To Erik, Frida, Oskar &

Camilla

List of Papers

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

I Sävmarker, J., Lindh, J., Nilsson, P. Deoxybenzoins from Stille

Carbonylative Cross-Couplings using Molybdenum Hexa-carbonyl. Tetrahedron Lett. 2010, 51, 6886-6889.

II Odell, L., Sävmarker, J., Larhed, M. Microwave-Promoted Aminocarbonylation of Aryl Triflates using Mo(CO)6 as a Solid CO Source. Tetrahedron Lett. 2008, 49, 6115-6118.

III Lindh, J., Sävmarker, J., Nilsson, P., Sjöberg, P. J. R., Larhed, M. Synthesis of Styrenes by Palladium(II)-Catalyzed Vinylation of Arylboronic Acids and Aryltrifluoroborates by Using Vinyl Acetate. Chem-Eur J. 2009, 15, 4630-4636.

IV Sävmarker, J., Lindh, J., Nilsson, P., Sjöberg, P. J. R., Larhed,

M. Oxidative Heck Reactions Using Aryltrifluoroborates and Aryl MIDA Boronates. Submitted.

V Sävmarker, J., Rydfjord, J., Gising, J., Odell, L., Larhed, M.

Direct Palladium(II)-Catalyzed Synthesis of Arylamidines from Aryltrifluoroborates. Submitted.

VI Behrends, M., Sävmarker, J., Sjöberg, P. J. R., Larhed, M.

Microwave-Assisted Palladium(II)-Catalyzed Synthesis Of Aryl Ketones from Aryl Sulfinates and Direct ESI-MS Studies Thereof. ACS Catal. 2011, 1, 1455-1459.

Reprints were made with permission from the respective publishers.

Related Publications and Manuscript Not Included in this Thesis

Trejos, A., Sävmarker, J., Schlummer, S., Datta, G. K., Nilsson, P., Larhed, M. Stereoselective Heck Arylation of a Functionalized Cyclopentenyl Ether using (S)-N-Methyl-Pyrrolidine as the Stereochemical Controller. Tetrahed-ron 2008, 64, 8746-8751. Andaloussi, M., Lindh, J. Sävmarker, J., Sjöberg, P. J. R., Larhed, M. Microwave-Promoted Palladium(II)-Catalyzed C-P Bond Formation Using Arylboronic Acids or Aryltrifluoroborates. Chem. Eur. J. 2009, 15, 13069-13074. Russo, F., Wångsell, F., Sävmarker, J., Jacobsson, M., Larhed, M. Synthesis and Evaluation of a New Class of Tertiary Alcohol Based BACE-1 Inhibitors. Tetrahedron 2009, 65, 10047-10059. Wångsell, F., Russo, F., Sävmarker, J., Rosenquist, Å., Samuelsson, B., Larhed, M. Design and Synthesis of BACE-1 Inhibitors Utilizing a Tertiary Hydroxyl Motif as the Transition State Mimic. Bioorg. Med. Chem. Lett. 2009, 19, 144-155. Wångsell, F., Nordeman, P., Sävmarker, J., Rosenquist, Å., Samuelsson, B., Larhed, M. Investigation of Alpha-Phenylnorstatine and Alpha-Benzylnorstatine as Transition State Isostere Motifs in the Search for New BACE-1 Inhibitors. Bioorg. Med. Chem. 2009, 19, 4711-4714. Sävmarker, J., Trejos, A., Russo, F., Rosenquist, Å., Samuelsson, B., Larhed, M. Synthesis and Evaluation of Stereopure Tertiary Alcohol Based

-Secretase Inhibitors. Manuscript.

Contents

1. Introduction ............................................................................................... 11 1.1 Palladium ............................................................................................ 11 1.2 Palladium Catalysis in C-C Bond Forming Reactions ....................... 11 1.3 Palladium Ligands .............................................................................. 13 1.4 Palladium(0) Catalysis ....................................................................... 14

1.4.1 Oxidative Addition ..................................................................... 14 1.4.2 CO Coordination and Insertion ................................................... 15 1.4.3 Transmetallation ......................................................................... 15 1.4.4 Reductive Elimination ................................................................ 15

1.5 Mo(CO)6-Mediated Carbonylation ..................................................... 15 1.5.1 Carbonylative Stille Coupling .................................................... 16 1.5.2 Aminocarbonylations .................................................................. 16

1.6 Palladium(II) Catalysis ....................................................................... 17 1.6.1 Transmetallation ......................................................................... 18 1.6.2 Desulfination............................................................................... 18 1.6.3 Insertion ...................................................................................... 19 1.6.4 Elimination ................................................................................. 20 1.6.5 Reoxidation ................................................................................. 21 1.6.6 The Aryl Source .......................................................................... 22

1.7 Styrene Synthesis ............................................................................... 26 1.8 The Oxidative Heck Reaction ............................................................ 26 1.9 Palladium-Catalyzed Nitrile Insertion ................................................ 28 1.10 Electrospray Ionization Mass Spectrometry ..................................... 29

2. Aims of the Present Study ......................................................................... 32

3. Mo(CO)6-Mediated Carbonylations (Paper I & II) .................................. 33 3.1 Synthesis of Deoxybenzoins under Gas-Free Conditions .................. 33

3.1.1 Vinyl and Allyl Halide Screening ............................................... 34 3.1.2 Benzyl Halide Screening ............................................................ 35

3.2 Aminocarbonylation of Aryl Triflates using Mo(CO)6 ...................... 37 3.2.1 Aryl Triflate Screen .................................................................... 38 3.2.2 Nucleophile Screen ..................................................................... 39

4. Palladium(II)-Catalyzed Heck-Type Reactions (Paper III & IV) ............. 42 4.1 Styrene Synthesis using Vinyl Acetate .............................................. 42

4.1.1 Solvent and Ligand Screen ......................................................... 42

4.1.2 Temperature and Vinyl Acetate Excess Screening ..................... 43 4.1.3 Screening of Arylborane Substrates ........................................... 44 4.1.4 Mechanistic Study ...................................................................... 46

4.2 Oxidative Heck Reactions using Aryltrifluoroborates and Aryl MIDA Boronates .................................................................................................. 50

4.2.1 Arylboronate Screening with an Electron-Poor Olefin ............... 51 4.2.2 Arylboronate Screening with an Electron-Rich Olefin ............... 53 4.2.3 ESI-MS Investigation ................................................................. 55

5. Palladium(II)-Catalyzed 1,2-Carbopalladation of Nitriles (Paper V & VI) ...................................................................................................................... 57

5.1 Synthesis of Arylamidines from Aryltrifluoroborates ........................ 57 5.1.1 Ligand Screen ............................................................................. 58 5.1.2 Screen of Aryltrifluoroborates .................................................... 58 5.1.3 Screen of Cyanamides with Different Aryltrifluoroborates ........ 61 5.1.4 Mechanism .................................................................................. 61

5.2 Synthesis of Aryl Ketones from Aryl Sulfinates ................................ 62 5.2.1 Ligand Screens............................................................................ 63 5.2.2 Screen of Aryl Sulfinates ............................................................ 64 5.2.3 Variation of Nitriles .................................................................... 65 5.2.4 ESI-MS Investigation ................................................................. 66

6. Concluding Remarks ................................................................................. 69

Acknowledgements ....................................................................................... 70

References ..................................................................................................... 72

Abbreviations

Ac aq Ar Bdpp Bn Bu CID dba DBU DFT DMAP DMF dmphen dppb dppp dppf EDG ESI Et EWG GC HTFA LC Nu Me MeCN MS(+) MS(-) MS/MS OAc p-BQ Pd Phen Ph Q RP

acetyl aqueous aryl 2,4-bis(diphenylphosphino)pentane benzyl butyl collision induced dissociation dibenzylideneacetone 1,8-diazabicyclo[5.4.0]undec-7-ene density functional theory 4-dimethylaminopyridine N,N-dimethylformamide 2,9-dimethyl-1,10-phenathroline 1,3-bis(diphenylphosphino)butane 1,3-bis(diphenylphosphino)propane 1,1'-bis(diphenylphosphino)ferrocene electron-donating group electrospray ionization ethyl electron-withdrawing group gas chromatography trifluoroacetic acid liquid chromatography nucleophile methyl acetonitrile mass spectrometry in positive mode mass spectrometry in negative mode tandem mass spectrometry acetate para-benzoquinone palladium 1,10-phenanthroline phenyl Quadrupole reversed phase

rt TEMPO TFA THF XPhos

room temperature 2,2,6,6-tetramethylpiperidine-1-oxyl trifluoroacetate tetrahydrofuran 2-dicyclohexylphosphino-2

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1. Introduction

1.1 Palladium Most of the palladium produced today is used in catalytic converters, which transform exhaust gases into less harmful substances.1 Other everyday appli-cations of palladium include jewelry, fuel cells, electronic components, pho-tography2 and the production of pharmaceuticals.3 Pd is a late transition- metal located at position 46 in the periodic table. It was discovered and iso-lated by Wollaston4 in 1803, and named after the asteroid Pallas, but was not recognized as a unique resource in organic synthesis until over 150 years later. The versatility of palladium in synthetic organic chemistry is due to a number of important fundamental properties of the metal. A selection of some of these properties and the chemical consequences will now follow. Firstly, palladium strongly prefers the oxidation states 0 and +2, which are separated by a relatively narrow energy gap, making palladium an excellent catalyst for both oxidation and reduction reactions. Secondly, the moderately large van der Waals radius of palladium together with the high number of d-electrons (favorable d10 and d8 complexes) means that the organometal is classified as rather “soft”, with a high tendency for concerted reaction as well as a high affinity to “soft” - and -donors, leading to useful chemose-lectivity. Finally, Pd is relatively electronegative, resulting in a rather nonpo-lar Pd-C bond, suppressing the reactivity towards polar functional groups.5

1.2 Palladium Catalysis in C-C Bond Forming Reactions The unique ability of palladium to selectively break and form bonds between two atoms without being consumed was not immediately realized upon its discovery, and although repeated reports of various synthetic transformations followed for the next 150 years, it was not until the discovery of the Wacker process6 (Scheme 1) in 1959 that the first milestone in the history of organo-palladium was achieved. Another important use of palladium is in catalytic hydrogenation which was reported several decades prior to the Wacker process.7-8 However, this process is not of direct interest for the development of C-C couplings. The second milestone was reached in 1968, when Richard F. Heck published seven consecutive articles on palladium-mediated trans-

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formations,9-15 including the arylation and vinylation of an olefin, later to be developed by Mizoroki16 and Heck,17 into the Mizoroki-Heck reaction (Scheme 2). Many groups have since contributed to the development of pal-ladium catalysis resulting in a vast number of transformations that are used routinely in drug discovery, and other industrial processes. In addition to Heck, two other important pioneers in this field should be mentioned, name-ly Akira Suzuki18-19 and Ei-ichi Negishi.5,20 The Nobel Prize in Chemistry was awarded to these three scientists in 2010 and can be regarded as the third milestone in the field of palladium(0)-catalyzed cross-couplings (Scheme 3).

In parallel with the progress in the cross-coupling reactions came the de-velopment of their carbonylative versions. Palladium-catalyzed carbonyla-tion was first reported by Heck and coworkers in the 1970s.21-23 They de-scribed the reaction of vinyl and aryl halides with carbon monoxide to form acylpalladium intermediates which reacted with various nucleophiles to pro-vide carboxylic acids, esters, aldehydes or amides. Since then, carbonyla-tions has become an industrially important technique for converting both bulk and fine chemicals into a diverse range of products used in everyday life.24-25

Scheme 1. The catalytic Wacker reaction

Scheme 2. The Mizoroki-Heck reaction

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Scheme 3. Typical palladium(0)-catalyzed cross-coupling reactions

Scheme 4. General palladium(0)-catalyzed carbonylative cross-coupling reactions

1.3 Palladium Ligands Given the favorable Pd(0) (d10) and Pd(II) (d8) oxidation states, palladium prefers the coordination of four ligands, each contributing two electrons, in order to form stable 18- and 16-electron complexes. A palladium ligand is defined as anything capable of coordination to the palladium center, such as solvent, a reactant, a base, an additive, etc.5,26 However, there are numerous commercially available dedicated mono- and polydentate ligands that can be used in palladium catalysis. Hence, the ability to fine-tune the catalytic prop-erties of palladium is closely related to the electronic and steric properties of the ligands.

Figure 1. Key ligands employed in the work presented this thesis

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1.4 Palladium(0) Catalysis Palladium(0)-catalyzed reactions have found widespread use in many areas of organic chemistry,27 e.g. medicinal chemistry3 and the preparation of fine chemicals,28 due to their impressive range of functional group tolerance and high chemo- and regioselectivity. Many different reactions are included in this type of reaction, all of which are initiated by the oxidative addition of an electrophile, typically an aryl/vinyl halide or a sulfonate such as a triflate or a tosylate (hereafter denoted X). Instead of discussing all the possible routes for the formation of organopalladium species, the following sections will briefly describe five fundamental processes involved in the catalytic cycles of the Pd(0)-catalyzed carbonylation reactions discussed in this thesis (Scheme 5).

