Palladium(II)-Catalysed Heck and Addition Reactions

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 221

Exploring Decarboxylative and Desulfitative Processes

BOBO SKILLINGHAUG

ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9717-0 UPPSALA urn:nbn:se:uu:diva-304746 2016 Dissertation presented at Uppsala University to be publicly examined in B21, BMC, Husargatan 3, Uppsala, Friday, 25 November 2016 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor Antonio de la Hoz Ayuso (Universidad de Castilla-La Mancha).

Abstract Skillinghaug, B. 2016. Palladium(II)-Catalysed Heck and Addition Reactions. Exploring Decarboxylative and Desulfitative Processes. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 221. 100 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9717-0.

Palladium complexes have the ability to catalyse cross-coupling of two organic moieties through the formation of transient metal-carbon bonds, thus bringing them closer to each other to facilitate the formation of a new bond. Palladium-catalysed coupling reactions are one of the most important carbon-carbon forming reactions available to organic chemists and many of these reactions rely on the reactivity of aryl-palladium complexes. The investigation of new aryl-palladium precursors is thus of great interest, especially as more sustainable and economic methods can be developed. This thesis describes the use of carboxylic acids and sodium arylsulfinates as such new arylating agents. Protocols for microwave-assisted palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes and 1,1-diarylethenes were developed. However, these transformations had very limited substrate scopes which prompted the investigation of sodium arylsulfinates as alternative arylating agents. These substrates were employed in the microwave- assisted palladium(II)-catalysed desulfitative addition to nitriles, and the substrate scope was demonstrated by combining a wide array of sodium arylsulfinates and nitriles to yield the corresponding aryl ketones. The application of the desulfitative reaction in a continuous flow setup was demonstrated, and aluminium oxide was identified as safe alternative to borosilicate glass as a reactor material. The mechanisms of the decarboxylative and desulfitative transformations were investigated by density functional theory (DFT) calculations. The desulfitative reaction was also investigated by direct electrospray ionization mass spectrometry (ESI-MS), providing further mechanistic insight. Finally, a protocol for the safe and convenient synthesis of a wide range of sodium arylsulfinates was developed.

Keywords: Palladium, catalysis, palladium(II) catalysis, synthesis, Heck, carboxylic acid, sulfinic acid, sodium sulfinate, nitrile, styrene, ketone, aryl ketone, electrospray ionization mass spectrometry, density functional theory, microwave heating, continuous flow

Bobo Skillinghaug, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry, Box 574, Uppsala University, SE-75123 Uppsala, Sweden.

ISSN 1651-6192 ISBN 978-91-554-9717-0 urn:nbn:se:uu:diva-304746 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-304746)

May you live in interesting times

List of Papers

This thesis is based on the following papers, which are referred to in the text by their Roman numerals.

I Fardost, A.,† Skillinghaug, B.,† Svensson, F.,† Wakchaure, P., Wejdemar, M., Larhed, M., Sköld. C. (2016) Mechanistic In- vestigation of Palladium(II)-Catalyzed Decarboxylative Synthe- sis of Electron-Rich Styrenes and 1,1-Diarylethenes. Manu- script. II Skillinghaug, B., Sköld., C., Rydfjord, J., Svensson, F., Beh- rends, M., Sävmarker, J., Sjöberg, P. J. R., Larhed, M. (2014) Palladium(II)-Catalyzed Desulfitative Synthesis of Aryl Ke- tones from Sodium Arylsulfinates and Nitriles: Scope, Limita- tions, and Mechanistic Studies. J. Org. Chem., 79, 12018−12032. III Skillinghaug, B., Rydfjord, J., Sävmarker, J., Larhed, M. (2016) Microwave Heated Continuous Flow Palladium(II)- Catalyzed Desulfitative Synthesis of Aryl Ketones. Org. Pro- cess Res. Dev., Under revision. IV Skillinghaug, B., Rydfjord, J., Odell, L. (2016) Synthesis of Sodium Aryl Sulfinates from Aryl Bromides Employing 1,4- Diazabicyclo[2.2.2]octane Bis(sulfur dioxide) Adduct (DAB- SO) as a Bench-stable, Gas-free Alternative to SO2. Tetrahe- dron Lett., 57, 533-536.

†These authors contributed equally.

Reprints were made with permission from the respective publishers.

Author Contribution Statement

The following contributions to the papers included in this thesis were made by the author:

I Performed preparative work and characterisation of compounds, performed single point energy calculations, collated experimental data and contributed significantly during the manuscript preparation. II Performed the majority of the preparative work and characterisation of compounds, aided in the design of and participated in the electrospray ionisation mass spectrometry (ESI-MS) study, collated experimental data and drafted the manuscript. III Performed the optimisation work and synthesised the majority of the compounds, collated experimental data and contributed significantly during the manuscript preparation. IV Performed the optimization work, the majority of the preparative work and characterisation of compounds, collated experimental data and drafted the manuscript.

Contents

Introduction ...... 11 Synthetic Organic Chemistry ...... 11 Catalysis ...... 13 Palladium Catalysis ...... 14 Palladium-Catalysed Cross-Coupling Reactions ...... 16 The Mizoroki-Heck reaction ...... 19 Palladium(II) Catalysis ...... 21 The Oxidative Heck Reaction ...... 22 Palladium-Catalysed Addition Reactions ...... 25 Metal-Catalysed Decarboxylative Reactions ...... 26 Sulfinic Acids and Metal-Catalysed Desulfitative Reactions ...... 28 Density Functional Theory ...... 31 Microwave-Assisted Organic Synthesis ...... 32 Continuous Flow Chemistry ...... 34 Electrospray Ionisation Mass Spectrometry ...... 35 Research Aims ...... 37 Palladium(II)-Catalysed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1-Diarylethenes (Paper I) ...... 38 Background ...... 38 Optimisation of Reaction Conditions for the Synthesis of Styrenes ...... 39 Investigation of the Scope of the Palladium(II)-Catalysed Decarboxylative Synthesis of Styrenes ...... 44 Investigation of the Reaction Mechanism using Density Functional Theory ...... 45 Palladium(II)-Catalysed Decarboxylative Synthesis of 1,1- Diarylethenes ...... 48 Palladium(II)-Catalysed Desulfitative Addition of Sodium Arylsulfinates to Nitriles (Paper II-III) ...... 51 Background ...... 51 Initial Investigation ...... 51 Optimisation of Reaction Conditions for the Synthesis of Aryl Ketones ...... 53 Investigation of the Reaction Mechanism using Electrospray Ionisation Mass Spectrometry ...... 55

Investigation of the Reaction Mechanism using Density Functional Theory ...... 56 Investigation of the Scope of the Microwave-Assisted Organic Synthesis of Aryl Ketones ...... 60 Continuous Flow Microwave-Assisted Organic Synthesis of Aryl Ketones ...... 65 Synthesis of Sodium Arylsulfinates Using a Solid Source of Sulphur Dioxide (Paper IV) ...... 72 Background ...... 72 Development of the Protocol ...... 73 Investigation of the Scope of the Synthesis of Sodium Arylsulfinates .... 73 Conclusions ...... 77 Acknowledgements ...... 79 References ...... 82

Abbreviations

TFA Trifluoroacetic Acid NMR Nuclear Magnetic Resonance GC-MS Gas Chromatography Mass Spectrometry ESI-MS Electrospray Ionisation Mass Spectrometry DBA Dibenzylideneacetone THF Tetrahydrofuran DMF Dimethyl formamide NMP N-methyl pyrrolidone DMSO Dimethyl sulfoxide DFT Density functional theory Ar Aryl CF Continuous flow CF-MAOS Continuous flow microwave-assisted organic synthesis TS Transition state p-BQ Para-benzoquinone TEMPO 2,2,6,6-tetramethylpiperidine-1-oxyl HPLC High Performance Liquid Chromatography or High Pressure Liquid Chromatography EDG Electron donating group LC Liquid chromatography UV Ultra violet

Introduction

Synthetic Organic Chemistry Organic chemicals were once believed to possess a vital force, which could only be imbued by living organisms. This mainstream theory, called vitalism, was effectively disproved in 1828 when Wöhler chemically synthesised urea without the need of a living kidney.1 Since then, the field of organic chemistry has flourished, leading to numerous important discoveries of novel compounds and materials prepared through abiotic chemical reactions. Today organic chemistry has been re-defined as the science regarding all carbon based molecules (without the influence of vitalism).2 Synthetic organic chemistry is the art of constructing such carbon-based organic molecules from smaller building blocks. These new organic molecules are formed through chemical transformations that are often performed in sequence and in a specific order. A schematic synthetic route from simple building blocks a more complex structure is illustrated in Figure 1. Reactions that form new carbon-carbon bonds are of particular interest as tools in synthetic organic chemistry and ever since the first carbon–carbon bond formation performed by Kolbe in 1845 in the synthesis of acetic acid, carbon– carbon bond-forming reactions have had a profound role in the evolution of chemical synthesis.3 Years of development have now provided organic chemists with a variety of reactions, enabling the construction of complex structures from relatively simple building blocks. The development of new such tools is often referred to as method development, and involves the ex- ploration of a certain transformation, especially with regards to investigation of the synthetic scope and limitations. A significant part of method development is the optimisation of the conditions for a transformation with regards to the selectivity and yield of the desired product.

Figure 1. Schematic synthesis of complex structures from simple building blocks.

11 Synthetic organic chemistry has come to include parts of organometallic chemistry, which is the study of compounds that include carbon-metal bonds. In the synthesis of organic molecules these carbon-metal bonds can often be transient, yet responsible for the desired chemical transformations. An important subset of organometallic chemistry is metal-mediated synthetic organic chemistry. Metal-mediated synthetic organic chemistry has become very important in this context through the development of transition metal- mediated cross-coupling reactions. A schematic representation of a metal- mediated cross-coupling reaction is shown in Figure 2.

Figure 2. Schematic representation of a metal-mediated cross-coupling reaction, a process where a metal successively forms transient metal-carbon bonds with two organic moieties, thus bringing them in close proximity to each other to facilitate the formation of a new bond.

The first metal-mediated coupling reactions ever reported were performed by Glaser in 1869 and involved the copper- and silver-mediated homocoupling of acetylenes.4 Half a century later, Ullmann developed homocoupling of ortho-halo-nitrobenzenes mediated by super-stoichiometric amounts of copper.5 In 1855 Wurtz6,7 demonstrated the sodium-mediated homodimerisation of alkyl halides, later extended in 1862 by Fittig8 to include aryl halides. However the high reactivity of sodium limited its synthetic utility, leading to the investigation and development of the less nucleophilic magnesium-based Grignard reagents.9 Early metal-promoted coupling reactions were non- catalytic, poorly selective and limited to homocoupling. Arguably, the Gri- gnard reaction remains one of the most important carbon-carbon forming tools at the chemist’s disposal to make new organic compounds. The reactivity of Grignard reagents stems from the highly polarised magnesium-carbon bond that allows them to react readily with a wide range of electrophiles. During the early days of the last century the use of organolithium reagents also became an essential part of the organic chemist’s toolbox. Undoubtedly, these reagents are of great importance in synthetic organic chemistry and have been exploited in this thesis.

12 The focus of this thesis is on synthetic organic chemistry and method development in the context of transition metal catalysis, and more specifically palladium(II) catalysis, to expand its applicability and scope. Over the past few decades, three major waves of synthetic development have occurred in the field of transition metal catalysed cross-coupling reactions. The first wave of discovery involved the use of different metals such as copper, silver, nickel and palladium as the catalyst. In the following wave of discoveries various coupling partners were investigated, and lastly, the scope of such reactions was progressively widened.10 Some of these important discoveries will be discussed herein.

Catalysis The term catalysis was introduced by Berzelius in 183511,12 and describes the phenomenon where a chemical entity (catalyst) lowers the energy barrier for a reaction and thus increases the rate of a reaction without being consumed itself. All life on earth is dependent on catalysis as the chemical reactions that take place in biological systems are often transformations catalysed by enzymes. Catalytic processes can either occur at the interface between two phases (heterogeneous) or in one phase, most often a solution (homogenous). A schematic mechanism of a catalytic process is illustrated in Figure 3 and the energy diagram is presented in Figure 4.

Figure 3. Schematic representation of a catalytic process, more specifically a metal- catalysed cross-coupling reaction.

One of the most recognised examples of catalysts are the catalytic converters used in the automobile industry to convert harmful pollutants into less toxic substances. These are heterogeneous catalysts (e.g. solid platinum or a com- bination of palladium and rhodium) and function by lowering the activation energies for the reduction of nitrous oxides, oxidation of carbon monoxide to carbon dioxide and combustion of unburnt hydrocarbons.13 Similarly, the same principle can be used to lower the activation energies for different transformations in synthetic organic chemistry.

13 Figure 4. A non-catalysed and a catalysed process, leading to the same product. The catalyst (metal) lowers the energy barrier for the reaction and thus increases the rate of the reaction without being consumed itself.

