTs 89



9 TsOH (2) 80 14 h OTs 61 a I2 (1 equiv), 1a (4 equiv) and mCPBA (3 equiv) in CH2Cl2 were used in all reactions. b Isolated yields. c Black tar was formed, no product could be isolated.

2.1.2 Symmetric Salts The optimized reaction conditions were applied to various arenes to explore the scope of the developed procedure (Table 2). Thiophene afforded salt 2b in acceptable yield, both at room temperature and at 40 ºC (entries 2 and 3). Since the alkyl-substituted arenes are less electron-rich, the reactivity of these arenes is lower and either longer reaction times or elevated temperatures were needed to obtain salts 2c-f (entries 4-8). Toluene gave a regioisomeric mixture of the symmetric salt 2f and the unsymmetric salt 2f’ in a 2:1 ratio due to the possibility of iodination occurring both para and ortho to the methyl substituent (entry 8). Unfortunately, diphenyliodonium tosylate 2g could not be obtained directly from molecular iodine and benzene. 2,2,2-Trifluoroethanol (TFE) had previously been reported to enhance the reaction rate of hypervalent iodine compounds with arenes.45 This phenomenon was also observed in this reaction when a 1:1 mixture of TFE and CH2Cl2 was used as the solvent. Higher yields were obtained than in pure CH2Cl2 for some of the salts (entry 7 and Table 3).

OMe

mCPBA, HXCH2Cl2

I2 + 4 2IX

OMeMeO1a 2a

17

Table 2. Application to various arenes.a

Entry Arene 1 Temp (°C) Time Product 2 Yield

(%)b

1

1a rt 14 h

2a 89

2 3

1b 1b

rt 40

14 h 15 min

2b 2b

66 68

4

1c rt 20 h

2c 59

5

1d 80 1 h

2d 66

6 7c

1e 1e

rt 80

18 h 30 min

2e 2e

10 76

8

1f 80 10 min

2f 2f’ 49d

9

1g 80 1 h

2g 0e

a Iodine (1 equiv), 1 (4 equiv), mCPBA (3 equiv) and TsOH (3-4 equiv) were used in all reactions. b Isolated yields of 2. c TFE was used as co-solvent. d Regioisomeric mixture (2:1). e No reaction took place.

ArH I2+mCPBA, TsOH⋅H2O

1 2

Ar I ArTsO

CH2Cl2

MeO

I

MeO OMe

TsO

SS SITsO

I

TsO

I

TsO

t-Bu

I

t-Bu t-Bu

TsO

ITsO

I

TsO

ITsO

18

Unfortunately, the facile purification in the previously developed procedure with TfOH, where ether was added to the concentrated crude reaction mixture to precipitate the salt, could not be applied to this procedure. Since an excess of TsOH is needed in the reaction, the treatment with ether also precipitated the remaining TsOH and the salts had to consequently be purified by column chromatography.

2.1.3 In Situ Anion Exchange Diaryliodonium triflates are generally more desirable than the corresponding diaryliodonium tosylates, due to the non-nucleophilic properties of the triflate anion.14a, 14b, 46 Therefore an investigation was carried out in order to see whether an anion exchange from the tosylate 2a to the triflate 3a could be achieved. Fortunately, it was discovered that addition of one equivalent of TfOH at room temperature to the crude reaction mixture, after complete conversion to the tosylate salt, followed by 1 hour of stirring resulted in a complete in situ anion exchange, yielding 3a in 71% (Scheme 19). The in situ anion exchange provides a one-pot route for the synthesis of electron-rich diaryliodonium triflates that are unobtainable by the TfOH-mediated reaction (see Scheme 6a).

Scheme 19. In situ anion exchange.

2.1.4 Unsymmetric Salts The one-pot procedure mediated by TsOH could also deliver unsymmetric salts 5 from aryl iodides 4 and arenes 1 in high yields (Table 3). Iodobenzene 4a was reacted with biphenyl 1h to give salt 6b (entry 3). This salt was not accessible previously via the TfOH-mediated protocol.23a, 23b Alkyl-substituted arenes could also be employed, affording the corresponding salts in good to excellent yields (entries 4-8). Notably, synthesis of diphenyliodonium tosylate 2g was achieved from 4a and benzene in 85% yield (cf. Table 2, entry 9 and Table 3, entry 8), which indicates that the iodination step is more difficult than the oxidation. 1-Iodonaphtalene, which is both electron-rich and sterically hindered, was also successfully employed, affording unsymmetric salt 5h on reaction with mesitylene, albeit in moderate yield (entry 9).

MeOI2+

40 °C, 15 minMeO

I)2 TfOHrt, 1 h

1a 2a 3a 71%

mCPBA, TsOH⋅H2OTsO

MeO

I)2TfO

19

Table 3. Synthesis of diaryliodonium salts from aryl iodides.a

Entry ArI 4 ArH 1 Salt 5/6 Yield (%)b

1c

4a 1a

5a 6a

100 100d

2e 4a 1b

5b 98

3e 4a

1h

5c 6b

50 48d

4c,e 4a 1c

5d 97

5c,e 4a 1d

5e 79

6 4a 1e

5f 72

7 4a 1f

5g 79f

8 4a 1g

2g 85f

9e

4b 1c

5h 34

a 4 (1 equiv), 1 (1 equiv), mCPBA (1 equiv) and TsOH (1-2 equiv) in CH2Cl2. b Isolated yields of 5. c The arene was added after 1 h. d Isolated yields of 6 after in situ anion exchange. e TFE was used as co-solvent. f NMR yield, salt could not be separated from TsOH.

Ar1I Ar2H+ TfOHrt, 1 h

4 1 5 6

mCPBA, TsOH⋅H2OAr1 I Ar2

TsOAr1 I Ar2

TfO

I I

OMe

X

ITsO

S

Ph

I

Ph

X

ITsO

I

TsO

ITsO

t-Bu

I

TsO

ITsO

I I

TsO

20

To prevent side reactions between the oxidant and the arene, this reaction was initially run in a stepwise manner, with formation of [hydroxy(tosyloxy)iodo]benzene (Koser’s reagent, HTIB)47 and subsequent addition of the arene 1c. However, in this case the one-pot procedure proved to be more efficient than the stepwise protocol, which failed to yield 5h. All reactions were found to be completely regioselective yielding only para-substituted salts. Using TFE as a co-solvent simplified the purification, as 1 equivalent of TsOH was now sufficient and treatment of the crude reaction mixture with ether precipitated the pure salt. The in situ anion exchange could also be employed in the synthesis of unsymmetric salts. In the case of both salts 6a and 6b the anion exchange took place in almost quantitative yield (entries 1 and 3). The main limitation of this novel protocol became apparent when employing more electron-deficient arenes, such as fluorobenzene, where tosylate salt 5i was identified as the only product (Scheme 20). This is the product of a reaction between oxidized iodobenzene and the aryl moiety of TsOH, rather than with the desired fluorobenzene.

Scheme 20. Byproduct formation by reaction with TsOH.

2.1.5 Mechanism The mechanism for the synthesis of diaryliodonium salts has not been established but a proposed mechanism is shown in Scheme 21. The iodoarene attacks the protonated mCPBA, forming a reactive iodine(III) compound, which is further activated with a second equivalent of TsOH. An electrophilic aromatic substitution reaction then occurs between the arene and the highly reactive hypervalent iodine compound, completing the synthesis.

+II

F

TsOmCPBA, TsOH⋅H2O

CH2Cl2, 80 °C5i

21

Scheme 21. Proposed mechanism for the synthesis of diaryliodonium salts.

2.2 Conclusion An efficient one-pot synthesis of both electron-rich and electron-neutral diaryliodonium salts has been developed, employing TsOH in combination with mCPBA. Both symmetric and unsymmetric salts can be synthesized in high yields, either starting with molecular iodine and arene or with iodoarene and arene. The tosylate salts can easily be converted to previously unobtainable electron-rich diaryliodonium triflates with a simple in situ anion exchange. We have later discovered that an aqueous anion exchange with NaOTf works as well (see appendix B)

I

HO O O

Ar

H

mCPBA

TsOH

OxidationIOH TsOH

Activation

H2O

Activation

mCBATsO

IOTs R I

R

EAS

TsO

TsO

23

3. Large Scale Synthesis of Koser’s Reagent and Derivatives (Paper II)

The first synthesis of [hydroxy(tosyloxy)iodo]benzene (HTIB) was reported in 1970 by Neilands and Karele.48 Gerald Koser discovered and developed several applications of this iodine(III) compound, which is now commonly referred to as “Koser’s reagent” in the chemical literature. The range of applications with this versatile reagent expanded over the following decades to include oxidation of olefins, ring contractions and expansions, dearomatization of phenols, synthesis of iodonium salts, and α-oxidation of carbonyl compounds (Figure 5).4c, 4d, 30, 49

Figure 5. Applications of HTIBs in organic synthesis.

In the one-pot synthesis of diaryliodonium tosylates described in Chapter 2, the likely intermediate is a Koser’s reagent derivative (see Scheme 21), which is not isolated but further reacted with an arene to deliver the salt. Our group subsequently developed a fast and efficient synthesis of a wide range of electron-deficient and electron-rich HTIBs starting with either an iodoarene or molecular iodine and an arene (Scheme 22).50 The reaction rates were increased compared to previously reported oxidations of iodoarenes by the use of TFE as co-solvent. The method represented the first synthesis of HTIBs directly from iodine and an arene.