Scheme 5. The five fundamental steps involved in palladium(0)-catalyzed carbonyl-ative cross-coupling reaction: i) oxidative addition, ii) CO coordination, iii) 1,1 insertion, iv) transmetallation v) reductive elimination

1.4.1 Oxidative Addition In general, to be useful as a pre-catalyst, the palladium source should be a “bench-stable” 16- or 18-electron species. This complex must quickly be-come an activated 14-electron species through the loss of two ligands in solution. This catalytically active Pd0L2 species then coordinates to the

-system in the electrophile, followed by the migration of Pd to a possible transition state, where the metal binds in a 2 fashion over the C-X bond in the electrophile. The actual mechanism behind the next step is still under

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debate,29-34 but involves the cleavage of one covalent bond (C-X) to form two new bonds (R-Pd-X). For this reason, a non-bonded electron pair on palladium becomes involved in a new bond which results in an increase in the oxidation state of Pd from 0 to +2. The oxidation of Pd will change the tetrahedral geometry into a square planar complex. Generally, this step is favored by electron-donating monodentate phosphine or carbene ligands35 or bidentate ligands with a small bite angle (Scheme 5, i).32,36

1.4.2 CO Coordination and Insertion The next step in the carbonylation reactions is the coordination of CO to palladium (Scheme 5, ii). This is considered to be an associative substitution supported by the relatively stable 18-electron intermediate,26 but could pos-sibly be a dissociative exchange with a weakly bound anion such as triflate or tosylate. With the CO and the electrophile in a cis relationship on palla-dium the organyl group migrates to the CO carbon and an acylpalladium complex is formed, or expressed another way, the CO undergoes a 1,1-insertion into the Pd-organyl bond (Scheme 5, iii).

1.4.3 Transmetallation The step following insertion in carbonylative cross-coupling usually in-volves the reaction of an organometallic or organometalloid nucleophile denoted M-R (M = Mg, Zn, B, Al, Sn, Si, Hg) with the Pd complex. This process is defined as transmetallation (Scheme 5, iv) and delivers the orga-nonucleophile to the Pd center. The process is driven by the difference in electronegativity of the two metals. Thus, palladium must be the more elec-tronegative metal for transmetallation to occur.

1.4.4 Reductive Elimination The product-forming step in most Pd(0)-catalyzed reactions, as well as in the carbonylative Stille coupling described in this thesis, is reductive elimina-tion. This step proceeds through a three-centered transition state in order to form a new C-C bond between the electrophilic acyl group and the nucleo-phile. The non-bonded electron pair in palladium that was involved in a new bond in the previous oxidative addition step is now returned and the catalyti-cally active Pd0L2 species is regenerated (Scheme 5, v).

1.5 Mo(CO)6-Mediated Carbonylation The term carbonylation covers a large number of closely related reactions, all of which have in common that carbon monoxide is incorporated into a

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substrate by the insertion of CO into an aryl-, benzyl- or vinylpalladium complex followed by reaction with various nucleophiles. The incorporation of CO is an important process in industry for the transformation of bulk chemicals into more precious products. For example, carbonylation of ole-fins, which comprise the basic raw materials in the chemical industry, pro-vides more valuable products such as aldehydes, alcohols and carboxylic acid derivatives.24-25,37 Despite large-scale applications in industry, reactions with carbon monoxide are comparatively uncommon in more complex or-ganic synthesis. This may be due to the general reluctance of synthetic or-ganic chemists to use gases as reagents and the necessity of using high-pressure equipment, as well as the fact that CO is a highly toxic and flamm-able gas. A convenient way to avoid these problems is to use a solid reagent with the ability to release carbon monoxide in situ during the reaction, examples of which are the metal carbonyls Cr(CO)6, W(CO)6, Co2(CO)8 and especially Mo(CO)6. The CO-releasing ability of molybdenum hexacarbonyl in Pd-catalyzed reactions has been extensively studied by our research group in Uppsala and represents one of the more convenient alternatives to CO gas currently availible.38-44 Recently, Skrydstrup and co-workers reported vari-ous non-metal containing CO-releasing systems which will probably provide useful alternatives in the future.45-47

1.5.1 Carbonylative Stille Coupling The typical cross-coupling reactions depicted in Scheme 3 are available in a carbonylative version, with one exception, namely Kumada coupling. The first reports of the palladium-catalyzed carbonylative Stille coupling of aryl diazonium salts with organotin reagents appeared in 1982 and 1987 (Kiku-kawa and coworkers).48-49 Shortly thereafter, Echavarren and Stille presented a similar carbonylative coupling of aryl triflates with organostannanes.50 Further developments expanded the scope of this reaction and various elec-trophiles have been coupled with different stannanes in the presence of CO gas.37 In 1995, Johansson and coworkers reported the first gas-free protocol using arene-Cr(CO)3 complexes of organostannanes. The Cr(CO)3 moiety provided the CO required for the coupling reaction.51 More recently, Nilsson and coworkers presented a Mo(CO)6-assisted coupling of arylstannanes with aryl triflates and aryl bromides.52 This protocol was further expanded to ben-zyl halides as described in Chapter 3.

1.5.2 Aminocarbonylations Amides constitute one of the most important functional groups in contempo-rary chemistry. They are essential for sustaining life, linking the amino acids in proteins such as enzymes. They are found in numerous natural products and are some of the most prolific moieties in modern pharmaceutical mole-

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cules. Despite their obvious importance, the majority of amide bond syn-theses require stoichiometric amounts of coupling reagents, making them generally expensive and wasteful procedures.53 This has led to greater efforts in the expansion and development of palladium-catalyzed methods, discov-ered by Heck in the mid 1970s, for amide bond formation.22

As previously described, the acylpalladium intermediate can be reacted with various nucleophiles, to provide various products. The use of amines as nucleophiles under catalytic conditions provides the desired amide functio-nality without producing stoichiometric amounts of waste. The mechanism is similar to the carbonylative cross-coupling discussed above, but differs in the final steps, as depicted in Scheme 6. Here, there are different possibilities for the incoming nucleophile, one being initial coordination to palladium followed by reductive elimination, and the other direct attack of the nucleo-phile on the acyl-carbon. The latter is believed to be the dominant route in aminocarbonylations.54

Scheme 6. Principal view of the palladium(0)-catalyzed aminocarbonylation reac-tion in relation to carbonylative cross-coupling

1.6 Palladium(II) Catalysis It might seem strange that Pd(II)-catalyzed C-C bond formation has often been overshadowed by the significant advances in Pd(0)-catalyzed cross-coupling, bearing in mind that Pd(II)-mediated processes is the actual start of palladium-catalyzed C-C bond chemistry i.e. the initial vinylation reactions described by Heck9 and the Fujiwara,55 as well as numerous Pd(II)-catalyzed

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oxidations.56 One of many reasons behind this development is the fact that many of the Pd(II)-catalyzed reactions require a stoichiometric reoxidant in order for the reaction to be catalytic. Mechanistically, the two pathways dif-fer in the way which palladium enters the catalytic cycle. In palladium(II) catalysis the organopalladium species is formed through a non-redox me-chanism, whereas in palladium(0) catalysis it is generated through oxidative addition.

Among the reactive organyl sources in Pd(II)-catalyzed coupling reac-tions, one will find arenes/heteroarenes, organometals, benzoic/cinnamic acids, aryl phosphonates and aryl sulfinates among others. The field of Pd(II)-catalyzed transformations is expanding rapidly, and a full description is outside the scope of this thesis. The sections below will therefore only describe the fundamental processes involved in the catalytic cycles of the Pd(II)-catalyzed reactions studied in this work.

1.6.1 Transmetallation There are a number of ways of generating the organopalladium species in Pd(II)-catalyzed coupling reactions, e.g. transmetallation, electrophilic pal-ladation, decarboxylation57 and desulfination among others. Although elec-trophilic palladation (C-H activation) and decarboxylation protocols are cur-rently “hot” topics, the author still believes that, from a practical synthetic point of view, the transmetallation process is a more robust and convenient method for the generation of aryl-palladium species. As described above (Section 1.4.3), transmetallation is defined as the exchange of a ligand be-tween two metal centers, or more precisely, between a transition metal and an organyl-metal or metalloid. In the Pd(II) pathway transmetallation is the first step in the catalytic turn rather than oxidative addition as in Pd(0) catal-ysis. As a consequence, the Pd(II) species undergoing transmetallation will not be associated with an organyl group, apart from the added ligands. None-theless, it is believed that the process proceeds through a similar four-center transition state, but whether this is formed by a dissociative or an associative pathway is yet to be determined.

1.6.2 Desulfination Although the first desulfitative palladium-mediated reaction was reported more than 40 years ago,58 this method of generating an aryl-palladium spe-cies experienced a revival in 2011.59-65 At the time of writing, no mechanistic studies of the process had been reported, but the author’s simplified view of the desulfination process is depicted below (Scheme 7). An aryl sulfinate or aryl sulfinic acid coordinates to X-PdIIL2, a four membered transition state is formed and sulfur releases the bond to the aryl-carbon. Finally, SO2 is elimi-nated through ligand exchange.

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Scheme 7. Proposed simplified mechanism for the Pd(II)-mediated desulfination

The proposed mechanism is analogous to the mechanism suggested for Pd(II)-mediated decarboxylation,66 but differs in that desulfination benefits from tolerating non ortho-substituted arenes.

1.6.3 Insertion Insertion is the C-C bond forming step in the palladium(II)-catalyzed reac-tions described in this thesis. The outcome of this step is essential in both the Pd(0)-catalyzed Mizoroki-Heck reaction and the oxidative version as it de-termines the outcome of the overall reaction. There are two principal path-ways by which insertion can occur: the neutral pathway and the cationic pathway (Scheme 8).67-68 In the neutral pathway (A), a neutral ligand or one of the coordinating atoms of a bidentate ligand dissociates and an alkene coordinates forming a neutral square planar complex (iiiA). In the subsequent carbopalladation, the R group migrates to one of the double bond carbons, while palladium binds to the other carbon to form ivA. In the cationic path-way (B), an anion dissociates to form a cationic complex (iiB). This complex coordinates with the alkene (iiiB) and migratory insertion follows to form ivB. In both pathways, the alkene must be located cis to the R group to facilitate insertion.

Scheme 8. Neutral (A) and cationic (B) pathways for alkene coordination and inser-tion. R = aryl/vinyl, Y = OAc, TFA, X = halide, L = ligand

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The cationic pathway is favored by polar solvents, bidentate ligands and weakly binding anions such as –OTf, –OAc and –TFA all in agreement with the conditions used in the reaction in this thesis, and therefore believed to be the dominant pathway herein.

1.6.4 Elimination The product of the oxidative Heck reaction is released through -hydride elimination and this step determines the cis/trans ratio in the case of linear products. A vacant site on palladium is required and the eliminating hydride must be orientated syn to the metal. Elimination leads to a palladium hydride (Pd-H) coordinated to the double bond of the newly formed product. As described in the previous section, the aryl-Pd inserts into the olefin in a syn fashion and therefore rotation around the former double bond is necessary to place a hydrogen in a syn relationship with palladium (Scheme 14).

In addition, -elimination of heteroatom groups such as OAc, OH, Br and Cl, serves as a possible pathway in the product-forming step. Compared with the -hydride elimination, the -heteroatom elimination is believed to pro-ceed through a trans mechanism with the rates in the following order: -halide > -OAc > -OR > -OH. It is generally faster than -hydride elimi-nation and the direct regeneration of the active Pd(II) complex is a unique advantage, obviating the need for an external reoxidant.69-71

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1.6.5 Reoxidation Originally, palladium(II)-mediated coupling reactions required stoichiome-tric amounts of palladium. This was due to the fact that palladium often un-dergoes reductive elimination at the end of each catalytic turn, ending up, in this case, with inactive Pd(0). In the oxidative Heck reaction the product is formed after -hydride elimination and Pd-H is formed. Under basic condi-tions, Pd-H is effectively reduced to Pd(0) by reductive elimination and an oxidant is needed to regenerate Pd(II).

Commonly used reoxidants are metal salts, such as copper-6 and silver salts,72 MnO2,73 p-BQ74 and other quinones,75 TEMPO,76 desyl chloride77 and peroxides.76 Recently, the introduction of oxygen as the sole reoxidant has resulted in more sustainable Pd(II) protocols.78-79

The mechanistic understanding of the oxygen-mediated reoxidation of palladium has increased as a result of important contributions by the research groups led by Stahl,80-94 Sigman,56 Bäckvall,76 Jutand95 and Goddard.96-101 In addition, the mechanistic similarities between oxygen and p-BQ have been highlighted by Stahl and coworkers.87,89,102 Two main reoxidation pathways have been proposed: the palladium(II)-hydride pathway and the palla-dium(0)-protonolysis pathway (Scheme 9).81,86,97,103

Mechanistic investigations have so far not been able to provide conclu-sive evidence for one mechanistic pathway over the other, and it seems like-ly that both pathways may be possible, depending on the ligands, solvents, additives and substrates used.

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Scheme 9. The two proposed pathways for the oxygen-mediated regeneration of Pd(II) and the related p-BQ mechanism as proposed by Stahl. The Pd(II)-hydride pathway for p-BQ is a route suggested by the author and has yet to be evaluated, see Section 4.2.