The Haber-Bosch process uses a heterogeneous catalyst to enable the reaction of atmospheric nitrogen with hydrogen to produce ammonia.14 This chemical transformation allows artificial fixation of nitrogen and represents the most important source of fertiliser world-wide. The drastic increase in the world population during the last 50 years has in part been accredited to the Haber-Bosch process, due to its impact on agriculture.15,16 In fact, it has been estimated that 80% of the nitrogen in the proteins of an average human originates from this process.17

Palladium Catalysis The focus of this thesis is on homogeneous palladium(II)-catalysed Heck and addition reactions but a brief introduction to certain palladium(0)- catalysed reactions that are of particular relevance to the work described herein will be given. The historical, mechanistic, theoretical, and practical aspects of palladium-catalysed carbon-carbon bond forming reactions have been immensely discussed in the literature, and the reader is referred to the books18–21 and reviews3,10,22,23 covering this well-established field for a comprehensive overview. Palladium is a late transition metal first discovered in 1803 by Wollaston as an impurity in platinum.24 It took more than 150 years before its usefulness began to be realised when PdCl2 was exploited in the catalytic transformation of ethene to ethanal in a reaction now known as the Wacker process.25 One of the properties that makes palladium such a useful element in

14 catalysis is that it can relatively easily switch between the oxidation states 0 and +II. Palladium has a relatively high electronegativity (2.2 on the Pauling scale) and forms a relatively non-polar palladium-carbon bond. Also, palladium is relatively soft due to shielding of the nuclear charge by the 10 or 8 d-electrons (for palladium(0) or palladium(II), respectively). In addition, the relatively large van der Waals radius promotes formation of bonds with soft π- and σ-donors. Due to these properties, and to the closely lying highest occupied molecular orbital (HOMO) and lowest unoccupied molecular orbital energies (LUMO), palladium is predisposed to undergo concerted reactions and displays lower reactivity than many other organometallic species toward polar functional groups such as ketones. Palladium prefers the formation of tetrahedral d10 and square planar d8 complexes.26 Importantly, palladium catalysis has provided chemists with the ability to forge carbon-carbon bonds between or within functionalised and sensitive substrates, leading to new opportunities in many fields of research. In modern days many important industrial processes rely on heterogenous palladium-based catalysts, while homogenous catalysts have become exceedingly important in chemical research for the formation of new carbon-carbon bonds, especially in drug discovery.23 Indeed, palladium has a wide array of applications - ranging from the use as a building block in optoelectronics,27 nanoelectronics,28,29 fuel cells,30 solar cells,31 cancer treatment,32 photogra- phy,33 to the use as a catalyst in the preparation of fine chemicals23,34 and pharmaceuticals23,35. Palladium-catalysed cross-couplings have a wide scope with regards to forming carbon-carbon bonds with exceedingly high selectivity, and this has been exploited in the total synthesis of complicated molecules.3 Since the early development of cross-coupling reactions, the use of palladium as a catalyst has competed with more cost-effective metals like copper and iron. However, due to the properties described above, palladium catalysis retains certain advantages such as enabling the conversion of less reactive substrates, better performance at relatively low temperatures and high catalyst turn-over numbers. The reactivity of the palladium catalyst can also be modulated by ligands since the polarity of the carbon-palladium bond can be tuned by coordinating species. The importance of palladium catalysis as a synthetic tool to make new compounds is illustrated by the fact that Richard Heck, Akira Suzuki and Ei- ichi Negishi were awarded the Nobel prize in 2010 for their contribution to the development of palladium catalysis.10

15 Palladium-Catalysed Cross-Coupling Reactions After being instructed at the Hercules Powder Company to “do something with transition metals”,36 Heck commenced his pioneering work and reported seven back-to-back articles on palladium-mediated reactions in 1968,37–43 including one of the first palladium-catalysed arylations of olefins (see Scheme 1).38 This reaction employed toxic arylmercury chlorides as arylating agents and used CuCl2 as a catalytic reoxidant together with oxygen as the terminal reoxidant. Fujiwara independently converted the previously stoichiometric arylation of olefins into a catalytic process, using silver acetate as the reoxidant.44 This type of palladium(II)-catalysed reaction is often referred to as the oxidative Heck reaction and is discussed in more detail in later chapters.

Scheme 1. Catalytic arylation of methyl acrylate reported by Heck.

The arylation of olefins was further developed independently by Mizoroki45 and Heck46 in 1971-1972 into a protocol that employed aryl iodides instead of the toxic arylmercury chlorides. Furthermore, the use of a base to regen- erate the palladium(0) catalyst obviated the need for an oxidant. During the same period Kumada47 and Corriu48 independently discovered that aryl Gri- gnard reagents could be used in the nickel-catalysed cross-coupling of olefinic halides, a reaction which was later translated into the corresponding palladium-catalysed process.49,50 The cross-coupling with nucleophiles was further developed by Negishi who was able to employ less reactive zinc reagents.51 In 1975 Sonogashira and Hagihara reported an elegant protocol for the direct use of alkynes via the corresponding cuprates formed in situ in the palladium-catalysed coupling with aryl halides.52 During the following dec- ade, several variations of the palladium-catalysed cross-coupling reaction using different coupling reagents such as stannanes (Stille-Migita),53,54 boronic acids (Suzuki-Miyaura)55,56 and silanes (Hiyama-Hatanaka)57 were developed. An overview of the most important palladium-catalysed cross- coupling reactions is shown in Scheme 2.

Scheme 2. Selected examples of palladium-catalysed cross-coupling reactions.

Although the Stille-Migita reaction has a very wide substrate scope and is probably the most powerful cross-coupling tool available, its usefulness is reduced by the need for toxic stannanes that also complicate purification. Conversely, the Suzuki-Miyaura reaction uses relatively environmentally benign boron compounds as substrates and has emerged as one of the most important tools in both synthetic organic chemistry and medicinal chemistry.58 Though the details of the mechanisms of the palladium-catalysed cross- coupling reactions in Scheme 2 vary in many different aspects, these coupling reactions share certain fundamental processes. The steps involved in the palladium cross-coupling reaction are illustrated in the general catalytic cycle in Scheme 3, and involves three major steps: oxidative addition, transmetalation and reductive elimination. Many palladium(0)-catalysed reactions are performed using palladium(II) salts that are reduced in situ to generate a complex where the palladium atom has the oxidation state 0. The palladium centre in these complexes prefers coordination to four ligands that each contribute two electrons to form a stable tetrahedral 18 electron complex. In solution, the loss of two neutral ligands (e.g. phosphines) leads to the formation of a catalytically active low coordinate d10 14 electron palladium complex to which an electrophile can undergo addition.59 Each catalytic cycle is initiated by the oxidative addition of an organohalide (I, Br, Cl) or pseudohalide (e.g. triflate, diazonium salt, tosylate), through the cleavage of a covalent C-X bond by a palladium(0) species. This generates an organo– palladium species and as implied by the name of the transformation, the oxidation state of palladium is in turn increased to +II. Bulky ligands dissociate more readily and thus promote oxidative addition due to the increased

17 concentration of the low coordinated palladium complex.60 It should be noted that alkyl halides that contain -hydrogens are often incompatible substrates due to rapid -hydrogen elimination and most cross-coupling reactions have been limited to aryl or vinyl halides (although examples of alkyl- alkyl cross-coupling reactions do exist).61–65

0 Pd L4 R X 0 Pd L2

Reductive Oxidative Elimination Addition

II II L2RPd L2XPd Trans- metalation

MX M R Scheme 3. General mechanism for palladium-catalysed cross-coupling reactions.

Following oxidative addition, a second organyl group is introduced to the palladium catalyst via transmetallation from an organometallic reagent to give the corresponding diaryl, aryl-alkenyl or aryl-alkynyl palladium(II) complex. The driving force for the transmetallation is the formation of a more stable and generally less polarised carbon-metal bond. Thus, transmetalation occurs more readily for organometals or organometalloids (Mg, Cu, Zn, Sn, B or Si) that contain elements with low electronegativity relative to palladium.66,67 In the last step of the catalytic cycle, the organyl groups must be oriented in a cis fashion and rearrangement occurs through a migration of one of the organyl groups. Through reductive elimination a new -bond is formed between the two organic palladium(II)-coordinating groups and the catalyst is reduced back to the original active palladium(0) complex.68

18 In traditional cross-coupling reactions, a nucleophile (e.g. an organometallic reagent) is coupled with an electrophile (e.g. an aryl halide) which acts as an organic oxidant that is included in the product. In oxidative coupling reactions, such as the oxidative Heck reaction, two nucleophiles are coupled and the reaction usually requires a terminal oxidant, which is not included in the final product. There is also an emerging field of reductive cross-coupling reactions, where the coupling between two electrophiles is facilitated by the use of a terminal reductant (see Scheme 4).

Scheme 4. Principal difference between traditional, oxidative and reductive cross- coupling reactions.69

The Mizoroki-Heck reaction Like the palladium(0)-catalysed cross-coupling reactions described above, the Mizoroki-Heck reaction45,46 proceeds via an initial oxidative addition. However, an organometallic reagent is not required to introduce the second organyl group as the Mizoroki-Heck reaction does not involve a transmetallation step.45,46 Instead, an olefin coordinates to the aryl-palladium intermediate to give a π-complex, followed by carbopalladation of the olefin (see Scheme 5). The palladium intermediate adds to the double bond through a concerted syn-insertion process (migratory insertion) forming a new carbon- carbon bond and a -complex is generated. Migratory insertion can either occur at the terminal or internal carbon of substituted olefins leading to the formation of the linear or branched product.

Scheme 5. Mechanism of the neutral Mizoroki-Heck reaction resulting in internal or terminal arylation.

Supposing that there is a vacant coordination site on the metal centre, an internal rotation of the Cα–Cβ bond with respect to palladium positions a - hydrogen syn to the metal centre. Subsequently, elimination of the - hydrogen generates a palladium hydride complex coordinated to the product.22,70–72 The product is released by reversible dissociation from the palladium hydride complex. Analogously to the cross-coupling reactions, the catalytically active palladium(0) complex is regenerated in the last step. However, this is achieved through a base-mediated removal of a proton from the palladium hydride complex instead of a reductive elimination. The palladium hydride complex needs to be quickly scavenged by a base after release of the product or addition to the product or the starting olefin can lead to double bond migration or double bond isomerisation (see Scheme 6). 22,70–73

Scheme 6. Double bond migration by re-addition and elimination of palladium hydride.

As mentioned above, the Mizoroki-Heck reaction can either result in terminal or internal arylation of the olefin, depending on the position in which insertion occurs. The regioselectivity of the insertion is dependent on the electronic and steric properties of the π-complex74,75 and the outcome of the reaction depends on the ligand,76 the solvent77 and the substrates78 used. Electron-poor olefins favour terminal arylation since the internal carbon is more electron-rich and coordinates the palladium centre more strongly. In addition, the -complex leading to terminal arylation is also sterically favoured.73,74,79,80 Electron rich substrates generally result in mixtures of the internal and terminal arylation products due to competing electronic and steric factors. In this case, migratory insertion to form the internal - complex is electronically favoured but sterically disfavoured.

Palladium(II) Catalysis Several important processes that rely on palladium(II)-catalysed transformations such as the synthesis of vinyl acetate from ethylene and acetic acid,81 the previously mentioned Wacker process82 and the oxidative Heck reaction37 were discovered over 50 years ago. However, the requirement of a stoichiometric amount of palladium or a palladium reoxidant in many palladium(II)-mediated reactions hampered further development of these processes.83 Instead, research was focused on palladium(0) catalysis which has en- joyed considerable development during the last part of the 20th century. Alt- hough palladium(II)-catalysed reactions have received relatively little attention in the academic literature until recently, there has now been a revival in the field of palladium(II)-catalysis fueled by the demand for more environmentally benign and sustainable methods as more benign substrates can potentially be employed. Palladium(II) catalysis is distinguished from palladium(0)-catalysed cross-coupling reactions in the way that the transition metal enters the catalytic cycle. Whereas the first step in the palladium(0) catalytic cycle is an oxidative addition of an aryl halide or pseudohalide, the first step in the corresponding palladium(II) catalytic cycle is an electrophilic palladation,44,84–88

21 a decarboxylation,89,90 desulfination91–93 or an organyl transmetalation of an arylmetal or arylmetalloid such as mercury,37 boron,94 tin,95 silicon,96 anti- mony97 or phosphorous98. Recently, considerable efforts to obtain the key organopalladium species by direct C-H activation has been demonstrated. Although this strategy is desirable from an economic and sustainability perspective, cross-coupling reactions generally display higher regiocontrol. The remaining steps are analogous to palladium(0)-catalysed reactions except the regeneration of the active catalyst where many palladium(II)- catalysed reactions require stoichiometric amounts of a reoxidant. Many 99–101 102–104 105 different oxidants such oxygen, para-benzoquinone, MnO2, desyl chloride,106 TEMPO,101 copper82 and silver89 salts, and peroxides101 can be used. However, the use of copper or silver salts is expensive, TEMPO and desyl chloride are also relatively expensive and para-benzoquinone is toxic. Additionally, the use of reoxidants produces stoichiometric amounts of waste which contributes to poor sustainability and can often complicate purification. However, there are palladium(II)-catalysed cross-coupling reactions acting through different mechanisms where the product releasing step does not produce metallic palladium or palladium hydride.107–109 Therefore, these reactions do not require an oxidant making them highly desirable. The use of more effective ligand and reoxidation systems has addressed the major problems associated with palladium(II) catalysis, allowing the use of catalytic amounts of palladium.100,110–113 The most common arylating agents used in palladium(II) catalysis are aryl boronic acids since these are widely commercially available, tolerate a broad variety of functional groups and are relatively environmentally benign. However, the shelf life of aryl boronic acids is limited due to protodeborona- tion and to the formation of trimeric cyclic anhydrides. Further, the handling of certain boronic acids is not convenient due to their waxy appearance.114 Consequently, there is great interest in developing new protocols employing alternative aryl-palladium precursors.

