Palladium(II)-Catalyzed Heck Reactions

Home , Heck reaction, Stille reaction, Suzuki reaction

Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 194

Domino Reactions, Decarboxylations, Mechanistic Studies & Continuous Flow Applications

ASHKAN FARDOST

ACTA UNIVERSITATIS UPSALIENSIS ISSN 1651-6192 ISBN 978-91-554-9149-9 UPPSALA urn:nbn:se:uu:diva-242259 2015 Dissertation presented at Uppsala University to be publicly examined in B41, Uppsala Biomedical Centre (BMC), Husargatan 3, Uppsala, Friday, 13 March 2015 at 09:15 for the degree of Doctor of Philosophy (Faculty of Pharmacy). The examination will be conducted in English. Faculty examiner: Professor Patrick Guiry (University College Dublin).

Abstract Fardost, A. 2015. Palladium(II)-Catalyzed Heck Reactions. Domino Reactions, Decarboxylations, Mechanistic Studies & Continuous Flow Applications. Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 194. 78 pp. Uppsala: Acta Universitatis Upsaliensis. ISBN 978-91-554-9149-9.

This thesis describes research efforts dedicated to the development of palladium(II)-catalyzed oxidative Heck and Heck/Suzuki domino reactions, and the applications of a new microwave heating technology, purpose-built for continuous flow in organic synthesis. Paper I describes the development of a ligand-modulated approach for attaching aryl groups to a chelating vinyl ether. By switching the ligand being used, selectivity for the arylation could be shifted to obtain three different outcomes: internal α- or terminal β-arylation, as well as a serendipitously discovered domino α,β-diarylation process. The latter was proposed to be an effect of para-benzoquinone, effectively acting as a stabilizing π-acidic ligand with the ability to suppress β-hydride elimination. Paper II explores the performance of a new microwave heating technology in combination with continuous flow. The novel nonresonant microwave applicator allowed rapid heating of common laboratory solvents and reaction mixtures above their boiling points with stable and reproducible temperature profiles. The technology was successfully applied to small-scale method development and subsequent scale-out of palladium-catalyzed reactions, heterocycle synthesis and classical organic transformations such as the Fischer indole synthesis. Paper III focuses on developing regioselective oxidative decarboxylative Heck reactions with electron-rich olefins. Successful internal α-arylations were achieved using various olefins and ortho-substituted aromatic acids. The mechanism was also studied by ESI-MS analysis. Key cationic organopalladium intermediates were identified, as well as an unexpected palladium(II)- complex which was isolated and characterized. Its experimentally deduced structure was in accordance with the lowest energy minimum found by DFT calculations. Preliminary findings suggested that the complex acts as a catalyst trap. Paper IV studies the mechanism of the reaction in Paper III by means of DFT calculations. Reductive elimination was identified as the rate-determining step when using a linear enamide as the olefin, due to its propensity to form low energy chelates. Its chelating properties also played a key role in the stability of the isolated palladium(II)-complex. The complex, which can act as a catalyst trap, was characterized by X-ray crystallography.

Keywords: palladium(II), dft, reaction mechanisms, esi-ms, heck, decarboxylation, microwave, continuous flow

Ashkan Fardost, Department of Medicinal Chemistry, Box 574, Uppsala University, SE-75123 Uppsala, Sweden.

ISSN 1651-6192 ISBN 978-91-554-9149-9 urn:nbn:se:uu:diva-242259 (http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-242259)

“I wanted to buy a candle holder, but the store didn’t have one. So I got a cake instead.”

Mitch Hedberg (1968–2005)

List of Papers

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

I Trejos, A., Fardost, A., Yahiaoui, S., Larhed, M. (2009) Palla- dium(II)-catalyzed coupling reactions with a chelating vinyl ether and arylboronic acids: a new Heck/Suzuki domino diarylation reaction. Chem. Commun., (48): 7587–7589. II Öhrngren, P., Fardost, A., Russo, F., Schanche, J-S., Fagrell, M., Larhed, M. (2012) Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications. Org. Process Res. Dev., 16(5): 1053-1063. III Fardost, A., Lindh, J., Sjöberg, P. J. R., Larhed, M. (2014) Pal- ladium(II)-Catalyzed Decarboxylative Heck Arylations of Acy- clic Electron-Rich Olefins with Internal Selectivity. Adv. Synth. Catal., 356(4): 870-878. IV Fardost, A., Svensson, F., Larhed, M., Sköld, C. (2014) Theo- retical Mechanistic Investigation of a Decarboxylative Heck Reaction with an Electron-Rich Olefin and Possible Catalyst Entrapment by the Heck Product. Manuscript.

