Catalytic Methods to Convert Allylic Substrates Through Hydride and Proton Shifts

Samuel Martinez-Erro Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts

Transition Metal-Catalyzed and Organocatalyzed Approaches Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts Samuel Martinez-Erro

Samuel Martinez-Erro Samuel was born in Pamplona, Spain. In 2015, he started his PhD at Stockholm University supervised by Prof. Belén Martín-Matute. He has expertise in Organic Synthesis, Metal and Organocatalysis and Mechanistic studies.

ISBN 978-91-7797-903-6

Department of Organic Chemistry

Doctoral Thesis in Organic Chemistry at Stockholm University, Sweden 2019 Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts Transition Metal-Catalyzed and Organocatalyzed Approaches Samuel Martinez-Erro Academic dissertation for the Degree of Doctor of Philosophy in Organic Chemistry at Stockholm University to be publicly defended on Friday 6 December 2019 at 10.00 in Magnélisalen, Kemiska övningslaboratoriet, Svante Arrhenius väg 16 B.

Abstract The present thesis describes the development of new catalytic protocols to transform allylic substrates into a wide variety of versatile carbonyl and vinyl organic compounds. All procedures that are described in this work have in common the existence of one or more hydrogen shifts as key steps in the mechanism of the reactions. The thesis is divided into two mayor sections depending on the strategy employed, metal catalysis or organocatalysis. The introductory chapter (Chapter 1) starts with an overview of the different types of catalysis and the importance of allylic substrates in organic chemistry. The chapter continues with an extensive description of the isomerization of allylic alcohols and finishes with a short introduction about hypervalent iodine chemistry. The goals of the thesis are also depicted at the end of this chapter. Chapters 2, 3 and 4 embody the use of iridium catalysis as an effective tool to synthesize α-functionalized carbonyl compounds selectively as single constitutional isomers from allylic alcohols. The first two chapters of this section describe the employment of several electrophiles to trap enolate derivatives formed from the corresponding allylic alcohols. Chapter 2 shows the development of two new protocols for the preparation of challenging α-iodinated carbonyl compounds. In chapter 3, the synthesis of α-aminooxy and α-hydroxyketones is investigated by employing an N-oxoammonium salt as electrophilic agent. Chapter 4 describes the development of an umpolung strategy that allows the synthesis of α- functionalized carbonyls through the reaction of two formal nucleophiles: enolate derivatives and alcohols. Mechanistic investigations performed in this section point to the presence of an iridium-catalyzed hydride shift operating in the reaction pathways. The last three chapters (5, 6 and 7) describe the development of metal-free methods for the conversion of allylic substrates into valuable products by means of base catalysis. Chapter 5 and 6 depict the stereospecific isomerization of a large scope of allylic alcohols, ethers and halides. A simple guanidine-type base, TBD (1,5,7-triazabicyclo[4.4.0]dec-5- ene), is an effective catalyst to isomerize allylic substrates with excellent levels of transfer of chirality. The mechanism of this transformation is studied in detail experimentally and computationally and it is suggested to involve a [1,3]- proton shift through the formation of a tight ion-pair. Chapter 7 shows that base-catalysis allows the isomerization of conjugated polyenyl alcohols and ethers which has been proved to be challenging with metal–catalysis. Experimental and computational investigations in this last chapter suggests that the mechanism may proceed through a series of iterative [1,3]-proton shifts or “base-walk”.

Keywords: Allylic substrates, Iridium catalysis, Base catalysis, Method development, Isomerization, Hydride shift, Proton shift, Mechanistic studies.

Stockholm 2019 http://urn.kb.se/resolve?urn=urn:nbn:se:su:diva-175359

ISBN 978-91-7797-903-6 ISBN 978-91-7797-904-3

Department of Organic Chemistry

Stockholm University, 106 91 Stockholm

CATALYTIC METHODS TO CONVERT ALLYLIC SUBSTRATES THROUGH HYDRIDE AND PROTON SHIFTS

Samuel Martinez-Erro

Catalytic Methods to Convert Allylic Substrates through Hydride and Proton Shifts

Transition Metal-Catalyzed and Organocatalyzed Approaches

Samuel Martinez-Erro ©Samuel Martinez-Erro, Stockholm University 2019

ISBN print 978-91-7797-903-6 ISBN PDF 978-91-7797-904-3

Cover image: "In a far away land called Organic Synthesis" by Silvia Martínez Erro designed using resources from freepik.com

Printed in Sweden by Universitetsservice US-AB, Stockholm 2019 To those who made it possible

“When life gets you down, do you wanna know what you´ve gotta do? Just keep swimming!”

Dory, Finding Nemo

Abstract

The present thesis describes the development of new catalytic protocols to transform allylic substrates into a wide variety of versatile carbonyl and vinyl organic compounds. All procedures that are described in this work have in common the existence of one or more hydrogen shifts as key steps in the mechanism of the reactions. The thesis is divided into two major sections depending on the strategy employed, metal catalysis or organocatalysis. The introductory chapter (Chapter 1) starts with an overview of the different types of catalysis and the importance of allylic substrates in organic chemistry. The chapter continues with an extensive description of the isomerization of allylic alcohols and finishes with a short introduction about hypervalent iodine chemistry. The goals of the thesis are also depicted at the end of this chapter. Chapters 2, 3 and 4 embody the use of iridium catalysis as an effective tool to synthesize a-functionalized carbonyl compounds selectively as single constitutional isomers from allylic alcohols. The first two chapters of this section describe the employment of several electrophiles to trap enolate derivatives formed from the corresponding allylic alcohols. Chapter 2 shows the development of two new protocols for the preparation of challenging a-iodinated carbonyl compounds. In chapter 3, the synthesis of a-aminooxy and a-hydroxyketones is investigated by employing an N-oxoammonium salt as electrophilic agent. Chapter 4 describes the development of an umpolung strategy that allows the synthesis of a-functionalized carbonyls through the reaction of two formal nucleophiles: enolate derivatives and alcohols. Mechanistic investigations performed in this section point to the presence of an iridium-catalyzed hydride shift operating in the reaction pathways. The last three chapters (5, 6 and 7) describe the development of metal-free methods for the conversion of allylic substrates into valuable products by means of base catalysis. Chapter 5 and 6 depict the stereospecific isomerization of a large scope of allylic alcohols, ethers and halides. A simple guanidine-type base, TBD (1,5,7-triazabicyclo[4.4.0]dec-5-ene), is an effective catalyst to isomerize allylic substrates with excellent levels of transfer of chirality. The mechanism of this transformation is studied in detail experimentally and computationally and it is suggested to involve a [1,3]-proton shift through the formation of a tight ion-pair. Chapter 7 shows that base-catalysis allows the isomerization of conjugated polyenyl alcohols and ethers which has been proved to be challenging with metal–catalysis. Experimental and computational investigations in this last chapter suggests that the mechanism may proceed through a series of iterative [1,3]-proton shifts or “base-walk”.

i Populärvetenskaplig sammanfattning

Organiska molekyler har många viktiga användningar i det moderna samhället. Från läkemedel och jordbrukskemikalier till sensorer, bränslen eller hushållsprodukter. Deras existens i vår vardag är enorm. En stor utmaning för kemister är att skapa metoder för att få tillgång till organiska molekyler på ett effektivt och selektivt sätt. Numera är det viktigare än någonsin att dessa metoder är hållbara och har minimal påverkan på miljön. Av dessa skäl är det extremt viktig att forskningen syftar till att utveckla nya effektiva och miljövänliga reaktioner för att få tillgång till viktiga organiska molekyler. I detta sammanhang presenteras i denna doktorsavhandling flera projekt som syftar till att söka nya metoder för syntes av användbara molekyler inom organisk kemi. Det övergripande målet är att utveckla effektiva och selektiva metoder med olika katalysatorer och använda vanligt förekommande allyliska substrat som råmaterial. Den första delen av denna avhandling handlar om användningen av iridiumkatalys som ett effektivt verktyg för selektiv syntes av a-funktionaliserade karbonylföreningar. Lättillgängliga allyliska alkoholer omvandlas effektivt till en mängd olika funktionaliserade aldehyder och ketoner som är extremt mångsidiga föreningar i organisk syntes. Därefter handlar den andra delen om upptäckten av nya metallfria reaktioner vilka utnyttjar baskatalys. Allyliska substrat såsom allyliska alkoholer, etrar och halogenider omvandlas till relevanta molekyler under milda reaktionsbetingelser och med användning av en enkel bas som katalysator. Reaktionsvägen har alltid studerats och undersökts i alla projekt genom denna avhandling. Att få en djup förståelse av reaktionsmekanismen möjliggör att metoden i framtiden förbättras och utvecklas på ett bättre och mer effektivt sätt.

ii List of publications

This doctoral thesis is based on the following publications, which would be referred hereafter with Roman numerals I-VII in the text. The contribution of the author in each publication is presented in Appendix A. Reprints of the publications were made with permission from the publishers and they are depicted in Appendix B.

Paper I

2,2-Diododimedone: A Mild Electrophilic Iodinating Agent for the Selective Synthesis of a-iodoketones from Allylic Alcohols Samuel Martinez-Erro,‡ Antonio Bermejo Gómez,‡ Ana Vázquez-Romero, Elis Erbing, and Belén Martín-Matute* Chemical Communications 2017, 53, 9842-9845.

Paper II

Synthesis of a-Iodoketones from Allylic Alcohols through Aerobic Oxidative Iodination Amparo Sanz-Marco, Štefan Možina, Samuel Martinez-Erro, Jernej Iskra, Belén Martín- Matute* Advanced Synthesis and Catalysis 2018, 360, 3884-3888.

Paper III

Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates Amparo Sanz-Marco, Samuel Martinez-Erro, and Belén Martín-Matute* Chemistry - A European Journal 2018, 24, 11564-11567.

Paper IV

An Umpolung Strategy to React Catalytic Enols with Nucleophiles Amparo Sanz-Marco, Samuel Martinez-Erro, Martin Pauze, Enrique Gómez-Bengoa and Belén Martín-Matute* Accepted for publication in Nature Communications.

‡ These authors contributed equally to the publication

iii Paper V

Base-Catalyzed Stereospecific Isomerization of Electron-Deficient Allylic Alcohols and Ethers through Ion-Pairing: Samuel Martinez-Erro,‡ Amparo Sanz-Marco,‡ Antonio Bermejo Gómez, Ana Vázquez- Romero, Mårten S. G. Ahlquist, and Belén Martín-Matute* Journal of the American Chemical Society 2016, 138, 13408-13414.

Paper VI

Selective Synthesis and Stereospecific Isomerization of Chiral Allylic Halides Samuel Martinez-Erro, Victor García-Vazquez, Amparo Sanz-Marco, Belén Martín- Matute* Manuscript

Paper VII

Base-Catalyzed [1,n]-Proton Shifts in Conjugated Polyenyl Alcohols and Ethers Nagaraju Molleti,‡ Samuel Martinez-Erro,‡ Alba Carretero Cerdán, Amparo Sanz-Marco, Enrique Gomez-Bengoa, and Belén Martín-Matute* ACS Catalysis 2019, 9, 9134-9139.

‡ These authors contributed equally to the publication

iv Abbreviations

Abbreviations and acronyms are in agreement with the standards in the field.* Common abbreviations and other non-conventional abbreviations are listed below.

Ac Acetyl COD 1,5-Cyclooctadiene Cp* 1,2,3,4,5-Pentamethylcyclopentadienyl p-cym p-Cymene DABCO 1,4-Diazabicyclo[2.2.2]octane DBU 1,8-Diazabicyclo[5.4.0]undec-7-ene DET Diethyltartrate DIBAL-H Diisobutylaluminium hydride DMAP 4-Dimethylaminopyridine DPE 1,1-Diphenylethylene ee Enantiomeric excess es Enantiospecificity HFIP Hexafluoroisopropanol i-Pr iso-Propyl I.S. Internal standard KHMDS Potassium hexamethyldisilazane MTBD 7-Methyl-1,5,7-triazabicyclo[4.4.0]dec-5-ene NCS N-Chlorosuccinimide NIS N-Iodosuccinimide o.n. Overnight PIDA (Diacetoxyiodo)benzene RT Room temperature TBAF Tetrabutylammonium fluoride TBD 1,5,7-Triazabicyclo[4.4.0]dec-5-ene TEMPO (2,2,6,6-Tetramethylpiperidin-1-yl)oxyl TFE Trifluoroethanol TMG 1,1,3,3-Tetramethylguanidine TON Turnover number TOF Turnover frequency TsDPEN N-Tosyldiphenylethylenediamine

*Following the ACS abbreviations and acronyms 2018 guidelines for authors. http://pubs.acs.org/paragonplus/submission/joceah/joceah_authguide.pdf

v Table of Contents

Abstract i Populärvetenskaplig sammanfattning ii List of publications iii Abbreviations v

1. Introduction 1

1.1 Catalysis 1 1.1.1 Catalysis and organic chemistry 1 1.1.2 Transition-metal complexes in catalysis 2 1.1.3 Organocatalysis 3 1.1.4 Homogeneous and heterogeneous catalysis 4 1.2 Allylic Compounds 4 1.2.1 Relevance and prevalence in nature 4 1.2.2 General reactivity 5 1.2.3 [1,3]-Sigmatropic hydrogen shifts 5 1.3 Isomerization of allylic alcohols 6 1.3.1 Metal-catalyzed protocols 7 1.3.1.1 Synthesis of chiral carbonyls from allylic alcohols 7 1.3.1.2 Proposed mechanisms 8 1.3.2 Transition-metal-free examples 10 1.3.3 Tandem isomerization / functionalization of allylic alcohols 11 1.4 Hypervalent Iodine Chemistry 12 1.4.1 The hypervalent bond of iodine 12 1.4.2 Iodine (III) reagents and their reactivity 13 1.5 Aim of this thesis 14

2. Synthesis of a-Iodocarbonyl Compounds as Single Constitutional Isomers via Isomerization of Allylic Alcohols (Paper I and II) 15

2.1 Aiming to the synthesis of challenging a-iodo carbonyl compounds 15 2.2 Synthesis of 2,2-diiododimedone and its application in the electrophilic iodination of electron-rich arenes 15 2.3 Iridium-catalyzed isomerization/iodination of allylic alcohols using 2,2-diiododimedone 16 2.3.1 Optimization 16 2.3.2 Control Experiments 18 2.3.3 Scope of the reaction 19 2.3.4 Mechanistic investigations 20 2.4 a-Iodoketones as versatile building blocks 21 2.5 Towards an atom-economical method for the synthesis of a-iodocarbonyl compounds 22 vi 2.6 Iridium-catalyzed isomerization/iodination of allylic alcohols using aerobic oxidative iodination 23 2.6.1 Optimization 23 2.6.2 Scope of the reaction 24 2.6.3 One-pot isomerization / iodination / amination of allylic alcohols 25 2.6.4 Mechanistic studies 26 2.7 Conclusions 27

3. Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates (Paper III) 28

3.1 Electrophilic oxygen transfer 28 3.2 Reaction of allylic alcohols with electrophilic oxygen species under iridium catalysis 28 3.2.1 Optimization 28 3.2.2 Selective synthesis of a-aminooxycarbonyl compounds 29 3.2.3 One-pot synthesis of a-hydroxyketones from allylic alcohols 31 3.2.4 Deuterium-labeling study 33 3.3 a´-Functionalization of a-aminooxyketones 33 3.4 Conclusions 34

4. An Umpolung Strategy to React Catalytic Enols with Nucleophiles (Paper IV) 35

4.1 Inversion of polarity of enol derivatives 35 4.2 Reacting allylic alcohols with nucleophiles via iridium catalysis 36 4.3 Selective synthesis of a-functionalized carbonyl compounds with oxygen nucleophiles 39 4.3.1 Intermolecular functionalization: a-alkoxy carbonyl compounds 39 4.3.2 Intramolecular functionalization: synthesis of 3(2H)-furanones 41 4.4 Mechanistic investigations 42 4.4.1 Deuterium-labeling studies, kinetic investigations and radical trapping experiments 42 4.4.2 DFT calculations and mechanistic proposal 45 4.5 Concluding remarks 46

5. Base-Catalyzed Stereospecific Isomerization of Allylic Alcohols and Ethers Through Ion-Pairing (Paper V) 47

5.1 Background of the project and initial aim 47 5.2 Base-catalyzed isomerization of allylic alcohols and ethers 47 5.2.1 Discovery and optimization of reaction conditions 47 5.2.2 Scope of the reaction 49 5.3 Transfer of chirality 51 5.4 Mechanistic investigations 54 5.4.1 Kinetic studies: Hammett plot 54 5.4.2 Deuterium-labeling investigations 54

vii 5.4.3 Radical trapping experiments 56 5.4.4 DFT calculations 56 5.5 Conclusions 57

6. Selective Synthesis and Stereospecific Isomerization of Chiral Allylic Halides (Paper VI) 58

6.1 Background and aim of the project 58 6.2 Selective synthesis of allylic halides 59 6.2.1 allylic chlorides 59 6.2.2 allylic bromides and fluorides 60 6.3 Base-catalyzed isomerization of allylic halides 61 6.3.1 Optimization of the reaction 61 6.3.2 Reaction scope 62 6.4 Synthesis of chiral allylic halides 64 6.5 Stereospecific isomerization of allylic chlorides 66 6.6 Mechanistic proposal 67 6.7 Final remarks 68

7. Base-Catalyzed [1,n]-Proton Shifts in Conjugated Polyenyl Alcohols and Ethers (Paper VII) 69

7.1 Conjugated polyenyl alcohols and ethers. Opportunities and challenges 69 7.2 Conjugated dienyl alcohols 70 7.2.1 Mechanistic insights 71 7.3 Conjugated polyenyl ethers 71 7.3.1 Isomerization of dienyl ethers 71 7.3.2 Selective formal [1,5]-proton shift: scope and limitations 73 7.3.3 Elevating the proton transfer to the next level: [1,9]-proton shift 75 7.3.4 Study of the reaction mechanism 75 7.3.4.1 Experimental mechanistic studies 75 7.3.4.2 DFT calculations 77 7.4 Conclusions 79

8. Concluding remarks 80

Appendix A: Author´s contributions 81

Appendix B: Reprint permissions 82

Appendix C: Numbering of starting materials and products 83

Acknowledgments 87

References 89

viii 1. Introduction

1.1 Catalysis

1.1.1 Catalysis and organic chemistry

Organic chemistry is the science that focuses on the synthesis and study of the properties of carbon-based substances, so-called organic molecules. One of the main goals of organic chemistry is the development of methods to access useful molecules applicable in different fields, such as medicine, materials science and technology. A great challenge in this respect is the discovery of new procedures with good efficiency and environmental benignity. As a result, a large part of the current research in organic chemistry is dedicated to this aspect. The objective is the development of methods to obtain organic compounds with better purity, avoiding the formation of side products, while reducing the amount of waste and the energy required in the synthesis. It is in these terms where catalysis arises as a powerful tool. A catalyst is a molecule that accelerates the rate of a chemical reaction without affecting the associated net thermodynamics. As a result, catalysts enable reactions to work faster and under milder conditions in a more efficient way. Catalysts are not consumed as the reaction reaches completion and, thus, they can be added in substoichiometric amounts, which allows the decrease of chemical waste associated with the transformation.1 For a reaction to happen, an energy barrier must be overcome, i.e., the activation energy (∆G‡) has to be reached. A catalyst can operate by different pathways. It can reduce the energy of the transition state that must be reached to access the products (Figure 1), it can increase the energy of the reactants or, alternatively, it can change completely the reaction pathway. In this last scenario, the highest activation barrier of this new mechanism must be lower than that of the uncatalyzed reaction.2

‡

ΔG uncatalyzed Energy Reactants ‡ ΔG catalyzed

Products

Reaction Coordinate Figure 1. Comparison of the ∆G‡ between an uncatalyzed and a catalyzed reaction.

Catalysts can be classified following different considerations. Here, two different classifications are examined. Depending on the nature of the catalyst, it is possible to divide them into metal catalysts or metal-free catalysts, the latter known as organocatalysts. In addition, catalysts can be classified as homogeneous or heterogeneous.

1 1.1.2 Transition metal complexes in catalysis

By the beginning of the 19th century, the synthesis of ammonia was a difficult and inefficient process. The high stability of the triple bond in the N2 molecule makes the reaction very energetically demanding. Thus, the formation of NH3 from N2 was until then, a problematic reaction. The great need of nitrate derivatives as fertilizers and ammunition resulted in a huge research effort towards the development of processes with the aim of improving the synthesis of ammonia. Fritz Haber and Carl Bosch discovered that the reaction of H2 and N2 gas at very high temperatures and pressures in the presence of certain metals, allowed the synthesis of NH3 in a very efficient manner.3 The key aspect of the success of their methodology was the use of specific catalysts that were able to adsorb the gases and make them react to produce NH3. Since then, the catalyst has been optimized to offer as much efficiency as possible. Although this is not the first example of the use of catalysts to improve the performance of chemical reactions in industry, it demonstrates how metal catalysts can increase the productivity of a certain transformation. Nowadays, the use of metals as catalysts is a common strategy in both industry and academic research to boost the efficacy of chemical reactions. Moreover, transition-metal catalysis has proved to be a powerful tool in organic synthesis. Transition metals can act as electron-sources or electron-sinks in organic transformations as they are able to change oxidation states relatively easily. For this reason, they are able to perform reactions that, otherwise, would not be accessible. Some of the most important metal catalysts in organic chemistry are summarized in Table 1, together with their applications in synthesis.4

Table 1. Common metal catalysts in organic chemistry.

Metal catalysts Applications

PdCl2, Pd(OAc)2, Pd(PPh3)4, NiCl2 Cross-coupling reactions Grubbs' catalysts Metathesis reactions (first and second generation) Pd/C, Pt/C Heterogeneous catalysts for reduction reactions

Wilkinson's catalyst [Rh(PPh3)3Cl] Homogeneous catalyst for reduction of olefins

Noyori's catalysts [RuCl2((S)- Asymmetric hydrogenations BINAP)], [Ru((S)-BINAP)diamine] Sharpless' catalyst Asymmetric epoxidations of olefins [Ti(O-iPr)4 /(-)-DET]

PdCl2 and CuCl2 Wacker process (oxidation of olefins)

Co2(CO)8 Oxoprocess (hydroformylation of olefins)

1.1.3 Organocatalysis

There are different types of organocatalysis in chemistry. Among the most important in the current research, and those covered in this report are: enamine/iminium catalysis, hydrogen-bond catalysis and phase-transfer catalysis. 5-6 The first class of organocatalytic reactions are based on the use of a nitrogen- containing molecule that reacts with the substrate (ketone or aldehyde) forming an enamine/iminium intermediate (Scheme 1). This transient compound can subsequently react with another reagent (electrophile or nucleophile) that, after a final hydrolysis, affords the product and regenerates the catalyst. An important feature in this type of catalysis is the possibility of using chiral organocatalysts to perform asymmetric synthesis. A relevant example is the asymmetric synthesis of β-hydroxyketones using (S)-proline as catalyst.7

COOH N N COOH O OH O H Cat. + via RCHO R enamine intermediate Scheme 1. Asymmetric synthesis of β-hydroxyketones using proline.

Hydrogen-bond catalysis embodies primarily the use of hydrogen bonds to control and enhance the rate of a certain chemical reaction. The organocatalyst interacts with the substrate, the product, or both of them facilitating the reaction. After that, the product dissociates the catalyst, and the latter can perform another cycle. Common organocatalysts that operate following this mechanism are ureas, thioureas, guanidines, binols or phosphoric acids (Figure 2). Asymmetric organocatalysis employing the corresponding chiral versions of these catalysts has been a prosperous topic in recent years especially using chiral phosphoric acids.8

O S NH a) R R b) R R c) R R N N N N N N H H H H H H

O OH O d) e) P OH O OH

Figure 2. Examples of general hydrogen-bond organocatalysts: a) ureas, b) thioureas, c) guanidines, d) binols, e) phosphoric acids.

Finally, phase-transfer catalysis has also proved to be an interesting tool in organic synthesis. It is based on the ability of a catalyst to carry the reagent from one phase to another, where the reaction takes place. Quaternary ammonium salts are the most important class of catalysts among this group. A typical example is the formation of alkyl cyanides from alkyl halides and sodium cyanide in a mixture of water/organic solvent. Without the catalyst, the sodium cyanide is not soluble in the organic phase and the reaction does not take place. However, the quaternary ammonium salt captures the cyanide group and promotes its transfer to the organic phase, where it can react with the alkyl halide, yielding the product.9

3 1.1.4 Homogeneous and heterogeneous catalysis

Homogeneous catalysis is a term used when the catalyst is in the same phase than the reagents, most commonly in a liquid phase that solubilizes both catalyst and reagents. The major disadvantage of this type of catalysis is that, upon completion of the reaction, the recovery of the catalyst is very difficult, making the recycling of the catalyst challenging. In cases where the catalyst is neither expensive nor synthetically demanding, recycling it is not vital. However, the recovery of the catalyst is highly desirable when precious metals are employed or when pricy ligands are required.10 In this regard, heterogeneous catalysis offers a solution to the problem since the recycling of the catalyst is much easier. The catalysts developed for the Haber-Bosch process are a good example of this fact.11 In this process, H2 and N2 gases are put into contact with a solid catalyst. After the reaction finishes, NH3 together with unreacted gases are flushed out of the system and the solid catalyst can be reused again. The other type of heterogeneous catalysis occurs when the reagents are in a liquid phase but the catalyst is an insoluble solid phase. In this case, upon completion of the transformation, the catalyst can be easily recovered by simple filtration or centrifugation of the mixture and it can be reused again.

1.2 Allylic compounds

1.2.1 Relevance and prevalence in nature

Allylic compounds can be defined as organic molecules which are constituted by an olefinic substituent in a a,b relationship to a carbon that bears a functional group (X, Figure 3). The nature of this group can be very extensive but the most common structures are: allylic alcohols or ethers (X = OH, OR6), allylic halides (X = F, Cl, Br or I), allylic amines (X = NH2, NHR7, N(R7)2) and allylic thiols or sulphides (X = SH, SR8). They can be also classified depending on the degree of substitution of the functionalized carbon into: primary (R1 = R2= H), secondary (R1= H, R2 ≠ H) or tertiary allylic substrates (R1 ≠ H, R2 ≠ H), respectively. Furthermore, the olefin can exhibit different degrees of substitution depending on the groups attached to the double bond (R3, R4 and R5).

R4 X R1 R5 R2 R3 Figure 3. General structure of allylic compounds.

Allylic systems are ubiquitous motifs in both natural and pharmaceutical compounds with broad properties and applications. Figure 4 depicts a variety of molecules that contains allylic motifs in their structure. Geraniol, linalool and allicin (Figure 4a-c) are natural products found in plants commonly used as additives in fragrances and essential oils. Allylic compounds can also be found in molecules with important biological activity like naftifine and morphine or in hormones, such as prostaglandins (Figure 4d-f). An example of a complex natural product having two allylic alcohols functionalities is ingenol (Figure 4g), a very potent promoter of cell death.12

OH OH O N S S

a) Geraniol b) Linalool c) Allicin d) Naftifine

HO COOH O O H O H H N HOHO CH3 HO HO OH HO OH

e) Morphine f) Prostaglandin E2 g) Ingenol Figure 4. Examples of organic molecules bearing allylic alcohol moieties.

1.2.2 General reactivity

As it has been previously stated, allylic compounds bear two different functional groups in their structure and, for this reason, they are able to undergo many types of transformations. Their reactivity can be classified depending on the group being transformed. In the case of allylic alcohols, amines or thiols, the functional group can be alkylated or acylated to form the corresponding alkyl and acyl derivatives, respectively. The olefinic group of the allylic system strongly activates the functional group and substitution reactions are very favorable. A clear example is that of the allylic halides, which undergo substitution reaction with nucleophiles. However, due to the high reactivity, rearrangements are also very common in this type of transformations and mixtures of isomers are usually obtained.13 An important reaction of allylic compounds that has found many applications in organic synthesis is the versatile “Tsuji-Trost” reaction. It is based on the use of transition metals (e.g., Pd, Ir) to substitute the functional group of an allylic system by a nucleophile through mechanisms involving π-allyl-metal intermediates.14 On the other hand, the olefinic part of the system can also undergo transformations, such as reduction, epoxidation, aziridination, halogenation, cyclopropanation or metathesis.15 Finally, there are some reactions where both functionalities are transformed such as the Johnson-Claisen rearrangement or the Eschenmoser-Claisen rearrangement.16

1.2.3 [1,3]-Sigmatropic hydrogen shifts

A [1,3]-sigmatropic hydrogen shift is a concerted reaction where a s-bonded hydrogen changes position in a hydrocarbonated chain while the p-bonds reorganize through a cyclic transition state.17 Allylic systems can theoretically undergo thermal alkene isomerization via the so called [1,3]-sigmatropic hydrogen shift (Scheme 2a). The transformation is symmetrically allowed according to the Woodward-Hoffmann rules as an antarafacial reaction but due to sterical reasons it is forbidden (Scheme 2b).18 As a result, thermal [1,3]- sigmatropic hydrogen shifts do not take place and catalysts are required to achieve this transformation in a stepwise manner. Thus, for a [1,3]-hydrogen shift to occur, catalysts are needed.

5 The isomerization of allylic alcohols is a good example of this reaction where catalysts are employed to accomplish [1,3]-hydrogen shifts. The isomerization of allylic alcohols will be covered extensively in next section (1.3).