The Oxidative Heck Reaction As described above, the pioneering work of Nobel Prize laureate Richard Heck in the field of palladium-promoted carbon-carbon coupling reactions was initially focused on the use of palladium(II) transformations.38 Inde- pendently of Heck,37 Fujiwara and Moritani84–86 reported on the palladium(II)-catalysed direct arylation of olefins with benzene using silver acetate as an oxidant in 1968.44 The palladium(II)-catalysed reactions were developed over time and Heck demonstrated that organoboron substrates could be used in the palladium(II) mediated reaction with alkenes, although stoichiometric amounts of 94 Pd(OAc)2 were required. Uemura later developed the first catalytic example of the oxidative Heck reaction using boronic acids for the arylation of

22 alkenes, although the mechanism originally suggested included the oxidative addition of palladium(0).115 Similar oxidative Heck reactions of organoboron reagents with alkenes and alkynes could be performed using Cu(OAc)2 as the oxidant.116 This development to render the reaction catalytic by inclusion of an oxidant suggested that the organopalladium species at the beginning of the catalytic cycle is formed through transmetallation. Subsequently, several different oxidant systems and arylating agents have been investigated.89,98,117 Notably, in 2003 the use of oxygen as the sole oxidant in the oxidative Heck reaction was developed which represents a more sustainable protocol than previous examples.99,100

Scheme 7. Mechanism of the cationic oxidative Heck reaction resulting in internal or terminal arylation.

The mechanism of the cationic oxidative Heck reaction is presented in Scheme 7. As in other palladium(II)-catalysed reactions the first step is an electrophilic palladation, a decarboxylation/desulfination or an organyl transmetalation. The subsequent steps are the same insertion and -hydride elimination processes as in the Mizoroki-Heck reaction. In contrast to the Mizoroki-Heck reaction, the active catalyst is generally regenerated by reoxidation of the palladium hydride intermediate.

The Mizoroki-Heck and the oxidative Heck reactions can proceed through either neutral (Scheme 5) or cationic (Scheme 7) pathways.80,118 The path-

23 way influences the regiochemical outcome of the reaction since the insertion step may be affected and result in different -complexes. The effect on regioselectivity is the same for the Mizoroki-Heck and oxidative Heck reaction since only the first step is different. Coordination of the olefin must be pre- ceded by the dissociation of a ligand. If a neutral ligand is dissociated the resulting -complex is neutral. However, if an anionic X ligand dissociated instead, the resulting -complex is cationic. Bidentate ligands are less likely to dissociate and thus favour a cationic reaction pathway. Weakly associated - - - anionic ligands such as OTf, O2CCF3 or OAc and polar solvents that assist in the exchange of the anionic ligands also favour a cationic mechanism. Analogously to the Mizoroki-Heck reaction, palladium insertion at the internal carbon is electronically favoured for electron-poor substrates but is less accessible due to unfavourable sterics. Conversely, palladium insertion at the terminal carbon is electronically favoured for electron-rich substrates and is more easily accessible. When electron-rich substrates are used, these factors compete and a mixture of the internal and terminal arylation products is often obtained. When the reaction operates through a cationic mechanism the electronic factor becomes more important and electron-rich substrates generally give predominantly the internal arylation product. The migratory insertion in the neutral and the cationic pathway is highlighted in Scheme 8.

Steric clash R R Ar Ar L Pd Ar L Pd X R X L R Neutral pathway Mixture of L Pd Ar R regioisomers X R Ar Ar L Pd Ar L Pd X R L X L L Pd Ar X

R L L L Ar L Pd Ar L Pd Ar L Pd X R Cationic pathway Ar R Steric R clash Scheme 8. Regioselectivity for electron-rich substrates in the oxidative Heck reaction acting through a neutral or cationic pathway.

-elimination from the palladium centre can also occur with heteroatom groups such as -OAc, -OH, -Br and -Cl. However, whereas -hydride elimination occurs in a syn fashion, -elimination of heteroatom groups occurs through a trans mechanism with the following relative rates: halide > -OAc > -OR > -OH. -elimination of a heteroatom group directly regenerates the

24 active palladium(II) catalyst which obviates the need for a stoichiometric amount of oxidant.107–109

Palladium-Catalysed Addition Reactions Despite the relatively non-polar metal-carbon bond, palladium shows some reactivity towards polar functional groups such as aldehydes and nitriles. The palladium-catalysed direct addition of boronic acids to aldehydes119 and conjugate addition to ,-unsaturated ketones120 has been reported. Formal addition-elimination reactions catalysed by palladium have been exploited in the synthesis of aryl ketones from in situ generated anhydrides from carboxylic acids and arylboronic acids.121–124 The palladium(II)- catalysed addition of boron compounds to alkynes and subsequent intramolecular cyclisation with esters has been reported.125 Interestingly, the direct palladium(II)-catalysed addition and cyclisation of alkynes containing an aldehyde, ketone, or nitrile functional group has also been demonstrated.126 Since the first report by Garves on the stoichiometric palladium-mediated addition of sodium sulfinates to nitriles in 1970, a considerable number of reports concerning the palladium-catalysed addition to nitriles has appeared in the literature.127 Larock has been especially active in the field, and has demonstrated the palladium-catalysed addition of aryl iodides to alkynes and subsequent cyclisation with a nitrile functionality to yield naphthylamines.128,129 This strategy was further expanded to give 2,3- diarylindenones by changing the substrate.130 Further, the synthesis of aryl ketones by palladium-catalysed addition of arylboronic acids131 or simple arenes132,133 to nitriles to give an intermediate ketimine134 and subsequent hydrolysis has been reported.132,135 Palladium-catalysed addition reactions of aryltrifluoroborates136 or arylcarboxylic acids136 to cyanamides results in the formation of amidines, which are less prone to hydrolysis and can be isolated in good yield. The palladium-catalysed addition of arylboronic acids to nitriles has also been exploited for subsequent formation of benzofurans.133 An overview of palladium-catalysed addition reactions is presented in Scheme 9.

Scheme 9. Principal palladium-catalysed addition reactions.

Metal-Catalysed Decarboxylative Reactions Highly activated carboxylic acids such as -oxo-acids, diphenylacetic acids, certain heterocyclic carboxylic acids, propiolic carboxylic acids and di-ortho substituted benzoic acids may protodecarboxylate spontaneously at moderate temperature or upon treatment with an acid. The decarboxylation of -oxo- acids has been exploited extensively as a textbook strategy for the synthesis of various organic compounds, especially via -alkylation of malonic esters (see Scheme 10).

Scheme 10. -Alkylation of a malonic ester and subsequent decarboxylation.

Although the ability of enzymes to catalyse the decarboxylation of a wide range of carboxylic acids has been used to some extent for the production of commodity chemicals,137 the use of metal catalysts is more convenient for the organic chemist. The first metal-mediated protodecarboxylation reactions were reported in 1901 by Pesci138 who employed mercury to effect the transformation, and later Shepard139 demonstrated the use of copper bronze or nickel in 1930. Subsequently, the corresponding silver-mediated decarboxylative process was reported.140,141 If protonolysis of the intermediate arylmetal species is avoided, it can be coupled with a carbon electrophile instead (see Scheme 11).

Scheme 11. Schematic metal-mediated decarboxylation and subsequent reactions.

In 1966, Nilsson developed a crossed Ullman type coupling reaction between aryl-copper reagents derived from ortho-nitrobenzoic acid and aryl iodides142 but the first highly useful protocol was achieved when the copper- mediated decarboxylation was combined with a palladium catalyst in the cross-coupling of benzoic acids and aryl bromides.143,144 However, stoichiometric amounts of Cu(II) salts were required until a catalytic Cu(I)-mediated system was developed. As described in previous chapters, there is great interest in developing new protocols employing alternative aryl palladium precursors. Decarboxy- lative metalation is a desirable strategy for the generation of aryl palladium intermediates in cross-coupling reactions since the only waste produced is carbon dioxide. Although decarboxylative processes are well-known, it was not until Myers developed the palladium-catalysed decarboxylative Heck reaction that it gained significant attention (Scheme 12).89,90 This reaction required high catalyst loading and used three equivalents of expensive silver salts as the reoxidant but was later developed to use para-benzoquinone as the palladium reoxidant.145

Scheme 12. The decarboxylative Heck reaction reported by Myers.

Since these early discoveries, different mono- and bimetallic palladium(II)- catalysed cross-coupling reactions of carboxylic acids have been developed.89,146,147 Some examples include non-oxidative Suzuki-Myaura and Sonogashira-Hagihara type cross-couplings,143,148,149 oxidative Suzuki- Myaura and Sonogashira-Hagihara type cross-couplings151,152 and oxidative Heck reactions.90,145,150–153 The scope of palladium-catalysed decarboxylative reactions is limited to ortho substituted substrates.154 Theoretical investiga-

27 tions suggest that the carboxylic acid functionality must be orthogonal to the plane of the aromatic system in order for decarboxylative metalation to occur and the ortho substituents help force the carboxyl group into this confor- mation.155,156 A simplified representation of the palladium-catalysed decarboxylation mechanism is presented in Scheme 13.

Scheme 13. Simplified palladium-catalysed decarboxylation mechanism.

Bimetallic catalyst systems that exploit the decarboxylative activity of cop- per143,147 or silver157,158 and subsequent transmetalation of palladium to initate palladium-catalysed cross-coupling have been used to expand the scope of decarboxylative reactions.146,159–161 However, high loadings of copper or silver salts are generally required in these systems which detracts significantly from the main advantage of using carboxylic acids as arylating agents, namely the formation of CO2 as the only by-product.

Sulfinic Acids and Metal-Catalysed Desulfitative Reactions The properties and reactivity of sulfinic acids were first reported in the beginning of the 1900s.162–164 Sulfinic acids are also naturally occurring in biological systems as cysteine is reversibly oxidised to the corresponding sulfinic acid.165 Sulfinic acids are sensitive to oxidation to the corresponding sulphonic acids and disproportionation to form sulfinyl sulfones, and are therefore most commonly handled as their sodium salt, since these are generally less prone to undergo these unwanted reactions.166 Several synthetic approaches have been suggested for the production of sulfinic acids or sulfinate salts. The most common strategy is the reduction of sulfonyl chlorides. This can be achieved either in the presence of sodium sulphite to give the sodium sulfinate167 or by direct reaction of sulfonyl chlorides and zinc to give zinc bis(sulfinates)168,169. Other examples include palladium-catalysed coupling of diazonium tetrafluoroborates with sulphur dioxide and hydrogen gas,170 Friedel–Crafts sulfination with sulfonyl chlo- rides171 and the reaction between Grignard172,173 or organolithium reagents174 and sulphur dioxide. From a retrosynthetic perspective, these latter examples are the most straightforward approach to sulfinate salts but rely on the use of toxic and corrosive sulphur dioxide gas. Sulfinates are valuable precursors in organic synthesis and act as either electrophiles or nucleophiles through either a sulfonylative or desulfitative

28 process depending on the reaction conditions.175 An overview of selected examples of the reactivity of sulfinic acids and sulfinates is presented in Scheme 14. Sulfinates can form sulfonyl thioesters in the presence of thiols,176 sulfonyl cyanides in the presence of cyanogen chloride177 and they can react with dinitrogentetraoxide to form sulfonyl nitrites178. Sulfinic acids are readily reduced to disulfides,179,180 which is a key process in the sulfenylation of indoles by sulfinic acids in the presence of toluenesulfonic acid and 181 n-Bu4NI . Sulfinates can react directly with sulphur to form sodium me- thanethiosulfonate182 or can act as electrophiles in electrophilic aromatic substitution reactions to give the corresponding aryl sulfoxides upon treatment with trifluoromethanesulfonic acid.183 Desulfitative gem- difluoroolefination of aldehydes and ketones has been demonstrated via in situ generated sodium sulfinates.184 Sulfinates can also be exploited as a source of sulfonyl radicals. Sulfinates can be oxidised directly by TBHP185 or CAN186 and also react with iodine to form sulfonyl iodides that can be homolytically cleaved to form sulfonyl radicals187. Sulfinates spontaneously form radicals in DMSO which has been exploited in the metal-free decarboxylative coupling with cinnamic acids to form vinyl sulfones.188 Sulfinic acids react via a postulated radical mechanism with NBS to form sulfonyl bromides, which were exploited in the synthesis of β-bromo sulfones from sulfinic acids and styrenes.189

Scheme 14. Selected examples of reactions illustrating the various transformation that sulfinic acids and sulfinate salts may undergo.

Sulfinic acids or sulfinate salts can also undergo desulfitative metalation and subsequent coupling reactions. As described in the previous chapter, palladium-catalysed decarboxylative processes require the use of additional metal salts or ortho-substituted very electron-rich aromatic substrates. Sulfinates have emerged as a promising analogous alternative to these arylating agents

29 without the requirement for ortho substitution. The first desulfitative palladium-mediated reaction was reported in 1970127 but it was not until 2011 that the first catalytic examples appeared in the literature when Miao,91 Deng92 and Larhed93 independently reported on the palladium-catalysed addition of sulfinic acids or sodium sulfinates to nitriles. The latter report was a com- munication of the preliminary findings in the project discussed in Paper II. Since 2011, the use of desulfitative metalation has been extended to So- nogashira cross-coupling,190 Heck-type reactions,191–194 homocoupling,195 palladium catalysed phosphonation196 and conjugate 1,4-addition197,198. Se- lected examples of reported palladium-catalysed desulfitative reactions are shown in Scheme 15. Several examples of palladium-catalysed desulfitative cross-coupling reactions by C-H activation of azoles,199,200 indoles,201,202 coumarins194 and polyfluoroarenes203 have been reported. Though C-H activation is a desirable strategy in synthesis for economic and environmental reasons, cross-coupling reactions generally display superior regioselectivity.