1.6.6 The Aryl Source There are many possible aryl sources and mechanisms behind the generation of the aryl-palladium species, as discussed in Section 1.6. This section de-scribes the Pd(II) active electrophiles included in this work, namely aryl boronic acids, aryltrifluoroborates, aryl MIDA boronates and aryl sulfinates.

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Organoboronic Acids Boronic acids are probably the most frequently used class of organometallo-id molecules in cross-coupling reactions. Unlike many organometallic deriv-atives, boronic acids are usually stable in air and resistant to moisture, and have relatively low toxicity and environmental impact.104 These widely commercially available substrates have served as robust coupling partners in the Suzuki-Miyaura reaction for the last three decades.

The mechanism behind, and the initiation of, the transmetallation between palladium and boronic acid are not completely understood. Available infor-mation on base assisted aryl-Pd transmetallation suggests two possible processes: one being the transmetallation of the pre-formed quaternized bo-ron, and the other transmetallation between the boronic acid and an oxo-palladium(II) complex (Scheme 10).105 For many years it was accepted that the R-B(OH)2 substrate was inactive and required activation by a nucleophile to form the active boronate (R-B(OH)2Nu). This issue was addressed by the introduction of the aryltrihydroxyborates as preactivated boronates.106 In a recent study by Hartwig, the second route was found to be dominant under the conditions studied, but both routes were energetically accessible and the strength of the base was found to play a role in the selection of pathway.107

Scheme 10. Simplified view of the suggested pathways for the transmetallation of arylboronic acids

Organotrifluroborates Organotrifluoroborates have been known for quite some time,108 but it was not until Vedejs and coworkers109 reported a convenient method for their preparation that these compounds became widely available (Scheme 11). The reaction occurs within minutes or hours depending on the starting ma-terial. In the author’s experience, when starting from boronic acids, the transformation is almost instant upon the addition of KHF2. Organotrifluoro-borates are today widely commercially available as a result of their success in cross-coupling chemistry, mainly due to the pioneering work of Genet110 and the continued work by Molander. A large number of valuable cross-coupling methods is now available.111-113

Scheme 11. General method for the preparation of potassium organotrifluoroborates

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In addition to their superior shelf-life, relative to boronic acids, organo-trifluoroborates are capable of withstanding a variety of reaction conditions, hence, providing the possibility to elaborate the organic substructure.113 Their comparatively high resistance towards the competitive proto-deboronation displayed in the classical cross-coupling reactions was disap-pointingly not achieved in the Pd(II) reactions presented in this thesis. Vir-tually all classes of organotrifluoroborates (aryl, heteroaryl, alkenyl, alkynyl and alkyl) have demonstrated the ability to undergo palladium(0)-catalyzed cross-coupling reactions, but the number of palladium(II)-catalyzed reac-tions is still limited.

There still remains much to learn regarding the nature of the transmetal-lating boron species in this class. In a recent study, the most reactive boro-nate was found to be the fully hydrolyzed trihydroxyborate. This implies that optimization of the conditions towards balanced hydrolysis would suppress the undesirable protodeboronation and oxidative homocoupling.114 In addi-tion, Jutand and coworkers recently published a kinetic study on the addition of fluoride in the Suzuki-Miyaura reaction. Their data indicated that the fluo-ride ion assisted both transmetallation and reductive elimination, but sup-pressed reactivity by the formation of the unreactive ArB(OH)3-nFn

-.115 Both investigations address the importance of the relative F- concentration in order to fine-tune the reaction, something that would be controlled by the added water and base in the use of organotrifluoroborates.

MIDA boronates The N-methyliminodiacetic acid (MIDA) boronates are in many ways related to the trifluoroborates and have recently also emerged as particularly attrac-tive alternative organoboron coupling partners. These boron reagents exhibit exceptional shelf-life, are easy to synthesize (Scheme 12) and isolate, and are compatible with many synthetic reagents. MIDA boronates are also un-reactive towards transmetallation. Burke and coworkers demonstrated that cross-coupling of unstable boronic acids via the in situ, rate-controlled hy-drolysis of MIDA boronates is a general solution for the Suzuki-Miyaura reaction. What the MIDAs lack in atom economy can be compensated for by the possibility of performing silica gel chromatography with these substrates, allowing wider application in the synthesis of complex organoboron building blocks.116-118

Scheme 12. The preparation of aryl MIDA boronates

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Aryl Sulfinates Compared with the aryl sources described above, aryl sulfinates or aryl sul-finic acids are by far the most anonymous. There are only a few commercial-ly available substrates, but this class of arylating agent can easily be pre-pared from the corresponding sulfonyl chloride (Scheme 13). They have occasionally appeared in Pd-mediated reactions,58,119-120 but it was somewhat unexpected that 2011 would be the year when the sulfinates reappeared as substrates in the Pd(II)-catalyzed field as depicted in Figure 2.

Scheme 13. General method for the preparation of sodium aryl sulfinate

Figure 2. The timescale for published Pd-mediated desulfination reactions

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1.7 Styrene Synthesis Styrene is an important monomer in the petrochemical industry as a building block for many different kinds of polymers. Most production is based on dehydrogenation of ethyl benzene, catalyzed by potassium-promoted iron oxide.121

Styrene derivatives are also frequently used on more moderate scale by synthetic chemists as substrates for e.g. oxidation,122 metathesis123 and Diels-Alder reactions.124 The versatility of styrenes has promoted the development of several transition-metal-catalyzed coupling methods, and many of the previously discussed cross-coupling reactions have been used, e.g. Hiyama, Stille and Suzuki, as well as the Heck reaction.125 Little or no attention has been directed towards the palladium(II)-catalyzed version of this reaction, a process that would avoid the use of gaseous vinyl halides or expensive vinyl sources (Figure 3). Figure 3. Prices from Sigma-Aldrich® for some typical vinyl sources used in styrene synthesis and vinyl acetate

1.8 The Oxidative Heck Reaction The oxidative version of the Heck reaction was actually the first catalytic Heck reaction to be discovered. In 1968 Heck reported the palladium(II)-catalyzed arylation of olefins from phenylmercuric chloride, using catalytic amounts of CuCl2 assisted by oxygen for the regeneration of Pd(II).9 Seven years later, he and Dieck reported the first palladium(II)-mediated vinylic substitution of organoboronic acid, using stoichiometric amounts of palla-dium acetate,126 today referred to as the oxidative Heck reaction. This non-catalytic coupling reaction was discontinued and efforts were focused on the catalytic palladium(0) reaction. Several years later, in 1994, the oxidative Heck reaction resurfaced with the introduction of arylboronic acids as arylat-ing agents,127 although the author regards the proposed mechanism as ques-

27

tionable. Seven years later, Mori et al. reported the first method using boron-ic acids in combination with a dedicated reoxidant, Cu(OAc)2, and proposed a more plausible mechanism.128 In 2003, Larhed and coworkers turned their attention to the oxidative Heck reaction and published the first microwave-assisted protocol using the same reoxidant.129 This work was followed by with more sustainable protocols using molecular oxygen as reoxidant,68,130 independently reported by the group led by Jung.78 The research group in Uppsala then started to use more convenient open-air conditions,79 and these two groups further optimized the reaction and developed the first base-free protocols in parallel.131-132 The following year, Xiao and coworkers were able to arylate both electron-rich and electron-poor olefins without the addi-tion of a reoxidant, using the Pd(II)-hydride pathway. The component acting as hydride acceptor could not be identified, but the non-arylated olefin itself was found to be reduced.133

Scheme 14. Proposed catalytic cycle of the oxidative Heck reaction, illustrating the different regioisomeric outcome of the product depending on the electronic proper-ties of the olefin

The mechanism behind the oxidative Heck reaction have largely been adopted from the Pd(0)-catalyzed reaction. These two reactions differ in the steps providing the arylpalladium intermediate and the regeneration of the active catalyst (Scheme 14). The regiochemical outcome using Pd(II) cataly-sis will be governed by the steric and electronic properties of the olefin, the aryl-palladium species and the ligand. In general, the electronic properties of the olefin will influence the regiochemistry. The electron-poor Pd(II) center will coordinate most strongly to the carbon with the highest electron density, while the Ar group will migrate to the carbon with the lowest charge density.

28

As a result, electron-poor alkenes will favor the linear product, and electron-rich alkenes will favor the branched product.67 Steric factors also influence the regioselectivity, but these are more dominant in the neutral pathway (Scheme 8) seen in the classical Heck reaction. Scheme 14 shows the out-come with the two extremes: electron-rich and electron-poor olefins, when olefins with intermediate electronic properties are used, it is often difficult to predict the regioselectivity. Sigman et al. recently reported a regioselective arylation method for electronically non-biased olefins,134 and it is reasonable to expect that similar methods will appear in the near future.

1.9 Palladium-Catalyzed Nitrile Insertion Nitriles are considered to be relatively inert towards palladium-mediated transformations, as acetonitrile is a commonly employed solvent in organo-palladium chemistry. The 1,2 carbopalladation of nitriles, providing the cor-responding carbon substituted imine, was first reported in low yield by Garves in 1970,58 and on rare occasions at the end of the 1990s.135-136 This fascinating insertion of an aryl-palladium species into the polar triplebond of the nitrile was later highlighted in a series of articles by Larock and cowork-ers, as an effective system for intramolecular carbocycle synthesis.137-139 Similar reactivity was reported by Lu et al. under Pd(II) conditions,140 but the reaction gained new ground when Larock et al. introduced the more ver-satile Pd(II)-catalyzed intermolecular coupling, using both arenes and aryl-boronic acids (Scheme 15).141-142 The scope of the boronic acids was later expanded by Lu et al.143-144

The insertion mechanism has not been studied in detail, apart from a re-cent online electrospray ionization mass spectrometry (ESI-MS) analysis of the formation of ketones from benzoic acids and alkyl nitriles (Scheme 16).145

Scheme 15. The Pd(II)-catalyzed intramolecular nitrile insertion reaction

29

Scheme 16. Proposed mechanism supported by ESI-MS-detected cationic palladium complexes

The catalytic cycle in Scheme 16 involves the following steps. First, benzoic acid coordinates to the Pd center through ligand exchange, to generate com-plex A. This is followed by decarboxylation, mediated via a four-membered transition state, which provides the aryl-Pd species B. Coordination of the nitrile then generates complex C, the aryl group migrates and is inserted into the nitrile carbon, forming the ketimine complex D. Finally, benzoic acid protonates the ketimine, which is then released from the palladium center.

This is a facile and atom efficient method for the generation of carbo-cycles, imines, ketones and amidines, and will be further discussed in Chap-ter 5.

1.10 Electrospray Ionization Mass Spectrometry ESI-MS has been used in some of the studies presented in this thesis to detect intermediates in an ongoing reaction. A simplified overview of the technique and its use as a tool in mechanistic investigations will be given below.

In 1968, Dole and coworkers produced charged polystyrene molecules us-ing the electrospray (ES) technique,146 after having visited a car manufactur-er where cars were painted by ES. Several years later, in 1984, Fenn and coworkers demonstrated that ES could be used as an ion source for mass spectrometry (MS),147 and the following year they reported the use of ESI-MS for the analysis of peptides and proteins.148 Fenn was later awarded the Nobel Prize in Chemistry together with Tanaka, for contributions to the field of mass spectrometry. The technique has since been extensively developed and has become a mild, robust and sensitive tool for studying non-volatile and thermally labile biomolecules149 and organometallic species.150

30

The process employed for the generation of separated ions is depicted in Figure 4, and can be described as follows. An applied electric field leads to the enrichment of ions of the same polarity as the capillary tube near the surface of the liquid front. The ion build-up destabilizes the liquid surface and droplets are formed. Evaporation of solvent brings the charges closer and further evaporation in combination with increased Coulomb repulsion produces ions in the gas-phase.151

Figure 4. Simplified illustration of electrospray in the positive mode

The ions are then separated in a mass analyzer, commonly a quadrupole mass analyzer, prior to detection. In the work described in this thesis, a triple-quadrupole instrument was used, which consists of two mass resolving quadrupoles with an intermediate quadrupole between them that acts as the collision cell. This allows for different modes of analyzing the sample such as, product ion scan, precursor ion scan, neutral loss scan and selected reac-tion monitoring.151

Today ESI-MS, together with the tandem version (MS/MS) has become a valuable tool in the mechanistic study of organometallic reactions. Analysis is fast, intermediates at low concentration can be detected, and complex mix-tures are tolerated, thereby providing the ability to monitor fully productive catalytic systems.

The use of ESI-MS for mechanistic investigations of Pd-catalyzed reac-tions is constantly growing, especially the C-C bond forming reactions, pro-viding new data through the identification of short-lived Pd intermediates at low-concentration.145,152-158 The detection of Pd complexes is straightforward due to the characteristic and easily identified natural isotopic distribution (Figure 5), but one obvious drawback is that only charged species can be detected. Additional complications are the lack of information on whether a complex is part of the catalytic cycle or an inactive resting state, and the cis/trans relationship of the coordinated ligands and substrates. Some of these problems could be circumvented e.g. a) by using a permanently charged ligand or substrate to make the previously neutral complex

31

charged;159-160 b) isolation of an intermediate complex (ion-trapping) fol-lowed by the addition of a reactant provides information regarding reactivi-ty;161 and c) density functional theory (DFT) calculation of the possible steric conformations of an identified complex can provide geometric information.