H (FG)

H H a) (FG) (FG)

H b) • Electronically plausible • Physically imposible • Antarafacial [1,3]-H shift

Scheme 2. Thermal [1,3]-Sigmatropic hydrogen shift

1.3 Isomerization of allylic alcohols

The transformation of allylic alcohols into the corresponding saturated carbonyl compounds can be achieved in a two-step process (Figure 5). The allylic alcohol can be oxidized to the a,β-unsaturated carbonyl compound followed by reduction of the olefin (Figure 5, path a), or vice versa. (Figure 5, path b). However, these methods have a number of drawbacks. They require the use of stoichiometric amounts of oxidizing and reducing agents and generate large quantities of waste. Thus, from the atom-economy point of view, the synthesis of saturated carbonyl compounds following these methodologies is not desirable. On top of that, other functional groups present in the molecule might not tolerate the oxidizing or reducing conditions. A more straightforward method is the isomerization of allylic alcohols through an internal redox process (Figure 5, path c). Several transition-metal catalysts have been used for this transformation, being the most common those based on Rh, Ru and Ir (Section 1.3.1).19 It is however possible to find examples of the use of non-precious metals for this transformation such as Fe, Co or Mn.20 Although not very commonly, it is also possible to encounter in the literature metal-free protocols for the isomerization of allylic alcohols. These protocols normally require superstoichiometric amounts of strong bases and harsh reaction conditions (Section 1.3.2). R3 O

R4 R1 R2 Path a)

R3 O R3 OH Isomerization R4 R1 R4 R1 Path c) R2 R2

R3 OH

R4 R1 R2 Path b) Figure 5. Transformation of allylic alcohols to saturated carbonyl compounds.

1.3.1 Metal-catalyzed protocols

Over the past decades, several transition-metal complexes have successfully catalyzed the isomerization of allylic alcohols, although early examples required high temperatures and longer reaction times.19 Besides, in these systems, chemoselectivity was difficult to control when extra saturated alcohols or double bonds were present in the molecules. Some of the first catalysts reported for the isomerization of allylic alcohols are: Fe(CO)5,21 RhH(CO)(PPh3)3 or RuCl3.22 In 1993, Trost and coworkers reported a ruthenium catalyst that, together with an additive, was able to isomerize allylic alcohols with complete chemoselectivity albeit at high temperatures and high catalyst loadings.23 Since these early examples, the field has substantially evolved and nowadays it is possible to perform the transition-metal-catalyzed isomerization of a variety of allylic alcohols under very mild reaction conditions employing very low catalyst loadings. In this sense, in 2006, Gimeno and coworkers described a Ru(IV) complex that could perform the reaction in water at 75 °C with very high turnover numbers (TONs) and turnover frequencies (TOFs) of up to 1500000 and 62500 h-1, respectively. Albeit with a limited substrate scope, this catalyst is one of the most efficient in the isomerization of allylic alcohols reported to date.24 Our research group has described a Rh- catalyzed isomerization of sec-allylic alcohols in water at R.T. using a water-soluble phosphine: 1,3,5-triaza-7-phosphatricyclo[3.3.1.13.7]decane (PTA).25,26 Very recently, a general Ir(III)-catalyzed method for the isomerization of primary and secondary allylic alcohols in aqueous solvent under remarkably mild conditions at R.T. has also been reported in our research group.27

1.3.1.1 Synthesis of chiral carbonyls from allylic alcohols

The asymmetric protocols for the isomerization of allylic alcohols can be classified as stereoselective or stereospecific. The stereoselective isomerization affords the corresponding chiral carbonyl compounds starting from racemic or non-chiral allylic alcohols and mediated by chiral metal complexes. In this regard, the stereoselective isomerization of primary allylic alcohols to yield chiral aldehydes with a stereogenic center at Cβ has been reported (Scheme 3).28

1 1 R [Mcat] R * R2 OH R2 O Chiral ligand L* Scheme 3. Stereoselective isomerization of primary allylic alcohols.

However, the same reaction with secondary allylic alcohols has proved to be much more challenging.29 A recent example is shown below where a chiral ruthenium catalyst is used in the transformation (Scheme 4).30

[Rh(COD)2]BF4 (2 mol%) OH O (R)-BINAP (5 mol%) 3 1 R3 R1 R R Ag CO (5 mol %) 2 R2 2 3 R 24 °C (±) up to 90% ee Scheme 4. Stereoselective isomerization of secondary allylic alcohols.

7 On the other hand, the stereospecific approach is based on the use of enantiomerically pure allylic alcohols yielding chiral carbonyl compounds through a process involving a transfer of chirality.31 In 2012, Cahard, Renaud and co-workers reported the first stereospecific isomerization of g-trifluoromethylated allylic alcohols using RuCl2(PPh3)3 as catalyst and Cs2CO3 as base in toluene at R.T. (Scheme 5).32 Using this method, they were able to construct chiral β-trifluoromethylated ketones with good yield and excellent transfer of chirality.

RuCl2(PPh3)3 (1 mol%) 2 2 R OH Cs2CO3 (1.0 equiv.) R O

1 1 F3C R Toluene, rt F3C R up to 99% ee Scheme 5. Stereospecific isomerization of g-trifluoromethylated allylic alcohols.

1.3.1.2 Proposed mechanisms

Three distinct mechanisms have been proposed to account for the metal-catalyzed isomerization of allylic alcohols. In all of them, metal-hydride species are key catalytic intermediates.19,27 These species can be formed either in a preactivation step with H2 or in situ under the reaction conditions. The first type of mechanism (mechanism A) is generally accepted when the catalyst is a metal-hydride species or when the precatalyst needs to be activated with H2 prior to the reaction (Scheme 6). After coordination of the catalyst to the double bond of the allylic alcohol, migratory insertion of the olefin into the M−H bond takes place. Then, β-hydride elimination affords an enol derivative that tautomerizes to the corresponding carbonyl compound and the metal-hydride species is recovered.

Mechanism A

R3 OH [M-H] R3 O

R4 R1 R4 R1 R2 R2

Coordination Tautomerization [M-H]

R3 OH R3 OH R4 R4 R1 H R1 2 2 [M-H] R R

Migratory insertion -[M-H] R3 OH R3 OH R4 R4 H R1 H R1 [M] R2 β-Hydride 2 elimination R [M-H] Scheme 6. Intermolecular hydrogen transfer mechanism.

The second type of mechanism (mechanism B) is based on the formation of a π- allyl metal intermediate through an oxidative addition process (Scheme 7). After that, reductive elimination takes place yielding the enol intermediate and regenerating the metal catalyst.33 Finally, the third type of mechanism involves the formation of an a,β-unsaturated intermediate (mechanism C, Scheme 8). The first step in this mechanism is the formation of a metal-alkoxide intermediate from the allylic alcohol and the catalyst.19 Mechanism B

R3 OH [Mn] R3 O

R4 R1 R4 R1 R2 R2

Oxidative Tautomerization addition [Mn]

3 R OH R3 OH -[M-H] R3 OH R4 R4 R4 R1 H R1 H R1 Reductive Decoordination n+2 2 2 [Mn] 2 [M -H]R elimination R R Scheme 7. Mechanism involving the formation of π-allyl metal complexes.

Mechanism C

R3 OH [M] R3 O

R4 R1 R4 R1 R2 R2

Alkoxide Tautomerization formation [M]

R3 OM R3 OH R4 R4 R1 H R1 R2 R2

M β-Hydride elimination H O Protodemetalaton R3 R1 R4 R2 R3 O [M-H] R3 OM R4 R4 R1 H R1 1,4 Hydride addition R2 R2

Olefin 3 O 3 coordination R R O R4 4 1 1 R R H R [M-H] R2 Migratory M R2 insertion B

R3 O R4 R1 Migratory M H R2 insertion A Scheme 8. Mechanism involving a,β-unsaturated carbonyl compounds.

9 In cases where a base additive is necessary in the reaction, it has been proposed that the base enables the formation of this metal-alkoxide species. Then, β-hydride elimination affords the a,β-unsaturated carbonyl compound and the metal-hydride intermediate. Two different pathways have been proposed for the subsequent step: a concerted 1,4- (Scheme 8 top) or a stepwise 1,2-migratory insertion (Scheme 8, bottom). In the first scenario, the hydride is placed in position 4 and an O-bound metal enolate is formed directly. In the second case, the metal-hydride needs to decoordinate from the carbonyl and further coordinate to the olefin, then, there are two different migratory insertions plausible. The first one, migratory insertion A, can only revert back into the metal-hydride coordinated enone. On the contrary, migratory insertion B produces a C-bound enolate in equilibrium with the O-bound enolate. In the final step, a molecule of solvent or starting material produces the enol molecule that tautomerizes to the carbonyl compound and the catalyst is recovered. The stereospecific isomerization of g-trifluoromethylated allylic alcohols reported by Cahard, Renaud and co-workers is an example of this type of mechanism.32 After a β- hydride elimination, a ruthenium-hydride species and an a,β-unsaturated ketone are formed. The subsequent migratory insertion occurs only from a single face resulting in an efficient transfer of chirality.

1.3.2 Transition-metal-free examples

The isomerization of allylic alcohols has also been reported in the absence of transition metals, albeit the reports are scarce and require the use of bases. Even though the first reports of the reaction date already from 1928, the field has not evolved significantly.34 The existing protocols require the use of strong bases in stoichiometric or even superstoichiometric amounts and the reactions are very dependent on the structure of the substrates.35 In 1976, Dimmel and co-workers reported the isomerization of allylic alcohols using 2 equivalents of n-BuLi (Scheme 9a).35a In 2001, Borschberg and Schmidt also reported an example where 2 equivalents of t-BuOK were needed for the reaction to occur (Scheme 9b).35b

BuLi OH 2.0 equiv. O a) Ar Ar

t-BuOK OH 2.0 equiv. O b) Ph Ar Ph Ar

NaH OH 1.5 equiv. O c) Ph R Ph R Br

1.5 equiv. R = Ar, or SiMe2Ph Scheme 9. Examples of base-mediated isomerization of allylic alcohols.

Cook et al. reported an interesting related process in 2013. In this publication, NaH was used to synthesize a-allylated-saturated ketones from allylic alcohols and the mechanism was proposed to be a 1,3-metallotropic shift followed by an allylation reaction (Scheme 9c).36 Later, similar transformations have been reported by the same group, starting from the corresponding allylic ethers bearing an allyl group at the oxygen atom.37 Protocols that use the base in catalytic amounts have been reported only recently in the literature. In 2015, Tang and co-workers published a method for the isomerization of allylic alcohols and allylic amines using phenanthroline and t-BuONa as the catalysts. The mechanism proposed followed a radical pathway through radical anions (Scheme 10a).38 Pan and co-workers have also reported the use of catalytic amounts of DABCO to isomerize g-keto primary allylic alcohols into the corresponding 1,4-ketoaldehydes (Scheme 10b).39 However, before 2016 the metal-free isomerization of allylic alcohols had only been performed in a racemic manner and no asymmetric protocols had been reported (Paper V).

Phenanthroline / 3 X R3 t-BuONa (cat.) O R a) R1 R2 R1 R2

X = O, NH R1, R2, R3 = Ar, Me or H

O R3 O R3 DABCO (cat.) OH O b) R1 R1 R2 R2

R1 = Ar, Alk R2, R3 = H, Me Scheme 10. Transition-metal-free, base-catalyzed isomerization of allylic alcohols.

1.3.3 Tandem isomerization / functionalization of allylic alcohols

Allylic alcohols can also serve as enolate precursors in the synthesis of a-substituted carbonyl compounds through tandem isomerization / functionalization. In the general mechanism of the transition-metal-catalyzed isomerization of allylic alcohols (vide supra, Scheme 8), two different metal enolates, i.e., C-bound and O-bound, can be formed. In the absence of any external reagent, these metal enolates are converted into enol derivatives via a protodemetalation process. However, if there is an external electrophile in the reaction medium, the metal enolates can be trapped, affording the corresponding a-functionalized ketones or aldehydes. The metal enolates are only formed in the position where the olefin was originally located. In substrates where the final ketone bears two different enolizable positions, this method allows the selective synthesis of a-substituted carbonyl compounds as single constitutional isomers. The application of classical enolate chemistry in unsymmetrical ketones creates mixtures that are, generally, difficult to separate (Scheme 11a). The tandem isomerization / functionalization of allylic alcohols solved this selectivity problem (Scheme 11b).

11 a) Classical enolate chemistry

O Electrophile O O 1 2 1 2 1 2 R R R R + R R E E R2 ≠ R1 Mixture of constitutional isomers

b) Isomerization / functionalization

OH [Mcat] O R1 R1 R2 R2 Electrophile E

Single constitutional isomer Scheme 11. Synthesis of a-substituted ketones.

Our group has employed this method to achieve the selective synthesis of a variety of a-substituted aldehydes and ketones.40 The use of aldehydes and imines as electrophiles afforded the selective synthesis of β-hydroxy- and β-aminoketones, respectively, using Ru or Rh complexes at R.T. (Scheme 12a).41 The selective synthesis of a-halogenated carbonyl compounds was first reported by our group using halogenating agents as electrophilic partners. In this manner, Selectfluor® and N-chlorosuccinimide (NCS) have been successfully applied in the Ir(III)-catalyzed synthesis of a-fluoro and a-chlorocarbonyl compounds. More recently, a protocol for the synthesis of a-bromocarbonyls has also been reported (Scheme 12b).42 O OH [Ru]cat or [Rh]cat 1 1 a) R R 2 R2 R R Y R YH Y = O or NR´

OH [Ir]cat O 1 1 R R 2 b) R2 R Halogenating X agent X = F, Cl and Br Scheme 12. Transition-metal-catalyzed selective synthesis of a-functionalized ketones.

1.4 Hypervalent iodine chemistry

1.4.1 The hypervalent bond of iodine

An hypervalent atom is defined as an atom that has more than eight electrons in its valence shell and, thus, breaks the octet rule. Iodine is a well-known example of an atom that is able to show hypervalency expanding its valence shell. Apart from the common -1, iodine can adopt three other oxidation states (I(III), I(V) and I(VII)).43 Figure 6 shows a variety of hypervalent iodine structures with different oxidations states. I(VII) and I(V) compounds

(Figure 6, a-c) have been extensively employed in organic synthesis as oxidants in numerous transformations.44 I(III) compounds (Figure 6, d-f) can also be used as oxidants (i.e., PIDA) but they can be also employed in a wide variety of processes (vide infra, section 1.4.2).43 O O O O I O O O O Na I I OAc OH AcO O OAc a) Sodium b) 2-Iodoxybenzoic c) Dess-Martin Periodate acid (IBX) periodinane (DMP)

AcO I OAc F3C I O F I O

d) (Bisacetoxyiodo) e) 1-(Trifluoromethyl)-1λ3-benzo f) 1-Fluoro-3,3-dimethyl- benzene (PIDA) [d][1,2]iodaoxol-3(1H)-one 1,3-dihydro-1λ3-benzo (Togni´s reagent II) [d][1,2]iodaoxole Figure 6. Examples of hypervalent iodine reagents.

In iodine, hypervalency is consequence of a L-I-L bond which is formed by an unhybridized p orbital with 4 electrons. As a result of this 3-centered 4-electrons (3c-4e) bond, the central iodine experiments a partial positive charge and the external ligands obtain an accumulation of negative partial charge (Figure 7a). As a direct result of this linear hypervalent bond, I(III) reagents have a distinctive T-shape. The Ar-I sp2 bond and the two lone pairs of I occupy equatorial positions whereas the hypervalent bond allocates the other two ligands (L) in axial positions (Figure 7b).43d Electronegative ligands that are able to stabilize the partial negative charge are placed in these positions.

a) b) axial L I equatorial L L I L δ- δ+ δ-

Figure 7. a) Molecular orbitals of a 3c-4e bond. b) T-shaped I(III) species.

1.4.2 Iodine (III) reagents and their reactivity

The reactivity of all iodine (III) reagents is a consequence of the nature of the hypervalent 3c-4e bond L-I-L (A). As previously mentioned, the central iodine bears a partial positive charge and thus, exhibit a strong electrophilic behavior. Nucleophiles are, therefore, able to interact with this electrophilic iodine replacing one of the ligands in a process that is known as ligand exchange (Figure 8). From the newly generated T-shaped intermediate B a final elimination of a reduced iodine specie (usually iodobenzene) affords the product Nu-L (C). Two distinctive mechanisms have been proposed for this elimination step: a direct reductive elimination or, after rotation, a concerted ligand coupling. An important feature of this chemistry is the excellent leaving abilities of these ArI species, which in turn drives the reaction forward.43b

13 Nucleophilic attack Reductive Ligand exchange elimination L L Ar I Ar I Nu L -L A L B Nu Nu

Nu I Nu L + ArI C Ar Ligand coupling

Figure 8. General reactivity of I(III) reagents.

In summary, iodine (III) reagents of the type ArIL2 react with nucleophiles, they transfer one of ligands (L) to the nucleophile while, at the same time, get reduced to ArI. I(III) are, hence, electrophilic ligand transfer agents.43b The most important functional groups that have been successfully transferred are: halides;45 the trifluoromethyl group;46 aryl, alkenyl or alkynyl groups;43c and oxygen- and nitrogen-containing functional groups.43 The latter are intrinsically nucleophilic in nature but, through the mediation of iodine (III), they can react with nucleophiles.47

1.5 Aim of this thesis

The aim of this work is the development of new organic transformations employing allylic compounds as substrates in order to synthesize functionalized carbonyl or vinyl compounds in an efficient manner. In parallel, and intimately related, the second goal of this thesis is the study of the mechanisms of these protocols to detect limitations and improve the methods. The thesis is divided into two distinctive parts that differ in the approach taken: iridium-catalysis (chapters 2-4) or organocatalysis (chapters 5-7). The transition-metal-catalyzed isomerization of allylic alcohols and the related tandem isomerization / functionalization are powerful methods to access highly functionalized aldehydes and ketones in good yields as single constitutional isomers. In the first part of this thesis, the aim is to develop new methods to increase the scope of the Ir(III)-catalyzed selective synthesis of a-substituted carbonyl compounds. First, the reaction of allylic alcohols with new electrophilic partners is set as a goal. In this sense, the aim is to develop protocols for the isomerization / iodination and the isomerization / aminoxylation of allylic alcohols to synthesize relevant a-iodo- or a-hydroxyketones and aldehydes. Besides, a novel umpolung strategy from allylic alcohols is also investigated in order to be able to react electronically mismatched enolate derivatives and nucleophiles in a selective manner. The second part of this work aims to employ base catalysis as an effective tool to isomerize allylic moieties into their corresponding products in a metal-free fashion. The investigation of base-catalyzed stereospecific transformations is one of the central goals of this part of the thesis. Likewise, an important aim is also the consideration of substrates that have been proved challenging to be transformed employing established metal-catalyzed methods.

2. Synthesis of a-iodocarbonyl compounds as single constitutional isomers via isomerization of allylic alcohols (Paper I and II)

2.1 Aiming to the synthesis of challenging a-iodinated carbonyl compounds

In 2014, a protocol for the iridium-catalyzed tandem isomerization / bromination of allylic alcohols was developed in our research group.42c This method enabled the selective synthesis of a-bromoketones and aldehydes with very good yields (Scheme 13). A key aspect of this method was the use of a mild brominating agent derived from dimedone (2,2- dibromo-5,5-dimethylcyclohexane-1,3-dione).42c The development of a protocol for the selective access to challenging a-iodinated carbonyl compounds was set as a goal in this project. From previous investigations, it was known that the use of a mild iodinating agent would be required to obtain good results. A strong electrophilic iodinating agent would generate higher amounts of side-products and / or inhibit the iridium-catalyzed hydrogen transfer. Besides, the resulting a-iodocarbonyls might not be stable under the reaction conditions. These reasons explain the fact that efficient methodologies for the synthesis of a-iodoketones and aldehydes are scarce in the literature.48

Br Br O O

(1.2 equiv.)

OH [(Cp*Ir)2(OH)3]独11H2O (1 mol%) O 1 1 R R 2 R2 R Acetone / H O (2:1, v/v) 2 Br RT Scheme 13. Selective synthesis of a-bromoketones from allylic alcohols.

2.2. Synthesis of 2,2-diiododimedone and its application in the electrophilic iodination of electron-rich arenes

Based on our previous work, 42c it was envisioned that an iodinating agent analogous to that used for the brominating protocol (Scheme 13) would yield good results in the tandem isomerization / iodination of allylic alcohols. The project was then started by synthesizing iodinating agent 1 (2,2-diiododimedone). This was achieved by stirring a mixture of readily available dimedone and iodine monochloride in 1,4-dioxane for 2 h at RT (Scheme 14). The addition of H2O upon completion of the reaction yielded 2,2-diiododimedone (1) which was collected by simple filtration and used without further purification (93% purity obtained using quantitative NMR). The synthesis could be performed in gram scale (up to 8 g) obtaining the product in 75% isolated yield.

15 I I O O O O ICl

1,4-Dioxane RT, 2 h 1 Scheme 14. Synthesis of 2,2-diiododimedone (1).

The reactivity of 1 was first investigated in the electrophilic iodination of electron rich aromatic compounds.[Note 1] The use of HFIP as solvent and catalytic amounts of a Lewis acid (FeCl3•H2O) were needed in order to obtain iodinated arenes 3 in good yields from electron rich aromatics 2 (Scheme 15). The need of these conditions (e.g., a catalyst and a fluorinated solvent) indicates the mild nature of iodinating agent 1. I I O O

(1, 1.2 equiv.) Ar-H Ar-I FeCl •H O (0.1 mol%) 2a-2c 3 2 3a-3c HFIP, 2 h

I OMe NMe2

I I N Piv 3a, 82% 3b, 68% 3c, 81% Scheme 15. Electrophilic iodination of electron-rich aromatic compounds using 1 (isolated yields).

2.3 Iridium-catalyzed isomerization/iodination of allylic alcohols using 2,2-diiododimedone

2.3.1 Optimization

The next step in the project was the investigation of an iridium-catalyzed isomerization / iodination of allylic alcohols in order to yield challenging a-iodocarbonyl compounds. The optimization studies were performed using commercially available allylic alcohol oct-1-en-3-ol 4a and iodinating agent 1. Different Ir(III) complexes and several solvents and conditions were screened (Table 2). All reactions were performed under an atmosphere of air. The use of [Cp*IrCl2]2 (2 mol%) as catalyst in a mixture of acetone and H2O (1:1 (v/v)) provided full conversion of allylic alcohol 5a. However, the desired product was only formed in 36% together with 64% of the a,b-unsaturated side-product (Table 2, entry 1). The amount of side-product could be reduced by replacing the acetone in the solvent mixture by other solvents such as 1,4-dioxane or THF (Table 2, entries 2 and 3). Of all the solvents tested, 2-methyltetrahydrofuran (2-MeTHF) afforded the least amount of unwanted 6a, while still providing good conversion of starting material 4a (Table 2, entry 4).

[Note 1] These results were obtained by Dr. Elis Erbing.

When [Cp*IrCl2]2 was changed to other [Cp*Ir(III)] catalysts, not only the conversion was improved but, more importantly, the amount of a,b-unsaturated ketone was reduced to 6-8% (Table 2, entries 5 and 6). Increasing the amount of H2O in the solvent mixture (2-MeTHF/H2O = 1:2 (v/v)) yielded higher amount of the undesired side-product (Table 2, entries 7 and 8). On the contrary, increasing the amount of the organic solvent (2-MeTHF/H2O = 2:1 (v/v)) managed to minimize it to 5-6% (Table 2, entries 9 and 10). When the catalyst loading was reduced to 1 mol%, complex [(Cp*Ir)2(OH)3]OH •11H2O showed better performance than [Cp*Ir(H2O)3]SO4 and product 5a could be obtained in 88% yield (Table 2, entries 11 and 12). The use of only 0.6 or 0.2 equiv. of iodinating reagent 1 afforded desired compound 5a in 69% and 27% yield, respectively, which suggest that slightly more than one iodine atom can be transferred from 2,2-diododimedone 1 to the product (Table 2, entries 13 and 14).

Table 2. Selective synthesis of 2-iodoocten-3-one (5a) using electrophilic iodinating agent 1.[a] I I O O

(1, 1.2 equiv.) OH O O [Cp*Ir(III)]cat + Solvent, 16 h I 4a RT 5a 6a

Conv. 5a/6a Entry Catalyst Solvent (v/v) [%][b] (%)[b,c]

1 [Cp*IrCl2]2 Acetone/H2O (1:1) >99 36/64

2 [Cp*IrCl2]2 1,4-Dioxane/H2O (1:1) 99 46/53

3 [Cp*IrCl2]2 THF/H2O (1:1) 86 58/28

4 [Cp*IrCl2]2 2-MeTHF/H2O (1:1) 96 85/11

5 [Cp*Ir(H2O)3]SO4 2-MeTHF/H2O (1:1) 99 93/6

6 [(Cp*Ir)2(OH)3]OH •11H2O 2-MeTHF/H2O (1:1) >99 92/8

7 [Cp*Ir(H2O)3]SO4 2-MeTHF/H2O (1:2) >99 91/9

8 [(Cp*Ir)2(OH)3]OH •11H2O 2-MeTHF/H2O (1:2) >99 90/10

9 [Cp*Ir(H2O)3]SO4 2-MeTHF/H2O (2:1) 98 93/5

10 [(Cp*Ir)2(OH)3]OH •11H2O 2-MeTHF/H2O (2:1) >99 94/6

11[d] [Cp*Ir(H2O)3]SO4 2-MeTHF/H2O (2:1) 86 79/7

12[d] [(Cp*Ir)2(OH)3]OH •11H2O 2-MeTHF/H2O (2:1) 92 88/4

13[e] [(Cp*Ir)2(OH)3]OH •11H2O 2-MeTHF/H2O (2:1) 70 69/1

14[f] [(Cp*Ir)2(OH)3]OH •11H2O 2-MeTHF/H2O (2:1) 27 27/- [a] Unless stated, the reactions were run using 4a (0.5 mmol, 0.1 M) and 2 mol% of [Ir] in the depicted solvent mixture. [b] Yield determined by 1H NMR spectroscopy. [c] Octan-3-one was not formed. [d] 1 mol% of [Ir]. [e] 0.6 equiv. of 1 were used. [f] 0.2 equiv. of 1 were used.

17 2.3.2 Control experiments

The reaction was next evaluated changing iodinating agent 1 by other common electrophilic iodinating agents (I2, ICl, NIS and IPy2BF4).49 When I2 and ICl were used 66% of conversion was observed, but the formation of 5a was not detected (Table 3, entries 2 and 3). The use of both N-iodosuccinimide (NIS) and IPy2BF4 afforded full conversion of allylic alcohol 4a. NIS yielded 17% of 5a along with a lot of unidentified compounds (Table 3, entry 4). However, Barluenga´s reagent (IPy2BF4) only showed decomposition (Table 3, entry 5). These experiments evidenced the necessity of a mild iodinating agent in order to successfully synthesize compound 5a. A control experiment was conducted where no iodinating agent was added. More than 95% of starting material 4a was recovered after 16 h (Table 3, entry 6). The need of a halide ligand on [Ir] has been previously reported by our group to be essential for the isomerization of allylic alcohols.27 A series of control experiments lacking the addition of iridium catalyst were also performed. 2,2-Diiododimedone 1 alone was not able to afford product 5a and only 4% of conversion was observed (Table 3, entry 7). On the contrary, other electrophilic iodinating reagents yielded some conversion of 4a, ranging from 25% in the case of I2 to 95% of ICl (Table 3, entries 8-11). However, a-iodoketone 5a was not formed, and a mixture of unknown products was produced instead.

Table 3. Control experiments for the iridium-catalyzed isomerization / a-iodination of 4a.[a]

Iodinating agent (1.2 equiv.) OH O O [Cp*Ir(III)]cat + Solvent, 16 h I 4a RT 5a 6a

Entry Catalyst Reagent Conv. (%) 5a/6a (%)[b]

1 [(Cp*Ir)2(OH)3]OH•11H2O 1 >99 94/6

2 [(Cp*Ir)2(OH)3]OH•11H2O I2 66 -/3[c]

3 [(Cp*Ir)2(OH)3]OH•11H2O ICl 66 -/1[c]

4 [(Cp*Ir)2(OH)3]OH•11H2O NIS >99 17/-

5 [(Cp*Ir)2(OH)3]OH•11H2O IPy2BF4 >99 -/-

6 [(Cp*Ir)2(OH)3]OH•11H2O - <5 - 7 - 1 4 -

8 - I2 25 -[d] 9 - ICl 95 -[d] 10 - NIS 90 -[d]

11[d] - IPy2BF4 76 -[d]

[a] Unless stated, the reactions were run using 4a (0.5 mmol, 0.1 M) and 2 mol% of [Ir] in 2-MeTHF/H2O (2:1, v/v). [b] Yield determined by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. [c] Octan-3-one was formed in 28% and 21% (entry 2 and 3, respectively). [d] Mixture of unidentified compounds.

2.3.3 Scope of the reaction

Using the best conditions (Table 2, entry 12), a library of allylic alcohols was successfully converted to their corresponding a-iodocarbonyl compounds (Scheme 16). Terminal allylic alcohols 4a-4f and 4k-4m afforded 5a-5f and 5k-5m in very good yields after 16 h of reaction time. Allylic alcohols bearing internal double bonds (4g-4j) showed lower reactivity in this transformation. However, the corresponding a-iodoketones could be obtained in good to moderate yields. The stability of the products during the purification process explained the difference between the isolated yield and the yield observed by 1H NMR spectroscopy using an internal standard. I I O O

(1, 1.2 equiv.) [(Cp*Ir)2(OH)3]OH独11H2O O OH (1 mol%) R1 R1 R2 R2 2-MeTHF / H2O (2:1, v/v) I 4a-4r RT, 16 h 5a-5r

O O O O Ph O

I I I I

5a, 96% (78%) 5b, 83% (68%) 5c, 86% (74%) 5d, 56% (48%)

O O O O

Ph Ph Ph I I I I

5e, 81% (67%) 5f, 78% (66%) 5g, 47% (43%) 5h, 78% (66%)

O O O O O

Ph I I I I I Cl i-Bu Br

5i, 70% (55%) 5j, 68% (55%) 5k, 87% (72%) 5l, 89% (74%) 5m, 70% (55%)

O O O

H Ph H H I I I Cl

5n, 87% (21%) 5o, 58% (37%) 5p, 61% (34%)

O O Ph O Ph H H I I 5q, 51% (41%) 5r, 38% (23%) Scheme 16. Scope of the iridium-catalyzed isomerization / a-iodination of allylic alcohols. Reactions performed on 1 mmol scale (0.1 M). Yield determined by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis.