Reprints were made with permission from the respective publishers.

Papers Not Included in This Thesis

I Lindh, J., Fardost, A., Almeida, M., Nilsson, P. (2010) Conven- ient Stille carbonylative cross-couplings using molybdenum hexacarbonyl. Tetrahedron. Lett., 51(18): 2470–2472. II Yahiaoui, S., Fardost, A., Trejos, A., Larhed, M. (2011) Chela- tion-Mediated Palladium(II)-Catalyzed Domino Heck−Mizoroki/Suzuki−Miyaura Reactions Using Arylboronic Acids: Increasing Scope and Mechanistic Understanding. J. Org. Chem., 76(8): 2433-2438. III Fardost, A., Russo, F., Larhed, M. (2012) A non-resonant microwave applicator fully dedicated to continuous flow chemistry. Chim. Oggi-Chem. Today., 30(4): 14-16. IV Svensson, F., Fardost, A., Wakchaure, P., Wejdemar, M., Sköld, C., Larhed, M. (2014) Palladium(II)-Catalyzed Decar- boxylative Synthesis of Styrenes. Manuscript.

Contents

Introduction ...... 11 The Mizoroki-Heck Reaction ...... 11 Regioselectivity ...... 13 The Oxidative Heck Reaction ...... 15 Decarboxylations ...... 17 Microwaves & Continuous Flow Chemistry ...... 18 Microwave Chemistry ...... 18 Continuous Flow Chemistry ...... 20 Microwave-Assisted Continuous Flow Chemistry ...... 21 Palladium(II)-Catalyzed Coupling Reactions With A Chelating Vinyl Ether & Arylboronic Acids: A New Heck/Suzuki Domino Diarylation Reaction (Paper I) ...... 23 Inspiration & Objectives ...... 23 Results & Discussion ...... 25 Internal α-Arylation ...... 25 Terminal β-Arylation ...... 26 α/β-Diarylation ...... 27 Conclusions ...... 30 Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications (Paper II) ...... 31 Inspiration & Objectives ...... 31 The Instrument ...... 31 Results & Discussion ...... 34 Initial Studies of Instrument Performance ...... 34 Model Reactions ...... 37 Conclusions ...... 44 Palladium(II)-Catalyzed Decarboxylative Heck Arylations of Acyclic Electron-Rich Olefins With Internal Selectivity (Paper III) ...... 45 Inspiration & Objectives ...... 45 Results & Discussion ...... 45 Preparative Chemistry & Scope ...... 45 Mechanistic Investigation by ESI-MS ...... 48 Conclusions ...... 53

Theoretical Mechanistic Investigation of a Decarboxylative Heck Reaction With an Electron-Rich Olefin and Possible Catalyst Entrapment by the Heck Product (Paper IV) ...... 54 Inspiration & Objectives ...... 54 Results & Discussion ...... 54 Computational Details ...... 54 Mechanistic Pathway ...... 55 Palladium Complex 3.5 ...... 60 Conclusions ...... 64 Acknowledgements ...... 65 References ...... 67

Abbreviations

6MBP 6-methyl-2,2’-bipyridine Ac acetyl Ar aryl DBU 1,8-diazabicyclo[5.4.0]undec-7-ene DFT density functional theory Dmphen 2,9-dimethyl-1,10-phenanthroline DMSO dimethyl sulfoxide Dppp 1,3-bis(diphenylphosphino)propane EDG electron-donating group Equiv equivalent ESI electrospray ionization EWG electron-withdrawing group FLIR forward looking infrared IR infrared LC liquid chromatography Me methyl MS mass spectrometry MS(+) mass spectrometry in positive mode MS(–) mass spectrometry in negative mode MW microwave NMP N-methyl-2-pyrrolidone NMR nuclear magnetic resonance OAc acetate p-BQ para-benzoquinone Pd palladium Ph phenyl Pr Propyl Q quadropole RQC quick reaction coordinate rt room temperature RT residence time Temp. temperature THF tetrahydrofuran TS transition state