Figure 5. Natural isotopic distribution of palladium

Recently, the technique has been applied to kinetic studies by measuring the intensities of key intermediates over the time course in a given reaction. Progress in this area has the potential to provide unique mechanistic infor-mation in the future.159,162

100 102 104 106 108 110 112

m/z

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2. Aims of the Present Study

The main aim of the work presented in this thesis was to study aryltrifluoro-borates as substrates in palladium(II)-catalyzed reactions, with the emphasis on developing new synthetic methods. Palladium(0)-catalyzed Mo(CO)6-assisted reactions were also explored. The specific aims were as follows.

To expand the carbonylative Stille cross-coupling reaction to ben-

zyl halides. To identify suitable conditions for the palladium(0)-catalyzed

aminocarbonylation of aryl triflates and aryl tosylates with weak amine nucleophiles.

To develop a method for the synthesis of styrene derivatives from arylborane species and vinyl acetate.

To evaluate aryltrifluoroborates as substrates in the oxidative Heck reaction, and to identify the active boronate complex.

To develop a palladium(II)-catalyzed method for the synthesis of arylamidines.

To employ aryl sulfinates in Pd(II) catalysis.

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3. Mo(CO)6-Mediated Carbonylations (Paper I & II)

As a result of increased safety considerations linked to the complicated han-dling of gas bottles and delivery systems, the identification of stable solid or liquid reagents that emit gases on demand is important for the modern medi-cinal chemist.

3.1 Synthesis of Deoxybenzoins under Gas-Free Conditions As discussed in the Introduction, the research group in Uppsala has focused on the use of Mo(CO)6 as CO releasing agent, and the idea of developing a gas-free carbonylative Stille cross-coupling came up. This three-component, Mo(CO)6-mediated protocol proved to be an effective carbonylation method for the preparation of unsymmetric diarylketones, as previously reported by our group.52 Having developed this method, the idea of expanding the range of electrophiles used in the reaction arose. The coupling of arylstannanes with alkyl, vinyl and benzyl halides under these carbonylative conditions (Scheme 17) would promote the formation of ketones, -unsaturated ke-tones and deoxybenzoins; the latter being a common motif in pharmaceuti-cals and a useful building block in heterocyclic chemistry.

Scheme 17. Carbonylative cross coupling using aryl stannanes and vinyl and alkyl halides (R = vinyl, methyl, styryl, allyl, benzyl; X = Cl, Br, and I)

The study was initiated with the screening of a small number of electrophiles e.g. vinyl and alkyl halides (Table 1), using 10 mol % of the palladium cata-lyst, Pd(dppf)Cl2·CH2Cl2, one equiv.alent of Mo(CO)6, and 10 mol % of DBU in DMF at 100 °C for 16 h.

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Table 1. Carbonylative cross-coupling of phenylstannane with different electro-philes

Reaction conditions: The reaction was conducted in closed vessels at 100 °C on a 1 mmol scale of (2a–g) with 1.4 equiv. of 1a, 10 mol % Pd(dppf)Cl2·CH2Cl2, 1 equiv. of Mo(CO)6, and 10 mol % DBU in DMF (2 mL). a Isolated yield, >95% pure according to GC-MS. b Estimated yield after subtraction of benzophenone (by-product) by 1H NMR integration.

3.1.1 Vinyl and Allyl Halide Screening The first attempts using simple vinyl bromide, 2a, and methyl iodide, 2b, proved unsuccessful, with only a trace amount of carbonylation products, 3a and 3b, being formed (Table 1, entries 1 and 2). Analysis of the crude prod-uct mixture by LC-MS revealed benzophenone to be the major product. However, the styryl substrates, cis/trans- -bromostyrene (50:50), 2c, and 2-bromoindene, 2d, produced 72% and 33% isolated yields of the carbonyla-tion products 3c and 3d, respectively (Table 1, entries 3 and 4). -Bromostyrene, 2e, was productive ( 60% yield) but 3e could not be sep-arated from the major side product benzophenone. The allylic bromides 2f and 2g furnished less than 10% yields (Table 1, entries 6 and 7). A plausible explanation is that a -allyl mechanism is competing, leading to dehalogena-tion of the substrate rather than entering the desired catalytic cycle. In addi-tion, molybdenum carbonyl species are known to undergo oxidative addition

35

and form -allyl complexes in rare cases. However, the major product formed was yet again benzophenone. It became evident that using vinylic and allylic substrates gave a rather limited protocol, and screening continued with the next logical substrate, benzyl halides, in the hope of the direct as-sembly of deoxybenzoins.

3.1.2 Benzyl Halide Screening The benzylic halides were evaluated under the same conditions as those de-scribed above (Table 2). The first coupling of benzyl bromide, 4a, with phe-nylstannane, 1a, provided deoxybenzoin, 6a, in an encouraging isolated yield of 72% (Table 2, entry 1). With this new starting point the 16 h proto-col was evaluated by a small temperature/time investigation using micro-wave heating. The increased temperature had a negative effect on the yields, although the 140 °C 1 h protocol delivered a similar isolated yield of 6a (67%). The microwave-assisted investigation was discontinued and the con-venient but somewhat slow 16 h reaction time was retained as the standard method. Benzyl chloride, 5a, furnished the identical product, 6a, in an im-proved isolated yield of 81% (entry 2). Electron-rich 4-methoxybenzyls pro-vided acceptable yields of both the bromide 4b and chloride 5b (53% and 61%) (entries 3 and 4). The weakly -donating 4-methylbenzyl bromide, 4c, furnished a slightly higher yield (73%, entry 5). Benzyl bromide, 4d, with the methoxy-substituent in the meta position improved the outcome of the reaction, indicating the weak influence of electronic factors (entry 6). A slight trend was observed for both benzylic substrates, as the highest yields from the bromides were obtained using strong electron-withdrawing groups (see, for example, entries 7 and 10), and the best outcome with the benzyl chlorides was seen for entries 9 and 11. The carboxylate moiety proved to be an exception to this trend and was not compatible with this reaction protocol (no product could be isolated) (entry 8). The mechanistic explanation behind this was not pursued, but could possibly be attributed to interference in the coordination to palladium by the carboxylate moiety. Accordingly, the cor-responding methyl ester was found to be productive (65%, entry 9). With a slightly smaller excess of arylstannane (1.1 equiv.) the chemoselectivity for activation of the C(sp2)-X and C(sp3)-X bond was in complete favor of the benzylic halogen, as is evident from entries 12-15. This is an important find-ing as halogen-substituted products provide useful building blocks for fur-ther synthetic elaboration. In general, benzyl chlorides performed slightly better than, or as well as, the corresponding bromides (cf. entries 1-4, 13 and 14). Nucleophilic heteroaromatic stannanes such as the 3- and 2-pyridines, 1b and 1c, were incompatible with this protocol, yielding none of the desired carbonylation products (entries 16 and 17). The competing SN2 reaction fur-nishing benzylation of the pyridine nitrogen seemed to be the cause of this, as the destannylated N-benzylpyridinium salt was the major by-product de-

36

tected with LC-MS. However, non-nucleophilic heteroaromatics such as thiophene and furan furnished workable yields (entries 18 and 19).

Table 2. Carbonylative cross coupling of arylstannanes with different benzyl ha-lides.

Reaction conditions: The reaction was conducted in closed vessels at 100 °C on a 1 mmol scale of (4a-i, 5a-f) with 1.4 equiv. of 1a-e, 10 mol % Pd(dppf)Cl2·CH2Cl2, 1 equiv. of Mo(CO)6, and 10 mol % DBU in DMF (2 mL). aIsolated yield, >95% pure according to GC-MS and 1H NMR. bMicrowave heating for 30 min at 140 °C. cMicrowave heating for 1 h at 140 °C. dMicrowave heating for 1 h at 160 °C. e 1.1 equiv. of 1a. n.d. = Product was not detected by LC-MS or GC-MS.

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3.2 Aminocarbonylation of Aryl Triflates using Mo(CO)6 In light of the successful development of an aqueous aminocarbonylation protocol using aryl halides by our group,163 attention was turned towards aryl triflates and tosylates. There was at that time only one report describing the use of aryl triflates in combination with Mo(CO)6 and water, providing the corresponding benzoic acids by a hydroxycarbonylation process.164 As a starting point for the investigation the in-house protocol for the aminocarbo-nylation of aryl chlorides in water was chosen using Herrmann’s pallada-cycle (5%), [(t-Bu)3PH]BF4 (10%) and Na2CO3 (3 equiv.) with 4-methoxyphenyl triflate, 7a, and piperidine, 8a (Table 3). The reaction was carried out in water for 30 min at 170 °C, but disappointingly no product was formed except the undesirable hydrolyzed triflate, 4-methoxyphenol. The ligand was replaced by the bulky electron-rich Xphos, which gave small amounts of product. Yet again, 4-methoxyphenol was the major product formed.

Abandoning water as solvent and using dioxane led to the production of the desired amide product. Using Cs2CO3 as base, the conditions were fine-tuned to give the final protocol using palladacycle (2.5%), Xphos (7.5%), Mo(CO)6 (1 equiv.), Cs2CO3 (3 equiv.) in 2.5 mL dioxane at 160 °C for 20 min. The choice of reaction conditions was driven by the aim of identifying a single, robust and convenient (air atmosphere) protocol producing overall good yields with a variety of electrophiles and nucleophiles. In other words, it might be possible to further optimize single entries.

38

Table 3. Aminocarbonylation of different aryl triflates with piperidine as nucleo-phile

Reaction conditions: The reaction was conducted under microwave irradiation in a sealed vial on a 0.25 mmol scale with 2.0 equiv. of 8a, 1.0 equiv. of 7a-k 1 equiv. of Mo(CO)6, 3.0 equiv. Cs2CO3, 2.5 mol % of palladacycle, and 7.5 mol % of Xphos in 2.5 mL of dioxane at 160 °C for 20 min. aIsolated yield, >95% pure according to GC-MS and 1H NMR. b5.0 equiv. of 8a at 180 °C for 40 min.

3.2.1 Aryl Triflate Screen Having developed the above protocol, different aryl triflates were investi-gated using 8a as nucleophile (Table 3). In general, the conditions proved to be productive with yields of the amide products ranging from an excellent 93%, for the best performing p-tolyl triflate, 7b, to a moderate 49% for the sterically demanding 7i. The electron-rich substrates, 7a and 7c, furnished similar yields of 78% and 84%, respectively, of the amide product. The elec-tron-poor triflates, entries 5, 6 and 10, preformed less well, and analysis of the crude mixtures using GC-MS indicated increased formation of the aryls derived from hydrogenolysis of the triflate functionality. The pyridine ring in 7g did not affect the productivity of the reaction, neither did the Pd(0) active chloride functionality in 7j, thereby demonstrating the useful chemoselec-tivity displayed by this protocol. Finally, the 2-naphthyl tosylate, 7k, was

39

successfully converted into the amide product, yielding 55% benzamide under modified conditions using 5 equivalents of amine 8a at 180 °C for 40 min. At the time, this was considered to be a success and various electron-rich aryl tosylates were screened, but the reactivity proved to be exclusive to the naphthyl substrate and instead of resulting in a separate publication it was included as a single entry.

3.2.2 Nucleophile Screen As the p-tolyl triflate, 7b, was found to produce the highest yield, it was chosen as the standard electrophile for the screening of various nucleophiles (Table 4). Bearing in mind the previous attempts to use an aqueous protocol, it was deemed interesting to evaluate an oxygen nucleophile in the dioxane protocol. The use of benzyl alcohol, 8b, as a co-solvent afforded the corres-ponding alkoxycarbonylation product 9l in a good yield (71%). The success-ful alkoxycarbonylation was noted, and the next nucleophile evaluated was methane sulfonamide, 8c. This amide nucleophile provided a moderate yield of acylsufonamide 9m, a functionality used as a carboxylic acid bioisostere in biologically active compounds.42 Attempts to access the Weinreb amide gave only the corresponding methyl amide, 9n, resulting from a competing reduction. Similarly, the use of hydroxylamine hydrochloride, which had been used previously by Larhed as a convenient solid ammonia source, af-forded the primary amide 9o in a moderate yield of 55%. The primary cyclic and acyclic amines, entries 5-7, proved effective as nucleophiles, furnishing good yields of the desired amide products. The more demanding substrates, entries 7-10, including the sterically disfavored nucleophiles 8i and 8j were then investigated. These amines reacted sluggishly providing only incom-plete conversion of the aryl triflate and consequently lower yields of isolated products.

Inspired by the previous findings of the Uppsala group165-166 and the work of others in this field,167 DMAP was added to improve these transformations. As demonstrated by entries 7-10, DMAP proved effective, and led to signifi-cant increases in the isolated yields of the amide products. The effect was maximized in the case of aniline, 8k. This nucleophile, weakened by reson-ance, furnished 70% of the isolated product when DMAP was added, com-pared with 21% under standard conditions.