19 Extra double bonds present in the starting material apart from that of the allylic alcohol moiety remained intact under these reaction conditions (4f and 4g). The substrates were all synthesized as single constitutional isomers as the iodination was only observed at the carbon originally part of the allylic moiety. The synthesis of these type of compounds starting from the corresponding ketones, which bear two different enolizable positions is challenging due to formation of complex mixtures of regioisomers. The herein described method allows the selective synthesis of a-iodoketones by using allylic alcohols as enolate synthons. The scope of the reaction is not only limited to secondary allylic alcohols and primary allylic alcohols were also successful substrates 4n-4r. Following this method, a small library of a-iodinated aldehydes was synthesized, otherwise difficult to achieve through described methods due to the strong oxidative conditions required in the synthesis.

2.3.4 Mechanistic investigations

To gain some insights into the mechanism of the isomerization / iodination of allylic alcohols using 2,2-diiododimedone, deuterated allylic alcohol 4i-d1 (95% D) was synthesized and subjected to the reaction conditions (Scheme 17a). In this way, a- iodoketone 5i was obtained with 95% of deuterium, and this was found only at C3. This suggests that the iridium catalyst enables a [1,3]-hydride shift in this reaction. In parallel, a crossover experiment was performed employing in the same reaction 0.5 equiv. of deuterated allylic alcohol 4i and 0.5 equiv. of non-deuterated 4e (Scheme 17b).

I I O O

(1, 1.2 equiv.) [(Cp*Ir) (OH) ]OH独11H O OH 2 3 2 D O D (2 mol%) a) Ph 3 1 Ph 3 1 2-MeTHF / H O (2:1, v/v) 2 I RT, 16 h 4i-d1 (95%D) 5i-d1 (95%D)

I I O O

(1, 1.2 equiv.)

OH OH [(Cp*Ir)2(OH)3]OH独11H2O D D O O b) + (2 mol%) Ph 3 1 Ph + Ph 3 1 Ph 2-MeTHF / H O (2:1, v/v) 2 I I 4i-d1 (95%D) 4e RT, 16 h 5i-d1 (95%D) 5e (0.5 equiv.) (0.5 equiv.) Scheme 17. Deuterium-labeling studies on the iridium catalyzed isomerization / iodination of allylic alcohols with 2,2-diiododimedone. a) reaction with 4i-d1. b) crossover experiment between 4i-d1 and 4e.

As deuterium could not be detected in a-iodoketone 5e, it can be assumed that the transformation follows an intramolecular reaction pathway without scrambling between substrates. These results are in fully agreement with previous investigations in the group about the mechanism of the iridium-catalyzed isomerization and isomerization / functionalization of allylic alcohols.24,42

2.4 a-Iodoketones as versatile building blocks a-Iodocarbonyls are very important building blocks in organic chemistry as they can be further transformed to molecules with other functional groups. These compounds bear two different electrophilic carbons that can react (C−I bond and C=O). Importantly, the derivatization reactions should be selective at one or the other. Iodinated compound 5e was taken as the model substrate to perform several transformations (Scheme 18). First, an imidazole derivative 7 was synthesized in 95% yield by refluxing compound 5e, benzamidine hydrochloride and K2CO3 in CH3CN overnight. In a one-pot protocol, allylic alcohol 5e afforded syn-halohydrin 8 in an excellent diastereomeric ratio (97:3) by performing a reduction using NaBH4 after the tandem isomerization / iodination protocol. Besides, compound 8 was further transformed to epoxide 9 in 70% yield upon basic treatment with the same diastereomeric ratio. Cyanoepoxide 10 was also prepared in good yield (74%) and diastereomeric ratio (80:20) by mixing KCN and substrate 5e in THF.

NH NC HCl Ph O O HN Ph KCN Ph NH2 Ph N Ph THF, 40 °C I K2CO3 10, 74% (80:20 d.r.) o.n. CH3CN, reflux 5e o.n. 7, 95%

NaBH4 MeOH, -60 °C 30 min

OH t-BuOK O Ph Ph THF, 0 °C I 30 min 8, 59% from 4e 9, 70% (97:3 d.r.) (97:3 d.r.) Scheme 18. Chemical transformations of a-iodinated compounds (isolated yields).

a-Aminocarbonyl compounds are very important motifs in organic molecules with biological activity. For example, many pharmaceuticals have this specific chemical moiety. However, the selective synthesis of a-aminoketones that have two distinctive enolizable positions is still a challenging transformation in organic synthesis.50 The iridium-catalyzed tandem isomerization / iodination of allylic alcohols has proved to be an effective method to achieve the selective synthesis of a-iodocarbonyls. A subsequent nucleophilic displacement of the iodine atom by an amine could afford the corresponding a- aminoketones as single constitutional isomers. Several aminoketones were successfully synthesized following this procedure in good isolated yields upon reacting the desired a- iodoketone with an amine in 1,4-dioxane at room temperature for 16 h (Scheme 19).

21 R3 O NH O R4 (3 equiv.) R1 R2 R1 R2 1,4-Dioxane I N RT, 16 h R3 R4 5e or 5h 11-15

O O O

Ph Ph Ph N N N 11, 89% 12, 51% 13, 73%

O O N N Ph Ph N N 14, 77% 15, 88% S

Scheme 19. Selective synthesis of a-aminoketones (isolated yields).

2.5 Towards an atom-economical method for the synthesis of a-iodocarbonyl compounds

As it has just been described, a-iodinated ketones and aldehydes can be synthesized from allylic alcohols as single constitutional isomers using iridium catalysis and a mild electrophilic iodinated agent: 2,2-diiododimedone (1). From the atom-economy point of view, this method has two clear drawbacks.51 First of all, iodinating agent 1 has two iodine atoms in its structure but it is mainly able to transfer one of them and the other ends up in the waste (vide supra, table 2, entries 13 and 14). Secondly, the molar mass of 2,2- diiododimedone 1 and its corresponding byproduct is quite large, which means that the amount of waste in this transformation is rather high. Commercial available and cheap elemental iodine I2 is also able to transfer only one electrophilic iodonium atom (I+) but it produces at the same time an iodide atom (I-) which could be oxidized by an external agent. In this sense, oxidative iodination with I2 is the best option from the point of view of atom-economy as both iodine atoms finish in the target compound. [Red.] I2 2 Nu-H

[Ox.] I- 2 Nu-I Figure 9. Concept of oxidative iodination.

Several oxidants have been employed for the oxidative iodination with I2 (CuO, oxone, hypervalent iodine compounds or H2O2 among others).52 In our case, however, the use of a milder oxidant such as air or oxygen would be essential in order to reduce the number of side-products and optimize the yield. Iskra and co-workers have described the use of NaNO2 as electron-transfer mediator catalyst for the oxidative iodination of several organic compounds using oxygen or air as the final oxidant.53 The use of this oxidative iodination protocol with I2 and our iridium chemistry, would yield an atom-economical and selective synthesis of a-iodinated ketones and aldehydes from allylic alcohols.

2.6 Iridium-catalyzed isomerization/iodination of allylic alcohols using aerobic oxidative iodination

2.6.1 Optimization

The optimization studies were performed using allylic alcohol 4e, I2 (0.5 equiv.) and NaNO2 (5 mol%) as the electron-transfer mediator.53 Different iridium catalysts, solvents mixtures and concentrations were evaluated in order to optimize the reaction. As the starting point, [Cp*IrCl2]2 was chosen as catalyst and the reaction was run in a mixture of THF/H2O (3:1, v/v) with a concentration of 0.2 M under air (Table 4, entry 1).42b Using these conditions only 47% yield of the desired product 5e was obtained. This result was very encouraging as I2 did not afford good results when used in stoichiometric amounts (vide supra, Table 3, entries 2 and 8). The use of other Ir(III) catalysts such as [Cp*Ir(H2O)3]SO4 or [(Cp*Ir)2(OH)3]OH •11H2O was beneficial for the reaction and the yield could be improved to 60% (Table 4, entries 2 and 3). It should be noted that in all these cases only 8% of a,b-unsaturated ketone (6e) was formed as side-product, the rest being decomposition. Catalyst [Cp*Ir(H2O)3]SO4 was chosen to continue with the optimization. Not surprisingly, using an O2 atmosphere in the reaction improved the results of the transformation and 5e was synthesized in 70% yield (Table 4, entry 4).

Table 4. Selective synthesis of 4-iodo-1-phenylpentan-3-one (5e) using I2 and NaNO2.[a] [Cp*Ir(III)] (2 mol%) OH I2 (0.5 equiv.) O O NaNO2 (5 mol%) + Solvent, 48 h I RT 4e 5e 6e 5e/6e Entry Catalyst atm Solvent (v/v) (M) (%)[b]

1 [Cp*IrCl2]2 Air THF/H2O (3:1) 0.2 47/8

2 [Cp*Ir(H2O)3]SO4 Air THF/H2O (3:1) 0.2 60/8

3 [(Cp*Ir)2(OH)3]OH •11H2O Air THF/H2O (3:1) 0.2 60/8

4 [Cp*Ir(H2O)3]SO4 O2 THF/H2O (3:1) 0.2 70/-

5 [Cp*Ir(H2O)3]SO4 O2 Acetone/H2O (3:1) 0.2 72/-

6 [Cp*Ir(H2O)3]SO4 O2 2-MeTHF/H2O (3:1) 0.2 13/7

7 [Cp*Ir(H2O)3]SO4 O2 2-MeTHF/H2O (3:1) 0.04 90/-

8[c] - O2 2-MeTHF/H2O (3:1) 0.04 -

9[d] [Cp*Ir(H2O)3]SO4 O2 2-MeTHF/H2O (3:1) 0.04 32/-

10[e] [Cp*Ir(H2O)3]SO4 O2 2-MeTHF/H2O (3:1) 0.04 -

11[f] [Cp*Ir(H2O)3]SO4 O2 2-MeTHF/H2O (3:1) 0.04 - [a] Unless stated, the reactions were run using 4e (0.2 mmol) and 2 mol% of [Ir] in the depicted solvent mixture, concentration of 4e and atmosphere (1 atm). [b] Yield determined by 1H NMR spectroscopy against an internal standard. [c] No catalyst was used. [d] No NaNO2 was used. [e] NIS instead of I2. [f] KI instead of I2.

23 The effect of the solvent was evaluated next. Changing THF for acetone gave similar results in the transformation (Table 4, entry 5). On the other hand, 2-MeTHF decreased drastically the yield of 5e (Table 4, entry 6). Remarkably, using the same solvent but reducing the concentration of the reaction from 0.2 M to 0.04 M gave an optimized 90% yield of 5e. The presence of 6e as a side-product could not be detected under these conditions. Both catalysts, [Cp*Ir(H2O)3]SO4 and NaNO2, were verified to be necessary in this transformation as without any of them the results were not satisfactory (Table 4, entries 8 and 9). Finally, other sources of iodine were also tested in this reaction but they failed to give the desired product. NIS gave a complex mixture of products (Table 4, entry 10), whereas KI provided no conversion (Table 4, entry 11).

2.6.2 Scope of the reaction

The conditions described in Table 4, entry 7 were taken as optimal for the reaction. Subsequently, the scope of the method was studied employing this aerobic oxidative iodinating strategy (Scheme 20). Terminal allylic alcohols were all transformed into the corresponding a-iodoketones in very good yields (5a, 5c, 5e, 5s, 5k, 5l, 5t, 5u and 5v).

[Cp*Ir(H2O)3]SO4 (2 mol%) I2 (0.5 equiv.) O OH NaNO2 (5 mol%) R1 R1 R2 R2 2-MeTHF / H2O (3:1, v/v) I 4a-4r O2 (1 atm), RT, 48 h 5a-5r

O O O O Ph O Ph Ph I I I I 5a, 89% (64%) 5c, 81% (66%) 5e, 90% (64%) 5s, 99% (65%)

O O O O TBSO O

I I I i-Bu I I

5k, 88% (79%) 5l, 86% (71%) 5t, 67% (47%) 5u, 81% (67%) 5v, 74% (62%)

O O O O O Ph Ph Ph Ph I I I I I

5g, 75% (60%) 5h, 57% (42%) 5w, 40% (35%) 5i, 45% (40%) 5x, 54% (49%)

O O O Ph O H Ph H H I I I 5n, 68% (57%) 5q, 80% (60%) 5r, 50% (47%) Scheme 20. Scope of the iridium-catalyzed isomerization / a-iodination of allylic alcohols using I2. Yield determined by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis.

Additional functional groups such as ethers, silyl ethers or alkenes were very well tolerated and did not affect the yields significantly. Starting materials bearing allylic alcohols with internal alkenes were also converted successfully into the corresponding iodocarbonyls from good to moderate yields. Remarkably, using this aerobic oxidative iodinating protocol, all compounds were obtained as single constitutional isomers as observed in the previous method employing 2,2-diiododimedone 1. Primary allylic alcohols could also be transformed using this strategy and a-iodoaldehydes 5n-5r were obtained in good yields. As it occurred in the previous protocol with electrophilic iodinating agent 1, there is a significant difference between the yield obtained by 1H NMR spectroscopy and the isolated yields. As previously mentioned, it is speculated that this fact is due to the precarious stability of the products during their purification process by chromatography.

2.6.3 One-pot isomerization / iodination / amination of allylic alcohols

In order to solve the problem of the stability of the final products during the purification, it was decided to transform them in-situ into more stable products. From all the transformations that a-iodocarbonyls can undergo (vide supra 2.4), their reaction with amines was selected because of the high stability and importance of the resulting a- aminoketones. It was already known in the group that amines were able to poison the catalytic activity of Ir(III) catalysts in the isomerization of allylic alcohols. For this reason, it was decided to add the amine after the isomerization / iodination reaction in a one-pot protocol.

1) [Cp*Ir(H2O)3]SO4 (2 mol%) I2 (0.5 equiv.), NaNO2 (5 mol%) 2-MeTHF / H2O (3:1, v/v) O OH O2 (1 atm), RT, 24 h 1 1 R R 2) H N N 2 3 R2 R3 (1.5 equiv.) R R 4a,4c, 4e, 4k RT, 16 h 16-22

O O O

N N N

16, 81% (60%) 17, 82% (77%) 18, 99% (98%)

O O O O Ph O Ph Ph Ph N N Ph N N

19, 76% (71%) 20, 78% (76%) 21, 68% (64%) 22, 93% (87%) Scheme 21. One-pot synthesis of a-aminoketones from allylic alcohols. Yield determined by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis.

In this way, the tandem isomerization / iodination of allylic alcohols was coupled with a one-pot displacement of the iodine by an amine to yield stable a-aminoketones in a cascade process (Scheme 21). Using this approach several a-aminoketones (16-22) were synthesized in good yields from different allylic alcohols and amines. Importantly, the isolated yields of this a-aminocarbonyls were higher than that of the corresponding a- iodoketones, which proves that it is possible to increase the overall isolated yields of the products by avoiding the isolation of the unstable a-iodocarbonyls.

2.6.4 Mechanistic studies

Finally, the mechanism of the transformation was investigated by performing the reaction using deuterated allylic alcohol 4i-d1 (97% D). As it occurred in the previous method, the corresponding deuterated a-iodoketone 5i-d1 was obtained with 96% D only at C3 which indicates a [1,3]-hydride shift operating in this mechanism (Scheme 22a). These results suggest that both iodinating methods described in this chapter have in common the formation of a nucleophilic iridium enolate species and only differ in the latter reaction with a different electrophilic source of iodine. A mechanistic proposal for the isomerization / iodination of allylic alcohols via aerobic oxidative iodination conditions is shown in Scheme 22b. First, the allylic alcohol reacts with the Ir(III) catalyst to yield, via an [1,3]-hydride shift, the corresponding iridium enolate (represented in the scheme as an h3-iridium enolate). The reaction of these species with elemental I2 would produce the iodinated carbonyl and an atom of iodide (I-), which in this acidic reaction conditions is better represented as HI. On the other hand, the electron-transfer mediator catalyst NaNO2 under acidic conditions forms nitrous acid (HNO2), which is very unstable and decomposes to NO2, NO and H2O. NO2 is able to oxidized back HI to I2, generating water and forming NO.53d,54 Finally, an aerobic oxidation of NO into NO2 with molecular oxygen closes the cycle and regenerates the oxidant catalyst.55

[Cp*Ir(H O) ]SO (2 mol%) OH 2 3 4 D O I (0.5 equiv.), NaNO (5 mol%) a) D 2 2 Ph 3 1 Ph 3 1 2-MeTHF / H2O (3:1, v/v), I O2 (1 atm), RT, 48 h 4i-d1 (97%D) 5i-d1 (96%D)

H2O O [Ir] III OH H Cp*Ir cat H 1 1 1 /2 O2 NO I R R 2 R2 R2 b) [1,3]-Hydride 2x O H shift NO HI R1 2 R2 I Precatalyst NO, H2O 2HI 2NaNO2 2HNO2 + 2NaI Scheme 22. a) Isomerization / iodination of allylic alcohol 4i-d1 under aerobic oxidative iodination conditions. b) Mechanistic proposal.

2.7 Conclusions

In this project, two protocols for the synthesis of challenging a-iodocarbonyls as single constitutional isomers have been developed. In the first one, a new electrophilic iodinating agent (2,2-diiododimedone, 1) has been designed and synthesized. The synthesis has been performed easily from commercially available materials and the product is purified by simple filtration. The mild nature of this reagent enabled the development of the iridium- catalyzed isomerization / iodination of allylic alcohols into a wide variety of a-iodoketones and aldehydes. The usefulness of the reaction has been demonstrated by transforming the a-iodoketones into other functionalized organic building blocks. In the second project within this chapter, an iodine-economical method for the synthesis of a-iodocarbonyls has been accomplished. The aerobic oxidative iodination with I2 and NaNO2 as electron-transfer mediator catalyst allows the synthesis of such compounds in an atom-economical process. Moreover, the problem of the instability of the products during the purification process has been solved by transforming a- iodocarbonyl compounds directly into a-aminoketones in a one-pot process.

27 3. Selective Synthesis of Unsymmetrical Aliphatic Acyloins through Oxidation of Iridium Enolates (Paper III)

3.1 Electrophilic oxygen transfer a-Hydroxycarbonyl compounds are important chemical moieties in organic chemistry. They are intermediates in the synthesis of more complex organic molecules and their presence in both drugs and natural products is notorious.56 Despite the existence of several methods to access these compounds, their synthesis is still challenging. Specifically, the high-yielding-selective syntheses of a-hydroxyketones from ketones bearing two different enolizable alpha positions has not been yet reported. A major difficulty in that class of compounds is the formation of several regioisomers. Although this fact can be solved by controlling the sterics and the electronic properties of the ketone, only a single regioisomer is typically accessible. A strategy that has been previously used for the synthesis of a-hydroxyketones is the reaction of enolates or enol derivatives with TEMPO or derived reagents.57 This method affords a-aminooxyketones that can be further reduced to a-hydroxycarbonyl compounds. The tandem isomerization / functionalization of allylic alcohols has proved to be a good method to access a-haloketones as single constitutional isomers (vide supra, Chapter 2). The aim of this project is to expand the scope of this reaction by reacting the enolate species with electrophilic oxygen reagents to achieve the selective synthesis of a- aminooxy and a-hydroxyketones from allylic alcohols. Using this strategy, the synthesis of both regioisomers is possible by selecting the corresponding allylic alcohol as starting material.

3.2 Reaction of allylic alcohols with electrophilic oxygen species under iridium catalysis

3.2.1 Optimization

In this project, N-oxoammonium salt 23 and allylic alcohol 4e were selected to perform optimization studies for the selective synthesis of a-aminooxyketones. The conditions previously reported to be successful in the tandem isomerization / halogenation of allylic alcohols were taken as starting point.42 Under these reaction conditions, 57% of the desired product was obtained together with 7% of a,β-unsaturated ketone 6e (Table 5, entry 1). When the temperature was raised from 20 to 35 °C, higher yield of a-aminooxyketone 24e was obtained (78%, Table 5, entry 2). Unfortunately, 5% of undesired saturated ketone 25e was also formed. Further increase of the temperature showed lower yield of 24e (Table 5, entry 3). The effect of the organic solvent was evaluated by changing THF by other common organic solvents (Table 5, entries 4-7). 1,4-Dioxane provided 24e albeit in low yield, while dioxolane gave 60% of 24e along with 11% of side-product 25e. The use of

28 acetone or of Et2O did not improve the results, and they gave similar yields of a- aminooxyketone 24e (51 and 53%, respectively). In light of these results, THF was the optimal solvent for this transformation. Next, the effect of different concentrations was studied. At a concentration of 0.1 M, 24e was obtained in 76% yield (Table 5, entry 8). More importantly, only 2% of a,β-unsaturated ketone 6e was detected and 25e was not obtained. Setting the concentration to 0.3 M afforded the best yield of 24e (82%, Table 5, entry 9) while increasing the concentration resulted in lower yields (Table 5, entry 10). Conditions in entry 9 were taken as optimal for the study of the scope of the reaction.

Table 5. Optimization of the iridium-catalyzed isomerization / a-aminooxylation of 24e.[a]

BF 4 O N O 23 (1.2 equiv.) Ph OH O 6e [Cp*IrCl ] (2.5 mol%) 2 2 + Ph Ph O Solvent / H O (1:2, v/v) 4e 2 24e OTEMP T, 30 min Ph 25e

Entry Solvent/H2O (1:2, v/v) T (°C) 24e/6e/25e (%)[b]

1 THF/H2O 20 57/7/-

2 THF/H2O 35 78/6/5

3 THF/H2O 45 63/5/2

4 Dioxane/H2O 35 30/4/2

5 Dioxolane/H2O 35 60/-/11

6 Acetone/H2O 35 51/6/3

7 Et2O/H2O 35 53/4/8

8[c] THF/H2O 35 76/2/-

9[d] THF/H2O 35 82/4/-

10[e] THF/H2O 35 53/5/- [a] Unless stated, the reactions were run using 4e (0.1 mmol, 0.2 M) and 23 (1.2 equiv.) in certain solvent / H2O (1:2, v/v) under air. [b] Yield determined by 1H NMR spectroscopy using 2,3,4,5- tetrachloronitrobenzene as I.S. [c] 0.1 M. [d] 0.3 M. [e] 1 M.

3.2.2 Selective synthesis of a-aminooxycarbonyl compounds

The reaction proved to be efficient for a wide range of allylic alcohols with a terminal alkene (24a-24e, 24s-24u, 24y and 24z) as the corresponding a-aminooxyketones could be accessed with yields ranging from very good to good in all cases (Scheme 23). Importantly, all compounds were synthesized as single constitutional isomers and the aminooxy group was only introduced at the a-carbon that was previously part of the allylic moiety. The additional enolizable carbon did not react under these conditions. Extra functional groups in the starting materials did not hinder the reaction. An ether group, additional alkenes, a

29 hydroxy group and a ketone were all well tolerated, and the products were achieved in good yields (24c, 24t, 24u, 24y and 24z). The reaction was also performed on non-terminal allylic alcohols. For these substrates, slow addition of the reagents was needed via a syringe pump in order to minimize the oxidation of the starting allylic alcohol into enone compounds. Using this protocol, a-aminooxyketones 24aa, 24g, 24h, 24w, 24ab were prepared in good yields (up to 72%). When the alkene was conjugated with an aromatic ring, the oxidation of the allylic alcohol was found to be faster than the desired reaction leading to low yields (24i). The method is not restricted to secondary allylic alcohols, but primary allylic alcohols also gave a-aminooxyaldehydes 24n and 24q, that were successfully produced in 65% and 61% isolated yields, respectively.

BF4 N O 23 (1.2 equiv.) O OH (Cp*IrCl ) (2.5 mol%) 2 2 R1 R1 R2 R2 THF / H2O (1:2, v/v) OTEMP 35 °C, 2 h 4a-4ab 24a-24ab

O O O O Ph O

OTEMP OTEMP OTEMP OTEMP

24a, 78% (76%) 24b, 86% (80%) 24c, 70% (58%) 24d, 71% (62%)

O O O O

Ph Ph OTEMP OTEMP OTEMP OTEMP

24e, 82% (74%) 24s, 71% (67%) 24t, 65% (60%) 24u, 57% (51%)

OH O O O O

OTEMP O OTEMP OTEMP OTEMP

24y, 62% (60%) 24z, 55% (46%) 24aa, 65% (58%)[a] 24g, 72% (60%)[a]

O O O O

Ph Ph Ph Ph Ph OTEMP OTEMP OTEMP OTEMP

24h, 56% (53%)[a] 24i, 27%[a] 24w, 56% (53%)[a] 24ab, 51% (49%)[a]

O O

H Ph H OTEMP OTEMP

24n, 70% (61%)[b] 24q, 70% (65%)[b] Scheme 23. Tandem isomerization / aminooxilation of allylic alcohols. Yields by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis. [a] The reaction was performed via slow addition of the reagents at 45 °C. [b] The reaction was performed via slow addition of the reagents.

3.2.3 One-pot synthesis of a-hydroxyketones from allylic alcohols

According to literature reports, a-hydroxyketones can be synthesized by reducing a- aminooxyketones employing Zn metal and AcOH in H2O.58 This transformation could be coupled to the previously described isomerization / aminooxylation protocol in order to access a-hydroxyketones directly from allylic alcohols in a one-pot method. In other words, we planned to perform a tandem isomerization / aminooxilation / reduction of allylic alcohols. In this manner, it could be possible to selectively synthesize a-hydroxyketones as single isomers from easily accessible allylic alcohols. An optimization was performed in order to select the best conditions for this reductive transformation (Table 6). When the reaction was run with 4 equiv. of Zn in AcOH 0.5 M during 4 h only 27% yield of the desired a-hydroxyketone was obtained (Table 6, entry 1). a- Aminooxyketone was detected together with saturated ketone 25e in the reaction media. Decreasing the amount of Zn metal to 2 equiv. had a negative impact on the reaction since 78% of a-aminooxyketone 24e was observed after 18 h of reaction (Table 6, entry 2). It could be concluded that more equivalents of Zn were needed in order to reduce compound 24e under these conditions. In fact, this effect is rather common in the literature for Zn mediated reductions.58 Effectively, with 10 equiv. of Zn and a concentration of AcOH of 0.1 M, 30% of a-hydroxyketone was obtained (entry 3). Further increase of the number of Zn equivalents gave compound 26e in 70% yield in AcOH (0.1 M) running the reaction for 18 h.

Table 6. Optimization of tandem isomerization / a-aminooxylation / reduction of 4e.[a]

BF4 N 1) O 23 (1.2 equiv.) [Cp*IrCl ] (2.5 mol%) 2 2 O O O OH THF / H2O (1:2, v/v) 35 °C, 15 min Ph + Ph + Ph Ph 2) Zn (X equiv.) OTEMP OH 4e AcOH, RT, time 24e 25e 26e

24e/25e/26e Entry time (h) Zn (equiv.) AcOH (M) (%)[b] 1 4 4 0.5 9/8/27 2 18 2 0.5 78/-/- 3 18 10 0.1 41/-/30 4 18 20 0.1 -/-/70(67)

[a] Unless stated, the reactions were run using 4e (0.1 mmol, 0.3 M) and 23 (1.2 equiv.) in THF /H2O (1:2, v/v) under air. [b] Yield determined by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene chloronitrobenzene as I.S. Isolated yield in parenthesis.

31 Next, a broad library of a-hydroxyketones was successfully synthesized using this newly developed reaction (Scheme 24). Eight different allylic alcohols bearing terminal olefins were transformed to their corresponding a-hydroxyketones in good yields in all cases (26a, 26b, 26d, 26e, 26s, 26t, 26u, 26y). It should be noted that the yields were comparable to those obtained for the synthesis of a-aminooxyketones (vide supra, Scheme 23). This indicates that the reducing step with Zn / AcOH yields the product almost quantitatively. Allylic alcohols bearing internal double bonds (26aa, 26g, 26h, 26w and 26ab) were also converted to a-hydroxyketones efficiently with isolated yields up to 62% over two steps. Additional alkenes or hydroxyl groups, apart from the ones in the allylic alcohol moiety, were not affected neither in by first nor by the second reductive step (26t, 26u and 26y).

BF4 N 1) O 23 (1.2 equiv.) [Cp*IrCl2]2 (2.5 mol%) O OH THF / H2O (1:2, v/v) 35 °C, 15 min R1 R1 R2 R2 2) Zn (20 equiv.) OH AcOH (0.1 M), RT, 18 h 4a-4ab 26a-26ab

O O O O

Ph OH OH OH OH

26a, 65% (50%) 26b, 74% (71%) 26d, 60% (56%) 26e, 70% (67%)

O O O OH O

Ph OH OH OH OH

26s, 60% (58%) 26t, 68 (65)% 26u, 57% (56%) 26y, 51% (40%)

O O O Ph OH OH OH [a] 26aa, 53% (47%)[a] 26g, 66% (62%) 26h, 62% (60%)[a] O O

Ph Ph Ph OH OH 26w, 50% (50%)[a] 26ab, 50% (49%)[a]

Scheme 24. Selective synthesis of a-hydroxyketones from allylic alcohols. Yields by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis. [a] The first reaction was performed via slow addition of the reagents at 45 °C.

3.2.3 Deuterium labeling study

Mechanistic investigations of the reaction were carried out by running the reaction with allylic alcohol 4aa-d1 (92% D). The analysis of the deuterium content in a-aminooxyketone 24aa-d1 showed 77% D at C3 and 8% D at C2. As in chapter 2, these results evidence the existence of an iridium-catalyzed [1,3]-hydride shift in this transformation. Besides, the deuterium distribution points to the presence of two competing migratory insertions in the reaction mechanism (vide supra, migratory insertion A and B, Scheme 8). Migratory insertion A is responsible for the presence of deuterium in C2 in this reaction.