Introduction

Palladium, the transition metal on which this thesis is based, was discovered and isolated for the first time by William Hyde Wollaston in 1803.1 Today, palladium is used in various fields, such as being a building block in opto-2 and nanoelectronics,3,4 fuel cells,5 and solar cells,6 to being a catalyst in the preparation of fine chemicals7 and pharmaceuticals.8 Its two latter applications have made palladium one of today’s most widely used catalysts.9 Pal- ladium’s importance in both industry and academia has been further confirmed as Richard F. Heck, Akira Suzuki and Ei-ichi Negishi, the inventors of three eponymously named notable palladium-catalyzed reactions, were awarded the Nobel prize in 2010.10 The evolution of palladium from discovery to becoming one of the most used catalysts involves many intricacies and developments.11 However, a detailed description of such timeline will not be presented in this work, since there are countless, excellent accounts already available in the literature.10,12– 14 Instead, the focus will be immediately directed to the specific use of palladium that comprises the main subject of this thesis, namely as a catalyst in the oxidative Heck reaction, to form new carbon–carbon bonds.

The Mizoroki-Heck Reaction Before moving on to the main subject, the oxidative Heck reaction, a brief overview of the more well-known Mizoroki-Heck reaction is merited. This is necessary since many of the problems that are encountered here also apply to oxidative Heck reactions – problems that the projects in this thesis were designed to tackle. The Mizoroki-Heck reaction is the result of an independent discovery by Mizoroki15 and Heck16 in 1971 and 1972, respectively, who reported the palladium(0)-catalyzed reaction between an aryl halide, vinyl halide or benzylhalide with an alkene (Scheme 1).

Scheme 1. The Pd(0)-catalyzed Mizoroki-Heck reaction.

11 Although Heck reported the arylation of alkenes using arylmercurial chlorides and stoichiometric loadings of palladium(II) as early as 1968,17 it was the catalytic palladium(0) version reported later that spurred the development of Heck chemistry into the versatile and indispensible, Nobel prize winning carbon–carbon bond forming tool it is today.9,10,13,12 Alongside the Mizoroki-Heck reaction, many other palladium(0)-catalyzed methods for forming carbon–carbon bonds have been developed as well. Some notable examples are the ones named after and invented by Negishi,18 Suzuki- Miyaura,19,20 Hiyama-Hatanaka,21 Stille-Migita,22,23 Sonogashira-Hagihara24 and Kumada-Corriu,25,26 as depicted in Scheme 2.

Scheme 2. Commonly used palladium(0)-catalyzed cross-couplings.

The mechanisms of these reactions vary in many different aspects when examined in detail, but they share a number of common steps: Step 1) the formation of an R–Pd(II) intermediate from the starting organohalide and Pd(0)-catalyst, via an oxidative addition mechanism;13 Step 2) transmetallation of an organic R2 substituent from a main group metal to the previously formed Pd(II) intermediate;27 3) Formation of a new carbon–carbon σ-bond between the R1 and R2 moieties through reductive elimination, which releas- es and regenerates Pd(0) that can partake in a new cycle.28 While initiated by oxidative addition, the subsequent steps in the Mizoro- ki-Heck reaction mechanism differ from the abovementioned cross- couplings (Scheme 3). Since olefins are used instead of organometallic substrates, the mechanism thus lacks a transmetallation step. Instead, in Step 2, the olefin will coordinate the Ar–Pd intermediate to form a π-complex. Step 3 comprises a carbopalladation, in which the aryl moiety in the Ar–Pd intermediate inserts into the double bond to form a σ–complex. This is followed by an internal rotation of the Cα–Cβ bond (with respect to Pd, not shown) and β–hydride elimination (Step 4). In Step 5, the newly formed Heck product is released from the Pd–hydride, that in turn is deprotonated by the base (Step 6) which regenerates the Pd(0)-catalyst.13,29

Scheme 3. General mechanism of the Pd(0)-catalyzed Mizoroki-Heck reaction.

Regioselectivity As for the cross-coupling reactions in Scheme 2, the carbon–carbon bond forming step leaves no room for regioselectivity issues simply due to the structural nature of the organyl moieties. For the Mizoroki-Heck reaction, however, the carbon–carbon bond forming step is preluded by a π-complex, from which the Ar–Pd intermediate can insert into both the internal (α) and terminal (β) alkene carbons, depending on the electronic and steric properties of the ligand as well as the solvent and substrates that are being used.30–32 The generally observed pattern is that β-insertion is favored by both electronic and steric factors for electron-poor olefins, as electron deficient Pd is biased towards the more electron-rich internal carbon (Scheme 4).33,34,14

Scheme 4. Electron-poor olefins yield the terminal (β) arylation product.