Scheme 15. Selected examples of reported palladium-catalysed desulfitative reactions.

The simplified proposed mechanism for desulfination is analogous to the mechanism suggested for palladium(II)-catalysed decarboxylation and the acid functionality is expected to be orthogonal to the plane of the ring in the transition state (Scheme 16).204 The mechanisms of the desulfination and decarboxylation processes are investigated in detail in Paper II.

Scheme 16. Simplified desulfination mechanism.

The reader is referred to the comprehensive reviews that have been published recently for a full account of the applicability and synthesis of sulfinate salts.175,205,206

Density Functional Theory

Quantum mechanical calculations enable the study of the energies associated with chemical transformations of molecules by studying their electronic properties. Arguably, one of the most fundamental developments in computational chemistry was the development of the Hartree-Fock method that can be employed to iteratively solve the time-independent Schrödinger equation.207 Ab initio quantum mechanical computational methods, such as the Hartree-Fock method, are very time consuming as they are dependent on 3N spatial coordinates and N spin coordinates, where N is the number of electrons.

General time-independent Schrödinger equation:208 HΨ = EΨ

Instead of solving the Schrödinger equation, density functional theory (DFT) calculations aim to solve a corresponding equation for the electron density. Becke developed a hybrid theory by merging Hartree-Fock and DFT which has been instrumental in the development of DFT as the standard method for calculations (especially the B3LYP hybrid functional) used today.209–211 DFT calculations rely on basis sets that are mathematical functions typically rep- resenting atomic orbitals that are linearly combined to represent the molecular orbitals. Different numbers of basis functions for the core and valence electrons can be used in conjunction with additional functions to account for polarisation. Also, additional corrections for long range electron-electron interactions (dispersion) have been developed, providing better accuracy of the calculations.212 The computational details will not be covered herein, instead a brief description of the use of these methods as tools in synthetic organic chemistry will follow.

Figure 5. An energy minimum (right) and a saddle point or transition state (left) on potential energy surfaces.

The energy of a molecule can be represented by a potential energy surface which is the energy as a function of the geometry of the molecule. The bond lengths and angles between the atoms in a molecule are the dimensions and the geometry is a point in these dimensions. If only two bond lengths are considered, an analogy can be made with a landscape where directions (east- west and north-south) represent the bond lengths and the height corresponds to the energy. To map out the reaction mechanism the geometries of hypoth- esised intermediates are optimised and the energies are calculated. The optimisation of the geometry finds the closest energy minimum and all isomeric forms and conformations must be investigated in order to find the global energy minimum. The transition state in a reaction is the point with the highest energy along the reaction coordinate, but is an energy minimum in all other dimensions. In mathematical terms, the transition state is a saddle point on the potential energy surface (see Figure 5). Due to the rapid development of computers and processing speed, the study of more complex systems by computational methods has become possible, and these methods constitute important tools for theoretical investigations of reaction mechanisms.

Microwave-Assisted Organic Synthesis For centuries, chemists and alchemists alike relied on open fires as a source of heat for their chemical transformations. The Bunsen burner was invented in 1855213 and improved the temperature control and probably reduced the number of accidents in chemical laboratories. Most modern laboratories now use even safer sources of heating such as oil baths, metal heating blocks or electric mantles. However, the principle of all these methods is the same type of thermal heating where the inner wall of the reaction vessel heats the reaction mixture by conduction. This results in a temperature gradient where the reactor walls have a significantly higher temperature than the average temperature in the reaction mixture (although the gradient is often reduced

32 by stirring the reaction mixture). The different temperature profiles for heating a reaction vial with conventional heating and microwave heating is presented in Figure 6. The first reports on the use of microwaves in organic synthesis appeared in the 1980s and these reactions were performed in domestic microwave ovens.214,215 Since then dedicated microwave instruments have become commonplace in organic chemistry labs since they enable safe processing at elevated temperatures and pressures, and because of the generally reduced reaction times.216–220 An additional benefit of using microwaves as a source of heating is often increased yields.221–224 The higher selectivity that is sometimes observed in microwave-heated reactions can probably be attributed to more homogenous heating and avoiding the wall effects associated with conventional heating. Reactions can typically be performed at higher temperatures (above the boiling point of the solvent) and pressures when using dedicated microwave instruments since the reaction vessels are sealed systems. In the event of an explosion there is also a safety benefit of these systems as the temperature and pressure is monitored on-line and the reaction is performed in a purpose-built steel cavity.

Figure 6. Temperature profiles for heating a reaction vial with conventional heating (left) and microwave heating (right).222

Microwaves are electromagnetic radiation with frequencies of 0.3 to 300 GHz and the frequency used for heating is typically 2.45 GHz. This frequency has been assigned to avoid interference with radar and telecommunica- tions.223,225 Microwave radiation can transfer energy to molecules as heat through ionic conduction or dipolar polarisation. When an electromagnetic field is applied, ions start to oscillate through the solution and the kinetic energy of the ions is transformed into heat in the solution (see Figure 7). This phenomenon is referred to as ionic conduction. Dipoles also respond to electromagnetic fields and will rotate in order to adjust to the alternating electric field. If a suitable frequency is applied there

33 will be a phase difference between the dipoles and the electromagnetic field which causes constant rotation and conversion of kinetic energy into heat by friction and collision between molecules. This phenomenon is referred to as dipolar polarisation.225

+ - + -

Figure 7. Microwaves are electromagnetic radiation (left) that transfers energy to molecules as heat through ionic conduction (middle) or dipolar polarization (right).

How a given molecule is affected by the electromagnetic field depends on the dielectric constant (’), and the dielectric loss constant (’’) is a measure of how efficiently the microwave energy is transformed into heat for a given substance. The loss tangent (tan  = ’’/’) is dependent on these constants and is often used to describe the properties of materials in microwave fields and represents the ability of a specific substance to be heated by microwaves at a certain frequency and temperature.226,227

Continuous Flow Chemistry Continuous flow processes have been considered an emerging technology for many years, but have not been widely adopted by organic chemistry laboratories. One reason for this is likely the technological hurdle associated with using complicated flow chemistry setups. As commercial systems become more user-friendly and affordable they will likely become yet another routine tool for the synthesis of compounds in both academia and industry, especially since there are certain benefits over conventional batch synthesis. Better selectivity and higher yields compared to batch can sometimes be achieved when reactions are performed in continuous flow systems.228,229 This can be explained by the constant reaction environment as the product and any side products are instantly removed from the reactor. Also, the safety associated with continuous flow chemistry processes is an important benefit. Highly toxic or explosive reagents can be used or highly exothermic reactions can be performed at relatively low risk, as only a small amount of the reaction mixture volume is heated.228 Also, instead of performing the reaction on a larger scale, the reaction can be continuously performed for a longer time (scaled out).

34 Flow processes were early on adopted for industrial applications but it was not until the 1970s230 that examples of flow chemistry appeared in the academic literature. However, the field did not receive much interest except for the development of continuous flow peptide synthesis.231 Continuous flow systems currently used in academia are typically based on microfluidics and microreactors but some examples of flow systems that use larger reactors exist. Most commercial continuous flow systems that are available today rely on conductive heating via oil,232 air,233 electric re- sistance234 or induction235,236. Microwave technology enables rapid heating and has been applied in both stop-flow and continuous-flow setups.237–244 The use of microwave technology in flow chemistry was first reported by Strauss in 1994.245 These early continuous flow setups used modified batch microwave systems. Dedicated continuous flow microwave systems have since been developed that allow for efficient direct heating of the reaction mixture. High performance liquid chromatography (HPLC) pumps or syringe pumps are commonly used to move the reaction mixture through the reactor. Syringe pumps tolerate a higher amount of particles and the use of harsh reagents while HPLC pumps tolerate higher pressures. Peristaltic pumps are another alternative that even allow the use of slurries. The main drawback of using continuous flow methodologies is that homogenous reaction setups are often needed, especially when micro-reactors are used since the capillaries are easily blocked by particles.246

Electrospray Ionisation Mass Spectrometry Mass spectrometry (MS) is arguably one of the most important analytical technique available to chemists. Coupled with electrospray ionisation (ESI), which is a soft ionisation technique that only gives few fragmentation products, large and relatively sensitive molecules and complexes can be studied. Examples include biomolecules247,248 and organometallic species. ESI-MS is an especially useful tool to directly detect and study charged reaction intermediates.249–251 The ionisation method also allows for the study of species that are not inherently charged in the sample. Certain elements have characteristic natural isotopic distributions that can be exploited in the analysis of the mass spectra to identify ions of interest. Bromine and chlorine are typical examples of such elements that show characteristic patterns. Analogously, palladium also naturally exists as several different isotopes which can be exploited in the analysis of mass spectra of palladium complexes (see Figure 8). By systematic replacements of palladium ligands and substrates, the identity of the ions can be elucidated. The mechanisms of e.g. Mizoroki-Heck251–254 and Suzuki-Miyaura255,256 reactions

35 have been investigated by electrospray ionisation mass spectrometry (ESI- MS).

100 102 104 106 108 110 112 m/z Figure 8. Natural isotopic distribution of palladium.

Although ESI-MS enables the detection of short-lived and unstable reaction intermediates at very low concentrations, only ions formed in the ion source are observed and complexes that remain neutral cannot be detected. Intensities correlate with abundance in the mass spectrometer, not in the original sample and care should be taken during the interpretation of the spectra.

36 Research Aims

In diverse research fields, ranging from biology to the development of new display materials, there is an increasing demand for custom molecules. This is especially true in contemporary drug discovery and the search for novel molecular features as potential new pharmacophores. The high level of com- plexity of these organic compounds has fuelled immense effort in the development of novel synthetic methods to carry out specific transformations, including carbon-carbon bond forming reactions. The formation of new carbon-carbon bonds allows extension and decoration of a carbon framework, providing a robust and versatile synthetic platform in organic and medicinal chemistry. In the last few decades, tremendous advancements in carbon-carbon bond formations have been observed. The palladium-catalysed coupling reactions that were developed during the end of the last century are among the most important carbon-carbon forming reactions. Many of these reactions rely on the reactivity of aryl-palladium complexes and the investigation of new aryl- palladium precursors is thus of great interest.

The aims of this thesis were: to explore the use of carboxylic acids and sodium arylsulfinates as such new arylating agents, to develop new useful tools for the organic chemist that are convenient and robust, and to provide experimental and theoretical insight into the mechanisms of these reactions.

37 Palladium(II)-Catalysed Decarboxylative Synthesis of Electron-Rich Styrenes and 1,1- Diarylethenes (Paper I)

Background As described in previous chapters, decarboxylative metalation has emerged as an attractive alternative to boronic acids to generate the key aryl- palladium complex in palladium-catalysed reactions, and Myers developed the first decarboxylative Heck reaction in 2002 that used substituted benzoic acids as the arylating agent.89 The use of arylcarboxylic acids is desirable as the only byproduct from the aryl palladium precursor is CO2. In addition, carboxylic acids are less sensitive to air and moisture compared to many commonly used organometallic reagents. Unfortunately the scope for palladium-catalysed decarboxylative reactions is currently limited to ortho- substituted arylcarboxylic acids.154,155,257 Styrene is traditionally produced by dehydrogenation of ethyl benzene, catalysed by potassium-promoted iron oxide.258 Styrenes are mainly used for the production of polystyrene materials but are also useful substrates in Diels-Alder,259 oxidation260 and metathesis261 reactions. Due to the usefulness of styrenes, several palladium(0)-catalysed cross-couplings such as Hiyama-Hatanaku,262 Stille-Migita,263–265 Mizoroki-Heck76,266–270 and Suzuki- Miyaura271,272 reactions for the synthesis of styrenes have been developed. However, these approaches have some drawbacks – the Hiyama-Hatanaku coupling relies on expensive vinyl silanes, the stannanes used in the Stille- Migita reaction are toxic, the Mizoroki-Heck reaction uses flammable ethylene and the Suzuki-Miyaura reaction either relies on unstable vinyl iodide, vinyl tosylates that are not commercially available, or expensive trivinylcy- clotriboroxane. To address these economic, safety and environmental issues, an adapted decarboxylative protocol was envisioned using vinyl acetate, an inexpensive vinyl source that only generates acetate as the byproduct, based on a previously reported synthesis of styrenes using boron compounds and vinyl acetate.273

38 Thus, starting from the reaction conditions for a similar decarboxylative protocol for electron-rich olefins,274 a model reaction between 2,6- dimethoxybenzoic acid 1 and vinyl acetate 2 was conducted employing Pd(O2CCF3)2 and 6-methyl-2,2’-bipyridyl (8f) as the catalyst system. Analy- sis of the product mixture by GC-MS showed formation of the desired styrene product 3 but also revealed the formation of several side products (see Scheme 17).

Scheme 17. Products observed by GC-MS during the initial reaction.