BF4 N O 23 (1.2 equiv.) H/D O OH (Cp*IrCl2)2 (2.5 mol%) D 3 1 3 1 THF / H2O (1:2, v/v) H/D OTEMP 35 °C, 2 h 4aa-d1 (92%D) 24aa-d1 (85%D) 77% D at C3 8% D at C2 Scheme 26. Isomerization / aminooxylation of allylic alcohol 4aa-d1

3.3 a´-Functionalization of a-aminooxyketones

Romea, Urpí and co-workers have reported the stereoselective a´-functionalization of a- benzyloxyketones by means of Lewis acids such as TiCl4.59 The first step in this transformation was the formation of a titanium enolate species that coordinates to the oxygen atom in the chiral benzyloxy group present in a position. The addition of an electrophile enables the functionalization of the a´ position stereoselectively. Inspired by this work, we tested the formation of titanium enolates from a-aminooxyketones, which could be trapped with an electrophile. Treatment of a-aminooxyketone 24e with TiCl4 and i-Pr2NEt at −78 °C followed by addition of an electrophile afforded the desired a´-functionalization with excellent diastereomeric differentiation (Scheme 25). The use of benzaldehyde and N- chlorosuccinimide (NCS) provided compounds 27 and 28 in 64% and 92% isolated yields and with good diastereomeric ratios of 72:28 and 80:20, respectively. N-Bromosuccinimide (NBS) was also a good electrophilic partner and the corresponding a´-bromo- a- aminooxyketone 29 was synthesized in 80% isolated yield.

33 Ln PhCHO TiCl O O 4 Ti (1.5 equiv.) i-Pr NEt O 2 OTEMP Ph Ph -78 °C Ph OTEMP OTEMP HO Ph 24e 27, 64% yield, d.r. 72:28 NXS (1.5 equiv.)

Ph X OTEMP

28, X = Cl, 92% yield, d.r. 80:20 29, X = Br, 80% yield, d.r. 60:40 Scheme 25. a´-Functionalization of a-aminooxyketone 24e (isolated yields).

3.4 Conclusions

In this project, a protocol for the selective synthesis of a-aminooxyketones has been successfully developed using the iridium-catalyzed isomerization / functionalization of allylic alcohols and an N-oxoammonium salt as the electrophilic partner. The reaction has a broad scope of a-aminooxyketones and aldehydes and yields the product as single constitutional isomers. Moreover, a one-pot procedure for the synthesis of a-hydroxyketones from allylic alcohols was also described through a tandem isomerization / aminooxylation / reduction process. The method was found to be very efficient and a series of a-hydroxyketones were obtained in good yields. Finally, the a´-functionalization of a-aminooxyketones was found to be possible using a method involving a titanium enolate stabilized by the oxygen atom on the aminooxy group, yielding highly functionalized ketones in a selective manner and with good diastereomeric ratios.

4. An Umpolung Strategy to React Catalytic Enols with Nucleophiles (Paper IV)

4.1 Inversion of polarity of enol derivatives

The a-functionalization of carbonyl compounds is a reaction of paramount importance in organic chemistry with numerous applications in synthetic organic chemistry. Besides, as it has been previously covered in this thesis, the corresponding a-functionalized carbonyl compounds are themselves important building blocks in the synthesis of more complex organic molecules.50,56,60 Due to the intrinsic nucleophilic nature of the enol derivatives, their rational reactive partners are electrophiles (Scheme 26a). For instance, lithium enolates, sodium enolates and silyl enol ethers are very prompted to react with electrophiles giving the corresponding carbonyl derivatives.61 Chapters 2 and 3 in this thesis show, in fact, clear examples of this type of reactivity where iridium enolates are able to react with a series of electrophiles to afford a-functionalized ketones and aldehydes. The reaction of enol derivatives with nucleophiles requires, therefore, an inversion of polarity of the corresponding enol species. This polarity inversion of enol derivatives, or also called umpolung reaction of enolates,62 has been smartly and successfully achieved through the use of iodine (III) reagents both in stoichiometric or in catalytic amounts.63 Several acyclic and cyclic I(III) reagents have been employed over the past decades being the most popular ones: (diacetoxyiodo)benzene (PIDA),64 [hydroxyl(tosyloxy)iodo]benzene (Koser´s reagent),65 p-iodotoluene difluoride66 and benziodoxol(on)es.67 a-Oxigenation, halogenation, trifluoromethylation, arylation, amination, alkenylation or alkynylation can be achieved using this umpolung strategy.63,64,68

a) Traditional α-functionalization of carbonyl compounds

Electrophile O O OX “E” R2 R2 R2 R1 R1 R1 E X = H, Li, Na, SiR3, Ir, Pd ... b) α-functionalization of carbonyl compounds via polarity inversion Iodonium enolate A O R2 I(III) R1 Nucleophile O O OX “Nu” reagent I(III) R2 R2 R2 R1 R1 R1 + (III)I Nu O X = H, Li, Na, 2 1 R SiR3, Ti ... R Iodonium enolate B

Scheme 26. Reaction of carbonyl compounds with a) electrophiles or b) nucleophiles.

35 The polarity inversion is accomplished due to the formation of two possible iodonium intermediates: C-bound iodonium enolate A or O-bound iodonium enolate B (Scheme 26b). The nucleophile can subsequently react with either of them to provide the corresponding a-functionalized carbonyl. The high reactivity of these species towards nucleophiles is due to the excellent leaving group ability of –IAr group, often called “superleaving group”.69 An important drawback of these methodologies is the absence of selectivity in substrates that have different enolizable positions in their structure. In these cases, mixtures of isomers are formed that are very difficult to separate, limiting the usefulness of the method.70 The tandem isomerization / functionalization of allylic alcohols using Ir(III) complexes comprises a useful and efficient approach to synthesize a-functionalized ketones selectively as single constitutional isomers (vide supra, charters 2 and 3).42 This strategy has, however, the inconvenience of the use of only electrophiles as coupling partners limiting, in this sense, the scope of the transformation. The development of a method for the inversion of polarity of iridium enolates would allow the reaction of this class of enolates with nucleophiles and, thus, increasing tremendously the scope of the a- functionalization. In other words, the umpolung of enolate species derived from allylic alcohols would result in a selective method for the synthesis of a-functionalized carbonyl compounds with nucleophiles increasing, in turn, the generality of the method and solving the previously observed lack of selectivity.

4.2 Reacting allylic alcohols with nucleophiles via iridium catalysis

We start our investigations by evaluating the performance of several iodine (III) reagents in the isomerization of allylic alcohol 4e using [Cp*IrCl2]2 as the catalyst (Table 7). [Cp*IrCl2]2 was chosen for the optimization studies since this catalyst has proven to be extremely efficient in the isomerization of allylic alcohols in water at room temperature.27 MeOH was first selected as both the nucleophile and as the solvent. Acetone was used as a cosolvent since it gave good results in our previous publication.27 The activation of I(III) reagents usually requires the addition of Lewis acids into the reaction mixture.71 An initial optimization of several catalysts showed that KBF4 gave the best results under our reaction conditions. It is worth mentioning that this transformation is specially challenging due to the high number of side-products that can arise from the reaction. I(III) reagents are well known for being oxidizing agents so a,b-unsaturated ketone 6e is expected as one of the side-products (vide supra, Chapter 1, Section 1.4.2). If the corresponding iridium-enolate species does not react with the I(III) reagent but they undergo protodemetalation, saturated ketone 25e can be formed. On the other hand, if the desired iodonium enolates are actually obtained, several nucleophiles present in the reaction media could attack them (i.e., H2O present in the solvents would produce a-hydroxy ketone 26e). Only the attack of methanol from the solvent could form the desired a-methoxy ketone 30e. First, common iodine (III) reagents used in the literature for umpolung transformations were tested. (Diacetoxyiodo)benzene (PIDA, I), gave only 21% of saturated ketone 25e while [hydroxyl(tosyloxy)iodo]benzene (Koser´s reagent, II)

36 produced a large amount of oxidized product 6e (Table 7, entries 1 and 2). p-Iodotoluene difluoride (III) gave a complicated mixture of different products but 15% of the desired a- methoxy ketone 30e was detected (Table 7, entry 3). Diphenyliodonium tetrafluoroborate (IV) failed to provide the desired umpolung reactivity and ketone 25e was formed in 89% yield (Table 7, entry 4). Next, a series of cyclic benziodoxol(on)es were tested in the transformation. Fluorobenziodoxole (V) provided the best yield of the desired product 30e (43% yield, Table 7, entry 5). Other benziodoxoles (VI, VII and VIII) afforded only decomposition of the starting material whereas trifluoromethylated benziodoxolone IX (Togni´s reagent II) gave only 23% of saturated ketone 25e (Table 7, entries 5-9).

Table 7. Optimization of iodine(III) reagents in the tandem isomerization / functionalization of allylic alcohol 4e with methanol.[a]

I(III) Reagent (1.2 equiv.) [Cp*IrCl2]2 (2.5 mol%) O O OH KBF4 (30 mol%) O O + + Ph + Ph Ph Ph Ph Acetone / MeOH (1:3, v/v) OH OMe 4e RT, 2h 6e 25e 26e 30e

AcO TsO F BF4 I I I I OAc OH F

I II III IV

F I O Br I O HO I O F3C I O F3C I O O

V VI VII VIII IX

Entry Iodine(III) Reagent 6e/25e/26e/30e (%) 1 I -/21/-/- 2 II 68/3/-/3 3 III 4/29/10/15 4 IV 3/89/-/- 5 V 12/12/10/43 6 VI -/-/-/-[b] 7 VII -/-/-/-[b] 8 VIII -/-/-/-[b] 9 IX -/23/-/-

[a] Unless stated, the reactions were run using 4e (0.15 mmol, 0.2M) and KBF4 (0.3 equiv.) in Acetone /MeOH (1:3, v/v) under air for 2h. Yields determined by 1H NMR spectroscopy using 2,3,4,5- tetrachloronitrobenzene chloronitrobenzene as I.S. [b] Decomposition.

37 The optimization of the reaction was continued with fluorobenziodoxole (V) as the I(III) reagent of choice for this transformation. In the first place, different cosolvents were evaluated in the reaction (Table 8, entries 2-5 vs entry 1). The use of THF provided lower yield of the desired compound than in acetone, while HFIP showed no improvement. Both TFE and trifluorotoluene gave better results and 30e was obtained in 54% and 52% yield, respectively.

Table 8. Optimization of the tandem isomerization / functionalization of allylic alcohol 4e with methanol and fluorobenziodoxole V.[a]

F I O

V (1.2 equiv.)

[Cp*IrCl2]2 (2.5 mol%) O O OH Additive (X mol%) O O + + Ph + Ph Ph Ph Ph Solvent / MeOH (1:3, v/v), OH OMe 4e [M], T, 2h 6e 25e 26e 30e

Entry Solvent T Additive (X mol%) [M] 6e/25e/26e/30e (%)[b]

1 Acetone RT KBF4 (30 mol%) 0.2 12/12/10/43

2 THF RT KBF4 (30 mol%) 0.2 6/11/12/27

3 HFIP RT KBF4 (30 mol%) 0.2 29/-/-/45

4 TFE RT KBF4 (30 mol%) 0.2 10/9/10/54

5 PhCF3 RT KBF4 (30 mol%) 0.2 7/6/9/52

6 TFE 35 KBF4 (30 mol%) 0.2 10/10/-/57

7 TFE 45 KBF4 (30 mol%) 0.2 2/7/-/48

8 TFE 35 KBF4 (30 mol%) 0.02 2/8/-/75

9 TFE 35 KBF4 (80 mol%) 0.02 6/4/-/89

10 TFE 35 NaBF4 (80 mol%) 0.02 5/7/-/85 11 TFE 35 TBAF (80 mol%) 0.02 -/20/10/65

12[b] TFE 35 KBF4 (80 mol%) 0.02 -/-/-/-

13[c] TFE 35 KBF4 (80 mol%) 0.02 -/-/-/- 14 TFE 35 - 0.02 3/5/10/67

15 - 35 KBF4 (80 mol%) 0.02 2/5/11/68

16[d] TFE 35 KBF4 (80 mol%) 0.02 -/99/-/- [a] Unless stated, the reactions were run using 4e (0.15 mmol, 0.2 M,) in Solvent /MeOH (1:3, v/v) under air for 2h. Yields determined by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. [b] Using [Cp*Ir(H2O)3]SO4 instead of [Cp*IrCl2]2. [c] In the absence of the catalyst, 86% of 4e was obtained. [d] No I(III) reagent V.

Out of all cosolvents tested, TFE proved to be the best alternative and the optimization was continued using TFE/MeOH (1:3) as the solvent mixture.72 The temperature was next evaluated. While warming the temperature of the reaction to 35 °C had a slight beneficial effect on the yield, rising further the temperature to 45 °C gave worse results (Table 8, entries 6 and 7). Delightfully, reducing the concentration of the reaction from 0.2 to 0.02 M had a positive effect on the yield and 30e was obtained in 75% yield (Table 8, entry 8). Finally, increasing the amount of KBF4 from 30 mol% to 80 mol% provided the optimal reaction conditions for this reaction affording an excellent yield of 89% (Table 8, entry 9). Other catalysts such as NaBF4 or TBAF were also tested in this transformation but they did not offer any improvement compared to KBF4 (Table 8, entries 10 and 11). The reaction conditions showed in Table 8, entry 9 were taken than as optimal for this reaction and a series of control experiments were performed. The use of [Cp*Ir(H2O)3]SO4 as catalyst or the absence at all of an iridium catalyst failed to give any conversion to the desired product (Table 8, entries 12 and 13). The need of a halide ligand in the iridium catalyst in the isomerization of allylic alcohols has already been reported in our research group.27 Both KBF4 as additive and TFE as cosolvent were verified to be important in this reaction since running the isomerization without any of them led to a significant decrease in the yield of a-methoxy ketone 30e (Table 8, entries 14 and 15). The absence of the hypervalent iodine reagent V in the reaction prevented the umpolung reactivity affording only saturated ketone 25e in quantitative yield (Table 8, entry 16).

4.3 Selective synthesis of a-functionalized carbonyl compounds with oxygen nucleophiles

4.3.1 Intermolecular functionalization: a-alkoxy carbonyl compounds

With the optimized reaction conditions in hand (Table 8, entry 9), the investigations were continued with the study of the generality of the method by applying the reaction to a wide variety of starting allylic alcohols. The scope of this reaction was focused on the synthesis of compounds that would be otherwise very difficult to access from the corresponding ketones due to regioselectivity issues. In order to test the actual usefulness of the method, the tolerance to several functional groups was evaluated and the reaction was even applied to complex biomolecules. Terminal allylic alcohols (R2 = H) gave the corresponding a-methoxy ketones from moderate to excellent yields (30a-30ae, ranging from 99% to 42%). The reaction could be even extended to the use of other alcohol nucleophiles such as ethanol 31e or n-propanol 32e albeit in low yields (40% and 20%, respectively). These results together with the moderate yield obtained with sterically demanding allylic alcohol 4b might suggest that steric effects have a crucial role in this transformation. Aromatic allylic alcohols were tolerated and the corresponding a-methoxy ketone 30k could be obtained with 58% isolated yield. Although this class of allylic alcohols are very prompted to oxidation, the mild reaction conditions of this method resulted in a minimization of the formation of a,b- unsaturated side-product 6k.

39 F I O

V (1.2 equiv.)

[Cp*IrCl ] (2.5 mol%) 2 2 O OH KBF4 (80 mol%) 1 1 R 2 R 2 R R TFE / MeOH (1:3, v/v) 35 °C, 2 h OMe 4a-4ah 30a-30ah, 31e, 32e

O O O O O

OMe OMe OMe X

30a 30b 30c 30e, X = OMe, 89% (78%) yield 52%(45%) yield 45%(36%) yield 99%(90%) yield 31e, X = OEt, 40% (32%) yield 32e, X = OPr, 20% (18%) yield O O TBS O O O

OMe OMe OMe OMe 30s 30k[a] 30t 30v 67%(66%) yield 64%(58%) yield 84%(67%) yield 80%(72%) yield O O O O

NC PhO2S Cl O OMe OMe OMe OMe

30z 30ac 30ad 30ae 42%(31%) yield 91%(88%) yield 74%(69%) yield 89%(53%) yield O O O O

N3 N OMe O OMe OMe OMe

30aea[b] 30aeb[b] 30aa 30g 69%(65%) yield 77%(70%) yield 82%(79%) yield 77%(81%) yield O O O O

OMe OMe OMe OMe

30h 30w 30x 30ab 77%(76%) yield 46%(45%) yield 67%(65%) yield 67%(66%) yield O O O OMe

OMe OMe

30af 30q 30n 73%(60%) yield 71%(62%) yield 70%(65%) yield O O H O H H H MeO OMe O H H O O 30ag 30ah 70%(65%) yield 71%(62%) yield Scheme 27. Tandem isomerization / methoxylation of allylic alcohols via polarity inversion of iridium enolates. Yields by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis. [a] The reaction was performed via slow addition of the reagents. [b]From 30ae in a one-pot two-step procedure.

The reaction was demonstrated to be tolerant to the presence of other functional groups in the starting allylic alcohols. Ethers, olefins or even carbonyl compounds were accepted, and a-methoxy ketones 30c, 30v, 30t and 30z were synthesized from moderate to excellent yields. Moreover, other functional groups such as a cyano (4ac), a sulphonyl (4ad) or a halide (4ae) that had never been tested before in the isomerization / functionalization of allylic alcohols were also very well tolerated. Nitrogen-containing functional groups in the starting allylic alcohols showed not to be compatible with the reaction conditions, probably since they are able to poison the iridium catalyst. Nevertheless, N-containing methoxy carbonyls can be obtained in a consecutive synthetic step through a substitution reaction. For example, after the tandem isomerization / a- methoxylation reaction of 4ae was completed, the addition of the nitrogen nucleophile yielded the amino-functionalized a-methoxy carbonyls (30aea and 30aeb). Starting substrates bearing internal allylic alcohols (i.e., R2 = alkyl) were successfully converted to the desired a-methoxy ketones in very good yields with an average yield of 70%. Primary allylic alcohols such as 4q and 4n were also efficiently transformed to the corresponding a-methoxy aldehydes with good yields of 70% and 71%, respectively. Finally, the reaction was applied to allylic alcohols derived from complex molecules with several functional groups and numerous stereocenters in their structure. Allylic alcohol 4ag derived from the hormone trans-androsterone and 4ah derived from lithocolic acid were converted to the desired a-methoxy derivatives in good isolated yields of ca. 65%, in both cases.

4.3.2 Intramolecular functionalization: synthesis of 3(2H)-furanones

During the study of the scope of the tandem isomerization / methoxylation of allylic alcohols, an interesting result was found when using allylic alcohols bearing a g-carbonyl group (4ai-4as). Under otherwise identical reaction conditions, these substrates were transformed to cyclic 3(2H)-furanones as a result of an intramolecular attack of the enol derivative of the carbonyl moiety. In all these cases, the intermolecular attack of the external solvent was not operative and the corresponding a-methoxy ketones derivatives were never detected. Allylic alcohol 4ai with no substituent at R3 gave the corresponding furanone with a good yield of 65%. However, it was found that substrates with alkyl substituents at R3 gave very good yields, up to 86% (33aj-33an). Cyclic allylic alcohols 4ao and 4ap were also cyclized successfully giving rise in these cases to byciclic 3(2H)-furanones in good yields. The reaction was not restricted to the use of g-keto allylic alcohols but the presence of amides in g position gave the same intramolecular umpolung reactivity. In fact, these starting materials provided the corresponding amino 3(2H)-furanones (33aq, 33ar, 33as) in outstanding yields of up to 94% yield. In summary, the inversion of polarity of iridium enolates with hypervalent iodine reagent V could be performed using not only an external nucleophile but also an internal enol derivative in an intramolecular fashion. This method allows the synthesis of biologically relevant cyclic 3(2H)-furanones from easily accessible allylic alcohols efficiently, using very mild reaction conditions.73

41 F I O

V (1.2 equiv.)

OH [Cp*IrCl2]2 (2.5 mol%) O 3 R3 KBF4 (80 mol%) R R2 R2 TFE / MeOH (1:3, v/v) 1 1 O R O 35 °C, 2 h R 4ai-4as 33ai-33as

O O O O O Me Me Me Et Me Me Et Me Me O O O Cy Cy Cy Et O Pr O 33ai 33aj 33ak 33al 33am 65%(61%) yield 85%(80%) yield 78%(75%) yield 75%(71%) yield 78%(75%) yield

Me O O O O O O Me Pr Et Me Me Me Me O O O O Me N N Ph N Bu O O iPr 33an 33ao 33ap 33aq 33ar 33as 86%(82%) yield 52%(46%) yield 77%(74%) yield 94%(91%) yield 89%(87%) yield 84%(74%) yield d.r. = 1:1 Scheme 28. Selective synthesis of 3(2H)-furanones from allylic alcohols via polarity inversion of iridium enolates. Yields by 1H NMR spectroscopy using 2,3,4,5- tetrachloronitrobenzene as I.S. Isolated yields in parenthesis.

4.4 Mechanistic investigations

4.4.1 Deuterium-labeling studies, kinetic investigations and radical trapping experiments

The complexity of the reaction under study required a thorough investigation of different aspects of the transformation to achieve a comprehensive understanding of the reaction pathway. We first decided to focus the investigations in the initial part of the transformation, that is, the isomerization of allylic alcohols under these specific reaction conditions. All final products were obtained as single constitutional isomers and the functionalization at the alpha carbon that was not initially part of the olefinic system was never detected under these reaction conditions. These findings suggest that the reaction does not follow a pathway where the allylic alcohol simply is converted to the ketone and then the ketone undergoes a polarity inversion with the help of hypervalent iodine reagent V. On the contrary, the selectivity observed in the transformation points to that the actual umpolung occurs at the iridium enolate species before they are converted to the corresponding carbonyl compounds. First, deuterated allylic alcohol 4e-d1 was subjected to the optimized reaction conditions and the reaction was compared to that starting with non-deuterated 4e. After only 1 minute the yield of both reactions were found to be very similar at 25% and 21%, respectively (scheme 29a and b), which may suggest that the cleavage or formation of this C-H bond might not be rate determining.

Besides, starting from 4e-d1, the resulting a-methoxy ketone 30e-d1 had 47% D at C3 and 49% D at C2 which points that, during the isomerization pathway, the migratory insertion occurs at both carbons of the olefin (vide supra, scheme 8c). Next, the effect of the additive KBF4 in the isomerization of allylic alcohol 4e was evaluated. In its absence, a decrease on the rate of the reaction was observed (Scheme 29c). It can be argued that KBF4 might promote the formation of a very active iridium species for the transformation (likely of the form [Cp*IrCl]BF4).

F I O

V (1.2 equiv.)

[Cp*IrCl2]2 (2.5 mol%) [Cp*IrCl ] (2.5 mol%) OH OH 2 2 O a) KBF4 (80 mol%) O c) KBF4 (80 mol%) Ph Ph TFE / MeOH (1:3, v/v) Ph Ph TFE / MeOH (1:3, v/v) 35 °C, 1 min 25e 4e 35 °C, 1 min OMe 4e 30e 21% yield 120 F I O 100 80 60 V (1.2 equiv.)

yield (%) yield 40 b) [Cp*IrCl2]2 (2.5 mol%) 20 OH KBF4 (80 mol%) O D H/D 0 Ph 1 3 TFE / MeOH (1:3, v/v) Ph 1 3 H/D 0 5 10 35 °C, 1 min OMe time (min) 4e-d1 (99% D) 1 30e-d Í with KBF 25% yield 4 without KBF 47% D at C3 and 49% D at C2 4

Scheme 29. a) and b) Deuterium-labeling studies of the tandem isomerization / methoxilation of allylic alcohol 4e. c) Kinetic investigations of the isomerization of 4e with and without KBF4.

Next we wanted to investigate whether the additive or the iridium catalyst had any effect in the second part of the reaction; the polarity inversion with I(III) reagent V. For this reason, the umpolung transformation was performed directly with a preformed enolate (silyl enol ether 34), with and without these species. Compound 34 in presence of methanol and hypervalent reagent V yielded a-methoxy ketone 30k. The mixture was then treated with NaBH4 in order to quench the reaction and obtain reliable results. After only 1 minute, the reaction gave 59% yield of the corresponding b-methoxy alcohol 35k (d.r. = 6:4, Scheme 30a). The addition of 80 mol% of KBF4 did not affect the yield and the product was still formed in 57% yield (Scheme 30b). On the other hand, the addition of the iridium catalyst did not only facilitate the reaction but seemed to inhibit it (Scheme 30c). These results indicate that neither the additive KBF4 nor the iridium catalyst have a positive effect on reaction of the enolate with a nucleophile in the presence of the I(III) reagent. Thus, their main role in the transformation lays on the isomerization of the allylic alcohol.

43 F I O

V (1.2 equiv.) O OH OTMS NaBH4 a) Ph Ph Ph 0 °C TFE / MeOH (1:3, v/v) OMe OMe 35 °C, 1 min 34k 30k 35k, dr = 6:4 F I O 59% yield

V (1.2 equiv.) O OH OTMS KBF (80 mol%) NaBH4 b) 4 Ph Ph Ph 0 °C TFE / MeOH (1:3, v/v) OMe OMe 35 °C, 1 min 34k 30k 35k, dr = 6:4 F I O 57% yield

V (1.2 equiv.) O OH OTMS [Cp*IrCl ] (2.5 mol%) NaBH4 c) 2 2 Ph Ph Ph 0 °C TFE / MeOH (1:3, v/v) OMe OMe 35 °C, 1 min 34k 30k 35k, dr = 6:4 30% yield Scheme 30. a) Reaction of silyl enol ether 34 with methanol in presence of I(III) reagent V and then direct reduction. b) same but in presence of KBF4 and c) in presence of [Cp*IrCl2]2.

Finally, the reaction was performed in the presence of several radical scavengers to test if the reaction might follow or not a radical pathway (Scheme 31). With 1 equiv. of TEMPO or DPE (1,1-Diphenylethylene), a-methoxy 30e ketone was formed in 70% yield. Even increasing the amount of DPE to 3 equiv. did not inhibit the transformation, and 30e was still obtained in 61% yield. These results are in agreement with the reaction mechanism not involving any type of radical species.

F I O

V (1.2 equiv.)

[Cp*IrCl2]2 (2.5 mol%) Radical trap (X equiv.) OH KBF4 (80 mol%) O

Ph TFE / MeOH (1:3) Ph 35 °C, 1 min 4e OMe 30e TEMPO (1 equiv.) = 70% yield DPE (1 equiv.) = 70% yield DPE (3 equiv.) = 61 % yield Scheme 31. Radical-trapping experiments in the tandem isomerization / methoxylation of allylic alcohol 4e.

4.4.2 DFT calculations and mechanistic proposal

In order to gain further information of mechanism of this reaction, DFT calculations were run by our collaborators using M06/6-31G(d,P).[Note 2] The aim of these in-silico investigations was to study the nature of the different iodonium species in the mechanism and the attack of the nucleophile. Based on our previous investigations25,27,41,42 and on the experimental results (vide supra 4.4.1), we proposed that the reaction starts with the transformation of the allylic alcohol to the corresponding iridium enolate species A via a formal [1,3]-hydride shift. Since KBF4 showed to accelerate the isomerization reaction, the most active iridium species of this reaction might be of the formula [Cp*IrCl]BF4. We hypothesize that the pathway for the isomerization deals with the formation of an a,b- unsaturated carbonyl compound followed by a migratory insertion of [Ir-H] into the olefin (vide supra, Scheme 8c). As mentioned before, the deuterium-labeling studies suggested that the migratory insertion occur at both C of the alkene indistinctly. In this way, iridium enolate species A are formed (represented in Figure 10 as h3).

F I O

1 V (1.2 equiv.) R H

R2 O [Cp*IrCl2]2 (2.5 mol%) O O OH KBF (80 mol%) MeO 4 I OH CF3 1 2 R1 R2 R R TFE / MeOH (1:3, v/v) OMe 35 °C, 1 min. [Cp*IrCl2]2 or / and for DFT 1 2 I OH [Cp*IrCl]BF4 R = Ph, R = H TS1 ΔΔG‡ = 16.2 kcal/mol

F I O CF H O 3 1 O R H R1 R2 R2 O O MeOH O [Ir] I O MeO I O H CF3 R1 R2 [Ir], KF

Iridium enolate A Iodonium enolate B Iodonium enolate C

I OH I OMe CF3 O O H O

R1 R2 R1 R2 Iodonium enolate B´ Iodonium enolate C´

Figure 10. Proposed reaction mechanism for the intermolecular functionalization of allylic alcohols with methanol.

[Note 2] DFT calculations were performed by Martin Pauze and Prof. Enrique Gómez-Bengoa.

45 The reaction of iridium enolate A with hypervalent iodine(III) V would generate and iodonium enolate that could be C-bounded (B) or O-bounded (B´). Previous experimental and computational investigations in the literature with acyclic I(III) reagents points that structures of B´ type are more favorable than that of B type. 68,74 However, we found the energy of iodonium enolate B to be 14.1 kcal/mol lower than that of B´. Actually, several reports suggest that when cyclic benziodoxoles are employed, C-bounded iodonium enolates might be plausibly formed during the reaction.75 From structure B, a molecule of MeOH can attack iodine opening the benziodoxole ring and forming another iodonium enolate. The calculations showed that, also in this case, the energy of C-bound iodonium enolate C was lower than that of the O-bound C´ by 5.3 kcal/mol. It should also be mentioned that other forms of both B and C with different disposition of the ligands around the iodine atom were computed but they all showed higher relative Gibbs free energies. From C, a reductive ligand-coupling type of transition state was obtained to get to the product via TS1. This transition state was computed to have only 16.2 kcal/mol which corresponds perfectly with the temperature of our reaction conditions. Additional transition states from other species (such as C´) were also investigated but no productive pathway was found. The calculations also revealed the role of the fluorinated solvent as the energy of TS1 in the absence of TFE was found to be 21.8 kcal/mol. The effective hydrogen-bonding interactions between the fluorinated solvent and the substrate accounts for the extra stabilization observed. The synthesis of 3(2H)-furanones was also studied using DFT calculations and a similar mechanistic pathway of that of the intermolecular reaction was found. The enol derivative of the g-carbonyl group is able to attack the iodonium group to form the cyclized furanone.