I OTsHO

R

RO

R

OOTs

S Ar S

TMSR

I

R RArI

R

TsO

TsO CH(OMe)2ArH

ArH

24

Scheme 22. Previously developed protocol for the synthesis of HTIBs.50

3.1 Synthetic Strategy The previously developed methodology utilized a CH2Cl2/TFE (1:1) solvent, which has been widely used in hypervalent iodine chemistry to enhance reaction rates.45b, 50-51 In large-scale syntheses designed for the industry, it is of great importance to bear in mind the environmental aspects of a protocol, as well as health and safety concerns.52 When designing a large-scale reaction, it is desirable to have both high atom economy and to make use of non-toxic and recyclable solvents and reagents where possible. We set out to develop a large-scale synthesis where the chlorinated solvent was avoided due to its toxicity, and carried out the reactions in neat TFE. Since the change in solvent would also increase the total cost of the reaction, the TFE should be recovered and recycled, which is also preferable from an environmental point of view.

3.2 Optimization Initially, iodobenzene (4a) was used as a substrate to determine whether the desired reaction could be performed in neat TFE (Scheme 23). The result was promising as 82% of the desired product 7 was isolated, which is comparable to the original protocol (94% yield). The lower yield can be explained by the fact that pure TFE can promote other reaction pathways as well, such as SET mechanisms.45b

IR

mCPBA, TsOH⋅H2OCH2Cl2/TFE 1:1, rt

IHO OTs

R

R1+I2 2 2

mCPBA (3 equiv)R2SO2OH (2 equiv)CH2Cl2/TFE 1:1, rt

IHO OSO2R3

R1

up to 95%

up to 88%

25

Scheme 23. Initial optimization reaction in neat TFE.

As HTIBs are used as electrophiles in various organic reactions, an electron-deficient analogue of Koser’s reagent can enhance the reactivity of the substrate and 3-iodobenzotrifluoride (4c) was therefore selected as the model substrate for further optimization reactions.53 The oxidization of an iodine(I) compound to iodine(III) by mCPBA is not generally initiated until acid is added to activate the oxidant. The mixing order of the different reagents can thus become a concern, with electron-rich arenes, as a fast exothermic reaction can occur. To make a more general procedure we therefore decided to firstly dissolve the mCPBA and the iodoarene in TFE and subsequently add TsOH. After completion of the reaction, the solvent was removed and diethyl ether was added to the crude reaction mixture to precipitate the product that was filtered and washed with additional diethyl ether. A small time and temperature study was performed, which revealed that a slightly elevated temperature was required to obtain product 8 in high yield (Table 4, entries 1-2). Reduced yield was observed however with longer reaction times at 40 °C (entry 3). The reaction was somewhat sensitive to temperature, as the yield decreased when the reaction was conducted at 80 °C, possibly due to partial decomposition of the product (entry 4). Table 4. Temperature and time optimization.a

Entry Temp (°C) Time (h) Yield (%)

1 rt 2 67

2 40 1 90

3 40 2 83

4 80 1 76 a mCPBA (1 equiv) and 4c (1 equiv) was dissolved in TFE, followed by addition of TsOH (1 equiv).

I OTsHOI mCPBA (1 equiv)

TFE, rt, 35 min

7 82%4a, 1 equiv

TsOH⋅H2O (1 equiv)


TFE (0.1 M)TsOH⋅H2O (1 equiv)

F3C F3C84c

26

Due to the decomposition of the product at elevated temperature, the recovery of TFE by distillation had to be performed at reduced pressure (86 mmHg at 40 °C). The optimized reaction conditions were applied to a large-scale synthesis as shown in Scheme 24. The length of the condenser turned out to be critical to recovering the solvent in appreciable quantities. Only a sufficiently long condenser was able to collect adequate amounts of the solvent (>90%) due to the low boiling point of TFE (77-80 °C at 760 mmHg). The product was precipitated from the crude residue by addition of diethyl ether, after removal of the solvent by distillation. As 8 is nearly insoluble in TFE the product could be isolated without distillation of the solvent if solvent recovery is of no interest.

Scheme 24. Optimized reaction conditions for the large-scale synthesis of 8.

3.3 Conclusion A large scale synthesis of [hydroxy(tosyloxy)iodo]-3-trifluoromethylbenzene 8 was developed where neat TFE was used as the solvent. The solvent can be recovered and recycled, which is desirable from an environmental point of view. The optimized large-scale protocol was repeated several times and the desired product was constantly obtained in 94-95% yield, which indicates high reproducibility of the procedure.


TFE (65 mL), 40 °C, 1 hTsOH⋅H2O (1 equiv)

F3C F3C8

7.45 g 95%4c

4.62 g

27

4. Asymmetric Synthesis of Chiral Diaryliodonium Salts (Paper III)

The synthesis of organic compounds with an α-arylated carbonyl moiety is of considerable interest. It has been shown that many compounds with these features possess interesting pharmacological and biological properties.54 There are two main ways of synthesizing these compounds from an enolate: nucleophilic aromatic substitution,55 which is limited by the necessity of electron-withdrawing substituents on the aryl moiety, and transition metal catalysis.56 Although the transition metal-catalyzed α-arylation reactions are fairly efficient, they suffer from disadvantages including cost and toxicity. In addition, the reactions are often run at elevated temperatures and the reaction times are relatively long. The reactions are also often limited to form only quaternary centers.57 Reactions employing diaryliodonium salts offer milder reaction conditions, less toxic reagents and easier handling, which makes the reactions more attractive, not only from an environmental but also from an industrial point of view. There have recently been several reports on the application of diaryliodonium salts in metal-mediated asymmetric α-arylation of carbonyl compounds with excellent results,29 however there are only a few examples of asymmetric reactions in which chiral enantiopure diaryliodonium salts are employed. Ochiai and co-workers reported the synthesis of enantiopure 1,1’-binaphthyl-2-yl(phenyl)iodonium tetrafluoroborates in 1999, by treatment of a preoxidized iodine(III) compound with a stannane.10 Zhdankin and co-workers have also reported an enantiomerically pure salt, which was synthesized in a similar fashion (Figure 6).58

Figure 6. Enantiopure diaryliodonium salts in the literature.

I Ph

BF4R

IO

NHO

MeO

PhTfO

Ochiai 1999 Zhdankin 2003

28

As there are only a few reports on the asymmetric α-arylation of carbonyl compounds, we set out to develop the synthesis of three enantiopure diaryliodonium salts, which would subsequent be used in arylation reactions.

4.1 Synthetic Strategy When unsymmetric diaryliodonium salts are employed, it has been shown that the most electron-deficient aryl moiety will generally be transferred to the nucleophile in the reductive elimination.10b, 26, 35b We therefore envisioned a diaryliodonium salt where one of the aryl moieties would be more electron-rich and have substituents bearing stereocenters. The substituents would be located ortho to the iodine and possess steric bulk in order to promote asymmetric induction in the transfer of the other, more electron-deficient aryl group to the nucleophile. When using the chiral salt in an α-arylation reaction, the chiral aryl iodide would be recovered and reoxidized, re-forming the chiral salt so that the reaction proceeds with good atom economy (Scheme 25).

Scheme 25. Expected chemoselectivity in the arylation of enolates.

Figure 7 shows the structures of the three salts that we set out to synthesize. The previously developed one-pot synthesis of electron-rich diaryliodonium salts, mediated by TsOH and mCPBA (Chapter 2), was thought to be suitable for the synthesis of the planned electron-rich salts I-III. The protocol would also enable the reoxidation of the recovered enantiopure iodoarene. This strategy had to be abandoned however, as many problems were encountered in the synthesis of the three target compounds, and we had to change approach several times.

R

O 1. Base

2. R

O

Ph

Ar I

recover and reoxidize

IPhAr

∗

∗

X

29

Figure 7. Retrosynthetic analysis.


4.2.1 Synthesis of Monosubstituted Chiral Salt I An enzymatic kinetic resolution of alcohol 9 with CALB (Candida Antarctica lipase B) and isopropenyl acetate (10) as acyl donor afforded enantiopure alcohol (R)-9 in 42% yield and >99% ee (Scheme 26).59 A catalytic amount of Na2CO3 was found to be crucial for complete conversion. The reason is that the weak base prevents isopropenyl acetate from hydrolyzing into acetic acid and acetone in presence of water in the reaction mixture. The reverse reaction, whereby the resulting acetate 11 is hydrolyzed, is also prevented in the presence of Na2CO3.

Scheme 26. Enzymatic kinetic resolution of 2-octanol.

The enantiopure alcohol was mesylated to give (R)-13 in 99% yield. 2-Iodophenol (12) was then alkylated with (R)-13 to deliver the desired iodoarene 14, with no loss of enantiomeric purity (Scheme 27). Attempts to oxidize 14 using the TsOH protocol proved to be problematic, possibly due to steric hindrance from the ortho-substituent. The oxidation was instead accomplished using the boronic acid protocol, (see Scheme 6c) with some slight modifications. As attempts to oxidize 14 at

O

O

IX

( )5

( )5

O

O

IX

( )5

( )5

O( )5

OI

X

( )5

IOHO

I

( )5

OH

( )5+

I II III

OHOAc

CALBNa2CO3, i-Pr2O

+

42%, >99% ee

( )5

(R)-9

OAc

( )5

OH

( )5

rac-9 11

10

30

ambient temperature in the presence of BF3⋅OEt2 led to decomposition, pre-oxidation of 14 had to be accomplished with mCPBA at elevated temperature, followed by cooling to −78 °C and addition of phenylboronic acid and BF3⋅OEt2. Diaryliodonium salt 15 and 16 could then be isolated in modest yield (Scheme 27). Salt 16 which is not separable from 15, is a byproduct which can be explained by incomplete oxidation of 14, resulting in a competing undesired EAS reaction between 14 and the iodine(III) intermediate.