Optimisation of Reaction Conditions for the Synthesis of Styrenes An optimisation study was undertaken to investigate the reaction conditions to improve the selectivity and productivity of the desired styrene product 3. The reaction outcome was monitored by GC-MS of the product and side products in the reaction mixture. The ratio between the integral for products 3a-7a and the internal standard (2,3-dimethylnaphthalene) was used to gauge the conversion. In conjunction, the conversion of the arylcarboxylic acid starting material 1a was monitored by LC-UV (254 nm) by comparing the integral to that of the internal standard. All optimisation reactions were carried out using Pd(O2CCF3)2 as the pre-catalyst and 6-methyl-2,2’- dimethylbipyridine (8f) as the bidentate ligand unless otherwise specified. An extensive solvent survey was carried out and the stoichiometry of 2 proved to be important for the generation of 3a. The optimal solvent system included 2 in a large excess as part of the solvent system (see Figure 9). Se- lected reactions performed in solvent systems that provided promising selectivity were repeated without an internal standard and the product was isolated by column chromatography. Encouragingly, the reaction performed in vinyl acetate (2):DMF 3:1 gave 68% isolated yield of the desired styrene product 3a.

3a 1a 4a+5a 6a 7a 1,2

65%a 0,8 68%a

0,6

0,4 Compound/IS ratio Compound/IS 0,2

0 O 2 H NMP THF DMF Neat 2a (75:25) 2a/DMF Dioxane DMF/DMSO No (95:5), 8f Figure 9. Selected results from the screening of solvent systems for the palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes. The propor- tions of the solvent systems are based on the volume. aIsolated yield.

The impact of the addition of an acid or the corresponding base was investigated. The addition of trifluoroacetic acid (TFA) or sodium trifluoroacetate (NaO2CCF3) in the reaction mixture did not significantly improve the reaction outcome. However, the use of 10% sodium trifluoroacetate led to increased inhibition of side product formation and slightly higher selectivity for 3a was observed. Thus, 10% sodium trifluoroacetate was included in subsequent reactions. Next, twelve different palladium salts and complexes were investigated as the palladium source for the reaction together with 8f as the ligand (see Fig- ure 10). Although no specific trend regarding the choice of pre-catalyst concerning the reaction outcomes could be discerned, the use of Pd(O2CCF3)2, Pd(OAc)2 and tetrakis(MeCN)Pd(BF4)2 provided the highest amounts of 3a as determined by GC-MS.

40 0,9 3a 4a + 5a 6a 7a 52%a 0,8 70%a a 0,7 68% 0,6 0,5 0,4 0,3 0,2 Compound/IS ratio 0,1 2

0 2 2 2 2 2 2 3 ) ) 3 3 Cl - Cl 2 2 2 2 ) ) 2 2 5 CH 3 ) PdCl 2 2 4 (dba) CCF H 2 Cl 2 3 2 PdCl 2 Pd(OAc) Pd(acac) (1-naph- Pd -C 2 3 Pd CCH 2 PdCl] Pd(BF Pd(O ( η Pd(PPh Pd(MeCN) thyl)] [(Cinnamyl)- [PPh Tetrakis(MeCN) Pd(O Figure 10. Screening of pre-catalysts for the palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes. aIsolated yield.

These reactions were repeated without internal standard and the styrene product was isolated. Pd(O2CCF3)2 and tetrakis(MeCN)Pd(BF4)2 have weakly coordinating counterions and gave 68% and 70% isolated yields of 3a, while Pd(OAc)2 gave lower yield. Using Pd(O2CCF3)2 as the pre-catalyst, a ligand survey was carried out in which a variety of bidentate nitrogen and phosphorous containing ligands were investigated. The structures of the ligands used in the screening are depicted in Scheme 18 and the reaction outcomes as determined by GC-MS in Figure 11. The nitrogen containing ligands could be divided into two different groups with different reaction outcomes. Ligands bearing a substituent next to one or both of the nitrogens (such as ligand 8f) favoured the formation of 3a, while all other ligands favoured formation of 7. The reactions with ligands 8f, 8m, 8n and 8p which produced the highest ratios of 3a/IS were repeated without internal standard and the styrene product was isolated. Ligands 8f and 8m gave comparable isolated yields, and 8m was selected as the ligand of choice due to its lower price and higher market availability.

Scheme 18. The bidentate ligands screened for the palladium(II)-catalysed decarboxylative synthesis of electron-rich styrenes.

1 3a 4a + 5a 6a 7a

58% 0,8 53% 68% 69%

0,6

0,4

Compound/IS ratio 0,2

0 8a 8b 8c 8d 8e 8f 8g 8h 8i 8j 8k 8l 8m 8n 8o 8p 8q 8r 8s

Figure 11. Screening of various bidentate ligands for the palladium(II)-catalysed decarboxylative synthesis of 3a.

Due to their equal catalytic performance, the use of Pd(O2CCF3)2 and tetrakis(MeCN)Pd(BF4)2 was investigated further in the evaluation of reaction time and temperature (see Figure 12). In general, lowering the reaction temperature (140 °C < 120 °C < 100 °C) seemed to be beneficial in the reaction using Pd(O2CCF3)2, and increasing the reaction time from 60 min to 120 min improved the yield of 3a. The reactions performed at 100 °C and 120 °C for 120 min were equally productive and both reactions were repeated without internal standard and 3a was isolated in 74% and 78% yield, respectively.

42 Conversely, the use of tetrakis(MeCN)Pd(BF4)2 was most productive at 100 °C and shorter reaction time (60 min), in which 3 was obtained at 71% yield. Lower conversion was observed at 80 °C and a drastic decrease in conversion was observed at 140 °C, possibly due to slower reaction rate and decomposition, respectively. Contrary to the observation seen in the use of Pd(O2CCF3)2, the conversions did not improve when the reaction time was increased to 120 min.

1,2 3a 1a 4a + 5a 6a 7a

1 71%a 0,8 74%a 78%a 0,6

0,4

Compound/IS ratio 0,2

0 Temp. (°C): 80 100 120 140 100 120 140 100 120 140 100 120 140 Time (min): 60 60 60 60 120 120 120 60 60 60 120 120 120

Tetrakis(MeCN)Pd(BF ) Pd(O2CCF3)2 4 2 Figure 12. Screening of time and temperature for the palladium(II)-catalysed decarboxylative synthesis of 3a. aIsolated yield.

Thus, Pd(O2CCF3)2 was identified as the catalyst of choice and subsequently an optimisation of the catalyst loading was carried out. The most productive loading was determined as 5 mol%, with the use of 8m as the bidentate lig- and in 10% excess. Reducing the catalyst loading to 2.5 mol% led to a slight decrease in reaction yield, while increasing the catalyst loading did not improve the yield.

OMe O 5 mol% Pd(O2CCF3)2 OMe 5.5 mol% 8m OH 10 mol% Na(O2CCF3) OMe 1.5 mL 2/DMF (3:1) OMe 120 CMW,2h 1a 3a Isolated yield: 78% Scheme 19. Optimised conditions for the palladium(II)-catalysed decarboxylative synthesis of 3a.

After optimisation of the reaction conditions the reaction between 1a and 2 provided the corresponding styrene 3a in a good isolated yield of 78% (see Scheme 19).

43 Investigation of the Scope of the Palladium(II)- Catalysed Decarboxylative Synthesis of Styrenes Using the optimised reaction conditions, a wide range of ortho-substituted arylcarboxylic acids were employed as substrates in the palladium(II)- catalysed decarboxylative Heck-type reaction (see Table 1). The alkoxy- substituted arylcarboxylic acids 1a and 1d gave good yields of the corresponding styrene products 3a and 3d, but disappointingly the use of all other arylcarboxylic acids resulted in poor yields. Arylcarboxylic acids 1c, 1g, 1i and 1j gave predominantly the corresponding transvinylation side products 7 (as determined by GC-MS).

Table 1. Scope of arylcarboxylic acids in the palladium(II)-catalysed decarboxylative synthesis of styrenes.

Isolated yields.

Arylcarboxylic acid 1f did not result in full conversion and the purification of the crude product was troublesome. No activation of the 3-bromo functionality during the reaction of arylcarboxylic acid 1b was observed by GC- MS, and the low yield compared to 1a is likely due to the lower electron density. The low yields obtained for most of the arylcarboxylic acids above can be explained by the formation of side products. Thus, to gain further insight into the reaction pathways leading to the formation of the desired product and side products a computational study was initiated.

44 Investigation of the Reaction Mechanism using Density Functional Theory To investigate the reaction mechanism and side reactions theoretical studies by DFT calculations were performed and focused particularly on the formation of 5. A schematic proposed catalytic cycle for the decarboxylative synthesis of styrenes is shown in Scheme 20. The carboxylic acid coordinates the palladium centre in a bidentate fashion and forms a cationic complex. Following decarboxylation, vinyl acetate is coordinated. Migratory insertion leaves one coordination site empty which is then occupied by a carboxylate ion. Finally, -acetate elimination forms the product and the palladium(II) catalyst is regenerated.

Scheme 20. Schematic proposed catalytic cycle the palladium(II)-catalysed decarboxylative synthesis of styrenes.

The detailed reaction mechanism involves both cationic and neutral complexes and calculations are associated with a high degree of uncertainty when comparing charged and neutral species. Previously this problem has been partially mitigated by calculating the final electronic energies at the B3LYP-LACV3P** level, after performing geometry optimisation and vi-

45 brational analysis using the LACVP* basis set.275 Inspired by the success in this study, this strategy was used for the calculations described herein. Though insight regarding the pathways to all the different side products are of value, the internal arylation of 3 to give electron-rich and sterically congested 1,1-diarylethenes 5 is especially interesting as these compounds have not previously been synthesised through Heck type reactions. The arylation of 3 may give both stilbene 4 and 1,1-diarylethene 5, and these were indeed among the observed side products in the initial synthesis of styrene 3. Arylation reactions of electron-rich 4-substituted styrenes acting through a cationic mechanism have previously been shown to favour internal arylation.276 A computational investigation to compare the competing arylation of 2 (producing 3a) and subsequent terminal or internal arylation of 3a (producing 4a or 5a) was performed. The calculated free energy profiles are shown in Figure 13.

100 L Ar L N L TS-IIb L Pd L = (87) L Pd Ar N Ar OAc L OMe L TS-I L Pd L Pd Ar (65) H Ar = Ar Ar Ar OMe TS-III L TS-IIa (52) L Pd Ar 50 (60) L L H Ar L L Pd L Pd V L L Pd Ar Ar (35) L Pd O Ar H Ar OAc Ar H Ar III O I (23) IV (19) (20) VI (17) ) -1 II 0 (0) (kJ mol

rel L

G L Pd Ar Ar

L L MeO Pd OMe OMe MeO OMe OMe -50 O O OMe OMe OMe OMe VII (-68) 3a 4a 5a Figure 13. Free energy profile for arylation of vinyl acetate 2 (green) and terminal (blue) or internal (purple) arylation of 3a.

Complex I was chosen as the starting point for this investigation since the decarboxylation step and formation of the aryl–palladium complex is identi- cal for the investigated arylation pathways (the study of the decarboxylation step by DFT calculations is discussed in Paper II). Thus, starting from I three

46 migratory insertion transition states (TS-I, TS-IIa, and TS-IIb) were investigated. Proceeding from complex I to TS-I to eventually form the product 3a is associated with a free energy requirement of 46 kJ mol-1. During the reaction the concentration of 3a is increased and thereby also the concentration of complex II, enabling the competing pathway to side products 4a and 5a. As complex II is actually 19 kJ mol-1 lower in energy than I, the calculations suggest that the product 3a impedes the migratory insertion step towards the formation of itself. Comparing TS-IIa and TS-IIb, which lead to the branched product 5a and the linear product 4a, respectively, shows that the internal arylation (TS- IIa) is favored with an energy difference of 27 kJ mol-1. This observation is in agreement with the expectations for an oxidative Heck reaction of an electron-rich olefin acting through a cationic pathway. According to the computational results the internal second arylation via TS-IIa is predicted to be preferred by 5 kJ mol-1 even compared to TS-I. However, the small energy difference between the transition states for the formation of 3a and 5a make conclusions sensitive for errors in the calculation method. Also, the large excess of 2 used in the reaction protocol optimised for the synthesis of 3a could influence the preferred reaction pathway. Complex III is formed through the arylation via TS-IIa and internal rotation results in IV where a -hydrogen is positioned for a syn-elimination which occurs via TS-III to form complex V. Ligand substitution with deprotonated 1a gives complex VI and the product 5a is released. The catalyst has to be regenerated from the palladium–hydride complex VI in order for the next catalytic cycle to begin. The only reoxidant included in the experimental protocol optimised for the synthesis of 3 was the atmospheric oxygen from air in the reaction vial. Para-benzoquinone was compu- tationally evaluated as a reoxidant to investigate the viability of a protocol for the selective synthesis of 5a. The formation of complex VII with para- benzoquinone associated to palladium(0) shows an exergonic pathway that should provide a thermodynamic driving force for the reaction towards 5a. Regeneration of palladium(II) has previously been investigated in a related system that indicates a viable low-energy pathway.277 Therefore, the regeneration of palladium(II) from complex VII was not included in the computational investigation presented herein.