4.5 Concluding remarks

In summary, we have developed a novel inversion of polarity of iridium enolates that allows them to react with nucleophiles in an inter and intramolecular manner to selectively synthesize a-alkoxy ketones and 3(2H)-furanones, respectively. The method relies on the use of a stable hypervalent iodine (III) reagent, fluorobenziodoxole V, that is able to react with the enolate species derived from the reaction of allylic alcohols with [Cp*IrCl2]2 complex. The subsequent iodonium species that are generated can then be coupled to alcohols in order to achieve a wide variety of a-alkoxy ketones in good yields (25 examples). The reaction tolerated several important functional groups such as olefins, halides, sulphones or cyano groups, and it could also be applied to complex biomolecules with various stereogenic centers. Remarkably, the reaction could also be performed in an intramolecular way by using g-carbonyl allylic alcohols in order to access 3(2H)-furanones in very good yields. A study of the reaction mechanism revealed that the a-methoxy ketones are formed via a reductive ligand-coupling pathway from the corresponding C-bound iodonium enolate species. The positive effect of the fluorinated solvent was confirmed by DFT calculations as it is able to stabilize several intermediates along the reaction pathway. Both KBF4 and the iridium catalyst have only a major role in the first part of the reaction, and their performance in the inversion of the polarity and the nucleophilic attack are believed to be negligible.

5. Base-Catalyzed Stereospecific Isomerization of Allylic Alcohols and Ethers Through Ion-Pairing (Paper V)

5.1 Background of the project and initial aim

In 2012, Cahard, Renaud and co-workers reported the stereospecific isomerization of g- trifluoromethylated allylic alcohols in the presence of RuCl2(PPh3)3 as the catalyst and of 1 equiv. of Cs2CO3 as base (vide supra, Scheme 5).32 In light of this report and in the course of our investigations in the group, we decided to study the iridium-catalyzed tandem isomerization / functionalization of g-trifluoromethylated allylic alcohols in order to synthesize a-substituted, β-trifluoromethylated carbonyl compounds. Furthermore, the use of chiral allylic alcohols as substrates could enable the stereospecific synthesis of such products bearing two contiguous stereogenic centers (Scheme 32).

[Mcat] 2 2 R OH Electrophile R O

1 1 F3C R F3C R E ee?, de? Scheme 32. Tandem isomerization / functionalization of chiral g-trifluoromethylated allylic alcohols.

5.2 Base-catalyzed isomerization of allylic alcohols and ethers

5.2.1 Discovery and optimization of reaction conditions

Numerous transition-metal catalysts and electrophiles under different reaction conditions were tested for the tandem isomerization / functionalization of g-trifluoromethylated allylic alcohols. However, none of these attempts yielded any successful results. Nevertheless, during the course of the investigations an interesting discovery was made. In the absence of the metal catalyst, the base itself was able to transform allylic alcohol (E)-4at into saturated ketone 25at. When the reaction was performed with 1.2 equiv. of Cs2CO3 at 60 °C in toluene, 45% yield of the product was formed after 16 h (Table 9, entry 1). Intrigued by this behavior, we studied the effect of different bases in the absence of a metal catalyst. Replacing Cs2CO3 by NaH, afforded only 25% of conversion, and 20% yield as determined by 19F NMR spectroscopy (Table 9, entry 2). However, the use of t-BuOK afforded full conversion to a variety of compounds, of which only 33% was identified as the desired product 25at (Table 9, entry 3). The amount of t-BuOK was then reduced to 0.1 equiv. and only 12% of starting material was converted (Table 9, entry 4). Therefore, it could be concluded that neither NaH nor t-BuOK are good choices as bases for this reaction.

47 Several organic nitrogen-containing bases were next tested in the isomerization of 4at. DMAP, DABCO, Proton-sponge® and TMG failed to yield the product, and only the starting material could be detected in the reaction media (Table 9, entries 5-8). On the contrary, the more basic nitrogen-containing base diazabicycloundecene (DBU), afforded 80% yield of the desired product 25at (Table 9, entry 9). When the amount of base was reduced to 0.1 equiv., the conversion significantly dropped to 18% (Table 9, entry 10). With these results, it was concluded that the basicity of the base played an important role in the transformation. The choice of the stronger guanidine-type base triazabicyclodecene (TBD) successfully afforded 25at in quantitative yield (Table 9, entry 11). More importantly, TBD was also able to afford the product with >99% yield when used in catalytic amounts (10 mol%, Table 9, entry 12). A bulkier TBD derivative, where the free NH group is protected with a methyl group (MTBD), only provided the product with 40% of yield (Table 9, entry 13).

Table 9. Screening of different bases in the metal-free isomerization of (E)-4,4,4-trifluoro- 1,3-diphenylbut-2-en-1-ol (4at).[a] N N N N N N N H N Me TBD DBU MTBD Ph OH Base (equiv.) Ph O NMe2 NH N F3C Ph Toluene, 60 °C F3C Ph (E)-4at 25at Me2N NMe2 N N TMG DMAP DABCO

Entry Base Equiv. Conv. (%)[b] Yield (%)[c]

1 Cs2CO3 1.2 65 45 2 NaH 1.2 25 20 3 t-BuOK 1.2 >99 33 4 t-BuOK 0.1 12 n.d. [d] 5 DMAP 1.2 <1 n.d. [d] 6 DABCO 1.2 <1 n.d. [d] 7 Proton-sponge® 1.2 <1 n.d. [d] 8 TMG 1.2 <1 n.d. [d] 9 DBU 1.2 80 80 10 DBU 0.1 18 n.d. [d] 11[e] TBD 1.2 >99 >99 12[e] TBD 0.1 >99 90 13 MTBD 1.2 42 40 [a] Unless otherwise stated, the reactions were run using (E)-4at (0.165 mmol, 0.1 M) in toluene (degassed, 1.65 mL) under inert atmosphere at 60 °C. [b] Determined by 19F NMR spectroscopy. [c] With trifluorotoluene as I.S. [d] Not determined. [e] Under an atmosphere of air.

5.2.2 Scope of the reaction

With these results in hand, the best conditions (Table 9, entry 12) were used for the isomerization of several substituted allylic alcohols (4at-4bj) (Scheme 33). First, different R1 groups were placed on the alpha carbon to the hydroxyl group and the different reactivity of the corresponding allylic alcohols was studied. The reaction worked well for R1 = aryl and in all cases the corresponding products were obtained in very good yields (25at-25ay). Both electron-withdrawing and electron-donating groups in p-position of the phenyl group were tolerated and quantitative yields were obtained. Interestingly, substrates with electron- withdrawing groups on the aryl at R1 had higher reaction rates compared to substrates with electron-donating groups. The reactions were completed in only 3 h and 1 h for the p-Br- and the p-CF3-substituted substrates, (4au and 4av), respectively. On the other hand, 36 h and 48 h were needed for the p-Me (4aw) and the p-OMe (4 ax) substrates, respectively. When the Z-isomer of the starting material was employed in the reaction, lower reactivity was observed.

R2 OH TBD (10 mol%) R2 O

R3 R1 Toluene, 60 °C R3 R1 (E)-4at-(E)-4bj Time 25at-25bj

Ph O Ph O Ph O

F3C F3C F3C X 25at: X = H, 6 h, >99 (85)% 25au: X = Br, 3 h, >99 (90)% 25ay: 18 h, >99 (85)% [a] 25at from (Z)-4at: 18 h, 85 (62)% 25av: X = CF3, 1 h, >99 (84)% 25aw: X = Me, 36 h, >99 (95)% 25ax: X = OMe, 48 h, >99 (89)%

Ph O Ph O Ph O

F3C CF3 F3C Me F3C H 25az: 18 h, >99 (50)%[b,c,d] 25ba: 18 h, 46%[b] 25bb: 18 h, 30%[b] X

O Me O H O

F3C Ph F3C Ph F3C Ph

25bc: X = Cl, 18 h, >99 (86)% 25bg: 72 h, 95 (74)% 25bh: 18 h, >99 (65)%[d] 25bd: X = CF3, 18 h, >99 (88)% 25be: X = Me, 18 h, >92 (80)% 25bf: X = OMe, 18 h, >99 (89)%

Ph O Ph O Ph F3CF2C Ph F3CF2CF2C [a] [a] 25bi: 48 h, 77 (62)% 25bj: 48 h, 82 (71)% Scheme 33. Scope of the base-catalyzed isomerization of g-fluorinated allylic alcohols. Yield by 19F NMR spectroscopy (isolated yield in parenthesis). [a] 80 °C. [b] TBD (20 mol%), reflux. [c] Yield by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. [d] Volatile.

49 A naphthyl group and an electron-deficient group, i.e., trifluoromethyl, were also tested as R1 substituents and, in both cases, high yields were obtained for the corresponding saturated carbonyl products (25ay and 25az). However, when R1 was a methyl group or just a hydrogen, very low reactivity was observed, and the products could only be detected in small amounts, even after long reaction times (25ba and 25bb). The substitution in R2 was proved to be much more general, and little influence on the reaction rates was found upon variation of the electronic properties. Thus, different p-substituted phenyl substituents, a methyl group or even a hydrogen atom yielded the corresponding products in quantitative yields in 18 h (25bc-25bh). Moreover, the trifluoromethylated group in R3 could also be substituted by longer fluorinated alkyl chains (i.e., −CF2CF3 and −CF2CF2CF3) and in both cases the base-catalyzed isomerization was successful with very good isolated yields (25bi and 25bj). Interestingly, the presence of an electron-withdrawing group at R3 was not essential for the reaction to proceed, and a number of non-trifluoromethylated allylic alcohols (4bk-4bo) were successfully isomerized (Scheme 34). For this type of substrates, the catalyst loading was increased to 20 mol% and reflux of toluene was required. Aliphatic and aromatic groups on R2 and R3 were very well tolerated and even terminal allylic alcohols (R2 = R3 = H, 4k-4m) afforded the desired carbonyl products.

R2 OH TBD (20 mol%) R2 O

R3 Ph Toluene, reflux R3 Ph Time (E)-4bk-4bo 25bk-25bo

O H O O

Ph Ph Ph Ph X 25bk: 6 h, >99 (85)%[a] 25k: X = H, 18 h, >99 (90)% 25bl from (E)-4bl: 18 h, 62 (50)% 25l: X = i-Bu, 18 h, 46 (40)% 25bl from (Z)-4bl: 18 h, 20 (12)% 25m: X = Br, 18 h, >99 (74)%

F Ph O Ph O F Ph O Ph Ph Ph Ph F F Br F 25bm: 18 h, >99 (65)%[a] 25bo from (E)-4bn: 18 h, >99 (73)% 25bo: 18 h, >99 (68)% 25bo from (Z)-4bn: 18 h, >99 (75)%

Scheme 34. Scope of the base-catalyzed isomerization of non-fluorinated allylic alcohols. Yield by 19F NMR spectroscopy (isolated yield in parenthesis). [a] Yield by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S.

The method is not restricted to allylic alcohols, and allylic ethers 36 could also be transformed into their corresponding enol ether products 37 (Scheme 35). Several fluorinated allylic ethers with different R4 groups were successfully isomerized in very good yields (36ata, 36bi, 36atb and 36atc). The products were obtained as single isomers, and the configuration of the double bond was assigned using 1H NOESY NMR spectroscopy on the product (Z)-37ata.

R2 OR4 TBD (10 mol%) R2 OR4

R3 Ph Toluene, 60 °C R3 Ph Time (E)-36ata-36atc, (E)-37ata-37atc, (E)-36bi, (E)-36bk, (E)-36k (E)-37bi, (E)-37bk, (E)-37k

Ph OMe Ph OMe Ph OPh

F3C Ph F3CF2C Ph F3C Ph

(Z)-37ata: 18 h, >99 (86)% (Z)-37bi: 72 h, 88 (69)% (Z)-37atb: 18 h, >99 (80)%

Ph OBn OMe OMe Ph F3C Ph Ph Ph

(Z)-37atc: 36 h, 94 (76)% (Z/E)-37bk: 18 h, 75 (53)%[a,b] (Z/E)-37k: 18 h, 60 (45)%[a,b] (Z/E = 92:8) (Z/E = 97:3)

Scheme 35. Scope of the base-catalyzed isomerization of allylic ethers 36. Yield by 19F NMR spectroscopy (isolated yield in parenthesis). [a] Yield by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. [b] TBD (20 mol%), reflux.

As it occurred with the non-fluorinated allylic alcohols, the isomerization of allylic ethers without an electron-withdrawing group at R3 required higher catalyst loadings and higher temperature. Nonetheless, non-fluorinated enol ethers were obtained in good to moderate yields (37bk and 37k).

5.3 Transfer of chirality

The work by Cahard and co-workers in the ruthenium-catalyzed isomerization of g- trifluoromethylated allylic alcohols showed that chiral β-trifluoromethylated ketones could be obtained from chiral allylic alcohols.32 In this case, the isomerization was proved to be highly stereospecific. Inspired by the results obtained in the TBD-catalyzed isomerization, we decided to investigate whether TBD was able to isomerize allylic alcohols with transfer of chirality, like the Ru-based catalyst. (R)-4at (99% ee) was synthesized according to a literature procedure32 and it was subjected to the optimal isomerization conditions (Table 9, entry 12). Gratifyingly, saturated ketone (R)-25at was obtained with 90% ee (Table 10, entry 1). The absolute configuration of the product was assigned according to the report mentioned above.32 The absolute configuration of the rest of the products was assigned by assuming a common stereochemical mechanism, and further supported by the uniform sign of the specific optical rotation.

51 Table 10. Optimization of the TBD-catalyzed stereospecific isomerization of (E)-4,4,4- trifluoro-1,3-diphenylbut-2-en-1-ol ((R,E)-4at).[a]

Ph OH TBD (X mol%) Ph O

F3C Ph Solvent, Temp. F3C Ph Time (R,E)-4at, 99% ee (R)-4at

Entry TBD [mol%] T [°C] Solvent t [h] Yield (%) ee (%)[b] 1 10 60 Toluene 6 85 90 2 5 60 Toluene 18 84 93 3[c] 5 60 Toluene 18 76 n.d.[d] 4[e] 5 60 Toluene 18 84 93 5 2.5 60 Toluene 72 84 94 6 2.5 80 Toluene 18 82 94(99)[f] 7 1 60 Toluene 96 14 94 8 2.5 80 Dioxane 18 71 84 9 2.5 80 Fluorobenzene 18 90 86 10 2.5 80 THF 18 30 74

11 2.5 80 CH2Cl2 18 28 80

12 2.5 80 CH3CN 18 27 60 [a] Unless otherwise stated, the reactions were run using (R)-4at (0.165 mmol, 0.1 M) in depicted solvent (degassed, 1.65 mL) under inert atmosphere. [b] Using chiral HPLC analysis. [c] 0.05 M. [d] Not determined. [e] 0.25 M. [f] In parentheses ee after recrystallization from hexane/ CH2Cl2.

Next, the effect of the amount of catalyst was examined. Decreasing the amount of base to 5 mol% yielded (R)-4at with 93% ee (Table 10, entry 2). Changing the concentration of the reaction showed no improvement on the chirality transfer: decreasing the concentration to 0.05 M involved a decrease in reactivity and an increase to 0.25 M yielded the same results (Table 10, entries 3 and 4). However, further decrease of the amount of TBD to 2.5 mol% gave the best results in terms of transfer of chirality (94% ee) albeit longer reaction times were needed (72 h, Table 10, entry 5). This problem could be solved by increasing the temperature to 80 °C, which did not affect the stereospecificity (Table 10, entry 6). Importantly, saturated ketone (R)-25at could be obtained with 99% ee by simple recrystallization. Attempts to decrease the catalyst loading to 1 mol% not only showed lower reactivity, but also the same ee (Table 10, entry 7). Different solvents were also screened (Table 10, entries 8-12). Unfortunately, worse results than with toluene were obtained in all cases. Polar solvents afforded lower stereospecificities and yields. With the optimized conditions for the stereospecific isomerization in hand, a library of chiral allylic alcohols was isomerized (Scheme 36) and the stereospecificity (es) of the transformation studied (es, calculated as the enantiomeric excess of the product divided by the enantiomeric excess of the starting material).

R2 OR4 TBD (2.5 mol%) R2 O R2 OR4

or 3 1 R3 R1 Toluene, 80 °C R3 R1 R R Time R4 = H, (R,E)-4at-4bj (R)-25at-25bj (R,Z)-37ata, 37bi, 37atb R4 ≠ H, (R,E)-36ata, 36bi, 36atb R4 = H R4 ≠ H

Ph O Ph O Ph O Ph O

F C F3C F C 3 3 F3C Br CF3 Me (R)-25au, 18 h, 93% yield [ (R)-25at, 18 h, 82% yield (R)-25av, 18 h, 76% yield (R)-25aw, 96 h, 75% yield 96% es 95% es 98% es 94% es

Cl CF3 Ph O Ph O F C 3 F3C O O OMe F3C F3C

(R)-25ax, 48 h, 88% yield[a] (R)-25ay, 24 h, 82% yield (R)-25bc, 48 h, 58% yield (R)-25bd, 48 h, 52% yield[a] 90% es 89% es 89% es 61% es Me OMe

Ph O Ph O O O C2F5 C3F7 F C 3 F3C

[a] (R)-25be, 24 h, 81% yield (R)-25bf, 48 h, 83% yield (R)-25bi, 48 h, 58% yield[a] (R)-25bj, 48 h, 42% yield[a] 98% es >99% es 93% es 96% es

Ph OMe Ph OMe Ph OPh

F3C F3CF2CF2C F3C

(R,Z)-37ata, 48 h, 67% yield[a] (R,Z)-37bi, 72 h, 66% yield (R,Z)-37atb, 18 h, 73% yield 99% es 97% es 99% es Scheme 36. Scope of the TBD-catalyzed stereospecific isomerization of allylic alcohols and allylic ethers. Isolated yields. [a] TBD (5 mol%).

Different substituents in R1 were tested and in all cases the ketones were obtained in very good yields and with stereospecificities of up to 98% es ((R)-25at-25ay). When several groups in p-position of the phenyl group in R2 were screened, an interesting phenomenon was observed. Electron-withdrawing groups in this position afforded higher loss of transfer of chirality. The effect was especially pronounced in compound (R)-25bd bearing a p-CF3. On the contrary, aryl groups bearing electron-donating groups showed perfect chirality transfer even yielding the products with >99% es ((R)-25be and (R)-25bf). Chiral allylic alcohols bearing longer fluorinated chains were also converted to the corresponding ketones showing very good values of stereospecificity ((R)-4bi-4bj). Interestingly, when chiral allylic ethers were subjected to the optimized reaction conditions, the corresponding enol ethers were obtained with almost perfect transfer of chirality between 97 and >99% es ((R)-37ata, 37bi and 37atb). In spite of their interest as building blocks, the asymmetric synthesis of these type of molecules was not reported until now.76

53 5.4 Mechanistic investigations

5.4.1 Kinetic studies: Hammett plot

The study of the mechanism was started by performing kinetic measurements on different allylic alcohols bearing a variety of substituents in p-position of the phenyl group on R1 (4at-4ax). Each allylic alcohol was subjected to the optimized reaction conditions and an aliquot was taken every 10-15 min. Using this method, a kinetic profile for each substrate could be constructed plotting conversion (%) against time (min). Next, the corresponding reaction rates for each allylic alcohol could be obtained and a Hammett plot was built representing log (kX/kH) versus the Hammett neutral sigma constants (σp) for the substituents on para-position. kX is the reaction rate for each allylic alcohol with a certain substituent and kH is the reaction rate for allylic alcohol bearing just a hydrogen on p- position 4at.77 A good linear fitting was obtained (R2 = 0.95) and a r(rho) value of +1.87 was found (Figure 11). Such a positive value for the Hammett constant r suggests that a partial negative charge is built at the benzylic carbon of the transition state of the rate- limiting step.

Figure 11. Hammett plot of base-catalyzed isomerization of allylic alcohols 4at-4ax.

5.4.2 Deuterium-labeling investigations

Deuterated allylic alcohol 4at-d1 (96% D) and allylic ether 36ata-d1 (96% D) were synthesized to perform the deuterium-labeling investigations. First, a kinetic isotope effect was obtained by running parallel reactions with allylic alcohol 4at and 4at-d1. Different aliquots were taken at 30, 45, 60 and 75 min and the conversions were measured using 1H NMR spectroscopy. After constructing a kinetic profile for both reactions, the kinetic isotope effect could be obtained by dividing the reaction initial rate of the non-deuterated substrate by the one of the deuterated substrate. A KIE of 5.0 ± 0.6 was obtained. This large value suggests that the deprotonation of the C−H bond is actually the rate-limiting step of the transformation, in agreement with the results obtained with the Hammett plot. When the reaction was performed with 4at-d1 (96% D) the product was found to have only a total amount of deuterium of 68% (20% in C2 and 48% in C3, respectively, Scheme 37a) distributed as 25at-d0 (32%), 25at-d1 (47%), 25at-d2 (17.6%), 25at-d3(3.4%). Importantly, the deuterium content of C1 was checked to remain constant as the reaction took place so no deuterium scrambling was observed at that position.

It can be then concluded that an obvious net loss of deuterium occurred in the transformation. In an attempt to explain it, partially deuterated TBD (N-d1-TBD)78 was synthesized and a 6% of incorporation of deuterium in C3 was detected suggesting that the proton at C3 is originated, at least partially, from the free NH of the base (Scheme 37b). Next, the reaction was performed with deuterated allylic ether 36ata-d1 (96% D). Product 37ata was obtained with a 78% of D in C3, which is only slightly lower than the expected 86%. The difference can be explained due to traces of H2O in the reaction medium (Scheme 37c). This experiment confirmed that the loss of deuterium in the reaction might be due to the the hydroxyl group. Finally, a cross-over experiment was performed using allylic alcohol 4at-d1 (96% D) and allylic alcohol 4bg (Scheme 37d). Only 4% of deuterium was observed at C3 in 25bg, which implies that the [1,3]-proton is mainly an intramolecular process.

N N H OH (10 mol%) O H/D a) D F3C Toluene F3C 3 1 60 °C

1 (E)-4at-d (96% D) N 25at (48% D at C3 )

N N D OH (10 mol%) O b) H/D F3C Toluene F3C 3 1 60 °C

4at (E)- 25at (6% D at C3 ) N

N N H OMe (10 mol%) OMe H/D c) D F3C Toluene F3C 3 1 60 °C

(E)-36ata-d1 (96% D) (Z)-37ata (78% D at C3 )

OH O D H/D F3C N F3C 3 1 N N H 25at (48% D at C3 ) (E)-4at-d1 (96% D) (10 mol%) d) + + Toluene O OH 60 °C H/D

F3C 3 1 F3C

3 (E)-4bg 4bg (4% D at C )

Scheme 37. Deuterium-labeling investigations.

55 5.4.3 Radical trapping experiments

A series of experiments was performed using radical traps in order to evaluate whether or not the mechanism can proceed through a radical pathway. In these studies, TEMPO and DPE (3 equiv.) were added as additives into the reaction under otherwise optimized reaction conditions. The TBD-catalyzed isomerization of 4at proceeded effectively and the product was obtained in 95% and 72% yield, respectively (Scheme 38). These results suggest that a radical mechanism for this reaction may not be operating under these conditions.

TBD (10 mol%) Ph OH Radical scavenger (3 equiv.) Ph O

F3C Ph F3C Ph Toluene, 60 °C (E)-4at overnight 25at TEMPO = 95% yield DPE = 72% yield

Scheme 38. Isomerization of 4at in presence of several radical traps.

5.4.4 DFT calculations

Computational investigations (B3LYP-D3/aug-cc-pVTZ) were performed to gain a final insight into the reaction mechanism (Figure 12).[Note 3] Starting from the allylic alcohol hydrogen-bonded to the base, and in accordance with the experimental observations, the rate determining step was found to be the deprotonation at C1 with an energy barrier of

Figure 12. DFT calculations of the TBD-catalyzed isomerization of g-trifluoromethylated allylic alcohols. The energies depicted are Gibbs free energies in kcal/mol.

[Note 3] DFT calculations were performed by Prof. Mårten S. G. Ahlquist from the Royal Institute of Technology (KTH).

19.6 Kcal/mol (TSI). After that, an intimate ion-pair is formed between the allylic anion of the alcohol and the conjugated acid of the base. The protonation at C3 can occur either from the free OH of the allylic anion (TSIIa) or from the NH (TSIIb). Both processes were calculated to have similar energy barriers, which explains the low deuterium content found at C3 after the reaction. The efficient transfer of chirality could also be explained through these calculations. The strong formation of an intimate ion-pair facilitates that the protonation takes place on the same face of the allylic system, resulting in a good chirality transfer. It is believed that the electron density of the allylic anion is concentrated on the carbon bearing the trifluoromethylated group. For this reason, when an electron-poor aromatic is present at R2, the negative charge of the allylic anion can be more efficiently delocalized. In this way, a less intimate ion-pair is created and it results in a separation of the anion and cation. This fact may explain the low stereospecificity observed in compound 4bd. This type of mechanism has been later proposed also in a report dealing with the stereospecific isomerization of arylindenols with DABCO as catalyst.79 DFT calculations in this work also pointed to the importance of a tight ion-pair for an efficient transfer of chirality within these systems.

5.5 Conclusions

In conclusion, in this project, the first stereospecific method for the metal-free isomerization of allylic alcohols and ethers has been developed using a simple type guanidine catalyst (TBD) under very mild reaction conditions. A large library of allylic alcohols and allylic ethers has been successfully transformed to their corresponding ketones or enol ethers, respectively with very good yields (32 examples, up to 95% isolated yields). The reaction has been shown to be stereospecific and excellent chirality transfer has been observed starting from enantioenriched allylic alcohols. In this way, chiral β- trifluoromethylated ketones and enol ethers have been synthesized with up to perfect enantiospecificities (>99% es). Mechanistic investigations including kinetic studies, deuterium-labeling investigations and DFT calculations suggest that a rate-determining deprotonation at CHOH is operating under these reaction conditions. The protonation at C3 might be performed either from the free OH of the allylic anion or from the NH of the protonated form of the base. The formation of a very intimate ion-pair is the responsible of the very efficient transfer of chirality observed in this transformation as protonation occurs before the ion-pair dissociates.

57 6. Selective Synthesis and Stereospecific Isomerization of Chiral Allylic Halides

6.1 Background and aim of the project

As previously described in chapter 5, the isomerization of chiral allylic alcohols and ethers using base-catalysis has proved to enable the synthesis of b-substituted ketones and enol ethers with excellent levels of transfer of chirality. So far, this stereospecific strategy has only been reported in examples were X = OH or OR4 (e.g., allylic alcohols and ethers).32 The extension of this method to other allylic substrates would be highly beneficial as it would increase the scope of the transformation. In this sense, the aim of the project is to isomerize chiral allylic halides into versatile chiral vinyl halides through our metal-free approach. In the literature, there are scarce examples of the isomerization of allylic fluorides promoted by base.80 Stereospecific examples are, however, unknown. Vinyl halides, or also called alkenyl halides, are an important class of organic compounds as they are outstandingly versatile as synthetic intermediates in organic chemistry. They serve as electrophilic partners in the well-known cross-coupling reactions. In these transformations, the C-X bond gets transformed into a C-C bond by means of a transition-metal catalyst. The Suzuki-Miyaura, Stille, Ullman, Sonogashira or the Heck reactions are examples were vinyl halides have found an important role in the synthesis of new compounds.81 Moreover, the halide can be replaced by a wide range of oxygen, nitrogen, sulfur or carbon nucleophiles in a nucleophilic vinylic substitution type of reactions (SNV).82 More recently, vinyl halides have even been employed successfully in olefin cross-metathesis reactions.83 Above all these, they are themselves present in several natural products with interesting biological response (e.g., kimbelactone A)84,85 and they even find applications in medicinal techniques such as PET (positron emission tomography) as imaging radiotracers with labeled molecules.86

a) Stereospecific isomerization of allylic alcohols and ethers (vide supra, chapter 5)

R2 OR4 [TBD]cat R2 O R2 OR4 + R3 R1 R3 R1 R3 R1 R4 = H R4 ≠ H

b) Goal of the project: stereospecific isomerization of allylic halides

2 2 R X [TBD]cat R X

R3 R1 R3 R1

X = F, Cl, Br

Figure 13. Stereospecific isomerization of allylic substrates. a) allylic alcohols and ethers. b) allylic halides

6.2 Selective synthesis of allylic halides

The most common strategy for the synthesis of allylic halides is to use allylic alcohols as starting materials since they are abundant and easily accessible via several synthetic methods. The reaction is referred as deoxyhalogenation, as the hydroxyl functional group is replaced by a halogen atom. Numerous procedures can be found in the literature for this transformation,87 being SOCl2, PCl3, PCl5 and PPh3/CCl4 (Appel reaction) the most frequently used reagents.88,89 However, regioselectivity problems are very common in most of these strategies and several side-products are usually formed. The issue is especially problematic in the case of secondary allylic alcohols, where compounds derived from SN1´and SN2´pathways are very likely to arise.87,90

6.2.1 Allylic chlorides

We started our investigations in this project by studying a selective method to convert g-trifluoromethylated allylic alcohols into allylic halides effectively, aiming at avoiding any side-products. The chlorination was evaluated first by subjecting allylic alcohol (E)-4at to different deoxychlorination conditions to synthesize allylic chloride (E)- 38at (Table 11).