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Table 4. Screen of different nucleophiles with p-tolyl triflate

Reaction conditions: The reaction was conducted under microwave irradiation in a sealed vial on a 0.25 mmol scale with 1.0 equiv. of 7b, 2.0 equiv. of 8b-k, 1 equiv. of Mo(CO)6, 3.0 equiv. of Cs2CO3, 2.5 mol % of palladacycle, and 7.5 mol % of Xphos in 2.5 mL dioxane at 160 °C for 20 min. aIsolated yield, >95% pure according to GC-MS and 1H NMR. bReaction performed in 1:1 (2.5 mL) dioxane / benzyl acohol 8b. c5.0 equiv. of Cs2CO3. d2.0 equiv. of DMAP was added to the reaction. In an attempt to obtain some information on the actual role of DMAP in this reaction, the aniline reaction (entry 10) was set up and irradiated for 5 min at 160 °C in the microwave cavity. A small amount was withdrawn from the reaction mixture and injected in an ESI-MS instrument, after dilution. Dis-appointingly, the DMAP acyl intermediated was not detected and no further ESI-MS analysis was performed. However, a mechanistic cycle was pro-posed based on previous publications in literature (Scheme 18).

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Scheme 18. Proposed role of DMAP in promoting the aminocarbonylation reaction.

The mechanisms governing steps i-iv in the catalytic cycle were discussed in Section 1.4 and no further discussion will be presented here. However, the nucleophilic DMAP was believed to attack the carbonyl carbon in the acyl palladium species, forming an activated acylpyridinium intermediate, A, susceptible to a second nucleophilic substitution into the desired amide, 9, simultaneously regenerating the Pd(0)L2 in order to initiate a new catalytic turn. The role of DMAP should thus be catalytic, but no attempt was made to reduce the amount of DMAP used.

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4. Palladium(II)-Catalyzed Heck-Type Reactions (Paper III & IV)

4.1 Styrene Synthesis using Vinyl Acetate Small-scale synthesis of styrenes often requires relatively expensive rea-gents, as mentioned Section 1.7. Vinyl acetate, on the other hand, can be regarded as a relatively inexpensive vinyl source in cross-coupling reactions, but low yields have been reported using aryl halides,168-169 apart from a sin-gle entry reported by Cabri et al.170 Recently, a cobalt-catalyzed version pro-viding styrenes in higher yields, when assisted by 10 equivalents of a reduc-ing agent to reactivate the catalyst, was published.171 Heck also tested vinyl acetate in his Pd(II)-catalyzed reaction with aryl mercuric chlorides in 1968,12 but only trace amounts of the styrene product was formed. However, a Pd(II)-catalyzed Heck-type reaction between arylboron substrates and vinyl acetate should proceed without the addition of a base or an external reoxidant, as -acetate elimination should regenerate the active Pd(II) spe-cies, thus providing a practical, convenient and low-cost route to obtain sty-rene derivatives, in a small scale.

4.1.1 Solvent and Ligand Screen To evaluate this idea, the reaction conditions from an in-house oxidative Heck protocol,132 were first investigated without addition of the reoxidant. In order to accelerate optimization the reactions were irradiated using micro-waves at 140 °C for 30 minutes in sealed vessels, employing 4-biphenylboronic acid (10a, 1 mmol) and vinyl acetate (10 mmol) as model substrates, to investigate the influence of different ligands and solvents (Ta-ble 5). The bidentate nitrogen ligand, dmphen, was found to be ineffective in this protocol, providing only small amounts of isolated styrene 11a. In addition extensive protodeboronation of 10a producing 13a was observed, together with the -hydride elimination product 14a. The favored solubility and mi-crowave-absorbing properties of DMF made it suitable as the standard sol-vent for a limited ligand screening. Various phosphine ligands were investi-gated and dppp soon emerged as the most promising one. This bidentate phosphine ligand seemed to have the appropriate properties for this trans-

43

formation (Table 5, entry 6), and was further investigated in combination with a variety of different solvents (Table 5, entries 6, 10-16). The best productivity was obtained using dppp as ligand and DMF as solvent, provid-ing styrene 11a in an isolated yield of 75% and only 6% of the by-product 13a (Table 7, entry 6). Fortunately, only trace amounts of the styryl ester, 14a, were formed, and no stilbene-type product, resulting from an additional oxidative Heck arylation of the styrene formed, was detected. At this time, the possibility of a Suzuki-Miyaura cross-coupling mechanism arose, and the reaction was performed using a Pd(0)-complex (Table 5, entry 16) yielding a moderate 57 % of the isolated styrene. Still, this was found interesting and the reaction was repeated in the presence of a base. However, basic condi-tions led to extensive formation of the protodeboronated by-product 13a.

Table 5. Screen of different solvents and ligands

Entry Ligand Solvent Yielda 11a 13a 14a

1 dmphen MeCN 14 8 14 2 dmphen DMF 5 2 17 3 PPh3 DMF 3 4 n.d. 4 P(o-tol)3 DMF trace 5 n.d. 5 dppe DMF 43 17 trace 6 dppp DMF 75 6 trace 7 dppb DMF 4 4 n.d. 8b none DMF n.d. trace n.d. 9 none DMF 5 trace n.d. 10 dppp MeCN 43 22 trace 11 dppp Toluene 21 21 trace 12 dppp Dioxane 48 24 trace 13 dppp Acetone 44 19 trace 14 dppp H2O 48 12 trace 15c dppp DMF 60 5 trace 16d dppp DMF 57 7 trace

Reaction conditions: A 5 mL Pyrex glass vial was charged with 10a (1.0 mmol), vinyl acetate (10.0 mmol), Pd(OAc)2 (0.02 mmol), ligand (0.022 mmol), and solvent (2 mL). The vial was thereafter sealed under air and exposed to microwave irradiation (140 °C, 30 min). aIsolated yield, >95% pure according to GC-MS. bNo catalyst added. cUsing 0.2 mmol Pd(OAc)2 and 0.22 mmol dppp. dUsing 0.1 mmol Pd2(dba)3 as Pd-source. n.d. = not detected by GC-MS analysis of the crude mixture.

4.1.2 Temperature and Vinyl Acetate Excess Screening A time and temperature investigation was performed with the aim of reduc-ing the reaction time and increasing the yield of styrene 11a (Table 6). A time and temperature of 140 °C and 30 min in the model reaction were found to provide a consistently high yield of 11a. Extending the reaction time to 60

44

min resulted in only a moderately improved yield (80% vs. 77%) (Table 6, entries 4, 5). Thus, 30 min of microwave heating at 140 °C was chosen as the standard conditions.

A number of reactions were performed with the aim of establishing a suit-able amount of vinyl acetate with respect to the 11a/13a ratio (Table 6, en-tries 9-13). Ten equivalents of vinyl acetate was established as the optimal amount, as smaller amounts increased the formation of 13a and larger amounts had no positive effect on the 11a/13a ratio (Table 6, entry 13). Al-though the price of DMF is similar to or even higher than that of vinyl ace-tate, the solubility of the substrates added decreased when less DMF was used, which could lead to future complications. Table 6. Variation of time, temperature and the excess of vinyl acetate

Entry Temp. (°C)

Time Vinyl acetate (equiv.)

Ratioa

11a:13a Yieldb 11a

1 100 6 h 10 90:10 77 2 100 3 h 10 90:10 68 3 120 1 h 10 90:10 74 4 140 1 h 10 90:10 80 5 140 30 min 10 90:10 79 6 140 10 min 10 90:10 66 7 160 5 min 10 90:10 58 8 rt 72 h 10 90:10 71c

9 140 30 min 2 60:40 -d

10 140 30 min 4 75:25 -d 11 140 30 min 6 85:15 -d 12 140 30 min 8 85:15 -d 13 140 30 min 15 90:10 -d

Reaction conditions: A 5 mL Pyrex glass vial was charged with 10a (1.0 mmol), vinyl acetate (2.0-15 mmol), Pd(OAc)2 (0.02 mmol), dppp (0.022 mmol), and DMF (2 mL). The vial was thereafter sealed under air and exposed to microwave irradiation. a Determined by GC-MS and 1H NMR. bIsolated yield, >95% pure according to GC-MS. cStirred at room temperature. dYield not determined.

4.1.3 Screening of Arylborane Substrates A variety of arylboronic acids were vinylated using the optimized conditions described above. Heavy substrates were used as low-molecular-weight sub-strates would complicate the otherwise straightforward purification proce-dure. All the arylboronic acids tested were successfully vinylated and good isolated yields were obtained (Table 7). The possibility of incorporating an aryl chloride into the product (11c) was demonstrated (Table 7, entry 2), without any side product formation from a possible Pd(0)-mediated oxida-tive addition. Moreover, the chemoselectivity observed was an indication of a strictly Pd(II)-catalyzed reaction, and the Pd(0) source utilized (entry 16 in Table 5) must thus undergo oxidation before entering the catalytic cycle. No difference in the outcome, based on substitution pattern, was observed for

45

the ortho-, meta- or para-biphenylboronic acids, which were isolated in yields of 78-82% (Table 7, entries 4 and 5, Table 6, entry 5).

Table 7. Screen of arylboron substrates

Reaction conditions: A 5 mL Pyrex glass vial was charged with 10 or 12 (1.0 mmol), vinyl acetate (10.0 mmol), Pd(OAc)2 (0.02 mmol), dppp (0.022 mmol), and DMF (2 mL). The vial was then sealed under air and exposed to microwave heating for 30 min at 140 °C. aIsolated yield >95% pure according to GC-MS. bNaTFA (2 mmol) was used as an additive. To broaden the scope of coupling partners, four different aryltrifluoroborates were included. At this time, work on the incorporation of aryltrifluoroborates into the previously reported oxidative Heck protocol132 (later to become the work presented in Section 4.2) had already been started and was running in parallel. It was found that using the boronic acid protocol without modifica-tions for the trifluoroborates resulted in Pd black precipitation and inconsis-tent yields. Trifluoroacetic acid (HTFA) was added in an attempt to stabilize the Pd(II) complex. This had the positive effects of giving complete conver-sion of the trifluoroborate and no formation of Pd black. As the aim was to

46

develop a mild protocol, HTFA was replaced with the corresponding sodium salt (NaTFA). The addition of 2 mmol of NaTFA was necessary in order to obtain useful yields of the styrene. The products were generally isolated in slightly lower yields than in the reactions with the corresponding arylboronic acid. The lowest yield was seen for the electron-deficient p-acetylphenyltrifluoroborate, 12g, probably due to the slower hydrolysis into the activated boronate (see Section 1.6.5). Finally, a vinylboronic acid, 10k, was successfully vinylated to generate the corresponding diene, 11k, in a yield of 64% (Table 7, entry 14).

4.1.4 Mechanistic Study As this particular reaction had not previously been reported in the literature, it was of interest to study the reaction mechanism. Having discarded the Pd(0) mechanism it was hypothesized that two alternative arylation path-ways could be the dominating route (Scheme 19). Either, i) ethylene is first generated from -acetate elimination of vinyl acetate and subsequently un-dergoes arylation, or ii) styrene formation occurs by carbopalladation of vinyl acetate, followed by a Pd- -acetate elimination.

Scheme 19. Proposed alternative vinylation pathways

To investigate the mechanism and obtain some insights into the pathways operating, ESI-MS analysis was used. In order to obtain as direct injection as possible of the reaction mixture room temperature conditions was considered to be the most appropriate. Thus, a reaction was performed in a sealed vessel at room temperature. The reaction time required to reach full conversion was long (72 h), but the product was isolated in a good yield of 71% (Table 7, entry 14). Initially, an aliquot was withdrawn from the reaction mixture after 6 h and was quickly diluted with DMF. The ESI-MS(+) spectrum recorded immediately and several groups of signals corresponding to the characteristic isotopic pattern of monopalladium complexes were detected (Figure 6).

47

Figure 6. ESI-MS-(+) spectrum from the reaction of 1f and vinyl acetate at room temperature

The apparent Pd-containing complexes were subjected to MS/MS(+) analy-sis by selecting the isotopic ions with the strongest and the second strongest intensity from each complex (corresponding to 106Pd and 108Pd, respectively). Structures were proposed for the complexes based on the information gained from the results of the MS and MS/MS analyses (Table 8). Certain assump-tions were made regarding the structure of possible intermediates with the same elemental composition, based on the fragmentation pattern. The com-plex with m/z = 605 containing 106Pd, which was separated and fragmented in the collision cell, resulted in a detected signal at m/z = 577, corresponding to the mother ion minus 28 mass units, which indicates the loss of ethylene. The loss of ethylene is followed by the loss of HOAc (m/z = 60). This MS/MS collision-induced-dissociation (CID) pattern supports the assign-ment of structure B 2 for the complex with m/z = 605 (Table 8). The CID pattern of the ion with m/z = 699 supports the structural assignment of palla-dium hydride H 2, resultion from the observed loss of the -coordinated styrene product (m/z = 180). Similarly, an m/z loss of 180 together with the following loss of HOAc, was observed in the MS/MS spectrum for the ion with m/z = 757 which was assigned as I 1.

Further validation of the proposed structures was carried out by stepwise component exchange. Each component in the reaction was substituted, one at a time, with a chemical equiv.alent, thus providing the analogous pal-ladium(II) complexes, but with different m/z ratios, and the products were analyzed with ESI-MS. Boronic acid, 10a, was replaced with 10h, DMF with DMSO, vinyl acetate with vinyl propionate, and dppp with the m/z = 28-unit-heavier (S,S)-bdpp. The catalytic activity was controlled in the mod-ified reactions by isolation of the styrene product. All the substitutions were

500 550 600 650 700 750 800m/z

48

found to furnish a catalytically active reaction system and provided the cor-responding styrene products at yields of 36-68%. All the structures previous-ly assigned to the intermediates were confirmed by identification of the ana-logous intermediates with the chemical equivalents.