Scheme 27. Synthesis of monosubstituted diaryliodonium tetrafluoroborate.

As it was clear that the substituent was acid-sensitive and byproduct formation was detected, we decided to change strategies and use basic conditions. Lithiation of 14, followed by reaction with vinyliodonium triflate 17,20a yielded the enantiopure diaryliodonium triflate 18 (Scheme 28, Pe = Pentyl).

Scheme 28. Synthesis of monosubstituted triflate salt 21.

4.2.2 Synthesis of Disubstituted Chiral Salt II Several conventional sets of reaction conditions were examined for the alkylation of 2-iodoresorcinol (19)60 with either mesylate rac-13 or the

OH

K2CO3, MeCNI 1. mCPBA, 80 °C

2. PhB(OH)2, BF3.OEt2, -78 °C

OMs

( )5 OI

( )5

OI

( )5

BF4

+

OI

( )5

BF4

I

O

( )5

(R)-13

15 17% 16 ≤ 9%

14 93%, >99% ee12

OI

( )5

n-BuLiTHF

Pe

TfO I

HPhTfO

Et2O, -78 °C to rt

17O

I

( )5

TfO

14 18 38%

31

corresponding tosylate rac-22. However, the results were poor and unreacted starting materials could always be recovered. The most encouraging result was obtained with the use of alcohol rac-9 under Mitsunobu conditions,61 which yielded iodoarene 20 in 33% yield (Scheme 29a.). Attempts to oxidize 20 with the TsOH protocol proved again to be problematic since the substituents in ortho position did not tolerate the acidic conditions. Decomposition was observed even at low temperatures and using BF3⋅OEt2 and phenylboronic acid gave similarly negative results. The characteristic protons on the aliphatic oxygen-bearing carbon atoms could never be detected in 1H-NMR of the crude product.

Scheme 29. Attempted synthesis of disubstituted salt II.

As both the synthesis of 20 and further conversion to the desired target salt II proved to be difficult we decided to change approach and employ the boronic acid protocol.23e Alkylation of 2-bromoresorcinol62 with tosylate rac-22 afforded disubstituted bromoarene 23, which was subsequently lithiated and treated with triisopropyl borate to finally afford arylboronic acid 24 (Scheme 29b). Unfortunately, all attempts at converting 24 to the corresponding diaryliodonium salt failed, both when using the one-pot method previously developed in the group23e and when applying preformed iodine(III) reagents such as (diacetoxyiodo)benzene or Koser’s reagent.17b We were once again forced to change approach and use the basic conditions, which had proved fruitful in the synthesis of the monosubstituted salt. The disubstituted salt was synthesized from 23 in 44% yield by lithiation and subsequent reaction with 17 (Scheme 30).

OH

OH

IEt3N, PPh3,DIAD, THF

19 20 33%

OH

( )5 rac-9O

O

I

( )5

( )5

mCPBA, acid

PhH or PhB(OH)2

O

O

IX

( )5

( )5

OH

OH

Br

OTs

( )5 rac-22

K2CO3, MeCN1. n-BuLi

2. B(OiPr)3

O

O

Br

( )5

( )5

O

O

B(OH)2

( )5

( )5

a.

b.

Target II

21 23 24% 24 99%

Target II

32

Scheme 30. Successful synthesis of 24.

This methodology was then repeated with enantiomerically pure material. Dialkylation of 2-bromoresorcinol with mesylate (R)-13 proved to be the most efficient way to obtain the required dialkylated bromoarene 25 (89% yield, Scheme 31). Bromoarene 25 was subsequently treated with BuLi and 17, furnishing the disubstituted target compound 26 in 36% yield.

Scheme 31. Synthesis of enantiopure disubstituted diaryliodonium salt 26.

4.2.3 Synthesis of Trisubstituted Chiral Salt III Synthesis of the trisubstituted salt proved to be far more straightforward. Commercially available phloroglucinol (27) was alkylated with rac-13, in the same fashion as previously, to provide compound 28 in 72% yield (Scheme 32). As the arene was symmetric, no regioselectivity issues had to be taken into account, and Koser’s reagent (7) could be reacted with 28 to give the desired diaryliodonium tosylate 29 in 96% yield.16

Scheme 32. Synthesis of the trisubstituted racemic salt 29.

23

Pe

TfO I

HPh

TfO

Et2O, -78 °C to rt

17O

O

I

( )5

( )5

TfO

24 44%

n-BuLiTHF

OH

OH

BrO

O

Br

( )5

( )5

K2CO3, MeCN

OMs

( )5 (R)-13

Pe

TfO I

HPh

TfO

Et2O, -78 °C to rt

17O

O

I

( )5

( )5

TfO

25 89%

21

26 36%

n-BuLiTHF

OH

OHHO27

OMs

( )5 rac-13

K2CO3, MeCN

O

O

( )5

( )5

O( )5

28 72%

CH2Cl2, -10 °C

O

O

( )5

( )5

O( )5

29 96%

ITsOI

OTs

OHPh 7

33

However, alkylation of 27 with enantiopure (R)-13 proved to be unachievable. The optimized reaction conditions shown in Scheme 32 did not yield the desired product and provided mainly mono- and dialkylated arenes. The procedure was therefore abandoned and as an alternative route a nucleophilic aromatic substitution was performed on trifluorobenzene (30) with enantiopure (R)-9 to afford compound 31 in 51% yield (Scheme 33). Compound 31 was subsequently reacted with Koser’s reagent (7) to afford the enantiopure trisubstituted diaryliodonium salt 32 in 82% yield.

Scheme 33. Synthesis of enantiopure diaryliodonium salt 32.

The enantiopurity of 31 or 32 proved to be difficult to determine by chiral GC or HPLC and the reaction between 31 and Koser’s reagent reagent was believed to not affect the enantiopurity. A nucleophilic aromatic substitution was therefore performed on fluorobenzene (33), under the same conditions used for the alkylation of 30 (Scheme 34). As the enantiopurity was retained after the model nucleophilic aromatic substitution, the enantiomeric excess of compound 31 was also expected to be >99.99%.63

Scheme 34. Nucleophilic aromatic substitution on fluorobenzene.

4.2.4 Structural Investigations The surprising difference in the synthesis of 29 and 32 led us to investigate the different structures of the salts. In the racemic synthesis of the trisubstituted salt, three different diastereomers can be formed (Figure 8).

F

FF30

OH

( )5 (R)-9

NaH, NMP, 100 °C

O

O

( )5

( )5

O( )5

31 51%

CH2Cl2, -10 °C

O

O

( )5

( )5

O( )5

(R,R,R)-32 82%

ITsOI

OTs

OHPh 7

33

OH

( )5 (R)-9

NaH, NMP, 100 °CF O

( )5

34 >99% ee

34

Figure 8. Possible diastereomers of 29.

Figure 9 shows a selected region in the 13C-NMR spectra of 29 and 32, where the ortho- and para-substituted carbons are clearly differentiated. The NMR data indicate that two diastereomers of 29 are formed, (R,S,R/S,R,S)-29 and (R,R,S/S,S,R)-29. This indicates that there is a diastereoselective synthesis of only the (R,S,R/S,R,S) diastereomer of arene 28, as only two unsymmetric diastereomers of 29 are detected. This conclusion also explains the different reactivity observed in alkylations of 27 with racemic and enantiopure mesylate 13. The third alkylation becomes more difficult, due to steric hindrance, and thus the conditions needed to be modified for the enantiopure synthesis.

Figure 9. Characteristic peaks in 13C-NMRs of 29 (green) and 32 (red).

O

O

( )5

( )5

O( )5

ITsO O

O

( )5

( )5

O( )5

ITsO O

O

( )5

( )5

O( )5

ITsO

(R,R,R)-29 (R,S,R)-29 (R,R,S)-29+ + +

(S,S,S)-29 (S,R,S)-29 (S,S,R)-29

O

O

C

C

( )5

( )5

OC( )5

ITsO O

O

C

CH

( )5

( )5

OC( )5

ITsO

H

H

H

H

H

29 32

35

4.2.5 Arylation of 2-(Ethoxycarbonyl)cyclohexanone Due to the lack of reports on the successful asymmetric α-arylation of ketones with diaryliodonium salts with high enantioselectivity in the literature, we decided to investigate our enantiopure diaryliodonium salts in reactions with β-keto esters, a substrate that has previously been used with some success.10b, 26 The results obtaining with salt 32 were not encouraging as the product was obtained with both low yields and enantiomeric purity (Scheme 35). One explanation for the poor results could be a ligand exchange in the salt, as recently reported in the literature (see Chapter 6).64

Scheme 35. Attempts toward asymmetric arylation of a carbonyl compound.

4.3 Conclusion Three different enantiopure diaryliodonium salts were synthesized in moderate to high yields. The route toward the three salts varies depending on the structure of the salts. Few examples of enantiopure salts are reported in the literature and the syntheses of these are more difficult than of enantiopure iodine(III) compounds with two heteroatom ligands. The enantiomerically pure trisubstituted salt 32 was used in an α-arylation of a β-keto ester with poor results. Further mechanistic investigations need to be performed in order to design chiral salts that are able to induce high enantioselectivity in arylation reactions.