Table 11. Regioselective synthesis of g-trifluoromethylated allylic chloride (E)-38at.[a]

Deoxychlorinating Ph OH agent (1 equiv.) Ph Cl Ph Ph Ph + + F C Ph F C F3C Ph Solvent, 0 °C F3C Ph 3 Cl 3 Cl overnight 4at 38at 38´at 38´´at

Deoxychlorinating Entry Solvent Yield (%)[b] 38at /38´at /38´´at (%) Agent (1 equiv.)

1 SOCl2 THF 78 82/12/6

2 SOCl2 Et2O 83 76/16/8

3 SOCl2 CH2Cl2 83 88/12/-

4 SOCl2 Toluene - -

5 SOCl2[c] CH2Cl2 47 80/14/6

6 SOCl2[d] CHCl3 76 87/13/-

7 PCl3 CH2Cl2 80 96/4/-

8 PCl5 CH2Cl2 50 98/2/-

9 POCl3 CH2Cl2 52 12/-/-[e]

10 PPh3/NCS[f] CH2Cl2 40 94/6/-

11 PPh3/NCS[f] THF 67 >99/-/- [a] Unless otherwise stated, the reactions were run using (E)-4at (0.10 mmol, 0.1 M) in the depicted solvent (1.00 mL) at 0 °C overnight. [b] Isolated yield. [c] With 0.1 mmol of pyridine. [d] With 0.1 mmol of NEt3. [e] An unknown product was formed. [f] 0.15 mmol of NCS and PPh3.

59 When thionyl chloride (SOCl2) was used as deoxychlorinating agent in THF, a good yield of 78% was obtained (Table 11, entry 1). However, the desired allylic chloride 38at was formed together with other two isomers (38át and 38´át). The presence of these side-products could not be avoided by changing the solvent to Et2O or to CH2Cl2 (Table 11, entries 2 and 3) and using toluene showed no conversion to the desired product (Table 11, entry 4). The addition of bases was also ineffective, and in all cases side products were observed together with 38at (Table 11, entries 5 and 6). Other deoxychlorinating agents such as PCl3, PCl5 and POCl3 were next tested (Table 11, entries 7, 8 and 9). Both PCl3 and PCl5 yielded allylic halide 38at with a very small amount of side product 38át (4% and 2%, respectively). On the contrary, POCl3 showed a different type of reactivity and a large quantity of an unknown product was produced (Table 11, entry 9). Interestingly, the mixture of NCS/PPh3, a very mild Appel-typed deoxychlorinating agent gave exceptional results in terms of regioselectivity.91 When the reaction was performed in THF, 38at was synthesized with 67% yield without traces of any of the side-products (Table 11, entry 11).

6.2.2 Allylic bromides and fluorides

Next, in a similar way, the synthesis of the corresponding g-trifluoromethylated allylic bromides was considered. The selective synthesis of (E)-39at was found to be somehow smoother and the number and quantities of the side products were smaller than in the case of the chlorides. PBr3 gave an excellent isolated yield of 93% but the desired product was mixed with ca 6 % of 39´´at (Table 12, entry 1). Based on the results obtained in the synthesis of allylic chlorides, Appel-type deoxybrominating agents were tested. The combination of CBr4/PPh3 did not improve the results and a side-product was also detected. Nevertheless, the mixture of NBS/PPh3 afforded allylic bromide 39at as a sole product both in CH2Cl2 and THF (entries 3 and 4). The yield was, though, higher in THF than in CH2Cl2 and these conditions were taken as optimal. The mixture of an N- halosuccinimide and PPh3 seems to be an excellent deoxyhalogenating agent for the regioselective synthesis of g-trifluoromethylated allylic halides.

Table 12. Regioselective synthesis of g-trifluoromethylated allylic bromide (E)-39at.[a]

Deoxybrominating Ph OH agent (1 equiv.) Ph Br Ph Ph Ph + + F C Ph F C F3C Ph Solvent, 0 °C F3C Ph 3 Br 3 Br overnight 4at 39at 39´at 39´´at

Deoxybrominating Entry Solvent Yield (%)[b] 39at /39´at /39´´at (%) Agent (1 equiv.)

1 PBr3 THF 93 94/-/6

2 PPh3/CBr4 CH2Cl2 56 93/-/7

3 PPh3/NBS CH2Cl2 40 >99/-/-

4 PPh3/NBS THF 62 >99/-/- [a] Unless otherwise stated, the reactions were run using (E)-4at (0.10 mmol, 0.1M) in the depicted solvent (1.00 mL) at 0 °C overnight. [b] Isolated yield.

Finally, g-trifluoromethylated allylic fluoride (E)-40at could be synthesized according to literature procedures without any optimization using DAST as deoxyfluorinating agent (1.2 equiv.).92 The product was obtained from 4at in 45% yield and, more importantly, in the absence of any side-products. The synthesis of the corresponding allylic iodide was attempted but could never be accomplished.

SF3

Ph OH DAST (1.2 equiv.) Ph F F C Ph 3 CH2Cl2, -78 °C F3C Ph overnight 4at 40at 45% yield Scheme 39. Synthesis of g-trifluoromethylated allylic bromide (E)-40at.

6.3 Base-catalyzed isomerization of allylic halides

6.3.1 Optimization of the reaction

With regioselective methodologies to synthesize g-trifluoromethylated allylic chlorides, bromides and fluorides in hand, we decided to test the performance of these new substrates in their transformation to vinyl halides catalyzed by a base (Table 13). First, the isomerization of allylic chloride 38at was examined using stoichiometric amounts of different bases. NEt3 and Cs2CO3 showed no reactivity under the reaction conditions and 38at was recovered (Table 13, entries 1 and 2). On the contrary, the use of both DBU and TBD provided full conversion to the desired vinyl chloride 41at, as confirmed by 19F NMR spectroscopy. The yields of the product were 71% and 46%, respectively, as decomposition was observed in both cases (Table 13, entries 3 and 4). When DBU and TBD were used in catalytic amount (10 mol%), the decomposition was avoided, and 41at was obtained in 86% and in >99% yield, respectively (Table 13, entries 5 and 6). The performance of the stronger base TBD seems to be superior than that of DBU, as it occurred also in the base-catalyzed isomerization of allylic alcohol and ethers (Chapter 5, Table 9). A screening of solvents was next performed to know if toluene is required in this transformation. THF, CH2Cl2, dioxane and MeCN were all investigated in the TBD- catalyzed isomerization of allylic chloride 38at (Table 13, entries 7-10). All of them provided worse results in terms of conversion and decomposition was spotted in many of the cases (Table 13, entries 7, 8 and 10). In light of this data, toluene was the most effective solvent for this transformation. The reaction conditions showed in Table 13, entry 6 were taken as optimal for the isomerization of allylic chlorides. The analogous transformation of allylic bromide 39at into the corresponding vinyl bromide 42at was more difficult. Very low conversion was obtained using 10 mol% of TBD at 60° C (Table 13, entry 11). By increasing the temperature of the reaction to 100 °C, a 64% conversion was obtained (Table 13, entry 12). It was only when more catalyst loading was used (30 mol%) than full conversion of 39at was achieved. Even though the decomposition could never be avoided, the desired product was synthesized in a good yield of 60% (Table 13, entry 13). Allylic fluoride 40at required more drastic conditions, and performing the isomerization with 10 mol% of TBD at 145 °C yielded the desired vinyl fluoride 43at in 60% yield (Table 13, entry 14).

61 Table 13. Base-catalyzed isomerization of g-trifluoromethylated allylic halides (E)-38at, (E)-39at, (E)-40at.[a] Ph X Base (X mol%) Ph X

F3C Ph Solvent, T F3C Ph overnight X = Cl, 38at X = Cl, 41at X = Br, 39at X = Br, 42at X = F, 40at X = F, 43at Base Conversion Yield Entry Substrate Solvent T (°C) (X mol%) (%) (%)

1 38at NEt3 (100) Toluene 60 <5 -[b]

2 38at Cs2CO3 (100) Toluene 60 <5 -[b] 3 38at DBU (100) Toluene 60 >99 71[c] 4 38at TBD (100) Toluene 60 >99 46[c] 5 38at DBU (10) Toluene 60 86 86 6 38at TBD (10) Toluene 60 >99 >99 7 38at TBD (10) THF 60 90 84[c]

8 38at TBD (10) CH2Cl2 60 67 60[c] 9 38at TBD (10) Dioxane 60 78 78 10 38at TBD (10) MeCN 60 38 20[c] n.d. 11 39at TBD (10) Toluene 60 34 [d] n.d. 12 39at TBD (10) Toluene 100 64 [d] 13 39at TBD (30) Toluene 100 >99 60[c] 14 40at TBD (10) Toluene 145 >99 60[c] [a] Unless otherwise stated, the reactions were run using (E)-38at, 39at or 40at (0.10 mmol, 0.1 M) in the depicted solvent (1.00 mL) overnight. Conversions measured by 19F NMR spectroscopy. Yields obtained against an internal standard [b] >95% starting material recovered [c] Decomposition into unidentified products. [d] Not determined.

6.3.2 Reaction scope

The generality of the transformation was next evaluated by subjecting different allylic chlorides, bromides and fluorides to the reaction conditions (Scheme 40). First, allylic chlorides bearing electronically diverse substituents in para position at R1 were examined (38au, 38av, 38cr, 38cs, 38aw). Outstandingly, both electron-withdrawing and electron- donating groups provided the desired product in quantitative yields and excellent (Z/E) ratios, of up to 97/3. A naphthyl group at R1 (38ay) was also tolerated and vinyl chloride 41ay could be formed in 86% yield and 96/4 (Z/E) ratio. On the contrary, the isomerization of substrates bearing alkyl groups at R1 (38ba) or of primary allylic halides (38bb) was much more demanding, and it only gave poor yields even when the catalyst loading was increased to 20 mol% and the temperature to reflux (30% and 51%, respectively).

R2 X TBD (10 mol%) R2 X

3 1 3 1 R R Toluene, 60 °C R R R4 overnight R4 X = Cl, 38at-38cu X = Cl, 41at-41cu X = Br, 39at-39ct X = Br, 42at-42ct X = F, 40at-40ay X = F, 43at-43ay

Vinyl chlorides

Ph Cl Ph Cl Ph Cl Ph Cl

F3C Ph F3C F3C F3C

Br CF3 CN 41at: >99 (94%) 41au: 97 (82%) 41av: >99 (92%) 41cr: >99 (88%) (Z/E) = 93:7 (Z/E) = 95:5 (Z/E) = 97:3 (Z/E) = 94:6

Ph Cl Ph Cl Ph Cl

F3C F3C F3C

SO2Me 41cs: >99 (77%) 41aw: >99 (80%) 41ay: >99 (86%) (Z/E) = 96:4 (Z/E) = 94:6 (Z/E) = 96:4

H Cl Me Cl Ph Cl Ph Cl

F3C Ph F3C Ph F3C Me F3C H 41bh: >99 (85%) 41bg: >99 (92%) 41ba: 30%[a] 41bb: 51%[a] (Z/E) = 99:1 (Z/E) = 97:3

Cl CF3 Ph Cl Ph Cl

PhO2S Ph F3C Ph Cl Cl 41ct: From (E)-38ct: >99 (85%) F F3C Ph F3C Ph (Z/E) = 93:7 38cu: 45% From (Z)-38ct: >99 (80%) (Z/E) = 54:46 41bc: 87 (80)% 41bd: 80 (75)% (E/Z) = 94:6 (Z/E) = 95:5 (Z/E) = 96:4

Vinyl bromides

Ph Br Ph Br Ph Br F3C F3C Ph PhO2S Ph CF3 42at: >99 (60%)[b] 42av: 83 (76%)[b] 42ct: From (E)-39ct 86 (50%)[a] (Z/E) = 93:7 (Z/E) = 90:10 (Z/E) = 92:8

Vinyl fluorides

Ph F Ph F Ph F F C 3 F3C F3C Ph CF3 43at: >99 (60%)[c] 43av: 88 (55%)[c] 43ay: 70 (67%)[c] (Z/E) = 98:2 (Z/E) = 92:8 (Z/E) = 95:5 Scheme 40. Scope and limitations for the TBD-catalyzed isomerization of allylic chlorides, bromides and fluorides. Yields by 19F NMR spectroscopy (isolated yield in parenthesis). [a] TBD (20 mol%), reflux. [b] TBD (30 mol%), 100 °C. [c] Xylene as solvent, 145 °C.

63 Substituents at R2 could be varied to a larger extent and not only aromatic substituent, but also aliphatic groups or a hydrogen were all accepted under our reaction conditions. For example, allylic chlorides 38bh and 38bg (with a H or a -Me at R2) provided the desired products in excellent yields and almost as pure (Z)-stereoisomers ((Z/E) = 99:1 for 41bh). Aromatic groups bearing a p-Cl and a p-CF3 were also successfully transformed to their corresponding vinyl halides 41bc and 41bd in very good yields (87% and 80%). The presence of a trifluoromethylated group at R3 was shown not to be a requirement for the reaction to proceed and g-sulphonyl allylic chlorides (E)-38ct and (Z)- 38ct provided the product in excellent yields. Finally, the substitution at R4 was examined too. A hydrogen in this position appears to be essential for the effectiveness of the reaction. When the reaction was tested with allylic chloride 38cu with a –F atom at R4, a moderate yield of 45% was obtained with a ratio of (Z/E) of ca 1:1. The isomerization of several allylic bromides and fluorides was next studied under their corresponding optimized reaction conditions (Table 13, entries 13 and 14, respectively). Allylic bromide 39av with a –CF3 in p- position at R1 and g-sulphonyl 39ct were both converted into their vinyl bromides derivatives in very good yields (83% and 86%). Besides, two other vinyl fluorides could also be synthesized in good (Z/E) ratios and yields (43av and 43ay).

6.4 Synthesis of chiral allylic halides

The synthesis of enantioenriched allylic halides is a process well-known to be very challenging in organic chemistry.93 From chiral allylic substrates, racemization pathways can occur during their synthesis due to their inherent electronic nature. The stabilizing effect of the allylic group towards carbocations favors the formation of SN1 type of mechanism that leads to a decrease of the enantiomeric excess of the products. This phenomenon is even more dramatic when the substrate is both allylic and benzylic as both can effectively stabilize free positive charges.93 With these ideas in mind, however, we decided to test our conditions for the selective synthesis of allylic chlorides starting from chiral allylic alcohols (Table 14). The ultimate aim was to evaluate the possibility of avoiding the racemization of the starting material and obtaining a good retention of the enantiomeric information. First, allylic alcohol (R)-4at was subjected to the optimized reaction conditions for the selective synthesis of allylic chlorides (vide supra, Table 11, entry 11). 75% of (S)-38at along with 25% of its enantiomer was detected (Table 14, entry 1). The use of these specific reagents implies an inversion of the absolute configuration of the starting material via a SN2- type of mechanism. Interestingly, despite all the stabilizing effects of the allylic and benzylic substituents, the racemization could be partially avoided. An optimization of the reaction conditions was next performed in order to avoid further the loss of enantiomeric excess. Decreasing the reaction temperature (from 0 °C to -20 °C) did not show any effect on the reaction and the same level of racemization was obtained (Table 14, entry 2). On the contrary, decreasing the amount of deoxychlorinating agents to only 1 equiv. was beneficial, and the ratio of (R/S)-38at could be improved to 77:23.

Table 14. Selective synthesis of g-trifluoromethylated allylic halide 38at from chiral allylic alcohol (R)-4at.[a]

Deoxychlorinating Ph OH agent (X equiv.) Ph Cl Ph Cl + F C Ph Ph 3 Solvent, 0 °C F3C F3C Ph (R)-4at (R)-38at (S)-38at 98% ee

Deoxychlorinating Entry Solvent - [b] - [b] agent (X equiv.) (R) 38at(%) (S) 38at(%)

1 PPh3/NCS (1.5) THF 25 75

2 PPh3/NCS (1.5) THF (-20 °C) 25 75

3 PPh3/NCS (1.0) THF 23 77

4 PPh3/NCS (1.0) Toluene 22 78[c]

5 PPh3/NCS (1.0) CH2Cl2 37 64

6 PPh3/NCS (1.0) DMF 50 50

7 PPh3/NCS/NaCl (1.0) THF 26 74

8 PPh3/NCS/Imidazole (1.0) THF 26 74

9 PPh3/NCP[d] THF 29 71

10 P(p-OMePh)3/NCS THF 24 76 [a] The reaction was performed using 4at overnight (0.1 mmol, 0.1 M). [b] Determined by chiral HPLC analysis. [c] 18% Yield. [d] N-chlorophthalimide.

The effect of the solvent in the stereospecificty was also considered. Toluene gave a slight improvement compared to THF but the yield was greatly compromised, probably due to the poor solubility of the deoxychlorinating agents in this solvent (Table 14, entry 4). More polar solvents had a negative effect and yielded the product in a lower enantiomeric ratio (Table 14, entry 5 and 6). The outcome was especially noticeable in DMF, where a racemic mixture was obtained. Two additives (NaCl and imidazole) were added to the reaction mixture in an attempt to increase the amount of (S)-38at but none of them could yield better results (Table 14, entries 8 and 9). Next we decided to investigate further the effect of placing different substituents on the allylic substrates (Scheme 41). Interestingly, when the reaction was attempted with chiral allylic alcohol (R)-4ay (96% ee) the product was formed as a nearly racemic mixture (54:46). The excellent ability of the naphthyl group to delocalize positive charges via resonance may direct the substitution reaction to occur via an SN1 mechanism for 4ay. In the same way, replacing the phenyl group at R2 by a methyl group also showed worse results and more racemization was observed (only 40% es).

65 PPh3 / NCS R2 OH (1 equiv.) R2 Cl

F C 1 1 3 R Solvent, 0 °C F3C R overnight (R)-4at-4bg (S)-38at-38bg

Ph Cl Ph Cl Me Cl F3C

F3C Ph F3C Ph

(S)-38at: 77:23 e.r. (S)-38ay: 54:46 e.r. (S)-38bg: 68:32 e.r. 55% es (from (R)-4at: 99:1) 8% es (from (R)-4ay: 98:2) 40% es (from (R)-4bg: 95:5)

Ph Cl Ph Cl Ph Cl Ph Cl

F3C F3C F3C F3C

Br CN SO2Me CF3

(S)-38au: 79:21 e.r. (S)-38cr: 82:18 e.r. (S)-38cs: 87:13 e.r. (S)-38av: 94:6 e.r. 61% es (from (R)-4au: 97:3) 73% es (from (R)-4bg: 94:6) 86% es (from (R)-4bg: 93:7) 98% es (from (R)-4bg: 95:5) Scheme 41. Effect of the substituent on the chiral synthesis of g-trifluoromethylated allylic chlorides.

We hypothesized that substituents that can destabilize carbocationic species formed via a SN1-type reaction, would lead to a higher level stereospecificity. For this reason, allylic alcohols bearing electron-withdrawing groups on the aryl ring at R1 were tested (4au-4av). Gratifyingly, the desired SN2 pathway was more favored and the racemization could be greatly diminished. A p-Br showed only a small increase in the stereospecificity (61% es) which is in agreement to the ability of halogens being able to remove electron density inductively but also donate it through resonance. On the contrary, high electronegative groups reacted with very high stereospecificty and allylic chlorides (S)-38cr, (S)-38cs and (S)-38av were obtained in very good enantiomeric ratios. Particularly impressive is the case of the substrate bearing p-CF3 as the product was obtained with almost no loss of enantiomeric excess from the corresponding allylic alcohol (98% stereospecificity). It must be mentioned that the synthesis of chiral allylic bromides and fluorides was also attempted starting from (R)-4at (Table 13, entries 13 and 14, respectively). Unfortunately, the undesired SN1 pathways were dominant and only racemic mixtures were formed.

6.5 Stereospecific isomerization of allylic chlorides

With a library of chiral allylic chlorides in hand, we continued with our original aim to develop a method for the isomerization of enantioenriched allylic halides to yield chiral vinyl halides using base-catalysis (Scheme 42). The optimal reaction conditions (Table 13, entry 6) were applied in order to study the effectiveness of the chirality transfer from allylic halides into their vinyl derivatives. In general, the reaction showed excellent results in term of stereospecificities, evidencing that the base is capable to transfer chirality very efficiently in these systems. For example, allylic halide 38at was transformed to its corresponding vinyl halide (41at) with an outstanding 96% es.

Despite their low original enantiomeric excess, 4ay and 4bg were also converted with very good levels of chirality transfer (88% and 94% es, respectively). Substrates bearing electron-withdrawing substituents at R1 reacted exceptionally as well (95%-98% es). As an exception, 38cs racemized partially during the reaction (70% es).

2 R Cl TBD (10 mol%) R2 Cl

F C 1 1 3 R Toluene, 60 °C F3C R overnight (R)-38at-38bg (S)-41at-41bg

Ph Cl Ph Cl Me Cl F3C

F3C Ph F3C Ph

(S)-41at: 76:23 e.r. (S)-41ay: 53.5:46.5 e.r. (S)-41bg: 66:34 e.r. 96% es 88% es 94% es

Ph Cl Ph Cl Ph Cl Ph Cl F C F C F3C F3C 3 3

Br CN SO2Me CF3

(S)-41au: 77:23 e.r. (S)-41cr: 81:19 e.r.[a] (S)-41cs: 76:24 e.r.[a] (S)-41av: 92:8 e.r.[b] 95% es 98% es 70% es 95% es Scheme 42. Base-catalyzed stereospecific isomerization of chiral allylic halides.[a] At 0 °C, 1h. [b] At RT, 1h.

6.6 Mechanistic proposal

Deuterated allylic halide 38at-d1 was synthesized to perform deuterium-labeling investigations. The difference in reactivity between the non-deuterated 38at and 38at-d1 was determined by running a series of kinetic studies.[Note 4] From their corresponding initial reaction rates, a KIE of 5.4 ± 0.6 was measured. In an analogous manner to the previous project (vide supra, Chapter 5), this large KIE points to the deprotonation of C1-H being the rate determining step. We propose that the reaction starts by the complexation of the base (TBD) to the corresponding allylic halide through a halide-bonding interaction (Figure 14, Int 1).94 After deprotonation, an ion-pair is created between the conjugated acid of the base and the allylic anion (Int2). Then, a protonation at C3 generates the vinyl halide coordinated to the base (Int3). Finally, decoordination regenerates the base catalyst and closes the cycle. Overall the proposed mechanism is a [1,3]-proton shift mediated by the base, TBD. The highly efficient transfer of the chirality suggests that a very tight ion-pair forms, and that it undergoes protonation before the ion pair breaks. Any effect from the media (e.g., the solvent or the substrate), would promote the separation of the ion-pair and it would lead to lower stereospecificities.

[Note 4] Experiments performed by Víctor García Vázquez.

67 R3 X R3 X H H N R2 R1 R2 R1 N N H

TBD Decoordination Coordination

N N N N Stereospecific Isomerization of N N H Allylic Halides H R3 X R3 X H H 2 1 2 1 R C3 R R C1 R Protonation Deprotonation Int3 Int1 at C3 N at C1 N N H H R2 R1

R3 X

Ion-pair Int2 Figure 14. Mechanism proposed for the TBD-catalyzed stereospecific isomerization of allylic halides. 6.7 Final remarks

In conclusion, this chapter describes the development of two novel methods dealing with electron-deficient allylic halides. First, regioselective protocols for the synthesis of allylic halides from the corresponding allylic alcohols have been established. Importantly, the reaction has been applied to chiral allylic alcohols for the synthesis of enantioenriched allylic chlorides with good levels of retention of the chiral information. Secondly, base-catalyzed protocols for the isomerization of these allylic halides have been successfully developed using triazabicyclodecene (TBD) as catalyst. In this way, a wide range of vinyl chlorides, bromides and fluorides have been synthesized in very good yields (up to quantitative yields). Notably, chiral allylic chlorides have been effectively transformed to their corresponding vinyl derivatives with outstanding levels of transfer of chirality (91% average es).

7. Base-Catalyzed [1,n]-Proton Shifts in Conjugated Polyenyl Alcohols and Ethers (Paper VII)

7.1 Conjugated polyenyl alcohols and ethers. Opportunities and challenges

Biomolecules bearing several alkenyl moieties alongside a hydrocarbon chain in a conjugated fashion are quite common in nature. Many of these structures such as leukotrienes, lipoxins or retinoids have important biological functions in the human body, and many others have been discovered in numerous families of bacteria and fungi.95 Commonly, in several of these cases a hydroxyl or an ether group is bonded to the first sp3 hybridized carbon after the conjugated chain. Figure 15 shows several examples of such polyenyl alcohol and ethers: dienyl alcohol (-)-bitungolide F, trienyl alcohol leukotriene B4, trienyl ether (+)-cytotrienin A and heptaenyl alcohol amphoteronolide B.

OH O O O OH OH HO N H Ph OH Et H O OMe (-)-Bitungolide F N O O (+)-cytotrienin A

O OH OH Me O OH HO OH OH HO O OH OH Me OH OH O CO2H Me OH Leukotriene B4 Amphoteronolide B Figure 15. Natural products bearing conjugated polyenyl alcohols and ethers.

Despite their prevalence among many natural products and their importance as synthetic intermediates in organic chemistry,96 the isomerization of such structures has been poorly studied. In fact, the metal-catalyzed isomerization of polyenyl alcohols has been reported to be very challenging. The formation of very stable h4-complexes between the polyenylic substrate and the catalyst prevents the hydride migration, poisoning the catalyst and inhibiting the reaction.97 The metal-free method reported in this thesis for the isomerization of allylic alcohols and ethers could provide an alternative solution for the isomerization of these challenging substrates, as the reaction proceeds through a different mechanism catalyzed by a base. At the same time, the base-catalyzed isomerization would generate other challenges as the proton transfer could occur at different positions on the polyenyl chain resulting in different products. With all these thoughts in mind, we decided to develop a selective method for the isomerization of polyenyl alcohols and ethers using base catalysis.

69 7.2 Conjugated dienyl alcohols

The investigations in this project were started by evaluating the reactivity of dienyl alcohols under base-catalysis (Scheme 43). All compounds in this section of the thesis have been synthesized with a (E, E) configuration in the double bonds and it will be omitted in the naming of the compounds for simplification purposes. Compound 4bp was first tested under our previously reported reaction conditions (i.e., 10 mol% of TBD at 60 °C) but the starting material was recovered. The reaction required reflux of toluene and 20 mol% of the catalyst to afford 45% yield of the corresponding g,d-unsaturated ketone 25bp. Importantly, no other side-products could be detected in the crude mixture so the reaction selectively delivers the product formed via a [1,3]-proton shift. Other compounds were never observed in the TBD-catalyzed isomerization of dienyl alcohols. The rest of the material decomposed under these conditions.

R4 R2 OH TBD (20 mol%) R4 R2 O

5 1 5 1 R 3 1 R Toluene, reflux, R 3 1 R R3 overnight R3 (E,E)-4bp-4ca 25bp-25ca

O O O O

Cl F3C 25bp, 45% (42%) 25bq, 32% 25br, 40% (36%) 25bs, 46% (41%)

O Me O Me O Me O

Me Me Br 25bt, 82% (76%) 25bu, 66% (63%) 25bv, 72% (69%) 25bw, 65% (58%)

Ph Ph O

Br O O O

F3C

25bx, 91% (86%) 25by, 82% (77%) 25bz, 74% (70%) 25ca, 90% (87%) Scheme 43. TBD-catalyzed isomerization of dienyl alcohols 4bp-4ca. Yields by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis.

The introduction of an electron-withdrawing group at para in the aryl group at R1 was detrimental for the yield, and more decomposition was detected (25bq). A terminal dienyl alcohol (4br; R4, R5 = H) and a dienyl alcohol with an electron-withdrawing group at R5 (4bs) gave similar levels of decomposition, and afforded the products in 40% and 46% yields, respectively. Fortunately, substitution alongside the conjugated dienyl chain (R2, R3 and R4) showed to be beneficial, and decomposition was significantly avoided.

In particular, the introduction of a methyl substituent at either R3 or R4 (4bt-4bw) yielded the corresponding g,d-unsaturated ketones in good yields (71% average yield), and even allowed the synthesis of ketones 25bv and 25bw bearing electron-donating and electron-withdrawing substituents at R5. When the second olefin was part of a cyclic system (4bx-4bz), good results were also obtained. Halide and alkyne substituents were perfectly tolerated, and products 25bx and 25by were synthesized in very good yields (91% and 82%, respectively). Finally, a -CF3 group at R2 yielded the corresponding b-trifluoromethylated- g,d-unsaturated ketone 25ca in 87% isolated yield.

7.2.1 Mechanistic insights

Deuterated compound 4bp-d1 (89% D) was synthesized and subjected to the reaction conditions to study the mechanism of the TBD-catalyzed isomerization of dienyl alcohols (Scheme 44). Kinetics studies were performed with 4bp and 4bp-d1 by running individual reactions and stopping them at a certain time. In this way, values for the initial rates were obtained and a KIE of 2.4 ± 0.5 was calculated. This data suggests that the cleaving of the C-H bond is partly limiting. Starting with 4bp-d1 (89% D), the corresponding 25bp was obtained with 24% D at C3 and 12% D at C2, which corresponds to a total transfer of deuterium to C3 of 54%. The presence of deuterium at C2 is due to keto-enol equilibria that occurs once the reaction is finished. These results are in agreement with our previously discussed investigations on allylic alcohol 4at (vide supra, section 5.4.2). Since no deuterium could be detected at C5, we propose that the mechanism for this transformation is a base-catalyzed [1,3]-proton shift, followed by a final tautomerization that yields the final ketone.

OH H/D O D TBD (20 mol%) H 3 1 Toluene, reflux 3 1 overnight 4bp-d1 (89% D) 25bp 24% D at C3, 12% D at C2 54% total transfer of D to C3 Scheme 44. Isomerization of deuterated dienyl alcohol 4bp-d1.