In addition, vinyl acetate was replaced by fully deuterated vinyl acetate ([D6]vinyl acetate), affording [D3]11a in 59% isolated yield, with no de-tected deuterium-hydrogen scrambling. Structures of the detected palladium-containing signals were proposed (Table 8) and again, the complexes identi-fied confirmed the previous structural assignments.

Table 8. Mono-charged cationic Pd(II) complexes detected with ESI-MS in the reaction with standard and deuterated vinyl acetate

aReported m/z values based on 106Pd, dppp as ligand and 10a as the aryl substrate (Ar). bStructures supported by MS/MS-(+) analysis. cReported m/z values based on 106Pd, dppp as ligand, 10a as the aryl substrate (Ar) and [D6]vinyl acetate.

In conclusion, the structural assignment of complex B 2 (m/z = 605) and 106Pd [D7]B 2 (m/z 612) in Table 8 indicates arylation of ethylene and not vinyl acetate (pathway i, Scheme 19). Furthermore, the presence of the Pd-hydride species, which is crucial for pathway a, could be confirmed by the CID pattern of the ionic complex with m/z = 699, with loss of the styrene product to giving signal with m/z = 519, assigned as H 2. In addition, the structure was also supported in the analogous [D6]vinyl acetate study, as it generated a signal with m/z = 520 corresponding to the [D1]palladium hy-dride complex.

At this point, the ESI-MS analysis supported pathway a, due to the identi-fication of the free ethylene. This pathway was believed to be dependent on the formation of a Pd-H, a class of species rarely detected under Heck-type conditions as it is often assumed to readily undergo reductive elimination, generating Pd(0). However the absence of an added base was believed to suppress the reductive elimination process.

49

As discussed in the Introduction, ESI-MS will not provide any information on the activity of the assigned complexes. Hence, a plausible catalytic cycle will have to be based on assumptions regarding the catalytic activity of the detected and assigned palladium complexes. Under these premises, a catalyt-ic cycle was proposed based on the palladium complexes identified (Scheme 20).

Scheme 20. Proposed mechanism based on MS-detected cationic palladium com-plexes

Initially, pathway ii is operating, starting with transmetallation (1) followed by a 1,2 insertion of aryl-Pd into vinyl acetate (3). Two elimination alterna-tives are possible: the presumably faster -acetate elimination, providing styrene and regeneration of the Pd catalyst (4), or, and less likely, -hydride elimination, generating the undetected internally arylated product. As this cycle is in operation, providing the desired styrene, no explanation is given for the Pd-H species observed with ESI-MS. The author suggests that the hydride is instead the result of the incomplete regioselectivity in the insertion step (3), providing a small amount of the linear product, avoiding the possi-bility of -acetate elimination. This route provides the Pd-H together with by-product 14, and moves palladium into pathway i. It is my belief that the route from pathway ii to i is energetically favored over the opposite route. The opposite route (i to ii) is assumed to occur when the Pd-H is inserted into the cis/trans styryl ester, 14, generating styrene and the initial Pd cata-lyst. The large excess of vinyl acetate would probably suppress this direc-tion. The catalytic process in the presumably dominant pathway i, starts with the association of vinyl acetate to a Pd-H complex (5 or 12) which affords the charged -intermediate B 1, followed by migratory insertion (6) and -

50

acetate elimination (7) to produce species B 2. Associative transmetallation (8) with an arylboronic acid and intermediate B 2 would generate the H 1 species. Alternatively, and perhaps less likely, olefin dissociation may gen-erate free ethylene and the intermediate C. It is reasonable to assume that transmetallation (9) subsequently occurs, leading to the formation of the intermediates D-G, followed by coordination (10) of ethylene to generate the cationic -intermediate H 1. 1,2 insertion (11) is followed by -hydride eli-mination (12) to form complex H 2, which dissociates (12) to give the free styrene product and a Pd-H species. Alternatively, complex B 1 might be generated directly from hydride H 2 in an associative ligand exchange process. The author suggests that the large excess of vinyl acetate promotes pathway i as well as the observed selectivity for monoarylation as a result of the high reactivity of the unsubstituted ethylene.

4.2 Oxidative Heck Reactions using Aryltrifluoroborates and Aryl MIDA Boronates The idea of using aryltrifluoroborates in the oxidative Heck reaction, arose from a publication by Darses and Genet.172 ArBF3K was used under base-free conditions to effectively arylate electron-deficient olefins through rho-dium catalysis. Regeneration of the catalyst was achieved by reduction of the solvent, acetone. This use of the solvent as a hydride acceptor was consi-dered by the author to be a perfect system in our Pd(II)-catalyzed reactions. In addition to being atom efficient, it could provide proof of the Pd(II) hy-dride pathway over the Pd(0) pathway in the regeneration of the active cata-lyst (Scheme 9). At that time, the organotrifluoroborates were already an established coupling partner in a number of Pd(0)-catalyzed C-C bond form-ing reactions, extensively explored by Molander’s group.112-113

Initial attempts to use the trifluoroborates under Pd(II)-catalyzed condi-tions employing acetone as solvent were unsuccessful as Pd black was often formed immediately upon the addition of ArBF3K to the Pd-ligand mixtures. Various conditions were tested with the aim of stabilizing the system, as well as identifying an alternative reoxidant. A few months later, Xiao and co-workers reported a Pd(II)-dppp-catalyzed oxidative Heck reaction using boronic acids in acetone without the addition of a separate reoxidant.133 The arylation of electron-poor olefins was assisted by the addition of HTFA. The conditions used were immediately evaluated by the author with the corres-ponding aryltrifluoroborates. These reaction conditions were not successful in the conversion of the arylboron species, but no Pd black was formed. The information obtained from these experiments facilitated the development of the conditions described in the previous styrene protocol (Section 4.1). Fol-lowing this, methanol, which is commonly used in the cross-coupling reac-

51

tions with the trifluoroborates, was successfully utilized as solvent in a Pd(TFA)2-dppp-aryltrifluoroborate protocol, giving complete monoarylation of the n-butylacrylate added, using p-BQ as the oxidizing agent. In addition, HTFA, or NaTFA, could be removed from the cocktail with maintained productivity.

4.2.1 Arylboronate Screening with an Electron-Poor Olefin The reaction times and heating methods used in the previously described screening reactions varied from 1 h to 64 h, using conventional heating or microwave heating for 10-40 min. A standard reaction using 1 equiv.alent of n-butyl acrylate, 1.5 equiv.alent of p-tolyltrifluoroborate 12c, 2% Pd(TFA)2, 3% dppp and 1 equiv.alent of p-BQ in 3 mL MeOH was used to identify the microwave-conditions affording a short reaction time together with complete conversion of the olefin. These demands were met at 120 °C for 20 min, and these conditions were then employed in the following screen.

To investigate the scope of this reaction regarding the aryl source, a range of aryltrifluoroborates were tested, as presented in Table 9. The electron-rich 12a gave 15a as the sole product in 51% yield after 20 min irradiation. How-ever, doubling of the reaction time provided complete conversion and an improved 73% isolated yield of 15a (Table 9, entry 1). The moderately elec-tron-rich 12b and 12c produced the corresponding cinnamic esters, 15b and 15c, in yields of 72% and 80%, respectively, using the standard 20 min processing at 120 °C. Reducing the temperature to the solubility limit of substrate 12c (65 °C) furnished 15c in 77% yield after 18 h under p-BQ free, open-air conditions (Table 9, entry 4). Simple phenylation using 12d pro-vided 15d in an excellent isolated yield of 89%. As expected, full chemose-lectivity was obtained in entries 7 and 8, where neither oxidation of the ben-zylic alcohol in 12e, nor any Pd(0) oxidative addition product of 12f, were detected by GC-MS or LC-MS, and the desired products 15e and 15f were obtained in 71% and 84% yields, respectively. The electron-deficient 12g and 12h were found to be highly productive furnishing 87% of 15g and 82% of 15h. In addition, the p-trifluoromethyl product 15h could be effectively produced under open-air conditions providing 90% isolated yield (entry 11). Ortho-substituted 12i furnished a surprisingly good isolated yield of 15i (91%), indicating that the protocol has good tolerance to steric hindrance. However, 2-naphthyltrifluoroborate gave a somewhat lower yield of 15j (70%), mainly due to competing protodeboronation. Heteroaromatic 2-furanyl suffered from incomplete conversion of n-butyl acrylate and pro-duced a moderate 51% yield of 15k at 120 °C (entry 14).

52

Table 9. Scope of arylboronates in the oxidative Heck protocol with n-butyl acrylate as olefin

aIsolated yield, >95% pure according to GC-MS and 1H NMR. Reaction conditions: ArBF3K 12 or ArMIDA 16 (1.5 mmol), n-butyl acrylate (1.0 mmol), Pd(TFA)2 (0.02 mmol), dppp (0.03 mmol), p-benzoquinone (1 mmol) and MeOH (3 mL), with microwave heating for 20 min at 120 °C in a sealed vial. bThe reaction was heated for 40 min. cOpen vessel charged with ArBF3K (1.5 mmol), n-butyl acrylate (1.0 mmol), Pd(TFA)2 (0.02 mmol), dppp (0.03 mmol) and MeOH 20 mL, stirred in an oil-bath at 65 °C for 18 h.

The more recent alternative to the aryltrifluoroborates, aryl MIDA boronates, were considered interesting for evaluation in this protocol. The electron-rich 16a, provided only 36% of the product 15a after 40 min at 120 °C. The time and temperature were varied in an attempt to optimize the reaction, but no improvement in the yield was achieved. Better results were obtained with the p-tolyl MIDA boronate, furnishing 67% of 15c after 40 min. Similar yields and chemoselectivity were observed with the bromide containing substrates 12f and 16c (cf. entries 8 and 9). It was thus clear that the electron-rich MIDA, 16a, was less efficient than the corresponding trifluoroborate, 12a, but as the electron-density decreased in the aryl group the difference de-creased (cf entries 4-5 and 8-9).

53

The terminally arylated E-alkene isomer was the major product in all reac-tions, and only trace amounts of the Z-isomer were observed, as expected under bidentate ligand promoted cationic conditions (Section 1.8).

4.2.2 Arylboronate Screening with an Electron-Rich Olefin After exploring arylations with an electron-poor olefin, the investigation continued with the electron-rich n-butyl vinyl ether. The question was whether the expected branched product would be exclusively produced or not. These internally arylated products, 17, were hydrolyzed into the corres-ponding methyl ketones prior to isolation due to their acid sensitivity (Table 10).

Initially, the same protocol, as for the n-butyl acrylate, was used produc-ing 36 % of the desired hydrolyzed product 18c (Table 10, entry 4) in the MW-assisted method and 43% under conventional heating. The decomposi-tion of the vinyl ether, as a result of the nucleophilic solvent, was identified as the problem. Among the solvents initially screened, acetone gave reason-able conversion and a 2:1 acetone/methanol mixture was found to be particu-larly productive.

With the modified protocol at hand, the scope of the trifluoroborates as arylating agents with an electron-rich olefin was investigated (Table 10). The electron-rich 12a gave, after hydrolysis, 18a in 69% yield after 20 min of MW irradiation at 120 °C. The -donating 12b, furnished a moderate yield of 12b (41%) and no improvement was seen upon increasing the reaction time to 40 min. The p-tolyl compound 12c provided 71% isolated yield of the methyl ketone 18c. Once again the chemoselectivity was investigated by evaluating 12f, furnishing 18d in a moderate 43% yield. In this case, it was believed that the poor outcome might be the result of a slow insertion rate rather than interfering Pd(0) oxidative addition of the aryl bromide, since the identified by-products (4,4’-dibromobiphenyl and protodeboronated phenyl bromide) both showed intact halogen functionality. The electron deficient 12g provided an excellent yield of 18e (89%), the non-hydrolyzed product 17g was isolated in a similar 81% yield (Table 10, entry 9). The -withdrawing F3C- substituent on 12h decreased the yield to a disappointing 58%.

54

Table 10. Scope of arylboronates in the oxidative Heck protocol with n-butyl vinyl ether as olefin

aIsolated yield, >95% pure by GC-MS and 1H NMR. Reaction conditions: ArBF3K 12 or ArMIDA 16 (1.5 mmol), n-butyl vinyl ether (1.0 mmol), Pd(TFA)2 (0.02 mmol), dppp (0.03 mmol), p-benzoquinone (1 mmol) and acetone/MeOH 2:1 (3 mL), with microwave heating for 20 min at 120 °C in a sealed vial. bMeOH (3 mL) as solvent. cOpen vessel charged with ArBF3K (1.5 mmol), n-butyl vinyl ether (1.0 mmol), Pd(TFA)2 (0.02 mmol), dppp (0.03 mmol) and MeOH 20 mL, stirred in an oil-bath at 65 °C for 18 h. dNon-hydrolyzed product was isolated.