O

OEt

O1. t-BuOK, t-BuOH2. (R,R,R)-32

O

OEt

O

Ph

18% yield, 10% ee

37

5. Synthesis of Diaryl Ethers (Paper IV and V)

Diaryl ethers are compounds of great importance in organic chemistry and numerous naturally occurring and synthetic compounds that contain this substructure are biologically active (Figure 10).65

Figure 10. Important diaryl ethers.

The conventional method for synthesizing diaryl ethers is the classic Ullmann ether synthesis, with the major drawbacks being harsh reaction conditions and stoichiometric amounts of copper.66 Recently, there have been many modified Ullmann-type reactions reported, with slightly milder reaction conditions and copper used in catalytic amounts.67 With the introduction of copper(II)-catalyzed cross-coupling reactions of phenols with arylboronic acids, diaryl ethers could be obtained in higher yields at room temperature.67-68 Pd-catalyzed coupling of phenols with aryl halides has also been intensely investigated over the last decade. Buchwald and co-workers recently reported a catalytic system that employs a reactive Pd source, that in combination with a ligand allows the synthesis of diaryl ethers under relatively mild reaction conditions.69 As mentioned in Chapter 1, the first synthesis of diaryl ethers from diaryliodonium salts and phenols was reported by Beringer in 1953.31 The

O

I

I

HO

I

I OH

O

NH2

OO OO

O

NH

Cl

Cl

OH

HNO

O

HO

HO

O HN

HOOH

H2N

NH

ONH

OH

OH2NO

HN

OO

OH

HN

OHHO

O

HO

Synthroid

Vancomycin

O

OHRodgersinol

HO

38

more recent protocols still utilize protic solvents that influence the reactivity of the nucleophiles.33 We anticipated that the use of polar aprotic solvents would increase the rate of the reaction between the diaryliodonium salt and the oxygen nucleophile. To this end, it was envisaged that varying the anion of the diaryliodonium salt, to improve the solubility in polar aprotic solvents would have a significant impact on the reaction, as would the nature of the solvent itself.


5.1.1 Optimization The initial optimization reactions were performed using diphenyliodonium triflate 3b and phenol 35a as model substrates. Aprotic solvents were examined and reactions with DMF, toluene, THF and dichloromethane all gave high conversions (>90%), within 4 hours at room temperature, using NaH as base. Acetonitrile gave significantly lower conversion and was therefore discarded. We also wanted to avoid halogenated solvents such as dichloromethane. THF was therefore regarded as the optimal solvent seeing that toluene and DMF both have high boiling points and DMF is further considered to be carcinogenic. Optimization reactions were performed and the results are listed in Table 5. Strong inorganic bases such as NaH, NaOH, KOH, t-BuOK and t-BuONa provided the desired diaryl ether at room temperature, within 4 h and in almost quantitative yields (entries 1-5). Weak inorganic bases such as K2CO3, Na2CO3 and K3PO4 were less efficient in the synthesis of the ether (entries 6-8). These outcomes are probably due to the low solubility of these bases in THF. Raising the reaction temperature to 40 °C afforded the product in quantitative yields within 15 min using either NaOH or t-BuOK (entries 10 and 11). The reaction could also be carried out at room temperature with longer reaction times to give the product in high yields (entries 12 and 13). The effect of the anion of the salt was also investigated. It was shown that salts with OTf, BF4 and Br anions afforded the product in high yields (entries 9, 14 and 15), whereas employing the tosylate salt resulted in the formation trace amounts of product, and the reaction mixture turned black as soon as the salt was added (entry 16). This result could be rationalized by the formation of byproducts by radical reactions as full conversion of the salt to iodobenzene could be observed, but not the corresponding arylated phenol. This theory was supported as the diphenyl ether could be isolated in 88% yield after addition of a radical scavenger (DPE) (entry 17),70 while addition of DPE to a reaction with the triflate salt did not affect the outcome of the reaction (entry 18).

39

Table 5. Optimization of the model reaction.a

Entry Base Salt (X) T (°C) Time Yield (%)b

1 NaH 3b (OTf) rt 4 h 93

2 NaOH 3b (OTf) rt 4 h >99

3 KOH 3b (OTf) rt 4 h >99

4 t-BuOK 3b (OTf) rt 4 h 97

5 t-BuONa 3b (OTf) rt 4 h 99

6 K2CO3 3b (OTf) rt 4 h 32

7 Na2CO3 3b (OTf) rt 4 h 1

8 K3PO4 3b (OTf) rt 4 h 6

9 NaOH 3b (OTf) 40 1 h 99

10 NaOH 3b (OTf) 40 15 min >99

11 t-BuOK 3b (OTf) 40 15 min >99



14 NaOH 37a (BF4) 40 1 h >99

15 NaOH 38 (Br) 40 1 h >99

16 NaOH 2g (OTs) 40 1 h <1

17c NaOH 2g (OTs) 40 1 h 88

18c t-BuOK 3b (OTf) 40 15 min >99

19d NaOH 2g (OTs) 40 1 h 89

20e t-BuOK 3b (OTf) 40 30 min 82 a To a solution of base (1.1 equiv) in THF was added 35a (1.1 equiv) at 0 °C and the mixture was stirred for 15 min. Ph2IX (1 equiv) was added and the reaction was stirred at the tabulated temperature and time. b Determined by GC with 1,4-dimethoxybenzene as internal standard. c DPE (1 equiv) was added. d Toluene was used as solvent. e All reagents added at once, without deprotonation time.

1. Base, THF2. Ph2IX

OOH

35a 36a

40

Performing the reaction with the tosylate salt in toluene, which is known to act as a radical scavenger,71 yielded the product in 89% without need for DPE (entry 19). Adding the salt to the reaction mixture before allowing the base to fully deprotonate the phenol resulted in a slight decrease in yield (entry 20).

5.1.2 Phenylation of Functionalized Phenols The scope of the method was explored by phenylation of substituted phenols with diphenyliodonium triflate 3b and tetrafluoroborate 37a. Diaryl ether 36a could be obtained in excellent isolated yield at 40 °C, from either salt (Table 6, entries 1 and 2). High yields were also obtained by using NaOH or performing the reaction at room temperature (entries 3 and 4). Phenols containing electron-withdrawing substituents could be phenylated in high yields (entries 5-7), and this was also the case for phenols with electron-donating substituents (entries 8-10). One of the major concerns with metal-catalyzed arylation reactions are issues with the chemoselectivity when the starting materials bear more than one halogen substituent.65a Pentachlorophenol was however phenylated in excellent yield with the developed methodology (entry 11). Additionally, para-chlorophenol and both para- and ortho-iodo phenol were phenylated in equally high yields (entries 12-14). Ortho-substituted phenols are also problematic substrates in metal-catalyzed reactions but these compounds were phenylated in high yields (entries 15-17), illustrating the potential of this methodology. Carbonyl-substituted ethers were synthesized both at room temperature and at 40 °C, in moderate to high yields (entries 18-22). Both heteroatom containing and vinyl-substituted phenols can also be phenylated and ethers 36q and 36r were isolated in high yields (entries 23 and 24).

41

Table 6. Phenylation of functionalized phenols.a

Entry Phenol 35 Salt T (°C) Product 36 Yield

(%)b

1

35a 3b

40

36a 93

2 3c

4

35a 35a 35a

37a

40 40 rt

36a 36a 36a

98 95 99

5 35b 3b 40

36b 82

6

35c 3b 40

36c 68

7

35d 3b 40

36d 72

8 9

35e 37a 37a

40 rt

36e 36e

96 99

10

35f 3b 40

36f 79

11

35g 3b 40

36g 99

12

35h 3b 40

36h 97

13

35i 3b 40

36i 87

14

35j 3b 40

36j 89

15

35k 3b 40

36k 75

1. t-BuOK , THF2. Ph2IX (3b/37a)

OHR

OR

35 36

OH ITfO

O

IBF4

OHF3C OF3C

OHNO2 ONO2

OHNC ONC

OHMeO OMeO

OH

MeO

O

MeO

OHCl

Cl

ClCl

Cl

OCl

Cl

ClCl

Cl

OH

Cl

O

ClOH

I

O

IOH

I

O

I

OH O

42

16

35m 3b 40

36m 89

17d

35l 3b 40

36l 99

18 19

35n 3b

37a 40 rt

36n 36n

75 80

20 21

35o 37a

37a 40 rt

36o 36o

97 91

22

35p 37a 40

36p 67

23

35q 3b 40

36q 87

24

35r 3b 40

36r 93

a 35 (1.0−1.1 equiv), t-BuOK (1.1 equiv), and 3b/37a (1.0−1.2 equiv) were used. b Isolated yields. c NaOH as base. d 2 equiv of 3b.