47 Palladium(II)-Catalysed Decarboxylative Synthesis of 1,1-Diarylethenes The computational investigation described above indicated that there is a low energy difference between the formation of the styrene product 3 and a second internal arylation to produce 1,1-diarylethene 5a. To favour the diarylation product the amount of 2 was reduced to 1 equivalent. Para- benzoquinone (p-BQ) was included in the reaction mixture as a palladium reoxidant since the computational results indicated that the formation of 5a results in the liberation of a palladium(0) complex. Different solvent systems, reaction temperature, time, and ligands were screened (Table 2). The solvent system proved to be the most important factor for the synthesis of 5a. The best results with regard to selectivity as determined by crude 1H NMR were obtained using DMF: H2O (90:10) as the solvent. Using the carboxylic acid in excess did not improve the reaction outcome but performing the reaction at 140 °C resulted in higher isolated yield.

Table 2. Selected examples from the optimisation of reaction conditions for the palladium(II)-catalysed decarboxylative synthesis of 5a.

Entry Ligand Solvent Time Temp. 5a:4a ratioa Yieldb 1 8m Dioxane 2 h 120 °C - - 2 8m DMSO 2 h 120 °C 3:1 - ° 3 8m DMSO: H2O (50:50) 2 h 120 C 13:1 - ° 4 8m [BMIM]BF4 2 h 120 C 10:1 - ° 5 8m H2O 2 h 120 C - - ° 6 8m DMF: H2O (75:25) 2 h 120 C 20:1 55% 7 8f DMF 2 h 120 °C 2.5:1 - ° 8 8f DMF: H2O (90:10) 2 h 120 C 28:1 63% ° a 9 8m DMF: H2O (90:10) 2 h 120 C 50:1 63% ° 10 8m DMF: H2O (90:10) 3 h 120 C 40:1 73% ° b 11 8m DMF: H2O (90:10) 3 h 120 C 50:1 69% ° 12 8m DMF: H2O (90:10) 2 h 140 C 28:1 74% ° 13 8m DMF: H2O (90:10) 3 h 140 C 28:1 70% a4 equivalents of the carboxylic acid was used. bNo sodium trifluoroacetate was included in the reaction mixture.

48 With the optimised reaction conditions the internal arylation product 5a could be isolated in 74% yield. The reaction also showed impressive selectivity over the terminal arylation product (4a) with a 5a/4a ratio of 28:1 as determined by 1H NMR (entry 12). Other arylcarboxylic acids were investigated but only 2,4,6-trimethoxybenzoic acid 1f and 2,4-dimethoxybenzoic acid 1k gave the corresponding diarylated products 5f and 5k in low isolated yields (37% and 29%, respectively). These arylcarboxylic acids showed poor selectivity and favoured the terminal arylation product with a 5/4 ratio of 1:1.5 and 1:2.5, respectively. The reaction outcomes for the synthesis of 5 are shown in Scheme 21.

Scheme 21. Palladium(II)-catalysed decarboxylative synthesis of 5 under the optimised reaction conditions.

Though the decarboxylative synthesis of styrenes using vinyl acetate as the vinylating agent constitutes a desirable strategy, the palladium-catalysed protocol reported herein is limited to 2,6-alkoxy substituted arylcarboxylic acids. Diarylation can be effected under adjusted conditions, but this reaction also has a similar limited scope. The proposed reaction mechanisms for the decarboxylative Heck reaction with vinyl acetate 2 and subsequent internal arylation of the in situ generated styrene 3 are shown in Scheme 22.

Scheme 22. Proposed reaction mechanisms for the oxidative Heck reaction with vinyl acetate 2 and internal arylation of in situ generated styrene 3.

Palladium(II)-Catalysed Desulfitative Addition of Sodium Arylsulfinates to Nitriles (Paper II- III)

Background Though palladium-catalysed decarboxylative coupling reactions are a very desirable strategy for carbon-carbon bond formation, the current limitation to electron-rich ortho-substituted benzoic acids generally prevents this approach from being truly synthetically viable. Decarboxylation of unsubstitut- ed benzoic acids have a high activation barrier and previous DFT studies on palladium-mediated decarboxylation reactions have suggested that the carboxyl group is orthogonal to the aromatic ring in the decarboxylative transition state and the conjugation between the carboxyl group and the aromatic ring must be broken in order to reach the transition state.159 Consequently, the energy required to reach the transition state for abstraction of an acid functionality should directly correlate with the rotational barrier of the acid moiety. Based on this assumption alternative aryl acids with lower rotational barriers may serve as potentially superior arylating agents as they are predicted to undergo metalation more readily. Once the key aryl-palladium complex is formed, a large number of divergent transformations can be achieved. For instance, imines could be formed by the insertion of the aryl group into the polar triple bond of nitriles and subsequently hydrolysed to the corresponding ketone.127–130 Due to the versatility of the ketone functionality many different methods for preparing ketones and aryl ketones have been developed. However, the synthesis of aryl ketones from carboxylic acids or acid derivatives using classic approaches generally requires harsh reaction conditions.278

Initial Investigation

Based on the hypothesis outlined above, phenyl sulfonic acid, phenyl phos- phonic acid and the sodium salt of phenyl sulfinic acid were employed in the protocol reported by Lindh for decarboxylative addition to nitriles.279 How-

51 ever, only sodium benzenesulfinate furnished the formation of the corresponding aryl ketone, albeit in trace amounts (see Scheme 23).

Scheme 23. Scouting reactions using benzenesulfonic acid, benzenephosphonic acid and benzenesulfinic acid as aryl-palladium precursors in the palladium-catalysed addition to acetonitrile under conditions from Lindh.279

The rotational barriers for the acid functionalities of the aryl acids of interest were calculated by performing dihedral drives for 2,6-dimethoxy-benzoic acid, benzoic acid and benzenesulfinic acid (see Figure 14). The energy required to break the conjugation of the aromatic ring was lower for benzenesulfinic acid compared to the carboxylic acid, hence the former should possess a lower free energy requirement to reach the transition state for desulfination than for the corresponding decarboxylation of arylcarboxylic acids. This was also supported by the preparative results above, as sodium 4- methyl-benzenesulfinate, bearing no ortho substituents, produced the desired product.

52 30 Benzenesulfinic acid

Benzoic acid

2,6-Dimethoxybenzoic 25 acid

) 15 -1

E (kJ mol 10 

0 0 30 60 90 120 150 180 Dihedral angle 1-2-3-4 (degrees) Figure 14. Dihedral drive energies for benzenesulfinic acid, benzoic acid and 2,6- dimethoxybenzoic acid.

A preparative investigation was initiated and the initial findings concerning the use of sodium arylsulfinates and nitriles for the Pd(II)-catalysed synthesis of aryl ketones were communicated93 simultaneously as the reports by Wang91 and Deng92. Subsequently, further efforts to investigate and optimise the microwave-assisted palladium(II)-catalysed addition of sodium arylsulfinates to organic nitriles and successive hydrolysis have been made and these results are discussed herein.

Optimisation of Reaction Conditions for the Synthesis of Aryl Ketones Encouraged by the results above, an optimisation of the reaction conditions for the palladium(II)-catalysed desulfitative addition of sodium 4- methylbenzene sulfinate 9a to acetonitrile 10a under microwave heating was pursued (see Table 3). Initially, the catalyst loading and the water component of the solvent system were increased. The presence of a strong acid to promote hydrolysis was crucial for the reaction outcome. Inclusion of trifluoroacetic acid (TFA) in the reaction mixture greatly improved the yield the de-

53 sired aryl ketone 11aa. This observation is attributed to the dependence of catalytic turnover on the hydrolysis of the intermediate ketimine. The solvent survey showed that dioxane worked as a substitute for THF in the solvent system with an equal proportion of water (entry 9), but using solvents with one equivalent of water did not provide satisfactory results (entries 6, 7 and 10-14). Also, neat water was not an efficient medium for the reaction.

Table 3. Optimisation of reaction conditions for palladium(II)-catalysed desulfitative addition of sodium 4-methylbenzene sulfinate to acetonitrile.

Entry Solvent Catalyst Acid Ligand Yielda

1 Water/THF (1:1) Pd(O2CF3)2 - 8f Traces 2 Water/THF (1:1) Pd(O2CF3)2 1 eq. TFA 8f 19% 3 Water/THF (1:1) Pd(O2CF3)2 5 eq. TFA 8f 72% 4 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8f 87% 5 Water/THF (1:1) Pd(O2CF3)2 20 eq. TFA 8f 83% 6 THF Pd(O2CF3)2 10 eq. TFA 8f 39% 7 Dioxane Pd(O2CF3)2 10 eq. TFA 8f 43% 8 Water Pd(O2CF3)2 10 eq. TFA 8f 28% 9 Water/dioxane (1:1) Pd(O2CF3)2 10 eq. TFA 8f 77% 10 Isobutanol Pd(O2CF3)2 10 eq. TFA 8f 64% 11 DMF Pd(O2CF3)2 10 eq. TFA 8f 54% 12 DME Pd(O2CF3)2 10 eq. TFA 8f 28% 13 NMP Pd(O2CF3)2 10 eq. TFA 8f 17% 14 DMSO Pd(O2CF3)2 10 eq. TFA 8f 5% 15 Water/THF (1:1) Pd(OAc)2 10 eq. TFA 8f 47% 16 Water/THF (1:1) Pd(OH)2 10 eq. TFA 8f 47% 17 Water/THF (1:1) Pd(dba)2 10 eq. TFA 8f 32% 18 Water/THF (1:1) PdCl2 10 eq. TFA 8f 5% 19 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8a 39% 20 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8h 8% 21 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8i 31% 22 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8m 8% 23 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8s - 24 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8r - 25 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8t, PPh3 15% 26 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA 8f, DMSO 10% 27 Water/THF (1:1) Pd(O2CF3)2 10 eq. TFA - Traces aIsolated yield.

54 The more reactive Pd(O2CCF3)2 proved to be more efficient than other palladium sources and the ligand (6-methyl-2,2’-bipyridyl, 8f) was crucial for catalytic activity. The structure of the ligands are shown in Figure 9. The use of similar nitrogen based bidentate ligands resulted in the formation of the desired product but in significantly lower yields. Under the optimised reaction conditions, aryl ketone 11aa was obtained in 87% isolated yield.

Investigation of the Reaction Mechanism using Electrospray Ionisation Mass Spectrometry In order to gain experimental insight into the reaction mechanism, stoichiometric reactions with varying ligands and sodium sulfinates were set up and heated at 100 °C for 10 minutes, diluted 10 times with 10a and then directly analysed using electrospray ionisation mass spectrometry. The characteristic isotopic distribution of palladium was exploited to identify palladium complexes and the composition of these complexes was further verified via MS- MS and MS-MS-MS analyses. Concomitantly, neutral loss experiments monitoring the loss of acetonitrile and SO2 (41 and 64 Da, respectively) were also performed to verify the identity of some of the proposed palladium complexes. Only a small number of signals for non-palladium ions were observed. ESI-MS(+) spectra and the identified complexes are depicted in Figure 15. The major signal in all the ESI-MS(+) spectra corresponded to the aryl- palladium complex coordinated only by the ligand with a free palladium coordination site. This observation is likely due to the formation of the complex in the ion source of the mass spectrometer through loss of weakly coordinated neutral SO2 and nitrile ligands.

55 300 400 500m/z 600 700 800 Sulfinate: Sodium benzenesulfinate Sulfinate: Sodium 4-methylbenzenesulfinate Ligand: Phenanthroline Figure 15. ESI-MS spectra and identified cationic palladium complexes with nu- mering according to their role in the catalytic cycle.

It is important to note that the intensity of the ESI-MS signals only correlate to the stability and formation of the ions in the mass spectrometer and not to their abundance or role in the reaction mixture. Although the majority of the complexes observed (shown in Figure 13) supported the previously suggested mechanism, further mechanistic investigation by an orthogonal method was warranted.

Investigation of the Reaction Mechanism using Density Functional Theory To further elucidate the mechanism of the desulfitative reaction developed herein, a computational study was performed. The reaction mechanism was investigated by DFT calculations and geometries were optimised at the B3LYP-LACVP* level of theory and single point energies were calculated at the B3LYP-LACVP**+ level of theory. The decarboxylative and desulfitative pathways were compared using water as the solvation model because the calculations did not allow solvent mixtures. The free energy profiles for desulfination and decarboxylation are shown in Figure 16 and the free energy profiles for 1,2-carbopalladation of 10a (acetonitrile) are shown in Figure 17. The starting point and reference energy level for the investigation was Pd(O2CCF3)2 (complex I) as it is the common lowest energy complex for all

56 three reactions. Stepwise dissociation of the trifluoroacetate ligands from the catalyst followed by association of a single aryl acid led to complex VI which has the lowest energy prior to the transition state for decarboxylation for 2,6-dimethoxybenzoate 1a. In contrast, the lowest energy complex for benzoate 1k is the neutral complex V bearing two aryl acid ligands. The lowest energy prior to desulfination of benzenesulfinic acid 9e was complex IVa. The binding mode of the aryl acid in IV is changed to allow an interaction between the aryl group and the palladium centre in complex VI which pre- cedes the desulfination/decarboxylation transition state (TS-I). The calculation of the free energy requirement for decarboxylation of benzoic acid involves comparison of neutral and cationic complexes, which is associated with a relatively large degree of uncertainty. However, the free energy requirement for decarboxylation is significantly higher (2.5 fold) than for the desulfitative process (117.9 kJ mol-1, Vb to TS-Ib, compared to 46.5 kJ mol-1, IVa to TS-Ia). The difference between the free energy requirements is larger than the expected error in the calculations. This is in agreement with previous observations regarding the relative free energy requirements in copper-mediated decarboxylation and desulfination reactions.204

Figure 16. Free energy profile for desulfination of benzenesulfinic acid and decarboxylation of benzoic acid and 2,6-dimethoxybenzoic acid.