In the case of electron-rich olefins, Pd is biased towards binding the electron-rich terminal (β) carbon in the insertion process, which is counteracted by steric congestion from the aryl group and the olefin substituent, resulting in poor regioselectivity and thus a mixture of both internal and terminal products (Scheme 5).31,33,34,14

Scheme 5. Electron-rich olefins yield a mixture of the internal and terminal arylation product.

The mechanisms depicted in Scheme 4 and 5 constitute the neutral pathway mechanism, as the subtrates involved generate neutral intermediates.14 It has been demonstrated for electron-rich olefins, however, that mainly the internal product is observed when the reaction is performed with aryl halides in the presence of halide scavengers,35,36 or when using aryltriflates as the arylating agent.37 This is rationalized by the formation of reactive cationic Pd complexes, which are more sensitive to the electronic effects due to them being positively charged. This constitutes the cationic pathway mechanism, which favors internal products for electron-rich olefins and terminal products for electron-poor olefins (Scheme 6).

Scheme 6. The cationic pathway of the Pd(0)-catalyzed Mizoroki-Heck reaction.

14 The Oxidative Heck Reaction The Mizoroki-Heck reaction has enjoyed a considerable spree of development since its discovery, but being able to use a wider and greener variety of Ar-Pd precursors has called for developments of the palladium(II)-catalyzed Heck reaction, today known as the oxidative Heck reaction. Selected key events in its emergence are as follows: 1. 1968: Heck reports the arylation of olefins using arylmercuric chlorides with catalytic amounts of Pd(II), with CuCl2 as a catalytic reoxidant together with oxygen as the terminal reoxidant.38 Note that it was discovered before the classical Mizoroki-Heck reaction. 2. 1975: Heck and Dieck report an anlogous reaction with vinylboronic acids and methyl acrylate, although with stoichiometric loadings of Pd(II).39 3. 2001: Remaining dormant for 26 years, the prospect is revived as the tedious use of pressurized oxygen or toxic reagents like mercuric chlorides are overcome by Mori and colleagues,40 in reporting the use of Cu(OAc)2 as a successful reoxidant of Pd(0). 4. 2003-2004: Jung41 and Larhed42 introduce the use of oxygen as the sole reoxidant.

These key events, amongst many others, led to the oxidative Heck reaction becoming the smooth and high yielding reaction that it is today.43 The mechanism of the oxidative Heck reaction (Scheme 7) is fairly similar to that of classical Pd(0)-catalyzed Mizoroki-Heck reactions, and problems with regioselectivity are shared among both, although there are two key differences worthy of a short discussion.

Scheme 7. General mechanism of the oxidative Heck reaction.

15 The first step (Scheme 7, Step 1), being one of the key differences from the classical Pd(0)-catalyzed Mizoroki-Heck reaction, is initiated with a Pd(II) species instead of Pd(0), to form the Ar–Pd intermediate. This can occur either by C–H activation of aromatic C-H bonds,44–46 decarboxylation of aryl- and vinylcarboxylic acids,47,48 or most commonly via transmetallation of a wide variety of organometallic substrates. These include the commonly used arylboronic acids,40,42,49–52 as well as, arylstannanes,53 arylsilanes,54,55 arylmercury,56 arylphosphonic acids,57 arylbismuth58 and arylantimony59 substrates. The impressive array of aryl substrates that the Pd(II)-catalyzed oxidative Heck reaction offers is evident with regards to the abovementioned examples. While this allows for great chemoselectivity in the synthesis of complex molecules, substrates such as arylboronic acids and carboxylic acids highlight its environmental benign feature. While steps 2-6 are fairly similar to that of the classic Mizoroki-Heck mechanism, another key difference is the catalyst regeneration at the end of the cycle, in which catalytically active Pd(II) must be formed (Scheme 7, steps 6-7). Some of these include p-benzoquinone (p-BQ), MnO2, desyl chloride, copper and silver salts, and peroxides. Oxygen has emerged as another alternative due to its low price (basically free for reactions run in open air) and minimal environmental impact.41,60 The mechanisms for catalyst regeneration by oxygen and p-BQ have many similarities and their understanding has increased significantly during the last decades thanks to the efforts of several research groups.43,61–67 The general mechanisms for reoxidation by O2 (A) and p-BQ (B), which are the reoxidation methods used in the works of this thesis, are shown in Scheme 8 with regards to the oxidative Heck cycle. Pathways A1 and B are formally identical, but it is noteworthy to mention that two competitive pathways (A1 and A2) are possible in reoxidation with oxygen.61,62,66,68 Pathway A1 occurs through the formation of Pd0 via reductive elimination followed by reaction with oxygen to give a η2- peroxo complex, while pathway A2 occurs through a direct insertion of oxygen into the Pd(II)-hydride, thus eluding the formation of Pd(0).66 The literature is not in agreement over which pathway is ultimately preferred, although recent work by Stahl and co-workers suggest that pathway A2 is un- likely in the presence of common Pd-catalysts, especially in the case of bidentate nitrogen ligands.62