7.3 Conjugated polyenyl ethers

7.3.1 Isomerization of dienyl ethers

Once investigated the isomerization of dienyl alcohols, we focused next our attention in the study of the related dienyl ethers.98 First, it was noticed that lower temperatures were needed in order to perform the isomerization. When compound 36bp was treated with 20 mol% at 60 °C, a mixture of two isomeric products in a ratio of 78:22 was obtained in 70% yield (Table 15, entry 1). The decomposition that had been prevalent in the isomerization of dienyl alcohols seemed to be much less noticeable in the case of the dienyl ethers. Extensive one- and two-dimensional NMR spectroscopy analysis concluded that the two isomeric compounds were dienol ethers (1Z, 3E)-37bp and (1Z, 3Z)-37bp, being the first one the major isomer.

71 Importantly, and contrary to the case of dienyl alcohols, only the product derived from a [1,5]-proton shift pathway was formed using 36bp and no other side-products were spotted in the crude mixture. The catalyst loading of the base could be further decreased to 10 mol%, and increasing the temperature to 85 °C gave an optimal yield of 83% yield with an identical ratio of [(1Z, 3E)/(1Z, 3Z)] (Table 15, entry 2). Other solvents were then evaluated. However, all of them afforded lower yield and very similar (1Z, 3E) / (1Z, 3Z)] ratios (Table 15, entries 3-6), thus toluene was taken as solvent of choice in this transformation. Other bases have also been tested in the isomerization of dienyl ether 36bp but none of them gave good results. Barton´s base (2-tert-butyl-1,1,3,3-tetramethylguanidine) failed to provide any conversion to the desired product (Table 15, entry 7). DABCO and DBU had the same effect, even when 40 mol% was used (Table 15, entries 8 and 9). It was only when DBU was used in stoichiometric amounts that 53% of yield was produced (Table 15, entry 10). Finally, the simple thermal reaction was tested by performing the reaction in the absence of any base and no conversion was observed. Thus, conditions in entry 2 were taken as optimal for this transformation.

Table 15. Optimization of the TBD-catalyzed isomerization of ((1E,3E)-5-methoxypenta- 1,3-diene-1,5-diyl)dibenzene (36bp).[a]

OMe OMe OMe Base (X mol%) 5 3 1 Solvent, T + overnight 36bp major minor

37bp [(1Z,3E)/(1Z,3Z)]

Entry Base [mol%] T [°C] Solvent Yield (%) [(1Z,3E)/ (1Z,3Z)] [b] 1 TBD (20) 60 Toluene 70 78:22 2 TBD (10) 85 Toluene 83 (80) 78:22 3 TBD (10) 85 Benzene 79 80:20 4 TBD (10) 85 p-Xilene 81 80:20 5 TBD (10) 85 THF 80 77:23 6 TBD (10) 85 Acetonitrile 68 76:24 Barton´s base 7 85 Toluene <5 - (10) 8 DABCO (40) 85 Toluene <5 - 9 DBU (40) 85 Toluene <5 - 10 DBU (100) 85 Toluene 52 77:23 11 - 85 Toluene <5 - [a] Unless otherwise stated, the reactions were run on 36bp (0.1 mmol, 0.1 M) in the depicted solvent (1.00 mL) under air. Yields determined by 1H NMR spectroscopy using 1,3,5-trimethoxybenzene as internal standard. Isolated yield in parenthesis [b] Determined by 1H NMR spectroscopy.

7.3.2 Selective formal [1,5]-proton shift: scope and limitations

The investigations were continued by studying the scope and limitations of the base- catalyzed isomerization of dienyl ethers into dienol ethers via a selective formal [1,5]-proton shift (Scheme 45). TBD 4 2 6 R4 R2 OR6 (10 mol%) R R OR

5 1 5 1 R 5 3 1 R Toluene, 85 °C R 5 3 1 R R3 overnight R3 36bp-36cq 37bp-37cq

OMe OMe OMe

Cl Cl F F 37bp, 83% (80%) [78:22] 37cb, 81% (76%) [80:20] 37cc, 82% (80%) [81:19]

OMe OMe OMe MeO OMe

MeO OMe Me Me 37cd, 72% (66%) [78:22][a] 37ce, 78% (70%) [78:22][a] 37cf, 75% (65%) [78:22]

OMe Cl OMe Cl OMe S S

F 37cg, 72% (60%) [80:20] 37ch, 57% (56%) [79:21] 37ci, 79% (72%) [82:18]

OMe OMe OMe

Me Cl Me 37cj, 70% (66%) [82:18] 37ck, 75% (68%) [81:19] 37bt, 75% (70%) [68:32]

Me OMe Me OMe Me OMe

Cl F 37bu, 61% (60%) [>95:5] 37cl, 60% (58%) [>95:5] 37cm, 60% (62%) [>95:5] ([1,5] : [1,3] = > 14 : 1) ([1,5] : [1,3] = > 10 : 1) ([1,5] : [1,3] = > 15 : 1) OMe OEt OiPr OBn O

37bpa, 85% (79%) [78:22] 37bpb, 77% (76%) [82:18] 37bpc, 70% (66%) [81:19] 37bpd, 82% (76%) [77:23]

Ph OMe OMe Ph OMe H3C H3C O F C 3 Ph

37cn, 53% (44%) [62:38][a] 37´cn, 20% [84:16] 37´ca, 71% (70) [96:4] 37co, 81% (71%) [>96:4] ([1,5] : [1,3] = 3 : 1) ([1,5] : [1,3] = 1 : 3) Scheme 45. Selective synthesis of dienol ethers from dienyl ethers via [1,5]-proton shift catalyzed by TBD. Yields by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis. [a] Reflux of toluene.

73 The ratio of [(1Z,3E)/ (1Z,3Z)] throughout the whole scope stayed very similar (ca 80:20 in most of the cases). This fact points that a thermodynamic equilibrium may be reached in the transformation, which explains the similar distribution of isomers. First, electronically different substituents were placed in p- positions of both aryl groups at R1 and at R5 (36cb-36ce). Electron-withdrawing p-Cl and p-F substituents gave very good results and the products were obtained in 81 and 82% yield, respectively. Electron-donating groups in para demanded higher temperatures to obtain dienol ethers 37cd and 37ce in good yields. However, when a –OMe substituent was placed in meta position of both aryl rings (36cf), the isomerization could be run using optimized reaction conditions. The ortho-substitution was also studied and ortho-Cl dienyl ether 36cg was successfully transformed into 37cg in 72% yield. Remarkably, the presence of heterocycles was tolerated and 37ch bearing two 2-thiophenyl substituents at R1 and at R5 was synthesized in 57% yield. The substitution effect in para at R1 was also studied, and the corresponding p-F, p-Cl and p-Me products (37ci-37ck) were formed in good yields (75% average yield). As with dienyl alcohols, methyl substituents were introduced at R3 and R4, and dienol ethers 37bt-37cm were synthesized in moderated to good yields. Interestingly, when the methyl group was placed at R4, an excellent stereoisomeric ratio was observed ([(1Z,3E)/ (1Z,3Z)] = >95:5). At the same time, a small amount of the product resulting from a [1,3]-proton shift could be detected using these of starting materials (36bu, 36bl and 36cm). Other alkyl dienyl ethers (i.e., with diverse substitution at R6) were synthesized (36bpa-36bpd) and they were subjected to the optimized reaction conditions. The scope at R6 was broad, and the introduction of bulky groups did not inhibit the isomerization. Ethyl, isopropyl, benzyl and 2-methoxyethyl dienyl ethers gave all the desired products in very good yields of up to 85% (37bpa-37bpd). Alkyl substituents at R5 (36cn) gave a mixture of products and lower yields, probably because the acidity of the C-H bond broken in the rate-determining step is decreased. When the reaction was performed with 10 mol% of TBD at 85 °C, only 20% yield was obtained, and the majority of the product was derived from a [1,3]-proton shift (37´cn). By increasing the amount of base and the temperature, 53% yield was formed with the major product being the desired dienol ether 37cn. The fact that the product derived from the [1,3]-proton shift is observed under milder conditions might suggest that it is actually an intermediate in this transformation. Dienyl ether 36ca with a –CF3 group at R2 was the only dienyl ether that did not show any conversion to the desired dienol ether, but it was selectively transformed to 37´ca via a selective [1,3]-proton shift. Finally, a pyran dienyl derivative was also tested (36co) and, interestingly, it afforded the desired selective [1,5]-proton shift in high yield and with excellent stereoselectivity (>96:4).

7.3.3 Elevating the proton transfer to the next level: [1,9]-proton shift

In order to test the generality of the method, we synthesized starting materials bearing even more extensive conjugated systems (Scheme 46). To our delight, compounds with four consecutive alkenes moieties could be isomerized effectively using 20 mol% of TBD at 85 °C. Tetraenyl ether 36cp was converted in 46% yield to the corresponding product through a formal [1,9]-proton shift. Increasing the degree of substitution alongside the conjugated chain was beneficial, and compound 37cq was obtained in 72% yield. In this case, however, some amount of the intermediates derived from the [1,3], [1,5] or [1,7]-proton shifts were formed but in less than 1:10 ratio with the desired product.

TBD OMe (20 mol%) OMe 4 1 4 1 R 9 7 5 3 1 R Toluene, 85 °C R 9 7 5 3 1 R R3 R2 overnight R3 R2 36cp-36cq 37cp-37cq

OMe OMe

37cp, 46% (42%) 37cq, 72% (69%), ([1,9] : [1,n] = > 10 : 1]) n = 3,5,7 Scheme 46. Isomerization of tetraenyl ethers under base-catalysis. Yields by 1H NMR spectroscopy using 2,3,4,5-tetrachloronitrobenzene as I.S. Isolated yields in parenthesis.

These results show how powerful this strategy is, as a simple guanidine base can transfer a proton as far as 9 carbons apart in good yields. In analogy with “chain-walking” or “metal-walk”,99 where a metal complex is able to transfer an alkene moiety via a series of hydride shifts, the base here can perform a number of iterative proton shifts to transfer a proton from one carbon to another (“base-walk”).

7.3.4 Study of the reaction mechanism

7.3.4.1 Experimental mechanistic studies

When a radical trap, 1,1-diphenylethilene was added to the TBD-catalyzed isomerization of 36bp, 72% yield of the desired product was obtained (as opposed to 83% without the radical scavenger). A radical pathway in this transformation may not be then running under these specific conditions. OMe Ph Ph OMe OMe (1 equiv.) TBD (10 mol%) + Toluene 85 °C, o.n. 36bp major minor

37bp, 72% yield Scheme 47. Isomerization of 36bp in presence of DPE as radical trap.

75 Kinetics studies were performed using 36bp and 36bp-d1 (92% D) by running individual reactions and stopping them at a certain time in order to obtain the initial rate for each reaction. A KIE value of 3.8 ± 0.5 was calculated in the case of dienyl ethers, which is also in agreement with the fact that the rate determining step involves the cleavage of the C-H bond at C1.

OMe H/D H/D OMe D OMe H D TBD (10 mol%) H 5 3 1 5 3 1 a) Toluene, 85 °C overnight 36bp-d1 (92% D) 37bp-d Int1 28% D at C5, 20% D at C3 61% total D transfer to C5

D OMe H/D H/D OMe TBD (10 mol%) H 5 3 1 b) Toluene, 85 °C overnight 36bp-d3 (98% D) 37bp-d 20% D at C5, 47% D at C3 41% total D transfer to C5

D OMe D OMe TBD (10 mol%) H 5 3 1 c) Toluene, 85 °C overnight 37bp-d5 36bp-d5 (92% D) 45% D at C5 98% total D kept at C5 Scheme 48. Isomerization of deuterated dienyl ethers a) 36bp-d1, b) 36bp-d3 and c) 36bp-d5.

Starting with 36bp-d1 (92% D), the corresponding product 37bp was found to have 28% D at C5 which is a total transfer of 61% of deuterium to this position (Scheme 48a). Intriguingly, deuterium was also detected at C3 (20%). The presence of deuterium at this position implies that the mechanism involves, to a certain extent, a pathway with two consecutive [1,3]-proton shifts and that Int1 must be an intermediate of this transformation. This type of mechanism explains why we observed formation of 37´cn in the isomerization of dienyl ether 36cn (bearing an alkyl substituent at R5). It also justifies why in some instances a small amount of the product derived from the [1,3]-proton shift was detected together with the desired product (36bu, 36bl and 36cm). To test our hypothesis dienyl ether 36bp-d3 (98% D) with deuterium at C3 was synthesized and subjected to the reaction conditions (Scheme 48b). Effectively, 20% deuterium was observed at C5 (a total transfer of 41%). The base is, thus, able to transfer a proton from C3 to C5, i.e., to perform a [3,5]-proton shift. Finally, the content of deuterium at C5 was confirmed to remain almost intact starting from 36bp-d 5 (92% D). This result indicates that any deuterium that has been transferred to that position does not get exchanged further (Scheme 48c). Next, a series of cross-over experiments were conducted with deuterated 36bp-d1 (90% D) and non-deuterated dienyl ether 36bpd. When the reaction was accomplished with one equiv. of each of the substrates, no scrambling was observed and deuterium was only detected in the substrate that had originally deuterium in the molecule (Scheme 49a).

When the conditions of the cross-over experiments where forced, and 10 equiv. of the deuterated substrate were employed, deuterium was indeed observed at both C3 and C5 of 37bdp (Scheme 49b). In light of these results, we can conclude that the base and the dienyl substrate may not stay fully coordinated during the reaction, and the proton transfer might not be fully intramolecular.

OMe OMe O H O H 5 3 1

37bdp 36bpd (1 equiv.) TBD (10 mol%) <5% D at C5, <5% D at C3 Toluene, 85 °C a) OMe H/D H/D OMe D overnight H 5 3 1

37bd-d 36bp (1 equiv., 90% D) 26% D at C5, 20% D at C3 58% total D transfer to C3

OMe OMe O H/D H/D O H H 5 3 1

37bdp-d 36bpd (1 equiv.) TBD (10 mol%) 27% D at C5, 20% D at C3 b) Toluene, 85 °C OMe H/D H/D OMe D overnight H 5 3 1

37bd-d 36bp (10 equiv., 90% D) 24% D at C5, 18% D at C3 53% total D transfer to C3

Scheme 49. Cross-over experiments with non-deuterated dienyl ether 36bpd and 36bp- d1 using a) 1 equiv. of both substrates and b) 1 equiv. and 10 equiv., respectively.

7.3.4.2 DFT calculations

Finally, DFT calculations employing dienyl ether 36bp were performed in order to gain a better knowledge of the pathway operating in this transformation (Figure 16).[Note 5] An initial study of the substrate showed that 36bp exists as a mixture of two different conformers I and I´ with a very low barrier for the rotation of 6.4 kcal/mol. The s-cis isomer (I´) is 1.9 kcal/mol more stable than the corresponding s-trans (I). From these conformers and in agreement with our experimental mechanistic investigations, the reaction starts with a rate-determining deprotonation at C1 (TSI-II, TSI´-II´).

[Note 5] DFT calculations were performed by Alba Carretero Cerdán and Prof. Enrique Gomez-Bengoa.

77 22.5 TSI’-II’ OMe TS [1,3]-proton transfer TSI-II 22.0 II-III 22.2 Ph 20.3 TSII’-IV’ Ph [1,5]-proton transfer 20.3 TSII-IV II’ 15.1

+ 14.0 TBD-H TBD H OMe II H OMe OMe Ph Ph 0.7 0 Ph Ph III Ph Ph I TBD OMe Common intermediate for Z -1.9 protonation at C1, C3 and C5 -2.0 Ph I' Z H OMe IV’ H Ph Ph IV H OMe -2.7 E Ph conformers I/I' of 36bp in Ph Z Ph equilibrium conditions Thermodynamic distribution

N N N N N N N N N N N N H N H N H H N H H OMe H H OMe H OMe OMe OMe H Ph Ph Ph Ph Ph Ph Ph Ph Ph Ph TSI-II TSI-II’ TSII-IV TSII’-IV’ TSII-III

Figure 16. DFT calculations of the TBD-catalyzed isomerization of dienyl ethers. The energies depicted are Gibbs free energies in kcal/mol.

After that, an ion-pair between the protonated form of the base and the conjugated anion of the dienyl ether is produced (II and II´). From these intermediates, the reaction can proceed by protonation at C3 (TSII-III), at C5 (TSII-IV, TSII´-IV´) or in a reversible way, at C1. The energies of all these different pathways are very similar, which suggest that the reaction is under thermodynamic conditions. All the species in the reaction mixture (I, I´, III, IV, IV´) are then under an equilibrium, and the distribution of the most stable products (IV and IV´) is purely based on the relative energy difference between them (0.7 kcal/mol). This fact is the reason behind why the stereoisomeric ratio observed ([(1Z,3E)/(1Z,3Z)]) remained similar for all different substrates along the scope of the reaction (ca. 78:22).

7.4 Conclusions

In conclusion, in this final chapter, the isomerization of polyenyl alcohols and ethers has been performed using a metal-free method employing triazabicyclodecene (TBD) as catalyst. Dienyl alcohols have been selectively transformed into g,d-unsaturated ketones via a [1,3]-proton shift (12 examples). Further, related polyenyl ethers have been converted into the corresponding dienol ethers throughout a selective [1,n]-proton transfer. A broad scope has been investigated (24 examples) and the products were synthesized in very good yields, of up to 85%. The base has been shown to be able to walk the proton alongside all the carbon chain to as far as 9 carbons apart (“base-walk”). The reaction mechanisms were studied by experimental and computational methods. The isomerization starts with a rate-determining deprotonation at C1, followed by an iterative number of [1,3]-proton shifts or a direct [1,n]-proton shift until the formation of the most thermodynamically stable product. DFT calculations have also confirmed that the reaction proceeds under thermodynamic control, and that the ratio of the different isomers of dienol ethers ([(1Z,3E)/(1Z,3Z)]) depends on their relative energy.

79 8. Concluding remarks

The present thesis describes a series of new methods for the transformation of allylic substrates into important versatile building blocks in organic synthesis. All protocols that have been developed in this work share a common mechanistic pathway via the isomerization of such substrates using metal catalysis or base catalysis. The use of these two approaches are complementary, and together they enable the access of a wide variety of important organic molecules. On the one hand, iridium catalysis has been used for the synthesis of a- functionalized ketones and aldehydes as single constitutional isomers from easily accessible allylic alcohols. The reaction of the corresponding nucleophilic enolate species with electrophiles has enabled the creation of selective protocols for the synthesis of a-iodo, a- aminooxy and a-hydroxycarbonyl compounds. Moreover, an umpolung strategy for the inversion of polarity of these iridium enolate species has allowed their reaction with nucleophiles as well, increasing the scope of the tandem isomerization / functionalization of allylic alcohols. In this way, a-alkoxy carbonyl compounds and 3(2H)-furarones have been synthesized effectively. Mechanistic investigations in this section suggest that the allylic substrate undergoes a [1,3]-hydride shift, mediated by the iridium catalyst. Subsequently, electrophiles react to afford selectively the corresponding a-functionalized carbonyl compounds. On the second part, a base catalyst has been used in a parallel approach to convert allylic substrates in a metal-free method. A very simple guanidine type of base: triazabicyclodecene (TBD) has proved to be an excellent catalyst in the isomerization of allylic alcohols, ethers and halides to their corresponding carbonyl or vinyl derivatives. Importantly, the use of chiral substrates in these procedures has enabled the synthesis of enantioenriched products with very good levels of transfer of chirality in all cases. Besides, this approach has also been expanded to the isomerization of conjugated polyenyl alcohols and ethers for which metal catalysts are not effective. Mechanistic investigations performed in this section revealed that, after a rate-limiting deprotonation, the base is able to accomplish a [1,3]-proton shifts through the formation of an intimate ion pair between the conjugated acid of the base and the allylic anion. In the case of conjugated polyenyl systems, TBD enables an iterative number of [1,3]-proton shifts or a straight [1,n]-proton shift until the most thermodynamically stable product is formed.

Appendix A: Author´s contributions

The author´s contribution to each of the publication (I-VII) is depicted below:

I. Contributed equally to A. Bermejo Gómez. Performed the control experiments and the isolation and characterization of around 90% of the products as well as the synthetic transformations. Wrote the manuscript and the supporting information.

II. Contributed to the synthesis of a-aminoketones and to the deuterium-labeling investigations. Contributed to the writing of the manuscript and the supporting information.

III. Performed the isolation and characterization of around 30% of the products. Wrote the supporting information.

IV. Contributed to the synthesis of the products and to the experimental mechanistic investigations together with A. Sanz-Marco. Wrote the supporting information and contributed to the writing of the manuscript.

V. Discovered the organocatalytic reaction and performed most of the optimization studies. Contributed equally to A. Sanz-Marco in the scope and mechanistic investigations. Wrote the manuscript and partly the supporting information.

VI. Performed the major part of the optimization studies and the synthesis of the products. Wrote the manuscript and the supporting information.

VII. Contributed equally to N. Molleti. Performed most of the investigations about dienyl alcohols, tetraenyl ethers and the major part of the experimental mechanistic studies. Contributed to the writing of the manuscript and the supporting information.

81 Appendix B: Reprint permissions

Reprint permissions were given by the publishers for each of the following articles:

II. A. Sanz-Marco, Š. Možina, S. Martinez-Erro, J. Iskra, B. Martín-Matute, Advanced Synthesis and Catalysis 2018, 360, 3884-3888. Copyright © © 2018 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim. Open access.

IV. This is a post-peer-review, pre-copyedit version of an article published in Nature Communications.

V. S. Martinez-Erro,‡ A. Sanz-Marco,‡ A. Bermejo Gómez, A. Vázquez-Romero, M. S. G. Ahlquist, B. Martín-Matute* Journal of the American Chemical Society 2016, 138, 13408-13414. Copyright © 2016 American Chemical Society. Further permissions related to the material excerpted should be directed to the ACS. Open access.

VI. Manuscript

Appendix C: Numbering of starting materials and products

All starting materials and products that can be found in this thesis are assigned to a unique number-letter code combination. The number (1-43) represents a type of organic compound (e.g., allylic alcohol, allylic ether …). On the other hand, the alphabetical code denotes a specific hydrocarbon core. In other words, identical combinations of R1, R2, R3… have the same letter code (a-cu). All compounds have been named in order of appearance. The whole list is included here as clarification. Starting materials

3 OH R OR4 R3 X R3 1 2 R R R1 R2 R1 R2

4 36 38 X = Cl 39 X = Br 40 X = I Final Products

O R3 O R3 O R3 OR4 R3 R1 R2 R1 R2 R1 R2 R1 R2 I OMe

5 25 30 37 3 3 O O R O R 3 3 R R2 X R 1 2 1 2 R R R R R1 R2 OTMP OH R1 O

24 26 33 41 X = Cl 42 X = Br 43 X = I

Allylic Alcohols

OH OH OH OH OH OH Ph O Ph Ph

4a 4b 4c 4d 4e 4f

OH OH OH OH OH

Ph Ph Cl 4g 4h 4i 4j 4k

OH OH OH OH OH H H Ph H i-Bu Br Cl 4l 4m 4n 4o 4p

83 OH OH OH OH OH Ph O Ph H H Ph

4q 4r 4s 4t 4u OH OH OH TBSO OH OH OH Ph Ph O 4v 4w 4x 4y 4z

OH OH OH OH OH

Ph Ph NC PhO2S Cl

4aa 4ab 4ac 4ad 4ae O OH OH H O H H H O H H 4af O OH 4ah 4ag OH OH OH OH OH Me Me Me Et

Cy O Cy O Cy O Et O Pr O

4ai 4aj 4ak 4al 4am

OH OH Me OH OH OH OH Pr Me

Bu O O O N O N O Ph N O iPr

4an 4ao 4ap 4aq 4ar 4as

Ph OH Ph OH Ph OH Ph OH Ph OH F C F3C F3C 3 F3C F3C

Br CF3 Me OMe 4at 4au 4av 4aw 4ax

Cl CF3

Ph OH Ph OH Ph OH Ph OH OH OH F3C

F3C CF3 F3C Me F3C H F3C Ph F3C Ph

4ay 4az 4ba 4bb 4bc 4bd Me OMe

OH OH Me OH OH Ph OH Ph OH

F3C Ph F3C Ph F3C Ph F3C Ph F3CF2C Ph F3CF2CF2C Ph 4be 4bf 4bg 4bh 4bi 4bj

OH OH OH OH

Cl F3C 4bp 4bq 4br 4bs

OH Me OH Me OH Me OH

Me Me Br 4bt 4bu 4bv 4bw

Ph Ph OH

Br OH OH OH

F3C

4bx 4by 4bz 4ca

Allylic Ethers

OMe Ph OMe Ph OMe Ph OPh Ph OBn OMe

F3C Ph F3C Ph Ph Ph Ph F3CF2C Ph F3C Ph

36ata 36bi 36atb 36atc 36bk 36k

OMe OMe OMe

Cl Cl F F 36bp 36cb 36cc OMe OMe OMe MeO OMe

MeO OMe Me Me 36cd 36ce 36cf OMe Cl OMe Cl OMe S S

F 36cg 36ch 36ci OMe OMe OMe

Me Cl Me 36cj 36ck 36bt

Me OMe Me OMe Me OMe

Cl F 36bu 36cl 36cm OMe OEt OiPr OBn O

36bpa 36bpb 36bpc 36bpd

85 Ph

OMe OMe Ph

H3C F3C O Ph

36cn 36ca 36co OMe OMe

36cp 36cq

Allylic Halides

Ph Cl Ph Cl Ph Cl Ph Cl Ph Cl F C F3C Ph 3 F3C F3C F3C Br CF3 CN SO2Me 38at 38au 38av 38cr 38cs

Ph Cl Ph Cl Ph Cl Ph Cl H Cl Me Cl

F3C F3C F3C Me F3C H F3C Ph F3C Ph

38aw 38ay 38ba 38bb 38bh 38bg

Cl CF3

Ph Cl Cl Cl Ph Cl Ph Br F3C Ph F3C Ph F3C Ph PhO2S Ph F F3C Ph 38bc 38bd 38ct 38cu 39at

Ph Br Ph F Ph F

F3C Ph Br Ph F F3C F3C

CF3 PhO2S Ph F3C Ph CF3 39av 39ct 40at 40av 40ay

Acknowledgments

I would like to express my most sincere gratitute to the following people without whom this doctoral thesis would not have been possible:

First and foremost, I would like to thank my supervisor Prof. Belén Martín-Matute for allowing me to perform my doctoral studies in her group and for all the enormous effort and dedication that I have always received from her. All of her support and guidance during these years is ultimately translated into this extraordinary thesis.

To Prof. Pher G. Andersson for showing interest in this thesis report and for dedicating his time and his effort in correcting and commenting it.

To Dr. Antonio Bermejo-Gómez, Dr. Amparo Sanz-Marco, Dr. Sergio Carrasco and Víctor García- Vázquez for accepting my request to proof-read this work and for helping me to improve it. If this thesis looks as it does is due to their analytical eye and their determination.

I would like to thank from the bottom of my heart my co-workers in all of the projects that comprise this doctoral thesis. Without their hard work, perseverance and dedication to science, this thesis would not be what it is today: Dr. Amparo Sanz-Marco, Dr. Antonio Bermejo- Gómez, Dr. Nagaraju Molleti, Dr. Ana Vázquez-Romero, Alba Carretero Cerdán, Víctor García- Vázquez, Martin Pauze, Dr. Elis Erbing, Dr. Štefan Možina, Prof. Jernej Iskra, Prof. Enrique Gómez- Bengoa and Prof. Mårten S. G. Ahlquist.

To present and past members of the BMM group that have ensured a cozy learning environment during all these years. Thanks for all of the help in the lab, the fun in the office and for the interesting group meetings: Dr. Antonio Bermejo-Gómez, Dr. Ana Vázquez-Romero, Dr. Elisa Martínez-Castro, Dr. Amparo Sanz-Marco, Dr. Marta Vico Solano, Dr. Nagaraju Molleti, Dr. Sergio Carrasco, Dr. Man Li, Dr. Vlad Pascanu, Dr. Greco González Miera, Dr. Elis Erbing, Alejandro Valiente-Sanchez, Aitor Bermejo López, Alba Carretero Cerdán, Víctor García-Vázquez, Erik Weis, Martin Pauze, Kenji Kopf and Pedro Tortajada Palmero.

To all of administrative and technical staff in the Organic Chemistry department for all the help during my time here: Jenny Karlsson, Louise Lehto, Sigrid Mattson, Kristina Linkyte, Carin Larsson, Kristina Romare, Martin Roxengren and Ola Andersson.

87 I would like to express my gratitude also to all my friends in Stockholm who have been such good party buddies during these years: Antonio, Markus, Elisa, Abraham, Amparo, Marc, Miguel, Ana, Sergio, Alejandro, Ferran, Aitor, Alba, Víctor, Jorge, Marta, Paz, Stefan, Mathias and Sandra. Thank you for making my life in Sweden so enjoyable and for creating such good memories. It is being so much fun hanging out with you and I will miss you deeply.

To my amazing “Cuadrilla” for an absolute friendship that does not know about distance or borders: Oihane, Alvaro, Miguel, Maite, Maria and Beatriz. Thank you for always being there and for all the fun in our reunions.

To my beloved family for all the unconditional encouragement and patience during all these long years in Sweden. I cannot express with words how grateful I am to have you. I feel so lucky to have such a caring and supporting family.

Finally, to my dearest partner Diego for always being by my side, for believing in me and for helping me coping with everything alongside this journey. I wouldn´t have made it this far if it hadn´t been for you, my love. Thank you for all these years, I am looking forward to our next adventures together!