5.1.3 Arylation of Phenols with Symmetric Diaryliodonium Salts The scope of the methodology was further investigated by employing functionalized phenols and symmetric diaryliodonium salts (Table 7). Electron-deficient salt 37b was used to arylate 35a, delivering CF3-substituted ether 36b in 90% yield (entry 1). Electron-rich salt 3a was used to prepare dimethoxy-substituted aryl ether 36s (entry 2). As mentioned previously, the synthesis of sterically hindered diaryl ethers can be problematic in metal mediated reactions. However, using this methodology ortho-substituted salts 37c and 37d were used to arylate phenols 35a and 35d respectively, delivering the desired ethers in good yields (entries 3-5). To our delight, introducing even more steric bulk to the salt 3c did not influence the outcome of the reaction and trimethyl-substituted diaryl ether 36w was isolated in almost quantitative yield (entry 6). However, further increasing the steric bulk in the ortho-position of the phenol resulted in a slight reduction in yield (cf. entries 8-9).

OH O

OHOH

OO

OHO

OO

O

OH

EtO

O

O

EtO

OH

NH

O O

NH

O

N

OH

N

O

OHOMe

OOMe

43

Salt 3d was also employed in a large-scale synthesis of ether 36x, which was isolated in 98% yield (entry 7). The resulting 4-tert-butyliodobenzene that is produced as a byproduct in this reaction could be recovered in quantitative yields and easily oxidized to reform the salt, providing better atom economy in large-scale reactions. The mild protocol also allows the synthesis of ether 36aa, which is a common substructure in pharmaceutics, in excellent yield from quinolin-8-ol (entry 10). Polybrominated diphenyl ethers (PBDEs) are a class of compounds that are widely used as flame retardants. Polyhalogenated diaryl ether 36ab was synthesized in 80% yield under the mild reaction conditions (entry 11). Additional diaryl ethers with alkyl substituents were also synthesized in excellent yields (entries 12-15). Table 7. Arylation of functionalized phenols with diaryliodonium salts.

Entry Phenol 35 Salt Product

36 Yield (%)b

1 35a

37b

36b

90

2

35f 3a 36s

86

3 35a

37c

36t

72

4 35a

37d

36u

90

5 35d

37d 36v

90

1. t-BuOK, THF2.

IR2 R2

X

OHR1

OR1 R2

35 36

OH IBF4

F3C CF3 O CF3

OH

MeO

ITfO

MeO OMe

O

OMeMeO

BF4

IFF

OF

BF4

I O

OHNC ONC

44

6

35k

3c

36w

99

7c 35a

3d

36x

98

8

35s

3e 36y

99

9

35t

3e

36z

81

10

35u

3e

36aa

98

11

35v

3f 36ab

80

12 35e

37d 36ac

>99

13 35e

3g

36ad

93

14 35e

3h 36ae

90

15 35e

3c 36af

96

a 35 (1.0−1.1 equiv), t-BuOK (1.1 equiv), and 3/37 (1.0−1.2 equiv) were used at 40 °C. b Isolated yields. c Performed on a 3.1 mmol scale.

OH ITfO

O

ITfO

t-Bu t-Bu

O

t-Bu

OH

t-Bu

ITfO

Cl Cl

O

t-Bu Cl

OH

t-Bu

t-BuO

t-Bu Cl

t-Bu

OHN

ON

Cl

OHBr

Cl

ITfO

Br Br

OBr

Cl Br

OHMeO OMeO

ITfO

OMeO

ITfO

OMeO

ITfO

OMeO

45

5.1.4 Arylation of Amino Acid Derivatives Diaryl ethers bearing racemization-prone amino acid residues are found in many natural products with medicinal properties.72 Classical Ullmann-type couplings tend to racemize the amino acid moiety, due to the generally harsh reaction conditions. Our mild protocol was therefore applied to the arylation of L-tyrosine derivative 36ag (Scheme 36a). The standard conditions were demonstrated to be adequate, affording the desired product in 95% yield and 99% ee. However, when the same conditions were used for the arylation of the racemization-prone 4-hydroxy-D-phenylglycine (35x),73 only small quantities of the desired product could be isolated. Surprisingly, an unexpected byproduct was isolated and later identified as the tetrahydrofuranylated phenol 39 (Scheme 36b).

Scheme 36a. Arylation of L-tyrosine derivative 35w. b. Byproduct formation in the arylation of 4-hydroxy-D-phenylglycine 35x.

There are previous reports on the tetrahydrofuranylations of alcohols enabled by hypervalent iodine(III) compounds74 and iodonium salts,75 although none where diaryliodonium salts have been utilized. In order to prevent this byproduct formation without resorting to additives, the solvent was changed. The initial optimization studies had revealed that solvents such as toluene and CH2Cl2 gave comparable results to THF and to our delight, the reaction in CH2Cl2 yielded the desired product 36ah in excellent yield and enantiomeric excess (Scheme 37).

Scheme 37. Successful arylation of 4-hydroxy-D-phenylglycine 35x in CH2Cl2.

OH

MeO

O

NHBoc

OH

MeONH

O

Boc

O

MeO

O

NHBoc

36ag95% yield, 99% ee

1. t-BuOK, THF

2. Ph2IBF440 °C, 2 h

O

MeONH

O

Boc

O

MeONH

O

Boc

O

39 21%

+

a.

b.

1. t-BuOK, THF

2. Ph2IOTf40 °C, 35 min

35w

36ah 28%35x

OH

MeONH

O

Boc

1. t-BuOK, CH2Cl2

2. Ph2IBF440 °C, 20 min

O

MeONH

O

Boc36ah

99% yield, 96% ee35x (96% ee)

46

5.1.5 Arylation of Phenols with Unsymmetric Diaryliodonium Salts The use of an unsymmetric diaryliodonium salt can cause chemoselectivity problems. As mentioned previously, it is known that the most electron-deficient arene is generally transferred to the nucleophile. However, the steric bulk of the substituents can also influence the outcome of the reaction.44 Control of the chemoselectivity is therefore clearly a concern when utilizing unsymmetric diaryliodonium salts. We thus synthesized several unsymmetric salts with methoxy substituents on one aryl group in order to investigate this phenomenon (see Chapter 6). It was clear that the number of substituents did not affect the outcome of the reaction, and only phenylated product was obtained in high yields (Table 8, entries 1-6). Several salts with anisyl moieties were subsequently synthesized and used in further arylations of phenols. Both ortho-substituted and electron-deficient arenes were transferred in the reactions in high yields (entries 7-9). Furthermore, pyridyl ether 36al was obtained using unsymmetric salt 6j, thereby avoiding the need for a difficult synthesis of a symmetric pyridyl salt (entry 10).27 Table 8. Arylation of functionalized phenols with unsymmetric diaryliodonium salts.a

Entry Phenol 35 Salt Product

36 Yield (%)b

1

35e

6a

36f

94

2 35e

6c

36f 93

3 35e

6d

36f 82

1. t-BuOK, THF2.

IMeO R2

X

OHR1

OR1 R2

35 36

OHMeO ITfO

OMe

O

MeO

IOMeTfO

IOMeTfO

OMe

47

4 35e

6e

36f 90

5 35e

6f

36f >99

6 35e

6g

36f 85

7 35e

6h

36ai 94

8c

35k

5j

36aj 94

9 35y

6i

36ak

93

10 35k

6j

36al

69

a 35 (1.0−1.1 equiv), t-BuOK (1.1 equiv), and 5/6 (1.0−1.2 equiv) were used at 40 °C. b Isolated yields. c Performed in toluene. When the standard conditions were employed in the reaction between phenol 35z and the extremely bulky salt 37e, several byproducts were formed (Scheme 38a). This outcome can be explained by either a radical byproduct formation (see section 5.1.1) or a ligand exchange in the salt (see section 6.1).64 We decided to carry out the reaction in toluene as we had observed that reactions in toluene showed comparable results to those in THF and toluene had inhibited radical reactions in the optimization study (Table 5, entry 19). Changing the solvent to toluene also allowed us to use the more easily prepared tosylate salt 5k. The exceptionally bulky ether 36am was isolated in satisfactory yield, as the problematic byproduct formation was suppressed in toluene (Scheme 38b).

IOMe

OMe

IOMeTfO

MeO

IOMeTfO

MeO OMe

ITfO

MeO

OMeO

OH I

MeO

CF3TsO

O CF3

OH

NC

ITfO

OEt

OMeO

O

NC OEt

O

I

N

TfO

MeO N

O

48

Scheme 38a. Observed byproduct formation in the reaction of 35z and salt 37e. b. Successful synthesis of bulky diaryl ether 36am.

5.2 Conclusion A fast and efficient method has been developed for the synthesis of diaryl ethers from diaryliodonium salts. Unsymmetric salts and salts with different anions can be employed, which widens the substrate scope considerably. The developed procedure permits facile preparation of products such as halogenated ethers, ortho-substituted ethers and bulky ethers in high yields, both in room temperature and at 40 °C. These are compounds that are generally difficult to obtain with metal-catalyzed procedures. The mildness of the protocol was also demonstrated by the synthesis of racemization-prone amino acid substituted diaryl ethers in excellent yields and enantiomeric excess.

OHt-Bu

I

MeO

i-Pr

i-Pri-Pr

BF4

+ t-BuOKTHF, 40 °C

ArOi-Pr

i-Pri-Pr

Ii-Pr

i-Pri-Pr

i-Pr

i-Pri-Pr

+

35z 37e

a.

+

35zI

TsO

i-Pri-Pr

i-Pr

MeO

t-BuOKToluene, 40 °C

+O

i-Pr

i-Pri-Pr

t-Bu

b.