In general slightly lower yields were obtained with n-butyl vinyl ether. One exception was observed with the electron-rich 12a, yielding 69% of the methyl ketone 18a compared with 51% of 15a when heating the reaction for 20 min. The expected regioselectivity was observed in all reactions, provid-ing exclusively the internal product before hydrolysis, according to GC-MS.

The aryl MIDA boronates were evaluated with n-butyl vinyl ether, using the same conditions, but furnished only 0-10% yield of 18 (Table 10, entries 2, 5 and 7). It was speculated that this could be the result of slower hydroly-sis into the corresponding active arylboron complex in this solvent mixture, and thus various amounts of water were added to the reaction mixture. In most cases, this resulted in the complete absence of product, leading to the conclusion that under these less basic conditions (compared with the condi-tions used in the cross-couplings) the MIDA boronates were more resistant to hydrolysis, thus allowing a substantial degree of competing decomposi-tion of the sensitive olefin before activation.

55

4.2.3 ESI-MS Investigation As it was believed that the rate of activation of the boronate was important for the outcome, an ESI-MS investigation was initiated in an attempt to gain information regarding the active boronate species, as well as the identifica-tion of certain key Pd-containing intermediates. This proved to be much more complicated than similar investigations previously conducted by the Uppsala group. The ESI-MS mother scan of an on-going reaction showed only three dominant Pd complexes, the simple dppp-Pd-H, dppp-Pd-H coor-dinating the olefin and dppp-Pd-H coordinating the product. The stoichiome-tric amount of K+ was assumed to complicate the ionization in this system and the study was thus directed towards the arylboron species formed in the reaction.

In order to detect the arylboronates formed, the reaction providing 15c (Table 9, entry 4) was set up at ambient temperature. This reaction was found to require around five days to reach complete conversion and a small amount was withdrawn after 12 h, diluted with MeOH and recorded in nega-tive mode (Figure 7). A number of negatively charged arylboron species were found, among them a weak signal from the deprotonated boronic acid.

Figure 7. ESI-MS(-) spectrum for the reaction of 12c and n-butyl acrylate after 12 h at ambient temperature and the proposed anionic arylboron species

120 130 140 150 160 170 180 190 200

m/z 149.08

BO

OMe

m/z 159.06

BF3

m/ z 137.06

BF

O

m/z 171.08

BF

OMeF

m/z 183.10

BF

OMeOMe

m/ z 135.06

BOH

O

56

Figure 8. ESI-MS(+) spectrum for the reaction of potassium 4-trimethylammonium phenyltriflouroborate iodide and n-butyl acrylate after 30 min at 60 °C and the pro-posed cationic boron species

As this did not provide the complete picture, as any neutral intermediates would not be detected, the permanently charged potassium 4-trimethyl-ammonium phenyltrifluoroborate iodide was employed. Due to poor solu-bility of this substrate in MeOH the reaction was heated to 60 °C and a small amount withdrawn after just 30 min to be diluted and analyzed. As depicted in Figure 8, several positively charged organoboron species were detected with ESI-MS, among them the important ArBF2 intermediate in the dissocia-tive hydrolysis of the trifluoroborates. The observation of hydrolysis into the boronic acid was in agreement with the recent findings of Lloyd-Jones et al.,114 who found that even without adding base, hydrolysis was complete when using a glass-walled reaction vessel. The amount of water was proba-bly limited in our system, but was obviously enough to provide a small con-centration of the active boronic acid.

Returning to one of the initial aims with this project, the regeneration of the active Pd(II)-catalyst, which seemed to start in a complete failure. Bear-ing in mind the Pd-hydride complexes identified with ESI-MS and with the observation in the previous styrene project, the hydride seemed to be an ac-tive species, probably promoting the Pd(II)-hydride reactivation pathway (Section 1.6.5). GC-MS analysis of the crude reactions with the electron-deficient olefin showed traces of an m/z signal that would correspond to the reduced product. In addition, the signal from the reduced olefin was a re-peated pattern. This is most likely products from the conjugate addition of Pd-H, a process that would provide 1,4-hydroquinone, subsequent to proto-nation, with p-BQ as substrate (Scheme 9).

160 180 200 220 240 260

I

IIIII

V

IV

IIIIII

IV V

m/z 180.12N

BOH

OH

m/z 194.14N

BOH

OMe

N

OBu

O

m/z 262.18

m/z 242.07N

BF3K

m/ z 184.11N

BF

F

m/z 226.16N

BOH

OHMeOMe

57

5. Palladium(II)-Catalyzed 1,2-Carbopalladation of Nitriles (Paper V & VI)

5.1 Synthesis of Arylamidines from Aryltrifluoroborates The 1,2 carbopalladation of the nitrile functionality, as described in Section 1.9, is indeed an interesting and appealing method for the generation of aryl ketones. The simplicity of this reaction with the release of imine upon proto-nation, providing the active Pd-catalyst, prompted the search for a more sta-ble “imine-type” product, in order to avoid hydrolysis prior to isolation of the product. Among the various nitriles available in-house, cyanamide was identified as an interesting substrate, as it would provide an arylamidine in the Pd(II)-catalyzed reaction with an arylboron substrate. In addition to be-ing valuable precursors in the formation of various heterocyclic ring sys-tems, e.g quinazolines, quinazolinones, pyrimidines, triazoles and benzimi-dazoles, amidines are also an important pharmacophore moieties in drug discovery.173

By screening a few aryl sources the aryltrifluorborates were soon identi-fied as the most promising candidate for this coupling. The conditions used in the work with arylsufinates were adopted (Section 5.2), apart from the fact that the THF:H2O mixture was replaced by methanol as this had previously been identified as the superior solvent in combination with trifluoroborates. The conditions were fine-tuned using a test reaction employing 4% Pd(TFA)2 and 6% 6-methyl-2,2 -bipyridyl as the catalytic system, and potas-sium 4-methylphenyltrifluoroborate (12c), 2 equivalents of cyanamide 19b and 5 equivalents HTFA in methanol. The mixture was heated with micro-waves for 20 min in a sealed vial at 120 °C. Full conversion of the yield determining 12c and concomitant formation of the arylamidine product 20n was observed according to 1H NMR analysis. No further modification was needed except that the HTFA excess could be reduced to 2 equivalents with-out affecting the productivity.

The isolation of the product was initially complicated as RP silica column chromatography was used, requiring the evaporation of large volumes of water. By reversing the stoichiometry and replacing cyanamide with 1-piperidine carbonitrile the arylamidine 20a (Table 11, entry 1) could effec-tively be isolated using an extraction procedure.

58

5.1.1 Ligand Screen Based on the findings reported above, a final ligand screen was performed (Table 11). Similar yields were isolated from the related bipyridyl ligands 21a and 21b, 88% and 86%, respectively (entries 1 and 3). The more rigid ligand, 21c, was found to reduce the yield to 69% (entry 4). Surprisingly, the two additional 2,9-methyl substituents on 21d totally suppressed the conver-sion of 12c, furnishing only trace amounts of product 20a (entry 5). A simi-lar lack of reactivity was found with the previously effective dppp ligand 21e (entry 6). Finally, two blank reactions were performed demonstrating the importance of the ligand and Pd (entries 7 and 8).

Table 11. Ligand screen

a Isolated yield >95% pure according to 1H NMR. Reaction conditions: Pd(TFA)2 (0.04 mmol), ligand 21 (0.06 mmol), HTFA (2 mmol), ArBF3K 12c (1.1 mmol), cyanamide 29a (1 mmol) and MeOH (3 mL), heated with MW in a sealed vial at 120 °C for 20 min. bWithout HTFA. c Without Pd(TFA)2. n.d.= Product not detected with LC-MS.

5.1.2 Screen of Aryltrifluoroborates To investigate the scope of the reaction regarding the arylboron substrates, various potassium aryltrifluoroborates were investigated and the results are presented in Table 12.

59

Table 12. Screen of Arylboron substrates

aIsolated yield >95% according to 1H NMR. Reaction conditions: Pd(TFA)2 (0.04 mmol), ligand 21a (0.06 mmol), HTFA (2 mmol), ArBYn 12a-b, d, f-k, 10l, 22 (1.1 mmol), cyanamide 19a (1 mmol) and MeOH (3 mL), heated wirh MW in a sealed vial at 120 °C for 20 min. The electron-rich aryltrifluoroborates 12b and 12c performed well, produc-ing the corresponding amidines 20b and 20c in 86% and 74% yield, respec-tively (Table 12, entries 1 and 2). Phenyltrifluoroborate also proved to be a productive substrate, giving benzamidine 12d in 73% isolated yield (entry 5). Complete chemoselectivity was observed in the reaction of 12f, as seen in the previously presented studies (Papers III & IV), furnishing 63% of 20e, and no trace of by-products resulting from Pd(0)-mediated oxidative addition of the aryl bromide was detected. The electron-deficient 12g and 12h (en-tries 7 and 8) afforded only 37% of 20f and only traces of 20g. The lower yields of these electron-deficient arylating agents could be explained by a slower insertion rate and a subsequent increase in the amount of by-products resulting from protodeboronation and homocoupling as observed by GC-MS analysis. The ortho-methyl group in 12i was tolerated yielding 66% of prod-uct. Surprisingly, 2-naphthyltrifluoroborate 12j afforded a somewhat lower yield of 12j (40%), mainly due to the competing protodeboronation. Finally, the heterocyclic, 12k, was found to be useful in this protocol, providing ac-ceptable yields of 20j (66%).

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Table 13. Scope of cyanamides with different aryltrifluoroborates

aIsolated yield >95% pure according to 1H NMR. Reaction conditions: Pd(TFA)2 (0.04 mmol), ligand 21a (0.06 mmol), HTFA (2 mmol), ArBF3K 12a, c, g (1.1 mmol), cyanamide 19b-f (1 mmol) and MeOH (3 mL), heated with MW in a sealed vial at 120 °C for 20 min.

61

5.1.3 Screen of Cyanamides with Different Aryltrifluoroborates The scope of the cyanamide substrates was extended to include initially tested unsubstituted cyanamide, 19b, the disubstituted cyanamides 19c-d and the cyclic cyanamide, 19f (Table 13). Cyanamide 19b was a productive sub-strate, providing the unsubstituted amidines 20k (70%) and 20n (73%) in good isolated yields (entries 1 and 4), but only disappointing trace amounts of the electron-poor 12g (entry 9). The bulky diisopropylcyanamide 19d, furnished only moderate yields of products 20l (31%) and 20p (24%), pre-sumably due to unfavorable steric effects. The cyclic cyanamide 19f (Table 13, entries 3, 8 and 10) performed well, giving excellent to moderate yields of the desired amidine products 20m (92%), 20r (58%) and 20t (33%). The dimethylcyanamide 19c (entry 5) was also well tolerated affording an excel-lent 82% isolated yield of the desired product 20o. Interestingly, the pres-ence of one bulky tert-butyl substituent as in 19e had only a minor influence on the reaction outcome, yielding 64% of 20q (Table 13, entry 7). Once again, the reaction was found to be dependent on the electronic nature of the aryltrifluoroborate, with the electron-rich substrates 12a and 12c affording consistently higher yields than the electron-poor substrate 12g.

5.1.4 Mechanism A plausible catalytic cycle, based on the mechanistic studies performed on the Pd(II)-catalyzed alkylnitrile insertion reactions,145 is depicted in Scheme 21. Starting with the ligand coordinated Pd(II)-complex A, transmetallation occurs with an arylboron species to generate the arylpalladium intermediate, B. Next, ligand exchange furnishes the cyanamide coordinated complex, C, followed by 1,2 carbopalladation into the nitrile bond, which affords com-plex D. Finally, the protonation of the charged amidine by HTFA liberates the product and the initial Pd(II) catalyst, A, is regenerated. Considering the mechanism, the need for one proton is obvious, and the large excess of HTFA is believed to be necessary to maintain acidic conditions throughout the course of the reaction. Additionally, a fully protonated and positively charged amidine functionality is assumed to be desirable in order to decrease competing amidine-Pd coordination.

62

Scheme 21. Plausible catalytic cycle for the synthesis of arylamidines with the key intermediates B-D

Two of the initially screened aryl sources 10l and 22, were re-evaluated un-der identical conditions (Table 12, entries 3 and 4), providing significantly lower yields of 20a (33% and 45%, respectively) than with the correspond-ing trifluoroborate 12c. In Section 1.6, it was stated that the comparably high resistance to the competitive proto-deboronation displayed in the classical cross-coupling reactions was disappointingly not achieved for aryltriflurobo-rates in the Pd(II) reactions presented in this thesis. The comparably high productivity of the trifluoroborates in this reaction may be the exception to this statement, but investigations are proceeding to gain a better understand-ing of this issue, as well as the incomplete conversions of the electron-deficient aryltrifluoroborates.

5.2 Synthesis of Aryl Ketones from Aryl Sulfinates This project was initiated based on the information gained from preliminary density functional theory (DFT) calculations related to the studies on ben-zoic acids as aryl sources in the nitrile insertion protocol, recently published by Lindh et al.145 To achieve palladium(II)-promoted decarboxylation the carboxylate moiety must rotate out of plane from the -system of the aryl group.66 The ortho-substitutuents on the benzoic acids used were therefore assumed to provide steric repulsions in order to lower this rotation barrier. In these calculations related acidic functionalities were included, among them the aryl sulfinates, which were assumed to undergo Pd(II)-mediated desulfi-nation from non-ortho functionalized aryls. This class of substrate was eva-luated in various Pd(II)-catalyzed transformations; the nitrile insertion reac-

63

tion appearing to be the most promising. A literature search regarding desul-fitative aryl-Pd formation from aryl sulfinates revealed only two non catalyt-ic Pd(II)-mediated transformations from the 1970s58,119 and a patent includ-ing a cross-coupling method from 1992.120 In other words, it was about time someone brought these substrates up to attention.