Scheme 8. General mechanism of Pd(0) reoxidation via O2 (A1 and A2) and p-BQ (B).

Decarboxylations Among the many different aryl substrates that are available in Pd(II)- catalyzed oxidative Heck chemistry, the use of arylcarboxylic acids has re- ceived substantial attention during the last two decades. This can be attributed to their low costs, ease of preparation and wide availability.47,69 Metal- mediated decarboxylations were discovered in 1930,70 and further explored during the following decades,71–77 but its use as a carbon–carbon bond forming tool did not take off until recently. Pioneered by Myers and colleagues in 2002, the first example of a Pd(II)-catalyzed decarboxylation of benzoic acids that in the presence of olefins yielded vinylarenes was reported (Scheme 9).48 More recently, Su and co-workers also showed that p-BQ can be used as the reoxidant, instead of the relatively expensive silver salt.78

Scheme 9. The oxidative decarboxylative Heck reaction as reported by Myers et al.48

Although the prospect of using carboxylic acids as substrates is promising, it is associated with a severe drawback: it is limited to ortho-substituted benzoic acids.79–81 Gooßen and colleagues have shown that the use of bimetallic catalyst systems may overcome this limitation, however only for non- oxidative decarboxylative reactions.82–84 Decarboxylations have to date been applied for non-oxidative Suzuki- and Sonogashira-type cross-couplings,85–88

17 their oxidative counterparts,89,90 various oxidative Heck-type reactions,78,91–95 and for the oxidative synthesis of aryl ketones.96

Microwaves & Continuous Flow Chemistry

Microwave Chemistry Conductive heating has been the main source of energy in the heating of chemical mixtures and materials. It began with alchemy and open fire until it was abandonded in 1855 in favor of the controllable Bunsen burner,97 which later shapeshifted to oil baths, metal plates and electric mantles. The problem with conductive heating, however, is that there will always be a temperature gradient from the heating source to the reaction mixture.98– 100 The source will obviously be hottest, followed by the walls of the reactor vessel and finally a decreasing gradient towards the reaction medium itself. This heating distribution gives rise to the “wall effect”, as in the walls of the reactor being hotter than the average temperature of the reaction mixture (Figure 1).101 While stirring circumvents this effect to a certain degree, the walls will still be hotter and the temperature inside the actual reaction medium remains difficult to control.

Figure 1. Heating profile of a conductively heated reactor vessel (Reproduced with kind permission from Molecular Diversity).99

A little less than 30 years ago, microwave chemistry was introduced as a novel way of transferring heat energy in organic synthesis, as a result of pioneering experiments using domestic microwave ovens.102,103 Since then, the technology has been dramatically improved into safe single- and multi-

18 mode instruments dedicated to small scale organic synthesis, as a way of allowing rapid and remote heating of reaction media.98,99,104–109 Benefits such as reduced reaction times and increased yields have rendered microwave technology a widely used tool,98,99,110,111 and attributed to the uniform and direct in situ heating which circumvents wall effects (Figure 2).99 This is especially the case when rapid heating up to high temperatures is required.99,100 Another benefit is the ability to perform reactions above the boiling point of the solvents, since sealed pressure-resistant reactors are used, which can help reduce the reaction times even further.112

Figure 2. Heating profile of a microwave irradiated reactor vessel (Reproduced with kind permission from Molecular Diversity).99

The most common type of microwave irradiation in organic chemistry is the use of so called single-mode reactors. By creating a standing wave, this technology ensures relatively good temperature control and high reproducibility (Figure 3).107,112,113

Figure 3. Schematic overview of a single mode microwave cavity (modified from Ondruschka et al.,114 used with kind permission from Chemical Engineering & Technology).