36am 61%5k

49

6. Chemoselectivity Investigation in Arylations of O, N and C Nucleophiles (Paper VI)

One of the main drawbacks in the application of diaryliodonium salts is the stoichiometric use of the salt, which results in one equivalent of iodoarene as a byproduct in any reaction. It is therefore of large interest to develop catalytic arylation systems in which an unsymmetric diaryliodonium salt is employed. The iodoarene acts as a “dummy” ligand and is reoxidized, reforming the diaryliodonium salt in situ. An advantage of a catalytic system like this would be that re-optimization of the reaction conditions for each arene would be unnecessary. Another approach to achieve greater atom efficiency is to use a polymer-bound diaryliodonium salt. The same principle applies as in this case; the iodoarene that is on solid support will act as a “dummy” ligand. The chemoselectivity in arylation reactions with unsymmetric diaryliodonium salts can however be problematic. As mentioned in Chapter 1, both the electronic and steric properties (the so-called ortho-effect) of the salt and the nucleophile will influence the outcome of which aryl group will be transferred. Even though the field of hypervalent iodine was discovered more than 100 years ago, the mechanism behind reactions with diaryliodonium salts have still not been thoroughly investigated. In order to create efficient catalytic systems that employ diaryliodonium salts, as well as designing polymer-bound reagents, it is important to have a deeper mechanistic insight into reactions with diaryliodonium salts. We therefore set out to study how steric and electronic properties influence the arylation of three different nucleophiles under previously reported conditions.26, 34, 76

6.1 Results and Discussions Figure 11 shows a selection of methyl- and methoxy-substituted unsymmetric salts that were synthesized and used in the investigation. The salts were chosen so that steric bulk and electronic effects would be represented to different extents.

50

Figure 11. Salts employed in the study.

We decided to use 3-methoxy phenol (35e), m-anisidine (40) and diethylmethyl malonate (41) as nucleophiles for the phenylation vs. the arylation study. The choice of nucleophiles gives an indication of possible differences in O, N, and C arylations and the combined yields for the reactions are given in Scheme 39.

Scheme 39. Arylation conditions for a. phenol 35e; b. aniline 40; c. malonate 41.

Results for the arylations of the three nucleophiles using salts 6k-p are listed in Table 9. The chemoselectivity in the arylation of phenol 35e influenced both by the ortho-effect and the electronic properties of the salt. Salt 6k gives a 3:1 preference for phenylation (i.e. electronic factors), while salt 6l gives a 1:2.5 transfer of the aryl group (entries 1 and 2). The two factors contradict each other in the case of salt 6m and 6n, which gives unselective reactions (entries 3 and 4). Two ortho-substituents in salt 6o show a clear ortho-effect (entry 5), while an additional methyl in para position diminish the apparent strong ortho-effect and the reaction becomes less selective (entry 6). Reactions with m-anisidine (40) show preferential phenylation in all cases (entries 1-6), which indicates that the ortho-effect is not important with this nucleophile. One methyl-substituent gives a slight selectivity for phenylation (entries 1 and 2), which is increased with two methyl-substituents (entries 3-5), and mesityl salt 6p gave high selectivity (entry 6).

IPhR

TfO6k R = 4-Me6l R = 2-Me6m R = 2,4-Me26n R = 2,6-Me26o R = 2,4,6-Me36p R = 2,5-OMe2

6a R = 4-OMe6c R = 2-OMe6d R = 2,4-(OMe)26e R = 2,6-(OMe)26f R = 2,4,6-(OMe)36g R = 2,5-(OMe)2

EtO OEt

O O NaH, DMFPhArIOTfrt, 18 h

OHMeO t-BuOK, THFPhArIOTf

40 °C, ≤120 min

EtO OEt

O

Ph

O

MeO O Ph

NH2MeO

PhArIOTf130 °C, 24 h

MeOHN PhDMF

a.

b.

c.

35e

40

41

EtO OEt

O

Ar

O

MeO O Ar 78-99%

26-95%

MeOHN Ar 30-75%

+

+

+

51

The reactions with malonate 41 all showed a preferential phenylation but the selectivity decreased despite added electron-donating substituents (entries 1-4). A surprising “anti-ortho-effect” could be observed in the arylation with salts 6k-p, as one ortho-substituent gives a ratio of 11:1 and two ortho-substituents give almost complete selectivity for phenylation (entries 2,5,6). The best selectivities were observed with salts bearing two ortho-substituents (entries 5 and 6). Table 9. Phenylation vs. arylation of the three nucleophiles using salts 6k-p.a

Entry Salt 6

1

6k 2.9:1 1.4:1 3.3:1

2

6l 1:2.5 1.4:1 11:1

3

6m 1.3:1 4.5:1 7:1

4

6n 1:1.7 2.5:1 2:1

5

6o 1:9 6.5:1 >20:1

6

6p 1:1.9 15:1 >20:1

a Product ratios from 1H NMR of isolated diaryl ether and crude mixtures from reactions with m-anisidine and malonate. Methoxy-substituted salts 6a,c-g showed complete chemoselectivity in the arylation of 35e, yielding only phenylated product (Table 10). The electronic factors have greater influence in these reactions, as the substitution pattern does not affect the phenylation vs. arylation ratio (entries 1-6). This effect was observed in the arylation of m-anisidine, however to a smaller extent, as complete phenylation was only observed with salts 6d,f,g (entries 3, 5, 6). Salts 6a,c,d gave selectivities similar to the corresponding methyl-substituted salts 6k-m (Table 9, entries 1-3). In the reaction with malonate 41 and para-substituted salt 6a there was a 13:1 ratio in favor of phenylation while the ortho-substituted salt 6c showed less selectivity, which is an indication of an existing ortho-effect. This is surprising, as the opposite effect was seen with the methyl-substituted salts

MeO O Ph/Ar MeOHN Ph/Ar EtO OEt

O

Ph/Ar

O

Ph ITfO

Ph ITfO

Ph ITfO

Ph ITfO

Ph ITfO

Ph ITfO

52

(cf. Table 9, entries 1 and 2). Complete selectivity was however observed with disubstituted salts 6d-f and trisubstituted salt 6g (entries 4-6). Table 10. Phenylation vs. arylation of the three nucleophiles using salt 6a,c-g.a

Entry Salt 6

1

6a Only Ph 5.4:1 13:1

2

6c Only Ph 3:1 2.6:1

3

6d Only Ph Only Ph Only Ph

4

6e Only Ph 2.3:1 Only Ph

5

6f Only Ph Only Ph Only Ph

6

6g Only Ph Only Ph Only Ph

a Product ratios from 1H NMR of isolated diaryl ether and crude mixtures from reactions with m-anisidine and malonate. Surprisingly, our results with 3-methoxyaniline differ from those previously reported with aniline and salts 6p and 6a with a trifluoroacetate anion instead of the triflate.34 The malonate results match those previously reported in terms of product ratios, but lower yields were consistently observed.26 We decided to investigate if the low chemoselectivity in the reaction of m-anisidine with salt 6e (Table 10, entry 4) could arise from a ligand exchange in the salt, as recently reported by DiMagno.64 They had observed a fluoride promoted aryl ligand exchange in reactions using an unsymmetric diaryliodonium salt in acetonitrile and benzene (Scheme 40).

Scheme 40. Fluoride-promoted ligand exchange in diaryliodonium salts.

MeO O Ph/ArMeO

HN Ph/Ar EtO OEt

O

Ph/Ar

O

Ph ITfO

OMe

Ph ITfO OMe

Ph ITfO OMe

OMe

Ph ITfO OMe

OMe

Ph ITfO OMe

MeO

Ph ITfO OMe

MeO OMe

Ar1IAr2

X F

Ar1IAr1

X

Ar2IAr2

X+

53

This phenomenon was not observed in the reaction of m-anisidine with 6e, according to HRMS analysis of the reaction mixture. However, HRMS analysis of the arylation of malonate 41 with salt 6e showed peaks corresponding to salts 3b and 3j within 5 min at room temperature (Figure 12). This result is unexpected as the phenylated product was isolated in 57% yield with complete selectivity (Table 10, entry 4), which indicates that salt 3j is very unreactive compared to 3b and 6e.

Figure 12. HRMS of ligand exchange observed in salt 6e.

6.2 Conclusion Chemoselectivity in arylations with unsymmetric diaryliodonium salts depends on the type of nucleophile. Both the electronic properties and the ortho-effect influence the arylation of phenols when using the methyl-substituted salts 6k-p. The electronic properties override the ortho-effect when using the methoxy-substituted salts 6a,c-g. In the arylation of m-anisidine it is clear that only electronic properties influenced the outcome. A clear “anti-ortho-effect” was observed in the reaction of malonate 41 with methyl-substituted salts 6k-p while reactions with methoxy-substituted salts followed both electronic and ortho-effects. Methoxy-substituted aryls are generally appropriate to use as dummy ligands in the salts, regardless of what nucleophile that is employed. The different chemoselectivities observed for the three nucleophiles could be a result of different transition states for the reductive elimination or of a radical mechanism in some reactions. Ligand exchange in the salts could also be an explanation for the low selectivities in some cases. The low yield and enantiomeric excess obtained in the arylation of 2-

Analysis Info 2012-04-12 09:56:14Acquisition DateAnalysis Name H:\Data2\Joel\JMC031-5min000001.dMethod piatune_low_dirk.m OperatorSample Name JMC031-5min micrOTOFInstrument / Ser# 125Comment

Acquisition ParameterPositive Ion Polarity 0.4 BarSet NebulizerESI Source Type

Set Dry Heater 170 °CFocus Not active 4.0 l/minSet Dry Gas4500 V50 m/zScan Begin Set Capillary

-500 VSet End Plate OffsetScan End Source Set Divert Valve3000 m/z

287.0346

304.2618

325.9791

341.0030

348.9416

369.1537

401.0237

+MS, 0.8-0.9min #(50-55)

341.0033

C14H14IO2, M ,341.000

2

4

6

8

4x10Intens.