5.2.1 Ligand Screens The catalyst system used in the reactions with benzoic acids was initially employed. Only 10% of the isolated methyl ketone, 25a, was achieved using p-tolyl sulfinate 23a as the arylpalladium source, 8% Pd(TFA)2 and 12% ligand 21a in a 1:2 mixture of H2O/MeCN. Screening was then carried out to identify an efficient supporting ligand. Disappointingly, none of the ligands tested (same ligands as in Table 14) led to improved outcome, but when the crude mixture was hydrolyzed prior to isolation the yield increased. It was thus believed that a one-step in situ hydrolysis by the addition of HTFA would benefit the reaction, as it would reduce the amount of any Pd coordi-nating ketimine. After evaluating various amounts of HTFA, 10 equivalents was found to give the best yield. The influence of temperature was then ex-plored and 100 °C was found to be the most effective. As this solvent system would impair the use of crystalline or more expensive nitriles, different ra-tios of water/dioxane and water/THF were investigated and a 1:1 mixture of the latter combination was identified to be the most productive. With the use of these conditions a second ligand screen was performed (Table 14).

Under MW-assisted condition at 100 °C for 1 h five bidentate nitrogen ligands (21a-e), one bidentate phosphine ligand (21f), DMSO (21g) and a control experiment with no ligand added were employed. The previously effective ligand, 21f, (Paper III & IV) failed to produce the desired product, and the ligand-free reaction provided only trace amounts of aryl ketone 25a. DMSO was also found to be a poor ligand for ketone formation. Among the bidentate nitrogen ligands, the dimethylated bipyridyl and phenantroline compounds 21c and 21e were found to be inferior to their non-methylated equivalents 21a and 21d, which were employed in the recently reported methods.63-64 The best result (87%) was achieved with 6-methyl-2,2 -bipyridyl 21a, which is more or less established as the superior ligand for 1,2 carbopalladation of nitriles in the different protocols recently developed by the Uppsala group.

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Table 14. The second ligand screen using an aryl sulfinate and MeCN

aIsolated yield >95% pure according to GC-MS and 1H NMR. Reaction conditions: Pd(TFA)2 (0.04 mmol), ligand 21 (0.06 mmol), HTFA (5 mmol), p-MePhSO2Na 23a (0.5 mmol), MeCN 24a (2.5 mmol) and H2O/THF (1.4 mL), heated with MW in a sealed vial at 100 °C for 1 h. b100 L DMSO were added.

5.2.2 Screen of Aryl Sulfinates In order to evaluate the scope and limitations of the method, a variety of different aryl sulfinates were investigated with respect to their reactivity towards MeCN (Table 15). The electron-rich sulfinate 23b furnished the product in a good yield of 79% (entry 3). The ortho-methylphenyl sulfinate (23c) led to the desired ketone 25c in a satisfying yield of 66% (entry 2), demonstrating good tolerance to steric effects. The simple phenyl sulfinate, 23d, readily afforded the corresponding ketone, 25d, in 77% yield (Table 15, entry 3). This reaction was also performed using a heating block, and gave 25c in a slightly lower yield of 61%. The electron-deficient sulfinates 23e and 23f provided yields of 75% (25e) and 73% (25f), respectively. In sum-mary, all the substrates tested gave comparable yields, indicating a robust protocol regarding different aryl sulfinates. Performing the reaction with conventional heating using sulfinates 23b and 23e led to a significant decrease in yields (Table 14, entries 1 and 4). It was speculated that the lower productivity was a consequence of an acctual temperature difference inside the reaction vessel, but this was not further investigated.

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Table 15. Scope of aryl sulfinates

aIsolated yield >95% pure according to GC-MS and 1H NMR. Reaction conditions: Pd(TFA)2 (0.04 mmol), ligand 21a (0.06 mmol), HTFA (5 mmol), ArSO2Na 23 (0.5 mmol), MeCN 24a (2.5 mmol) and H2O/THF (1.4 mL), heated with MW in a sealed vial at 100 °C for 1 h. Conventional heating 100 °C for 16 h.

5.2.3 Variation of Nitriles In order to extend the scope of the reaction, a range of nitriles (24b-e) was reacted with four different aryl sulfinates (23b,a,d,e). Most reactions gave moderate to excellent yields, and nitrile insertion was successfully per-formed with aliphatic (66-91%) as well as aromatic (51-84%) and benzylic nitriles (66-87%). In addition, the use of only 3 equivalents of p-bromo ben-zonitrile (24e) afforded good isolated yields (51-67%) of the benzophenone derivatives (Table 16, entries 4, 8, 12 and 16).

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Table 16. Scope of nitriles

aIsolated yield >95% pure according to GC-MS and 1H NMR. Reaction conditions: Pd(TFA)2 (0.04 mmol), ligand 21a (0.06 mmol), HTFA (5 mmol), ArSO2Na 23 (0.5 mmol), RCN 24 (2.5 mmol) and H2O/THF (1.4 mL), heated with MW in a sealed vial at 100 °C for 1 h. bConventional heating at 100 °C for 16 h. RCN 24 reduced to 1.5 mmol.

Moreover, the same chemoselectivity towards Pd(0)-mediated by-product formation was observed as in all Pd(II)-catalyzed reactions previously pre-sented in this thesis (Table 16, entries 4, 8, 12-16). The yields in the conven-tionally heated reactions were lower than those in the microwave reactions; and again it was speculated that this could be the result of a lower effective temperature in the conventionally heated vessels.

5.2.4 ESI-MS Investigation As little was known about the desulfination process a standard reaction was selected and heated with microwaves for 10 min at 100 °C for ESI-MS analysis (Table 14, ligand 21a). A small amount of the crude mixture was

67

withdrawn and diluted with MeCN. An ESI-MS(+) spectrum was immedi-ately recorded, showing several groups of peaks with m/z signals characteristic for the isotopic pattern of singly-charged monopalladium complexes (Figure 9).

Figure 9. ESI-MS(+) spectrum with assigned Pd(II) containing intermediates

Structures for the detected Pd(II) complexes were proposed based on MS/MS and MS3 analysis including scanning for specific neutral loss. The intermediates were assigned to different classes using the letters A-E, based on their plausible role in the reaction (Scheme 22). Despite their identical masses, complex classes A and B were seen to occur separately using differ-ent MS/MS detection modes (i.e. neutral loss of aryl sulfinate and SO2, re-spectively). In order to obtain more information, two additional reactions were run one with 21d as the ligand and one with phenyl sulfinate, 23d. The two reactions gave analogous and chemically equiv.alent palladium interme-diates.

Based on these results together with previously published results concern-ing nitrile insertion, a catalytic cycle was proposed (Scheme 22), consisting of the following key steps:

1. coordination of the aryl sulfinate to the active Pd(II) species gene-

rating intermediate A, 2. desulfination via a four-membered transition state, and transfer of

the aryl to the metal center providing B,

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3. dissociation of SO2 from the Pd(II) center, which upon contact with water is hydrolyzed into bisulfite, leading to complex C, which is believed to be a fairly stable complex due to its high abbundance,

4. coordination of the nitrile to the metal in a process regarded as dissociative, forming intermediate D, and

5. a 1,2 insertion into the tripple bond producing the charged ketimine E, which dissociates upon protonation, thereby regenerating the active Pd(II) complex.

Scheme 22. The proposed catalytic cycle with the key intermediates A-E

In all cases, the corresponding amide, formed by hydrolysis of the organic nitrile, was observed as a by-product in the crude mixture, and this compet-ing hydrolysis is believed to be responsible for the slightly lower yields when only using 3 equivalents of nitrile. While analyzing the ESI-MS re-sults, the first publication, in what would become a whole series of papers, appeared in the literature. Although it is disappointing not to be the first to publish novel findings, the work presented here was carried out independent-ly and is thus valuable in confirming the results of others.

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6. Concluding Remarks

The work presented in this thesis describes the development of novel palla-dium(0)-catalyzed and palladium(II)-catalyzed coupling methods. The spe-cific results and conclusions are summarized below.

A Mo(CO)6-mediated carbonylative Stille cross-coupling reaction was developed for the preparation of various deoxybenzoins. Convenient gas-free conditions facilitated the carbonylative coupl-ing of benzyl bromides and chlorides with aryl and heteroaryl stannanes. In addition, halogen substituted aryls were tolerated, thus, providing a straightforward method for the production of useful building blocks for further elaboration.

A general Mo(CO)6-assisted protocol, suitable for the amino-carbonylation of aryl triflates was developed. Both electron-poor and electron-rich triflates were coupled with primary-, secondary- and aryl amines. In addition, DMAP was found to be beneficial additive when sterically hindered or poorly nucleophilic amines were employed.

An efficient and convenient method for the synthesis of styrenes from arylboranes was developed, employing the relatively inex-pensive vinyl acetate as the ethene source under Pd(II)-catalyzed conditions. The reaction mechanism was studied using ESI-MS and a plausible catalytic cycle was proposed.

A method for the oxidative Heck reaction employing aryltrifluo-roborates and aryl MIDA boronates was developed. Electron-rich and electron-poor olefins were regioselectively arylated under MW-assisted conditions. Various arylboron species were identi-fied by ESI-MS in an ongoing reaction.

A direct method for the synthesis of arylamidines was developed. Aryltrifluoroborates were inserted into primary, secondary and tertiary cyanamides under Pd(II) catalyzed condition.

A desulfitative method for the synthesis of aryl ketones was de-veloped. A variety of aryl sufinates were effectively inserted into alkyl- and aryl nitriles. The mechanism was further investigated by ESI-MS and a plausible catalytic cycle was proposed.

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Acknowledgements

I would like to express my sincere gratitude to the following people.

My supervisor, Professor Mats Larhed, for having all the skills one can wish for in a supervisor. I am especially grateful for your enormous patience; allowing me to continuously explore new ideas instead of dealing with old ones.

Dr. Peter Nilsson, my co-supervisor, for introducing me to this field during my Master’s project and for your enormous enthusiasm for chemistry, which has inspired me throughout the years. Professor Anders Hallberg, for giving me the opportunity to start my PhD studies and for your inspiring guidance during my first years at the depart-ment.

Dr. Per Sjöberg, for your impressive skills in handling the ESI-MS instru-ment and valuable input regarding the ESI-MS techniques. My co-authors at the department, Dr. Jonas Lindh, Dr. Luke Odell, Jonas Rydfjord, and Johan Gising for your valuable contributions. My former roommate, Dr. Jonas Lindh; this journey would not have been the same without your friendship; to be able to work as close together as we have done, with such a good friend must be considered a great privilege.

My roommate, Johan Gising, for being such a nice chap.

Mats, Peter, Jonas, Robert, Christian and Jonas R for proof reading and con-structive criticism of this thesis.

Marc Stevens and Alejandro Trejos, for your hard work and valuable contri-butions during your summer project and Master’s work, respectively.

Former and present lab mates: Jenny, Henrik, Jonas, Olle, Krz, Francesco and Johan, for making the lab a dynamic and pleasant place to work.

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All past and present colleagues at the department, for creating such a posi-tive atmosphere to work in. Special thanks to Jonas, Robert, Johan, P-A and Peter for all sorts of sporting activities during the years; to my conference companions Jonas, Johan, Anna and Rebecca, for those unforgettable travel-ing moments. Gunilla and Eva, for your excellent administrative work and other things. Thanks to Sorin for keeping the computers running. Rönn, many great moments, cross-country skiing, biking, running, snowmo-bile, memories for life; Gising, biking, writing, skating, running, playing with our kids, invaluable time; Lindström, we had a lot of things, same kind of bikes, cars, rackets, tools, bags, computers, phones, name, lived on the same street and worked in the same room, but it was never too much. Till mina gamla vänner, Tomas, Nicke, Krattan och Sven. Kul, nu får ni vara med i en bok. Mina vänner under studietiden, Gustav, Jakob, Fillip, Christian, Mattias Jonatan, Christian S, Oskar, Björn m.fl. det var roliga tider det. Till mina barns mostrar med respektive, för att ni förgyller mina barns liv med presenter m.m. Till mina svärföräldrar som så gärna tar hand om alla mina barn sommar som vinter, så att jag kan ägna tid åt att bygga hus eller skriva avhandling. Till min syster med familj, för att du är så mån om din lillebror och också givit mina barn hela tre jämngamla kusiner. Till min mamma och pappa för att ni alltid finns där med ert ändlösa stöd på alla sätt, bättre förebilder för ett livslångt föräldraskap finns inte. Till mina barn, Erik, Frida och Oskar för att ni gör livet underbart och alltid kommer springande med öppna armar när man kommer hem. Hoppas det håller i sig. Till min underbara hustru Camilla, tack för att du finns och för att du fått allt att fungera medan jag har suttit och skrivit. Vad vore livet utan dig?

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