Figure 17. Free energy profile for 1,2-carbopalladation of acetonitrile 10a.

The free energy requirement for the carbopalladation of acetonitrile with phenyl was calculated to 99.1 kJ mol-1 (VIIIa-b to TS-IIa-b). The free energy requirement for the more electron-rich 2,6-dimethoxy-phenyl was consid- erably lower (81.6 kJ mol-1, VIIIc to TS-IIc), which is in agreement with previous studies on the carbopalladation of cyanamides.136 It should be noted that the free energy requirement backward from complex VIIIa to complex IVa (67.3 kJ mol-1) is lower compared to the carbopalladation (Figure 18). Thus, the backward reaction should occur more easily than the forward reaction. However, further transformation of complex IXa to give the product 11aa and regeneration of the low energy complex Va is associated with a free energy gain of 17.0 kJ mol-1 which provides a thermodynamic driving force for the reaction.

Figure 18. The free energy requirement for the backward reaction from VIIIa to IVa is and for carbopalladation in the desulfitative reaction.

In the computational model, the imine and ammonia were released as neutral species, although the reaction is performed in the presence of 10 equivalents of TFA. The protonation states and subsequent hydrolysis was not computa- tionally investigated. Assuming that these processes occurred without significant free energy requirements, the insertion step was rate determining for benzene sulfinic acid 1e and 2,6-dimethoxybenzoic acid 1a. Conversely, the decarboxylation step was rate determining for benzoic acid. The results from the computational and ESI-MS studies are in agreement with the previously proposed mechanism but provide greater insight and validity to the mechanism. The proposed reaction mechanism is shown in Scheme 24.

Scheme 24. Proposed reaction mechanism for the palladium(II)-catalysed desulfitative addition of sodium arylsulfinates to nitriles.

Investigation of the Scope of the Microwave-Assisted Organic Synthesis of Aryl Ketones The scope of the protocol developed herein was first investigated by employing a range of sodium arylsulfinates, purchased commercially or synthesised in-house, with different electronic properties using acetonitrile 10a as the reaction partner. As seen in Table 4, the desulfitative reaction tolerated a much wider scope of aryl acids compared to the corresponding decarboxylative reaction. Electron-rich and moderately electron-deficient substrates performed well and ortho substitution was not a requirement for productive reactions. In fact, sterically congested sodium 2,4,6-trimethylbenzene sulfinate 9k resulted in very low conversion. The corresponding carboxylic acid provided acceptable yield in the decarboxylative reaction, which illustrated the orthogonality of these protocols. The amide functionality of sodium 4-acetamidobenzene sulfinate was hydrolysed under the optimised reaction conditions, but the desired aryl ketone product could be obtained in satisfying 57% yield by performing the reaction with 10% water in 10a as the solvent.

60 For selected entries, the reaction was performed under both conventional and microwave heating. In all these examples microwave heating proved more efficient with shorter reaction times and higher isolated yields. The reactions were performed in 2-5 ml microwave transparent borosilicate glass vials and were either heated in a dedicated batch microwave instrument or using a metal heating block with the temperature maintained at 100 °C. Un- fortunately, highly electron-deficient substrates resulted in homocoupling, probably due to sluggish carbopalladation, and poor yield of the desired aryl ketones were obtained regardless of the heating method used.

Table 4. Preparation of aryl ketones by palladium(II)-catalysed desulﬁtative addition of various sodium arylsulﬁnates to 10a.

Isolated yields. aPerformed under microwave heating. bPerformed under conventional heating. cPerformed using 10% water in 10a as the solvent.

Next, the scope of nitriles was investigated. A wide range of aliphatic, benzylic and aromatic nitriles was employed and the reactions proceeded smoothly to produce the corresponding aryl ketones in moderate to excellent yields (see Table 5). Both electron-rich and electron-poor nitriles performed well as substrates, as illustrated by the yields obtained for the reactions em-

61 ploying 4-methoxy- and 4-acetyl-benzonitrile (68% and 51%, respectively). 4-Formyl substituted benzonitrile also yielded the desired aryl ketone, albeit in slightly lower yield. Reactions using different bromobenzonitriles did not show any bromine activation by the palladium catalyst which illustrates the orthogonality of the palladium(II)-catalysed reaction developed herein to conventional palladium(0) processes. In addition, ethyl 2-cyano-2- phenylacetate could be employed without hydrolysis of the ester functionality, highlighting the functional group tolerability of the reaction. Selected entries were also performed under both conventional and microwave heating and the results were consistent with the previous observations.

Table 5. Preparation of aryl ketones by palladium(II)-catalysed desulﬁtative addition of 9a to various nitriles.

Isolated yields. aPerformed under microwave heating. bPerformed under conventional heating.

62 Next, heterocycles containing the nitrile functionality were investigated to access an array of heterocyclic ketones. Interestingly, the palladium(II)- catalysed desulfitative reaction of (2-hydroxyphenyl)acetonitrile led to the formation of 2-arylbenzofuran in 49% isolated yield through aryl ketone formation and subsequent intramolecular condensation (Scheme 25). Related desulfitative coupling with 2-(gemdibromovinyl)phenols280 and addition of arylboronic acids to nitriles133 followed by cyclisation to the corresponding benzofurans have previously been reported.

Scheme 25. Aryl ketone formation and subsequent intramolecular condensation.

The scope of the reaction was further investigated by combining an array of sodium arylsulfinates and nitriles to give 22 additional examples of diverse aryl ketones (see Table 6). All these reactions proceeded smoothly, in which high yields were obtained for the reaction between electron-rich to moderately electron-poor sodium arylsulfinates and aliphatic, benzylic and aromatic nitriles. These results highlighted the consistency and versatility of the method developed herein.

63 Table 6. Preparation of aryl ketones by palladium(II)-catalysed desulﬁtative addition of sodium arylsulfinates to nitriles.

Isolated yields. aPerformed under microwave heating. bPerformed under conventional heating.

64 Continuous Flow Microwave-Assisted Organic Synthesis of Aryl Ketones The application of the palladium(II)-catalysed desulfitative addition of sodium arylsulfinates to nitriles was further extended to continuous flow under microwave heating. As described in the introduction to this thesis, the rapid heating associated with microwave technology makes it useful for flow applications. The reaction mixture is directly heated when microwave transparent reactors such as borosilicate glass reactors are used. Borosilicate glass has previously been used as a reactor material in microwave-assisted metal- catalysed flow reactions.281,282 However, microwave induced superheating due to metal precipitation leading to potential reactor failure constitutes a major problem. Due to their higher durability, silicon carbide reactors have been suggested as a safe alternative for microwave heated metal-catalysed flow reactions. These reactors have the ability to withstand the stress caused by microwave induced hot-spots at higher temperature that may form if metal is deposited on the internal surface of the reactor.289 However, un- like borosilicate glass, silicon carbide absorbs microwaves and the reaction mixture is heated in a more conventional manner using these reactors.283 Aluminium oxide is thermostable with a maximum operating temperature of 1950 °C and is microwave transparent. Thus, this material should serve as a safe alternative that has microwave properties more similar to borosilicate glass. Aluminium oxide is a common material used in standard flow chemistry applications but has not been exploited as a reactor material for microwave-assisted continuous flow processes. The continuous flow setup is shown in Figure 19 and Figure 20.

65 Figure 19. Schematic representation of the continuous flow setup.

Figure 20. Photograph of the continuous flow setup. Setup for CF-MAOS showing pump, generator with MW applicator on top and fraction collector (left), and close- up of microwave applicator with the front piece unmounted and a borosilicate glass tube reactor inside the helical antenna (right).

The temperature profiles for heating benzene in the continuous flow system (Figure 21) illustrate the properties of these materials under microwave heating. Benzene absorbs very little of the microwave radiation which resulted in a slow increase in temperature for the microwave transparent materials. Sili- con carbide absorbs microwaves and the temperature increases more quickly. For microwave-absorbing solvents or reaction mixtures, the temperature profiles are similar. It must be noted that different sensors were used to measure the temperature for the different materials. A study correlating the measurements to a fiber-optic sensor has previously demonstrated that an

66 Optris CSmicro 3M IR sensor provides an accurate estimation of the temperature of the solution in borosilicate glass reactors.284 Hence, this sensor was used for temperature measurements of reactions performed in borosilicate glass reactors. For the aluminium oxide and silicon carbide reactors, an Optris CT IR sensor with a LT22 sensing head was used which measures the outside temperature of the reactor.

100 100

80 80

60 60 Borosilicate glass 40 40 Aluminium oxide Temperature (C) Temperature (C) Silicon carbide 20 20

0 0 0 60 120 180 0 60 120 180 Time (s) Time (s) Figure 21. Heating profiles with the set temperature 100 °C for different reactor materials pumping benzene (left) and THF:H2O (1:1) (right) at flow rate 1 ml/min.

In comparison to the batch protocol, the stock reaction mixture was diluted 10-fold to avoid excessive metal precipitation in the reactor. Reactions employing hydrophobic nitriles resulted in biphasic reaction mixtures and were particularly challenging to perform in a continuous flow setup. However, upon vigorous stirring, the reaction mixture formed an emulsion that could be pumped into the reactor in a controlled fashion using an HPLC pump (see Figure 22).

Figure 22. Reaction mixture prepared for the synthesis of aryl ketone 11ad without (left) and with stirring (right).

67 The reaction conditions were optimised for the palladium(II)-catalysed addition of sodium 4-methylbenzene sulfinate 9a to benzyl cyanide 10d (see Table 7). The temperature and flow rate were varied, and the highest isolated yield of 79% was obtained at 120 °C and a flow rate of 1 mL/min which corresponds to 50 s residence time in the microwave heated zone that covers 120 mm of the 200 mm tube reactor.

Table 7. Optimisation of process parameters for microwave-heated continuous flow palladium(II)-catalysed desulfitative synthesis of aryl ketone 11ad.

Entry Temperature Flow rate Residence time Isolated yield

1 80 °C 1 mL/min 50 s Trace 2 100 °C 1 mL/min 50 s 78% 3 120 °C 0.5 mL/min 100 s 66% 4 120 °C 1 mL/min 50 s 79% 5 120 °C 2 mL/min 25 s 74% 6 140 °C 1 mL/min 50 s 53% The temperature was measured using an Optris CSmicro 3M IR sensor.

Next, three different reactor materials (see Figure 23) were compared for the continuous flow microwave-assisted synthesis of aryl ketone 11ad. The reaction was performed at three different temperatures for each reactor material (100 °C, 120 °C and 140 °C). The productivity of these reactions were determined by GC-MS using 2-methylnapthalene as an internal standard, and the product from the reaction with the highest product to internal standard ratio was isolated.

Figure 23. Flow reactors made from aluminium oxide (top), borosilicate glass (middle) and silicon carbide (bottom).

The borosilicate glass and aluminium oxide reactors provided equal yields of the aryl ketone product at 120 °C. The best result was achieved at 100 °C for the silicon carbide reactor and the isolated yield was comparable to the other reactors (see Table 8). It should be noted that the heated zone corresponds to the length of the microwave heated zone (120 mm) for the borosilicate glass and aluminium oxide reactors, but to the full length of the reactor (200 mm) for the silicon carbide reactor. For the aluminium oxide and silicon carbide reactors the temperature was measured using an Optris CT IR sensor with a LT22 sensing head which measures the outside temperature of the reactor. By using the microwave-absorbing silicon carbide reactor, conventional heating can be mimicked and be used to investigate a potential microwave activated liquid interface. However, the use of this reactor material gave comparable results and no non-thermal beneficial microwave effect was observed. The influence of a phase transfer catalyst (tetrabutylammonium hydro- gensulphate) was also investigated, but no improvement of the reaction outcome was observed.

Table 8. Comparison of flow reactors for the continuous flow microwave-assisted synthesis of aryl ketone 11ad.

Entry Reactor material Temperature Sensor Yielda 1 Borosilicate glass 120 °C Optris CSmicro 3M 79% 2 Silicon carbide 120 °C Optris CT IR sensor, LT22 sensing head 78% 3 Aluminium oxide 100 °C Optris CT IR sensor, LT22 sensing head 74% aIsolated yields.

69 Encouraged by the positive results obtained above, the scope of the palladium(II)-catalysed desulfitative ketone synthesis under continuous flow conditions further was explored using both the borosilicate glass and aluminium oxide reactors (see Table 9). The palladium(II)-catalysed addition of arylsulfinates 9a, 9b and 9e to 10a under continuous flow conditions afforded the corresponding aryl ketones in 55%/50%, 68%/62% and 61%/58% yields, respectively. The reaction employing sodium 4-acetamidobenzenesulfinate 9d showed no trace of the corresponding hydrolysed product and 11da was obtained in 60%/56% yield. However, the moderately electron-poor sodium 4- bromobenzenesulfinate 9r only afforded trace amounts of 11ra, likely due to the short reaction time of the CF-MAOS protocol. Reactions employing 10c and 10g as the nitrile furnished the corresponding aryl ketone in 71%/54% and 53%/50% yield, respectively. 3-thiophenecarbonitrile could be used to introduce a heterocyclic functionality and gave a satisfying 66%/58% yield of 11eq. No traces of side products from palladium(0)-catalysed activation of the phenyl bromide functionality was observed when 4-bromobenzonitrile 10h was employed as the nitrile. However, the CF-MAOS protocol only furnished 47%/56% isolated yield of the desired product for this substrate.