0

500

1000

1500

2000

280 300 320 340 360 380 400 m/z

Display Report

printed: 1 of 1Page 2012-04-13 09:26:58Bruker Compass DataAnalysis 4.0

280.9822

I

3b C12H10I+m/z 280,9822

3j C16H18IO4+

m/z 401,0244

IOMe

OMe

OMe

OMe

6e C14H14IO2+

m/z 341,0033

IOMe

OMe

54

(ethoxycarbonyl)cyclohexanone (section 4.2.5) could also be a result of this types of ligand exchange. Only phenylated product could be observed in those reactions albeit in low yields. Further mechanistic and computational studies need to be performed in order to draw more precise conclusions.

55

Concluding Remarks

In this thesis, new and efficient methodology for the synthesis of hypervalent iodine(III) compounds has been developed. Both symmetric and unsymmetric salts can be synthesized in high yields, starting with either molecular iodine and an arene or an iodoarene. These salts can further be converted to the corresponding diaryliodonium triflates. An environmentally benign large-scale synthesis of a Koser’s reagent derivative has been developed. The use of this new methodology together with other synthetic routes enabled the synthesis of three different enantiopure diaryliodonium salts. A fast and high-yielding synthesis of diaryl ethers has also been developed. The reaction conditions are mild, metal-free, and avoid the use of halogenated solvents, additives, or excess reagents. The scope of the reaction is wide and ortho-, halo- and bulky-substituted diaryl ethers were synthesized in good to excellent yields. A chemoselectivity study on the reaction of unsymmetrical diaryliodonium salts with nucleophiles has been conducted.

57

Appendix A

Contribution to Paper I-VI

I. Shared the synthetic work with Dr. Mingzhao Zhu.

II. Performed the synthetic work and took part in writing the paper.

III. Performed the synthetic work.

IV. Performed the major part of the synthetic work and supervised the work done by diploma worker Eloisa E. Ishikawa. Wrote the supporting information.

V. Performed the synthetic work done on diaryl ethers. Took part in

writing the supporting information.

VI. Developed the synthesis of the various salts. Performed the arylation of the phenol and took part in writing the supporting information.

58

Appendix B

Synthesis of Diaryliodonium Salts Used in Chapter 5 and 6 Numerous diaryliodonium salts have been synthesized for Chapter 5 and 6. The various methods used are listed here. Method I and II.23a-c

Method III and IV.77

Method V.23e

Method VI. PhI2X (5 mmol) was dissolved in dichloromethane (30 mL) and extracted with an aqueous NaX solution (3 x 50 mmol). The organic layer was concentrated without drying. Et2O (20 mL) was added and the mixture was stirred at room temperature for 30 min to precipitate a solid. The solid was isolated by filtration, washed with Et2O and dried under vacuum to give the desired salt. The anion exchange was confirmed by NMR analysis.

IR1 R2+

mCPBA (1 equiv)TfOH (2-3 equiv)

CH2Cl2, rt, 1 hI

R1 R2

51-92%

TfO

1 equiv 1 equiv

I.

R+I2 4 2

24-93%

IR R

TfOmCPBA (3 equiv)TfOH (4-6 equiv)

CH2Cl2, rt, 10 min - 21 h

1 equiv 4 equiv

II.

+Ar1 I Ar2 H

1 equiv 1 equiv

mCPBA (1 equiv)TsOH (1 equiv)

CH2Cl2/TFE, rt, 6 h Ar1 I Ar2

TsO

32-100%

Ar1 I Ar2

TfO

quant.

TfOH(1 equiv)

rt, 1 h

+ Ar HmCPBA (3equiv)TsOH (4 equiv)CH2Cl2, rt, 6 hor 80 °C, 1 h

Ar I Ar

TsO

58-89%

Ar I Ar

TfO

80%

TfOH(1 equiv)

rt, 1 hI2 4

1 equiv 4 equiv

III.

IV.

rt, 15 min

IR1

mCPBA, BF3⋅OEt2CH2Cl2, rt, 30 min

B(OH)2R2 I

R1 R2

BF4

31-88%

V.

59

Novel salts and other methods for synthesis of different diaryliodonium salts are listed below. Table 11. Synthesis of Salts in Chapter 5-6.

Salt Method Acid (equiv)

Temp (ºC) Time Yield

(%)

2g V+VI 2 rt 30 min +

15 min 50

3a IV 1 rt 6 h 71

3b I

II 3 4

rt 80

10 min 10 min

92 93

3c I 2 rt 3 h 64

3d II 4 rt 10 min 78

3e I

II 3 4

rt rt

19 h 21 h

83 57

3f II 3 0 1 h 91

3g II 4 rt 12 h 47

3h II 4 rt 24 h 88

3k II 4 rt 2 h 88

5k III 1 40 65 h 70

6a III 1 rt 6 h >99

ITsO

I

MeO OMe

TfO

ITfO

ITfO

ITfO

t-Bu t-Bu

ITfO

Cl Cl

ITfO

Br Br

ITfO

ITfO

ITfO

ITsO

i-Pri-Pr

i-Pr

MeO

ITfO

OMe

60

3k Isolated in 88% yield as a beige solid; mp 173-174 °C; 1H NMR (500 MHz, DMSO-d6) δ 8.14 (d, J = 8.2, 2H), 7.35 (s, 2H), 7.10 (dd, J = 1.9, 8.3, 2H), 2.54 (s, 6H), 2.30 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 143.1, 140.3,

ITfO

6i III+VI 1 rt 20 min 60

6j I 4 60→0 30 min +

15 min 91

6k I 2 0→rt 25 min 90

6l I 2 rt 30 min 52

6m I 2 0 2 h 95

6n I 2 rt 5 h 69

6o V 2.5 rt 30 min +

30 min 76

6p I 2 rt 1 h 79

37a V 2 rt 30 min +

15 min 82

37d V 2 rt 30 min +

15 min 74

37c V 2.5 rt 30 min +

4 h 91

37b V 2 rt 60 min +

30 min 51

ITfO

OEt

OMeO

I

N

TfO

MeO

Ph ITfO

Ph ITfO

Ph ITfO

Ph ITfO

Ph ITfO

Ph ITfO

IBF4

BF4

I

BF4

IFF

IBF4

F3C CF3

61

137.0, 132.1, 129.9, 120.7 (q, 1JC-F = 322), 117.0, 24.7, 20.7; HRMS (ESI) m/z calculated for C16H18O+ ([M-OTf]+) 337.0448, found 337.0466.

5j A previously published procedure4 was modified slightly: anisole (1.0 equiv) was added dropwise at 0 °C to a stirred solution of 8 in 1:1 CH2Cl2:TFE (6 mL/mmol). The reaction mixture was allowed to reach rt and stirring was continued overnight before concentrating to dryness by rotary evaporation. This crude material was triturated with Et2O. Isolation by filtration and multiple washes with Et2O yielded salt 5j. Isolated in 94% yield as a colorless solid; mp 180–182 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.71 (s, 1H), 8.49 (d, J = 8.4, 1H), 8.25–8.21 (m, 2H), 8.03 (d, J = 8.0, 1H), 7.74 (t, J = 7.8, 1H), 7.48–7.45 (m, 2H), 7.11–7.08 (m, 4H), 3.80 (s, 3H), 2.28 (s, 3H); 13C NMR (125 MHz, DMSO-d6) δ 162.1, 145.5, 139.0, 137.8, 137.5, 132.5, 131.6 (q, 3JC-F = 3.6), 131.2 (q, 2JC-F = 32.6), 128.5 (q, 3JC-F = 3.5), 128.1, 125.5, 123.0 (q, 1JC-F = 271.5), 117.5, 117.4, 105.9, 55.7, 20.8; 19F NMR (376 MHz, DMSO-d6) δ −61; HRMS (ESI) m/z calculated for C14H11F3IO+ ([M-OTs]+) 378.9801, found 378.9803.

5k Isolated in 70% yield as a light orange oil; 1H NMR (400 MHz, DMSO-d6) δ 7.87 (m, 2H), 7.47 (m, 2H), 7.28 (s, 2H), 7.09 (m, 4H), 3.78 (s, 3H), 3.42 (m, 2H), 2.96 (m, 1H), 2.29 (s, 3H), 1.23 (m, 18H); 13C NMR (100 MHz, DMSO-d6) δ 162.2, 154.5, 151.4, 146.3, 138.0, 136.6, 128.5, 126.0, 125.0, 124.2, 118.1, 104.2, 56.2, 39.0, 33.8, 24.5, 24.0, 21.2; HRMS (ESI) m/z calculated for C22H30IO+ ([M-OTs]+) 437.1336, found 437.1347.

6c Synthesized by a known method,36a followed by an anion exchange. Isolated as a light yellow solid in 56% yield over 2 steps; mp 148-150 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.3 (dd, J = 1.4, 7.9, 1H), 8.2-8.1 (m, 2H), 7.70-7.61 (m, 2H), 7.54-7.47 (m, 2H), 7.31 (dd, J = 1.3, 8.4, 1H), 7.09 (td, J = 1.4, 7.9, 1H), 3.94 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 156.4, 137.2, 135.1, 134.9, 131.9, 131.6, 123.4, 120.7 (q, 1JC-F = 322), 115.8, 113.1, 106.5, 57.1; HRMS (ESI) m/z calculated for C13H12O+ ([M-OTf]+) 310.9927, found 310.9912.