References

1 Rothenberg, G. Catalysis: Concepts and Green Applications; Wiley-VCH, 2008. 2 Anslyn, V. E.; Dougherty, D. A. Modern Physical Organic Chemistry; University Science Books, 2006; part II, chapter 9, pp 489-494. 3 Leigh, G. J. Haber-Bosch and Other Industrial Processes, pp 33-54. In: Smith, B. E.; Richards, R. L.; Newton, W. E. (Eds) Catalysts for Nitrogen Fixation. Nitrogen Fixation: Origins, Applications and Research Progress, vol 1. Springer, 2004. 4 Hartwig, J. F. Organotransition Metal Chemistry: From Bonding to Catalysis, University Science Books, 2010. 5 Rothenberg, G. Catalysis: Concepts and Green Applications; Wiley-VCH, 2008; chapter 3, pp 104-108. 6 (a) List, B. Chem. Rev. 2007, 107, 5413-5415. (b) MacMillan, D.W.C. Nature 2008, 455, 304-308. 7 (a) Danishefsky, S.; Cain, P. J. Am. Chem. Soc. 1976, 98, 4975-4983. (b) List, B.; Lerner, R. A.; Barbas, C. F. III. J. Am. Chem. Soc. 2000, 122, 2395-2396. (c) Notz, W.; Sakthivel, K.; Bui, T.; Zhong, G.; Barbas C. F. III. Tetrahedron Lett. 2001, 42, 199-201. (d) Dalko, P. I.; Moisan, L. Angew. Chem. Int. Ed. 2001, 40, 3726-3748. 8 (a) Taylor, M. S.; Jacobsen, E. N. Angew. Chem. Int. Ed. 2006, 45, 1520-1543. (b) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713-5743. (c) Visco, M. D.; Attard, J.; Guan, Y.; Mattson, A. E. Tetrahedron Lett. 2017, 58, 2623-2628. 9 (a) Starks, C. M. J. Am. Chem. Soc. 1971, 93, 195-199. (b) Tan, J.; Yasuda, N. Org. Process Res. Dev. 2015, 19, 1713-1746. 10 Rothenberg, G. Catalysis: Concepts and Green Applications; Wiley-VCH, 2008; chapter 4. 11 Cherkasov, N.; Ibhadon, A. O.; Fitzpatrick, P. Chem. Eng. Process Process Intensif. 2015, 90, 24–33. 12 Maimone, T. J.; Baran, P. S. Nat. Chem. Biol. 2007, 3, 396-407. 13 De Wolfe, R. H.; Young, W. G. Chem. Rev. 1956, 56, 753-901. 14 Butt, N. A.; Zhang, W. Chem. Soc. Rev. 2015, 44, 7929-7967. 15 Lumbroso, A.; Cooke, M. L.; Breit, B. Angew. Chem. Int. Ed. 2013, 52, 1890-1932. 16 Martín Castro, A. M. Chem. Rev. 2004, 104, 2939-3002. 17 Spangler, C. W. Chem. Rev. 1976, 76, 187-217. 18 Woodward, R. B.; Hoffmann, R. J. Am. Chem. Soc. 1965, 87, 395-397. 19 (a) Van der Drift, R. C.; Bouwman, E.; Drent, E. J. Organomet. Chem. 2002, 650, 1-24. (b) Uma, R.; Crevisy, C.; Gree, R. R. Chem. Rev. 2003, 103, 27-51. (c) Cadierno, V.; Crochet, P.; Gimeno, J. Synlett 2008, 1105-1124. (d) Ahlsten, N.; Bartoszewicz, A.; Martín-Matute, B. Dalton Trans. 2012, 41, 1660-1670. 20 (a) Emerson, G.; Pettit, R.; J. Am. Chem. Soc. 1962, 84, 4591–4592. (b) Goetz, W.; Orchin, M. J. Am. Chem. Soc. 1963, 85, 1549–1550. (c) Cherkaoui, H.; Soufiaoui, M.; Grée, R. Tetrahedron 2001, 57, 2379–2383. (d) Xia, T.; Wei, Z.; Spiegelberg, B.; Jiao, H.; Hinze, S.

De Vries, J. G. Chem. Eur. J. 2018, 24, 4043–4049. (e) Spiegelberg, B.; Dell´Acqua, A.; Xia, T.; Spannenberg, A.; Tin, S.; Hinze, S. De Vries, J. G. Chem. Eur. J. 2019, 25, 7820–7825. 21 Damico, R.; Logan, T. J. J. Org. Chem. 1967, 32, 2356-2358. 22 Strohmeier, W.; Weigelt, L. J. Organomet. Chem. 1975, 86, C17. 23 Trost, B. M.; Kulawiec, R. J. J. Am. Chem. Soc. 1993, 115, 2027-2036. 24 Cadierno, V.; García-Garrido, S. E.; Gimeno, J.; Varela-Álvarez, A.; Sordo, J. A. J. Am. Chem. Soc. 2006, 128, 1360-1370. 25 Ahlsten, N.; Lundberg, E.; Martín-Matute, B. Green Chem. 2010, 12, 1628-1633. 26 For other examples of isomerization of allylic alcohols in water see: (a) García-Álvarez, J.; Gimeno, J.; Suarez, F. J. Organometallics 2011, 30, 2893-2896. (b) Lorenzo-Luis, P.; Romerosa, A.; Serrano-Ruiz, M. ACS Catal. 2012, 2, 1079-1086. (c) Horváth, H.; Kathó, Á.; Udvardy, A.; Papp, G.; Szikszai, D.; Joò, F. Organometallics 2014, 33, 6330-6340. 27 Erbing, E.; Vázquez-Romero, A.; Bermejo Gómez, A.; Platero-Prats, A. E.; Carson, F.; Zou, X.; Tolstoy, P.; Martín-Matute, B. Chem. Eur. J. 2016, 22, 15659-15663. 28 Selected examples: (a) Matilli, L.; Gérard, D.; Torche, S.; Besnard, C.; Mazet, C. Angew. Chem. Int. Ed. 2009, 48, 5143-5147. (b) Li, J.-Q.; Peters, B.; Andersson, P. G. Chem. Eur. J. 2011, 17, 11143-11145. (c) Cahard, D.; Gaillard, S.; Renaud, J.-L. Tetrahedron Lett. 2015, 56, 6159-6169. (d) Li, H.; Mazet, C. J. Am. Chem. Soc. 2015, 137, 10720-10727. 29 Ito, M.; Kitahara, S.; Ikariya, T. J. Am. Chem. Soc. 2005, 127, 6172-6173. 30 Liu, T.-L.; Ng, T. W.; Zhao, Y. J. Am. Chem. Soc. 2017, 139, 3643-3646. 31 (a) Clark, W. M.; Tickner-Eldridge, A. M.; Huang, G. K.; Pridgen, L. N.; Olsen, M. A.; Mills, R. J.; Lantos, I.; Baine, N. H. J. Am. Chem. Soc. 1998, 120, 4550-4551. (b) Hedberg, C.; Andersson, P. G. Adv. Synth. Catal. 2005, 347, 662-666. 32 Bizet, V.; Pannecoucke, X.; Renaude, J.-L.; Cahard, D. Angew. Chem. Int. Ed. 2012, 51, 6467-6470. (b) Bizet, V.; Pannecoucke, X.; Renaud, J.-L.; Cahard, D. J. Fluorine Chem. 2013, 152, 56-61. 33 García-Yebra, C.; Janssen, J.-P.; Rominger, F.; Helmchen, G. Organometallics, 2004, 23, 5459-5470. 34 Burton, H.; Ingold, C. K. J. Chem. Soc. 1928, 904. 35 (a) Dimmel, D. R.; Fu, W. Y.; Gharpure, S. B. J. Org. Chem. 1976, 41, 3092-3096. (b) Schmidt, G. A.; Borschberg, H. Helv. Chim. Acta 2001, 84, 401-415. 36 Johnston, A. J. S.; McLaughlin, M. G.; Reid, J. P.; Cook, M. J. Org. Biomol. Chem. 2013, 11, 7662-7666. 37 Reid, P. R.; McAdam, C. A. Johnston, A. J. S.; Grayson, M. N.; Goodman, J. M.; Cook, M. J. Org. Chem. 2015, 80, 1472-1498. 38 Zheng, H.-X.; Xiao, Z.-F.; Yao, C.-Z.; Li, Q.-Q.; Ning, X.-S.; Kang, Y.-B.; Tang, Y. Org. Lett. 2015, 17, 6102-6105. 39 Mondal, K.; Mondal, B.; Pan, S. C. J. Org. Chem. 2016, 81, 4835-4848. 40 For examples of the selective synthesis of a-substituted ketones from a,b-unsaturated ketones see: (a) Sugiura, M.; Sato, N.; Sonoda, Y.; Kotani, S.; Nakajima, M. Chem. - Asian J. 2010, 5, 478-481. (b) Teng, Y.; Lu, J.; Toy, P. H. Chem. - Asian J. 2012, 7, 351-359. 41 (a) Bartoszewicz, A.; Livendahl, M.; Martín-Matute, B. Chem. Eur. J. 2008, 14, 10547-10550. (b) Bartoszewicz, A.; Jezowska, M. M.; Laymand, K.; Möbus, J.; Martín- Matute, B. Eur. J. Inorg. Chem. 2012, 1517-1530.

42 (a) Ahlsten, N.; Martín-Matute, B. Chem. Commun. 2011, 47, 8331-8333. (b) Ahlsten, N.; Bermejo Gómez, A.; Martín-Matute, B. Angew. Chem. Int. Ed. 2013, 52, 6273-6276. (c) Bermejo Gómez, A.; Erbing, E.; Batuecas, M; Vázquez-Romero, A.; Martín-Matute, B. Chem. Eur. J. 2014, 20, 10703-10709. 43 (a) Zhdankin, V. V.; Stang, P. J. Chem. Rev. 2008, 108, 5299-5358. (b) Zhdankin, V. V. Hypervalent Iodine Chemistry: Preparation, Structure and Synthetic Application of Polyvalent Iodine Compounds; John Wiley & Sons Ltd.: New York, 2014. (c) Wirth, T., Ed. Hypervalent Iodine Chemistry. Top. Curr. Chem. 2016, vol 373. (d) Yoshimura, A.; Zhdankin, V. V. Chem. Rev. 2016, 116, 3328-3435. 44 (a) Duschek, A.; Kirsch, S. F. Angew. Chem., Int. Ed. 2011, 50, 1524-1552. (b) Bernini, R.; Fabrizi, G.; Pouysegu, L.; Deffieux, D.; Quideau, S. Curr. Org. Synth. 2012, 9, 650-669. 45 (a) Zanka, A.; Takeuchi, H; Kubota, A.; Org. Process Res. Dev., 1998, 2, 270-273. (b) Geary, G. C.; Hope, E. G.; Singh, K.; Stuart, A. M. Chem. Comm. 2013, 49, 9263-9265. (c) Granados, A.; Jia, Z.; del Olmo, M.; Vallribera, A. Eur. J. Org. Chem. 2019, 2812-2818. 46 Charpertier, J.; Früh, N.; Togni, A. Chem. Rev. 2015, 115, 650-682. 47 (a) Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239-258. (b) Seebach, D.; Kolb, M. Chem. Ind. (London), 1974, 687-692. 48 (a) Jereb, M.; Stavber, S. Zupan, M. Synthesis, 2003, 853-858. (b) Kano, T.; Ueda, M.; Maruoka, K. J. Am. Chem. Soc. 2008, 130, 3728-3729. 49 (a) Barluenga, J. Pure Appl. Chem. 1999, 71, 431-436. (b) Barluenga, J.; González, J. M.; Martín, M. A. G.; Campos, P. J.; Asensio, G. J. Org. Chem. 1993, 58, 2058-2060. (c) Johnsson, R.; Meijer, A.; Ellervik, U. Tetrahedron 2005, 61, 11657-11663. (d) Wang, X.-C.; Hu, Y.; Bonacorsi, S.; Hong, Y.; Burrell, R.; Yu, J.-Q. J. Am. Chem. Soc. 2013, 135, 10326-10329. (e) He, J.; Duan, J.; Shi, H.; Huang, J.; Huang, J.; Yu, L.; Zeller, M.; Hunter, A. D.; Xu, Z. J. Inorg. Chem. 2014, 53, 6837-6843. (f) Racys, D. T.; Sharif, S. A. I.; Pimlott, S. L.; Sutherland, A. J. Org. Chem. 2016, 81, 772-780. (g) Yang, Y.; Zhang, L.; Deng, G.-J.; Gong, H. Sci. Rep. 2017, 7, 40430-40439. 50 (a) Meltzer, P. C.; Butler, D.; Deschamps, J. R.; Madras, B. K. J. Med. Chem. 2006, 49, 1420-1432. (b) Evans, R. W.; Zbieg, J. R.; Wu, S.; Li, W.; MacMillan, D. W. C. J. Am. Chem. Soc. 2013, 135, 16074-16077. (c) Liang, S.; Zeng, C.-C.; Tian, H.-Y.; Sun, B.-G.; Luo, X.- G.; Ren, F.-Z. J. Org. Chem. 2016, 81, 11565-11573. 51 (a) Trost, B. M. Science 1991, 254, 1471-1477. (b) Trost, B. M. Angew. Chem. Int. Ed. Engl. 1995, 34, 259-281. (c) Trost, B. M. Acc. Chem. Res. 2002, 35, 695-705. 52 (a) Le Bras, G.; Provot, O.; Bekaert, A.; Peyrat, J.-F.; Alami, M.; Brion, J.-D. Synthesis 2006, 9, 1537–1544. (b) Moorthy, J. N.; Senapati, K.; Kumar, S. J. Org. Chem. 2009, 74, 6287–6290. (c) Podgoršek, A.; Zupan, M.; Iskra, J. Angew. Chem. Int. Ed. 2009, 48, 8424– 8450. (d) Gao, M.; Yang, Y.; Wu, Y.-D.; Deng, C.; Cao, L.-P.; Meng, X.-G.; Wu, A.-X. Org. Lett. 2010, 12, 1856–1859. (e) Bedrač, L.; Iskra, J. Adv. Synth. Catal. 2013, 355, 1243–1248. (f) Cao, H.; Yuan, J.; Liu, C.; Hu, X.; Lei, A. RSC Adv. 2015, 5, 41493–41496. (g) Zhang, J.; Li, S.; Deng, G.-J.; Gong, H. ChemCatChem 2018, 10, 376–380. 53 (a) Stavber, G.; Iskra, J.; Zupan, M.; Stavber, S. Green Chem. 2009, 11, 1262–1267. (b) Stavber, G.; Iskra, J.; Zupan, M.; Stavber, S. Adv. Synth. Catal. 2008, 350, 2921–292. (c) Iskra, J.; Murphree, S. S. Tetrahedron Lett. 2017, 58, 645–648. 54 (a) Liu, R.; Liang, X.; Dong, C.; Hu, X. J. Am. Chem. Soc. 2004, 126, 4112–4113.

55 (a) Stamier, J. S.; Singel, D. J.; Loscalzo, J. Science 1992, 258, 1898-1902. (b) Wang, P. G.; Xian, M.; Tang, X.; Wu, X.; Wen, Z.; Cai. T.; Janczuk, A. J. Chem. Rev. 2002, 102, 1091-1134. 56 (a) Hashiyama, T.; Morikawa, K.; Sharpless, K. B. J. Org. Chem. 1992, 57, 5067-5068. (b) Nicolaou, K. C.; Vassilikogiannakis, G.; Simonsen, K. B.; Baran, P. S.; Zhong, Y.-L.; Vidali, V. P.; Pitsinos, E. N.; Couladouros, E. A. J. Am. Chem. Soc. 2000, 122, 3071-3079. (c) Tanaka, T.; Kawase, M.; Tani, S. Biorg. Med. Chem. 2004, 12, 501-505. (d) Scheidt, K. A.; O´Bryan, E. A.; Knochel, P.; Molander, G. A. (Eds). Comprehensive Organic Synthesis 2nd ed. vol 3, 2014, pp 621-655. (e) Palomo, C.; Oiarbide, M.; García, J. M. Chem. Soc. Rev. 2012, 41, 4150-4164. (f) Park, J-S.; Kagaya, N.; Hashimoto, J.; Izumikawa, M.; Yabe, S.; Shin-ya, K.; Nishiyama, M; Kuzuyama, T. ChemBioChem. 2014, 15, 527-532. 57 (a) Hayashi, M.; Shibuya, M.; Iwabuchi, Y. Org. Lett. 2012, 14, 154-157. (b) Xie, Y.-X.; Song, R.-J.; Liu, Y.; Liu, Y.-Y.; Xiang, J.-N.; Lia, J.-H. Adv. Synth. Catal. 2013, 355, 3387-3390. (c) Schroll, P.; König, B. Eur. J. Org. Chem. 2015, 309-313. 58 Dinca, E.; Hartmann, P.; Smrček, J.; Dix, I.; Jones, P. G.; Jahn, U. Eur. J. Org. Chem. 2012, 4461-4482. 59 (a) Solsona, J. G.; Romea, P.; Urpí, F.; Vilarrasa, J. Org. Lett. 2003, 5, 519-522. (b) Rodríguez-Cisterna, V.; Villar, C.; Romea, P.; Urpí, F. J. Org. Chem. 2007, 72, 6631-6633. (c) Fàbregas, M.; Gómez-Palomino, A.; Pellicena, M.; Reina, D. F.; Romea, P.; Urpí, F.; Font-Bardia, M. Org. Lett. 2014, 16, 6220-6223. 60 (a) Kimpe, N. D.; Verhé, R. The Chemistry of a-Haloketones, a- Haloaldehydes and a- Haloimines, Wiley, New York, 1990. (b) Guillena, G. Alpha-Heteroatom Functionalization of Carbonyl Compounds. In Comprehensive Enantioselective Organocatalysis: Catalysts, Reactions, and Applications. Dalko, P. L. Ed. Wiley-VCH, 2015. 61 (a) Weber W.P. Electrophilic Reactions of Silyl Enol Ethers. In: Silicon Reagents for Organic Synthesis. Reactivity and Structure Concepts in Organic Chemistry, vol 14. Springer, Berlin, Heidelberg, 1983. (b) Braun, M. Modern Enolate Chemistry: From Preparation to Applications in Asymmetric Synthesis. Wiley-VCH, 2016. 62 Seebach, D. Angew. Chem. Int. Ed. 1979, 18, 239 –258. 63 (a) Prakash, O.; Saini, N.; Tanwar, M. P.; Moriarty, R. Contemp. Org. Synth., 1995, 2, 121- 131. (b) (b) Moriarty, R. M.; Prakash, O. Org. React. 1999, 273-418. (c) Merrit, E. A.; Olofsson, B. Synthesis, 2011, 4, 517-538. 64 Mizar, P.; Wirth, T. Angew. Chem. Int. Ed. 2014, 53, 5993 –5997. 65 Shneider, O. S.; Pisarevsky, E.; Fristrup, P.; Szpilman, A. M. Org. Lett. 2015, 17, 282-285. 66 Yu, J.; Tian, J.; Zhanga, C. Adv. Synth. Catal. 2010, 352, 531-546. 67 Hari, D. P.; Caramenti, P.; Waser, J. Acc. Chem. Res. 2018, 51, 3212-3225. 68 (a) Maksymenko, S.; Parida, K. N.; Pathe, G. K.; More, A. A.; Lipisa, Y. B.; Szpilman, A. M. Org. Lett. 2017, 19, 6312−6315. (c) Arava, S.; Kumar, J. N.; Maksymenko, S.; Iron, M. A.; Parida, K. N.; Fristrup, P.; Szpilman, A. M. Angew. Chem. Int. Ed. 2017, 56, 2599–2603. 69 Okuyama, T.; Takino, T.; Sueda, T.; Ochiai, M. J. Am. Chem. Soc. 1995, 117, 3360-3367. 70 Ochiai, M.; Takeuchi, Y.; Katayama, T.; Sueda, T.; Miyamoto, K. J. Am. Chem. Soc. 2005, 127, 12244-12245. 71 (a) Ilchenko, N. O.; Tasch, B. O.; Szabó, K. J. Angew. Chem. Int. Ed. 2014, 53, 12897-12901. (b) Yuan, W.; Szabó, K. J. Angew. Chem. Int. Ed. 2015, 54, 8533-8537. (c) Zhou, B.; Xue, X.-S.; Cheng, J.-P. Tetrahedron Letters, 2017, 58, 1287-1291.

72 The beneficial effect of the use of fluorinated solvents for the activation of hypervalent fluoroiodoxolanes has already been described: Minhas, H. K.; Riley, W.; Stuart, A. M.; Urbonaite, M. Org. Biomol. Chem. 2018, 16, 7170-7173. 73 (a) Uchida, R.; Lee, D.; Suwa, I.; Ohtawa, M.; Watanabe, N.; Demachi, A.; Ohte, S.; Katagiri, T.; Nagamitsu, T.; Tomoda, H. Org. Lett. 2017, 19, 5980−5983. (b) Li, Y.; Hale, K. J. Org. Lett. 2007, 9, 1267−1270. (c) Chimichi, S.; Boccalini, M.; Cosimelli, B.; Dall’Acqua, F.; Viola, G. Tetrahedron 2003, 59, 5215−5223. (d) Han, Q.; Wiemer, D. F. J. Am. Chem. Soc. 1992, 114, 7692-7697. 74 (a) Norrby, P.-O.; Petersen, T. B.; Bielawski, M.; Olofsson, B. Chem. Eur. J. 2010, 16, 8251–8254 (b) Beaulieu, S.; Legault, C. Y. Chem. Eur. J. 2015, 21, 11206–11211. 75 (a) Geary, G. C.; Hope, E. G.; Singh, K.; Stuart, A. M. RSC Adv. 2015, 5, 16501-16506. (b) Zhang, J.; Szabó, K. J.; Himo, F. ACS Catalysis 2017, 7, 1093-1100. (c) Mai, B. K.; Szabó, K. J.; Himo, F. ACS Catalysis 2018, 8, 4483-4492. 76 Effenberger, F. Angew. Chem. Int. Ed. 1969, 5, 295. 77 (a) Hammett, L. P. J. Am. Chem. Soc. 1937, 59, 96. (b) Lupp, D.; Christensen, N. J.; Fristrup, P. Understanding Organometallic Reaction Mechanisms and Catalysis: Computational and Experimental Tools, 1st ed.; Ananikov, V. P., Ed.; Wiley-VCH: Weinheim, Germany, 2015; pp 187−215. 78 Kämphen U.; Eschenmoser, A. Helv. Chim. Acta 1989, 72, 185. 79 Ascough, D. M. H.; Duarte, F.; Paton, R. S. J. Am. Chem. Soc. 2018, 140, 16740−16748. 80 Scarce examples of base-mediated isomerization of allylic fluorides: a) Oldendorf J.; Haufe, G.; J. Prakt. Chem. 2000, 342, 52-57. b) Hammond, G. B.; deMendonca, D. J.; J. Fluorine Chem. 2000, 102, 189-197. c) Guo, R.; Huang, J.; Zhao, X. ACS Catal. 2018, 8, 926-930. 81 (a) Stille, J. K.; Groh, B. L. J. Am. Chem. Soc. 1987, 109, 813-817. (b) Marshall, J. A. Chem. Rev. 2000, 100, 3163-3186. (c) Corsico, E. F.; Rossi, R. A. J. Org. Chem. 2004, (d) Nicolaou, K. C.; Bulger, P. G.; Sarlah, D. Angew. Chem., Int. Ed. 2005, 44, 4442-4489. 69, 6427-6432. (e) Venkat Reddy, C. R.; Urgaonkar, S.; Verkade, J. G. Org. Lett. 2005, 7, 4427-4430. (f) Barluenga, J.; Moriel, P.; Aznar, F.; Valdés, C. Org. Lett. 2007, 9, 275-278. (g) Tsai, W.-T.; Lin, Y.-Y.; Chen, Y.-A.; Lee, C.-F. Synlett. 2014, 25, 0443-0447. (h) Cherney, A. H.; Reisman, S. E. J. Am. Chem. Soc. 2014, 136, 14365-14368. (i) Mondal, S. ChemTexts 2016, 2:17. (j) Johnson, K. A.; Biswas, S.; Weix, D. J. Chemistry, 2016, 22, 7399-7402. 82 (a) Bernasconi, C. F.; Rappoport, Z. Acc. Chem. Res. 2009, 42, 993-1003. (b) Chiba, S.; Ando, K.; Narasaka, K. Synlett. 2009, 16, 2549-2564. (c) Shi, A.-F; Xu, L.-N; Chen, J.; Luo, H.-X.; Zhang, J.; Cao, X.-P. Asian J. Org.Chem. 2019, 8, 161–170. 83 (a) Macnaughtan, M. L.; Johnson, M. J. A.; Kampf, J. W. J. Am. Chem. Soc. 2007, 129, 7708–7709. (b) Sashuk, V.; Samojlowicz, C.; Szadkowska, A.; Grela, K. Chem. Commun. 2008, 2468–2470. (c) Koh, M. J.; Nguyen, T. T.; Zhang, H.; Schrock, R. R.; Hoveyda, A. H. Nature, 2016, 531, 459-465. 84 Nunnery, J. K.; Engene, N.; Byrum, T.; Cao, Z.; Jabba, S. V.; Pereira, A. R.; Matainaho, T.; Murray, T. F.; Gerwick, W. H. J. Org. Chem. 2012, 77, 4198-4208. (b) Akiyama, T.; Takada, K.; Oikawa, T.; Matsuura, N.; Ise, Y.; Okada, S.; Matsunaga, S. Tetrahedron, 2013, 69, 6560-6564. 85 Fang, W.-Y.; Ravindar, L.; Rakesh, K. P.; Manukumar, H. M.; Shantharam, C. S.; Alharbi, N. S.; Qin, H.-L. Eur. J. Med. Chem. 2019, 173, 117-153.

86 Gillis, E. P.; Eastman, K. J.; Hill, M. D.; Donnelly, D. J.; Meanwell, N. A. J. Med. Chem. 2015, 58, 8315−8359. 87 (a) Smith, M. B.; March´s Advanced Organic Chemistry: Reactions, Mechanisms, and structure 7th ed.; John Wiley & Sons: Hoboken, New Jersey, 2013. Chapters 10 and 12. (b) Larock, R. C.; Zhang, L. Halogenation of Alcohols. In Comprehensive Organic Transformations; Larock, R. C., Ed.; Wiley- VCH: Weinheim, 2018. 88 Appel, R. Angew. Chem., Int. Ed. 1975, 14, 801−811. 89 Caserio, F. F.; Dennis, G. E.; Dewolfe, R. H.; Young, W. G. J. Am. Chem. Soc. 1955, 77 , 4182-4183. 90 (a) Young, W. G.; Caserio, F. F.; Brandon, D. D. J. Am. Chem. Soc. 1960, 82, 6163-6168. (b) Snyder, E. I.; J. Org. Chem. 1972, 37, 1466-1466. (c) Corey, E. J. Kim, C. U.; Takeda, M. Tetrahedron lett. 1972, 4339-4344. 91 (a) Hanessian, S.; Ponpipom, M.M.; Lavallee, P. Carbohydr. Res. 1972, 24, 45-56. (b) Jaseer, E. A.; Naidu, A. B.; Kumar, S. S.; Rao, R. K.; Thakur, K. G.; Sekar, G. Chem. Commun. 2007, 867-869. 92 (a) Middleton, W. J. J. Org. Chem. 1975, 40, 574-578. (b) Pacheco, M. C.; Purser, S. Gouverneur, V. Chem. Rev. 2008, 108, 1943-1981. 93 (a) Shandala, M. Y.; Waight, E. S.; Weinstock, M. J. Chem. Soc. B, 1966, 590-592. (b) Zhang, Q.; Mixdorf, J. C.; Reynders, G. J., III; Nguyen, H. M. Tetrahedron 2015, 71, 5932−5938. (c) Mixdorf, J. C.; Sorlin, A. M.; Zhang, Q.; Nguyen, H. M. ACS Catal. 2018, 8, 790-801. 94 Cavallo, G.; Metrangolo, P.; Milani, R.; Pilati, T.; Priimagi, A.; Resnati, G.; Terraneo, G. Chem. Rev. 2016, 116, 2478-2601. 95 Thirsk, C.; Whiting, A. J. Chem. Soc., Perkin Trans. 1, 2002, 999-1023. 96 (a) Dalko, P. I.; Moisan, L.; Cossy, J. Angew. Chem. Int. Ed. 2002, 41, 625-628. (b) Tiefenbacher, K.; Arion, V. B.; Mulzer, J. A Angew. Chem. Int. Ed. 2007, 46, 2690-2693. (c) Zhang, M.; Jiang, H.-F.; Neumann, H.; Beller, M.; Dixneuf, P. H. Angew. Chem. Int. Ed. 2009, 48, 1681–1684. (d) Brandt, D.; Bellosta, V.; Cossy, J. Org. Lett. 2012, 14, 5594-5597. 97 Cherkaoui, H.; Soufiaoui, M.; Grée, R. Tetrahedron 2001, 57, 2379-2383. 98 Barluenga, J.; Fañanás, F. J.; Sanz, R.; García, F.; García, N. Tetrahedron Lett. 1999, 40, 4735-4736. 99 (a) Grotjahn, D. B.; Larsen, C. R.; Gustafson, J. L.; Nair, R.; Sharma, A. J. Am. Chem. Soc. 2007, 129, 9592-9593. (b) Larionov, E.; Lin, L.; Guénée, L.; Mazet, C. J. Am. Chem. Soc. 2014, 136, 16882-16894. (c) Crabtree, H. R. The Organometallic Chemistry of the Transition Metals; John Wiley & Sons, Inc.: New Haven, CT, 2014; p 229-231. (d) Sommer, H.; Juliá- Hernández, F.; Martin, R.; Marek, I. ACS Cent. Sci. 2018, 4, 153-165. (e) Kapat, A.; Sperger, T.; Guven, S.; Schoenebeck, F. Science, 2019, 363, 391-396. (f) Kathe, P.; Fleischer, I. ChemCatChem 2019, 11, 3343–3354.