Table 9. Preparation of aryl ketones by microwave-heated continuous flow palladium(II)-catalysed desulﬁtative addition of sodium arylsulfinates to nitriles.

Pd(O2CCF3)2 O 8f O S + RCN CF-MAOS Ar ONa TFA, THF/H2O Ar R 1 mL/min, 120 °C 9 10 11 75 mM 5 eq. øi 3mm O O O O O Me Me Me Me N MeO H 11aa 11ba 11da 11ea 55%a/50%b 68%a/62%b 60%a/56%b 61%a/58%b O O O Me

Br 11ra 11bc 11bd Trace/Trace 71%a/54%b 79%a/63%b O O O

S Br 11bg 11bh 11bq 53%a/50%b 47%a/56%b 66%a/58%b Isolated yields. aPerformed in a borosilicate glass reactor and the temperature was measured using an Optris CSmicro 3M IR sensor. bPerformed in an aluminium oxide reactor and the temperature was measured using an Optris CT IR sensor with a LT22 sensing head.

70 Lower yield than for the batch protocol were obtained for all entries except for the reaction between 9a and 10d. However, when palladium(II)- catalysed addition reactions of 1b with 2a and 2e were performed in batch at the same diluted concentrations that were used for flow applications, identi- cal yields were obtained. The yields for reactions performed in the aluminium oxide reactor were generally slightly lower compared to the results obtained using the borosilicate glass reactor. No problems with reactor failure due to metal precipitation and microwave induced superheating was observed for either reactor material.

71 Synthesis of Sodium Arylsulfinates Using a Solid Source of Sulphur Dioxide (Paper IV)

Background As outlined in the previous chapters, sodium arylsulfinates are an increasingly important class of building blocks, especially as aryl-palladium precursors in palladium(II)-catalysis. Potential applications include the preparation of pharmaceuticals, functional materials and bioactive compounds. The commercial availability of sulfinic acids and their corresponding salts is limited. However, they can be prepared by the methods described in the introduction, such as the reaction of organometallic reagents with sulphur dioxide. However, the use of toxic sulphur dioxide gas and the requirement for spe- cialised equipment is considered inconvenient. A solid source of sulphur dioxide would allow for safer and more convenient synthesis of these compounds. The complex of sulphur dioxide with DABCO (depicted in Scheme 26) was chosen as the gas surrogate, which has previously been exploited for in situ generation of sulfinates for further reactions.285–291

Scheme 26. Formation of the sulphur dioxide complex DABSO.

The aim of this project was to develop a convenient method for the synthesis and isolation of sodium arylsulfinates.

72 Development of the Protocol An initial reaction between commercially available phenylmagnesium chloride and DABSO in THF was conducted. Gratifyingly, this resulted in almost quantitative conversion to the magnesium chloride sulfinate 9b, however purification of the crude sulfinate proved to be difficult due to rapid decomposition. Liquid-liquid extraction using 2 M HCl, attempted purification of the sulfinic acid by silica gel, aluminum oxide, or reverse phase chromatography resulted in almost quantitative conversion to the corresponding sulphonic acid. Due to the stability issues above and the promotion of disproportionation of sulfinic acids by HCl,292 an alternative purification strategy was devised in which the sulfinate salt was isolated by treatment with aqueous Na2CO3 and purification by liquid–liquid and solid–liquid extraction. Importantly, sulfu- ric acid was used in the liquid–liquid extraction and it does not promote dis- propotionation of sulfinic acids.170 This purification strategy proved success- ful as purification of crude 9b afforded the desired sodium arylsulfinate in 90% yield, without any traces of the corresponding sulphonic acid. Next, different approaches to the formation of the Grignard reagent were investigated since the classical generation of the Grignard reagent proved sluggish. The halogen-metal exchange reagent iPrMgCl*LiCl has previously been used with great success for this process but often requires long reaction times for neutral or electron-rich aryl bromides.293 A previously developed microwave heated protocol proved to be a rapid and convenient strategy for the generation of the Grignard reagents.294

Investigation of the Scope of the Synthesis of Sodium Arylsulfinates To explore the scope the two-step synthesis of sodium sulfinates developed herein, a series of aryl halides were processed in the microwave protocol for the generation of the Grignard reagents and subsequently allowed to react with DABSO at 0 °C. As seen in Table 10, electron-poor substrates were more productive than electron-rich substrates which is illustrated by comparing the outcomes of the reactions with 4-methoxy- and 3- methoxybromobenzene (48% and 85%, respectively). Electron-poor 4-CF3- bromobenzene gave an excellent yield of the desired product 9h but introducing a steric factor by moving the substituent to the ortho position resulted in a lower yield (91% and 75%, respectively). However, treatment of the sterically congested 2,4,6-trimethyl-substituted aryl bromide 12k was well- tolerated and the corresponding sodium arylsulfinate was obtained in 69% yield.

73 Table 10. Preparation of sodium arylsulfinates by the reaction of Grignard reagents with DABSO.

Isolated yields. aIodobenzene. bCommercial phenylmagnesium chloride. cBromobenzene. dIodobenzene.

Sodium 4-biphenyl sulfinate is inaccessible through the common protocol employing sulfonyl chlorides in an aqueous solution due to poor solubility of the starting material in water. However, the use of 4-bromobiphenyl in the developed protocol returned the desired sodium sulfinate 9q in 87% yield. Next, the corresponding reactions via lithium halogen exchange and subsequent reaction with DABSO were investigated (see Table 11). In general, the yields obtained were comparable to those using the Grignard reagents previously investigated. Electron-poor substrates were also favoured in the synthesis via lithiation, e.g. 3-methoxy substituted aryl halide 12r afforded higher yield than the 4-methoxy substituted regioisomer 12b (91% compared to 59%). However, contrary to the trend seen for the corresponding Grignard reagents, the use of 4-CF3-bromobenzene resulted in significantly lower yield than using 2-CF3-bromobenzene (48% compared to 99%). Notably, sodium sulfinate 9e could be obtained in better yield than via the corresponding protocol employing the generated Grignard reagent (85% compared to 72%). Sodium 4-biphenyl sulfinate 9q was obtained in low yield due to the poor solubility of the generated aryl lithium reagent and problematic addition to the reaction mixture.

74 Table 11. Preparation of sodium arylsulfinates by the reaction of lithium reagents with DABSO.

Isolated yields.

Treatment of 2-bromo-thiophene with n-butyl lithium at -78 °C resulted in the formation of butyl-thiophene sulfinate by direct substitution and subsequent reaction with DABSO (see Scheme 27). This sodium sulfinate could be isolated in 68% yield.

Scheme 27. Formation of undesired product using n-butyl lithium. Isolated yield.

The prospect of direct deprotonation of heteroaryls and reaction with DAB- SO to generate sulfinates was also investigated.By using the more basic and less nucleophilic t-BuLi the desired thiophene sulfinate could be obtained. However, the isolated yield was poor due to the high polarity of the product resulting in problematic purification by liquid-liquid extraction. The reaction with furan furnished the corresponding sodium sulfinate in similar disap- pointing yield, but when the more hydrophobic benzofuran was employed the yield of the desired product was improved to 50% (see Table 12).

75 Table 12. Preparation of sodium arylsulfinates by the reaction of deprotonated heteroaryl compounds with DABSO.

Isolated yields.

The protocols developed herein constitute convenient and safe routes to a wide range of sodium arylsulfinates, and is especially efficient for electron- poor aryl bromides which are often difficult to prepare using existing methods. Both electron-poor and electron-rich aryl bromides can successfully be employed in the reaction between aryl Grignard or aryl lithium reagents and DABSO, without the need for handling gaseous SO2. Thus, a wide range of sodium arylsulfinates can be produced, which can then be deployed as substrates in reactions such as the palladium(II)-catalysed transformations described in Papers II-III.

76 Conclusions

Palladium(II) catalysis has developed over the last few decades and has become a useful synthetic tool that often complements other palladium(0)- catalysed reactions. In the first part of this thesis, the development of a palladium(II)-catalysed Heck protocol for decarboxylative synthesis of styrenes is described. The reaction mechanism was investigated by means of DFT calculations and the theoretical investigation, which was in agreement with the experimental results, indicated that both the formation of the corresponding styrene and 1,1-diarylethene are possible outcomes of the reaction. Based on the computational study a one-pot synthetic protocol could be developed to produce sterically congested di-ortho alkoxy-substituted 1,1- diarylethene. However, the transformation had a very limited substrate scope and high selectivity for the 1,1-diarylated product was only observed for 2,6- dimethoxybenzoic acid. Sodium sulfinates were identified as a suitable alternative to carboxylic acids as arylating agent. A palladium(II)-catalysed protocol for the synthesis of a wide range of aryl ketones by desulfitative addition to nitriles was developed. Importantly, these substrates do not require 2,6-dialkoxy substitution to be productive in the reaction. The desulfitative and decarboxylative processes of benzenesulfinic acid, benzoic acid and 2,6-methoxy-benzoic acid were investigated using DFT calculations. The results gave insights into the mechanisms of these processes and support that palladium(II)-catalysed desulfination of arylsulfinic acids is a viable route to aryl-palladium intermediates. Additional experimental support for the proposed reaction mechanism was provided by direct ESI-MS studies. The wide scope of the desulfitative reaction was demonstrated by combining 15 different sodium arylsulfinates and 21 nitriles to give 56 examples of aryl ketones. An adapted protocol for continuous flow synthesis of aryl ketones was also developed. Though certain reaction mixtures were biphasic, acceptable to good yields of the desired products were obtained with a production capacity of up to 4.3 mmol/h. Microwave transparent borosilicate glass reactors performed well and aluminium oxide reactors were identified as safe alternatives. A gas-free synthesis of sodium arylsulfinates from Grignard and organolithium regents using the SO2 surrogate DABSO was developed. The developed protocol is a convenient and safe route to a wide range of sodium arylsulfinates and especially the use of electron-poor substrates resulted in high yields.

77 Decarboxylative processes have great potential and are environmentally benign but current monometallic systems suffer from serious limitations. Sodium arylsulfinates have emerged as alternative and more versatile arylating agents in palladium(II) catalysis and are becoming increasingly important. This thesis illustrates the interplay between experimental chemistry and mechanistic insight from theoretical investigations in the development of new useful synthetic tools.

78 Acknowledgements

This thesis is the result of several people’s hard work and would not have been possible without their contributions. Everyone at the department of organic pharmaceutical chemistry has contributed to a fantastic workplace and many have contributed directly or indirectly to the material presented herein. I would like to thank the following people in particular:

Professor Mats Larhed for taking me on as a PhD student, allowing me to work independently but not hesitating to answer research questions in the middle of the night while dining at the castle.

Professor Anders Karlén for supervising me during the medicinal chemistry projects that did not make it into this thesis.

Dr. Luke Odell for providing invaluable practical and theoretical guidance during the different projects and for setting an example for all organic chemists.

Dr. Christian Sköld for introducing me to the world of computational chemistry.

Dr. Jonas Sävmarker for always being a helpful mentor regarding palladium and flow chemistry.

Dr. Ulrika Rosenström for support during my struggles in research, but mainly for all the support and confidence placed in me during teaching.

Jonas Rydfjord for remaining my faithful sidekick since high school, and making contributions to the majority of the projects described in this thesis.

Dr. Shiao Chow for entertaining discussions regarding all fields of science, help with graphical design and particularly all the help regarding this thesis.

Dr. Fredrik Svensson for discussions regarding reaction mechanisms, math- ematics, science and totally unrelated topics.

79 Dr. Ashkan Fardost for all the speculative discussions and having the cour- age to think big.

Dr. Sanjay Borhade who helped me perfect the art of column chromatography.

Dr. Anneli Nordqvist for taking the time to introduce me to the chemistry and teaching at the department, even during the preparations for her own thesis defence.

Dr. Rajiv Sawant for setting an example for how to work in the lab and for providing encyclopedic knowledge regarding organic chemistry.

Mohammed Al-Tikriti and Mostafa Haitham for their valuable contributions to research projects that were not included in this thesis.

Gunilla Eriksson all the help with small and big things. You always went the extra mile and made the department an amazing workplace.

Sorin Srbu for the swift assistance with IT stuff that went haywire.

Dr. Per Sjöberg for introducing me to ESI-MS and help with the elucidation of mountains of mass spectra.

Dr. Peter Brandt for critical feedback and support with calculations.

Dr. Johan Gising for support during the medicinal chemistry projects and Dr. Charles Hedgecock for always providing useful feedback and the invaluable perspective from the pharmaceutical industry.

Dr. Anja Sandström and Dr. Charlotta Wallinder for help with and discussions regarding teaching.

Dr. Marc Stevens for challenging me to keep up to date with the literature and collecting obscure knowledge.

Linda Åkerbladh for struggling even more than I with the synthesis of an- titubercular compounds, but always retaining a positive outlook.

Linda Wikberg for invaluable moral support and for providing a perspective from a non-chemist point of view.

80 Apotekarsocieteten, Apotekare C. D. Carlssons stiftelse and IFs stiftelse for giving me the opportunity to participate at international research confer- ences.

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Acta Universitatis Upsaliensis Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 221 Editor: The Dean of the Faculty of Pharmacy

A doctoral dissertation from the Faculty of Pharmacy, Uppsala University, is usually a summary of a number of papers. A few copies of the complete dissertation are kept at major Swedish research libraries, while the summary alone is distributed internationally through the series Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy. (Prior to January, 2005, the series was published under the title “Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy”.)

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