ITsO

MeO

CF3

ITsO

i-Pri-Pr

i-Pr

MeO

Ph ITfO OMe

62

6d Synthesized by a known method,16 followed by an anion exchange. Isolated as a light yellow solid in 96% yield over 2 steps; mp 92-94 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.18 (d, J = 8.8, 1H), 8.09- 8.03 (m, 2H), 7.66-7.59 (m, 1H), 7.53- 7.45 (m, 2H), 6.80 (d, J = 2.6, 1H), 6.69 (dd, J = 2.6, 8.8, 1H), 3.93 (s, 3H), 3.83 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.7, 158.2, 138.3, 134.62, 131.7, 131.5, 122.3, 120.7 (q, 1JC-F = 322), 119.1, 116.3, 108.9, 99.7, 95.8, 57.3, 56.0; HRMS (ESI) m/z calculated for C14H14IO2

+ ([M-OTf]+) 314.0033, found 314.0030.

6e Synthesized by a known method,36a followed by an anion exchange. Isolated as a light yellow solid in 68% yield over 2 steps; mp 168-170 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.12 (app. d, J = 7.4, 2H), 7.96 (d, J = 2.5, 1H), 7.65 (t, J = 7.4, 1H), 7.51 (m, 2H), 7.29-7.18 (m, 2H), 3.86 (s, 3H), 3.77 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 154.2, 150.7, 135.0, 131.9, 131.6, 122.1, 120.7 (q, 1JC-F = 322), 119.9, 115.9, 113.5, 106.3, 57.4, 56.2; HRMS (ESI) m/z calculated for C14H14IO2

+ ([M-OTf]+) 314.0033, found 314.0030.

6f Synthesized by a known method,36a followed by an anion exchange. Isolated as a light yellow solid in 47% yield over 2 steps; mp 152-153 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.95 (dd, J = 1.0, 8.3, 2H), 7.62-7.54 (m, 2H), 7.48-7-41 (m, 2H), 6.87 (t, J = 8.4, 2H), 3.94 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 158.1, 135.7, 134.6, 131.4, 131.4, 116.8, 105.3, 99.1, 57.3; HRMS (ESI) m/z calculated for C14H14IO2

+ ([M-OTf]+) 314.0033, found 314.0023.

6g Synthesized by a known method,16 followed by an anion exchange. Isolated as a white solid in 94% yield over 2 steps; mp 114-116 °C; 1H NMR (400 MHz, DMSO-d6) δ 1H NMR (500 MHz, DMSO-d6) δ 7.92 (d, J = 7.4, 2H), 7.61 (t, J = 7.4, 1H), 7.47 (t, J = 7.8, 2H), 6.46 (s, 2H), 3.94 (s, 6H), 3.86 (s, 3H); 13C NMR (100 MHz, DMSO-d6) δ 166.2, 159.4, 134.4, 131.6, 128.1, 125.5, 122.31, 120.7 (q, 1JC-F = 322), 119.1, 116.1, 92.1, 87.0, 57.4,

Ph ITfO OMe

OMe

Ph ITfO OMe

OMe

Ph ITfO OMe

MeO

Ph ITfO OMe

MeO OMe

63

56.2; HRMS (ESI) m/z calculated for C15H16IO2+ ([M-OTf]+) 371.0139,

found 371.0144.

6h The salt was synthesized through a modification of a previously published procedure:17b 4-Iodoanisole (468 mg, 2 mmol) was dissolved in CH2Cl2 (20 mL), followed by addition of mCPBA (371 mg, 2 mmol, 93%) and TsOH·H2O (380 mg, 2 mmol). The reaction mixture was stirred at rt for 50 min and 2,6-dimethylphenylboronic acid (315 mg, 2.1 mmol) was added. Stirring was continued 18 h before concentrating to dryness by rotary evaporation. Et2O was added to the crude residue to precipitate the tosylate salt, which was submitted to an aqueous anion exchange without further purification to give salt 6h in 40 % yield over 2 steps. Isolated as a light white solid; mp 190-191 °C; 1H NMR (400 MHz, DMSO-d6) δ 7.97 (d, J = 9.1, 2H), 7.47 (d, J = 7.5, 1H), 7.39 (d, J = 7.5, 2H), 7.06 (d, J = 9.1, 2H), 3.80 (s, 3H), 2.67 (s, 6H); 13C NMR (100 MHz, DMSO-d6) δ 161.8, 141.6, 136.8, 132.7, 129.1, 126.8 (q, 1JC-F = 322) 126.7, 117.6, 103.2, 55.7, 26.5; HRMS (ESI) m/z calculated for C15H16IO+ ([M-OTf]+) 339.0240, found 339.0245.

6i Isolated in 60% yield over 2 steps as a beige solid; mp 158-160 °C; 1H NMR (400 MHz, DMSO-d6) δ 8.30 (d, J = 8.6, 2H), 8.19 (d, J = 9.4, 2H), 8.00 (d, J = 8.6, 2H), 7.08 (d, 9.4, 2H), 4.32 (q, J = 7.1, 2H), 3.80 (s, 3H), 1.30 (t, J = 7.1, 3H); 13C NMR (100 MHz, DMSO-d6) δ 164.6, 162.1, 137.3, 135.0, 132.6, 131.7, 125.5, 121.8, 120.7 (q, 1JC-F = 322) 117.6, 105.6, 61.4, 55.7, 14.0; HRMS (ESI) m/z calculated for C16H16IO3

+ ([M-OTf]+) 383.0139, found 383.0152.

6j Isolated in 91% yield as a brown oily residue; 1H NMR (400 MHz, MeOD-d4) δ 9.19 (dd, J = 0.5, 2.3, 1H), 8.82 (dd, J = 1.4, 4.8, 1H), 8.56 (ddd, J = 1.4, 2.4, 8.4, 1H), 8.14 (app. d, J = 9.2, 2H), 7.56 (ddd, J = 0.7, 4.8, 8.3, 1H), 7.09 (app. d, J = 9.2, 2H), 3.86 (s, 3H); 13C NMR (100 MHz, MeOD-d4) δ 164.8, 154.3, 153.4, 143.6, 138.8, 128.2, 121.8 (q, J = 316), 119.1, 116.1, 104.4, 56.4; HRMS (ESI) m/z calculated for C12H11NOI+ ([M-OTf]+) 311.9880, found 311.9891.

ITfO

MeO

ITfO

OEt

OMeO

ITfO

NMeO

64

38 Known salt in the literature and synthesized by a known method.78 Isolated in 58% yield as a beige solid.

IBr

65

Acknowledgements

Berit Olofsson för att du gav mig möjligheten att doktorera i din grupp. Din dörr har alltid stått öppen och du har delat med dig av din kunskap på bästa möjliga sätt. Tack även för ditt stöd och din uppmuntra, både i framgång och när det har varit riktigt tungt. Jan-Erling Bäckvall för visat intresse i mitt arbete och för att jag fick göra mitt examensarbete i din grupp. Joel Malmgren, Dr Tue B. Petersen, Thore Frister, Eloisa E. Ishikawa, Jan Caspar and Dr Mingzhao Zhu for fruitful collaborations. Dr Ellie Merritt and Joel Malmgren for linguistic improvements of the thesis. Past and present members of the BO group! Special thanks to Ellie for all your support and help during these years. Iris Tébéka and her mother Alda Simonetti. Eu adorava passar o tempo com vocês e muito obrigado por ser como uma família para mim quando eu estava no Brasil \o/ All the people at Universidade de São Paulo that made my stay in Brazil rememberable. All of the people at the Department of Organic Chemistry for making it a nice place to work. TA-personalen för all hjälp med saker runt omkring. Tack till K&A Wallenberg Stiftelsen, Ångpanneföreningens Forskningsstiftelse, Kungliga Skogs och Lantbruks Akademin, AstraZenecas resestipendium till minne av Nils Löfgren, Svenska Kemistsamfundet och John Söderbergs fond för finansiellt stöd. Elina, min “partner in crime”, för att du har gjort 1/3 av mitt liv lite lättare och framför allt mycket roligare. Tiden som doktorand hade inte varit den samma utan dig.

66

Andreas, för att ha gjort hela min studietid roligare. Allt från Betapet till meningslösa ramsor till galna danser, du får mig alltid att bli på bättre humör! Mina alldeles underbara vänner, även om ni inte alltid har förstått vad jag har sysslat med de senaste 5 åren så har ni alltid funnits där med råd och stöd (ibland även lite alkohol )! Ni är bäst!!! Tack till min fantastiska bonusfamilj Jan, Karin, Sara, Markus, Nora, Ella, Viggo och Pompe. Min älskade Mamma, Pappa och Negin! Tack för att ni alltid tror på mig. Jag har allt jag någonsin gjort och åstadkommit er att tacka för!

ششمماا ببهه ااننددااززييهه ییکک ددننییاا ببرراایی ممنن ااررززشش ددااررییدد Viktigaste av allt, Johan. Ditt stöd och din uppmuntran under de här åren har varit ovärderlig. Du är det finaste jag vet och jag är så glad över att jag hittade just dig. Älskar dig! ♥

67

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