19 Due to the limited penetration depth of 2.45 GHz microwaves (a few centi- meters when using microwave-absorbing solvents), and the focused field, the single-mode technology is limited to small scale syntheses (0.2 – 20 mL). Multi-mode instruments, which are designed with large cavities that allow large volumes or multiple reactions to be heated in parallel, have been designed in order to increase the scale.98 In contrast to the controlled standing wave in single-mode reactors, multi-mode reactors are based on the same technology as domestic microwave ovens, in which microwaves are distributed randomly.100 Since this results in a non-uniform heating profile due to nodes, which in turn compromises the reproducibility, “mode stirrers” are used to minimize this adverse effect (Figure 4).98

Figure 4. Schematic overview of a multi-mode microwave cavity (illustration modified from Ondruschka and colleagues,114 used with kind permission from Chemical Engineering & Technology).

Continuous Flow Chemistry Continuous flow chemistry has since the 1970’s made its way from the in- dustrial plant to the research laboratory,115,116 partially since the synthesis of peptides in continuous flow systems became popular.115–117 In principle, the approach of continuous flow constitutes the use of stock solutions, from which reactants are transferred continuously in small portions through a heating zone in order to react and finally yield the crude product (Figure 5).

Figure 5. Simplified schematic overview of the continuous flow approach.

This approach may harbor a variety of benefits, mainly: 1. The large surface-to-volume ratio allow fast heating and temperature changes, especially when employing micro-flow systems with flow channels less than 1 mm in diameter.118–121 2. Certain reactions enjoy better selectivity and higher yields in continuous flow than in batch synthesis, 120,122 which may partially be due to reaction mixture constantly being flushed out of the heated reaction zone and replaced with fresh reactants, thus reducing the risk for side-reactions. 3. Since only a fraction of the reactants are actually reacting at any given time, there is a safety benefit when using explosive substrates or running highly exothermic reactions. 4. Increasing the volume of the stock solutions (i.e. the scale of the reaction) does not require any changes in the reaction conditions, since the heating zone remains unchanged. Thus, a “scale-out” can be performed by simply increasing the stock solutions’ volumes and run the system for a prolonged time, or set up several reactions for parallel processing, without the need of expensive re-optimizations that are usually necessary when changing reaction scales.118

As with any technology there are always drawbacks. As the name suggests, continuous flow chemistry requires exactly that: continuous flow. Thus, more or less particle-free solutions are required, both as stock solutions and as crude products, as clogs forming in the system will interrupt the process. This is especially the case for micro-flow systems.121 The flow is produced mainly by means of HPLC or syringe pumps. While syringe pumps generally tolerate a higher amount of particles and harsher reagents than HPLC pumps, the latter can handle higher pressures.

Microwave-Assisted Continuous Flow Chemistry The majority of the commercial continuous flow systems available today utilize conductive heating via heated oil,123 heated air,124 electric resistance,125 or induction.126,127 Microwaves were combined for the first

21 time with continuous flow chemistry by Strauss and colleagues in 1994.128 Other examples followed, also by using modified batch microwave systems to allow either continuous flow,129–131 or stop/flow.110,129 These modified systems housed flow cells constructed as helical-shaped borosilicate glass,132 U-formed borosilicate glass loops,133,134 standard microwave vessels filled with sand135 or glass beads,136 or microcapillary flow cells.137 The combination of microwave technology with the continuous flow approach can be beneficial in many ways. Reactions can for example be rapid- ly optimized as the temperature of the heating zone can be adjusted almost in real-time, without being restricted to a micro-flow system. This in turn results in reduced dead volumes and thus less waste, as steady-state can be achieved faster. The increased power density in the heating zone, thanks to microwaves, may also allow faster flow and thereby larger product throughput. The heating can also be quickly stopped, since the microwaves heat the reaction mixture, and normally not the reactor vessel. The microwave-assisted continuous flow instrument used in this thesis was purpose-built for continuous flow, using a novel microwave applicator rather than a modified batch instrument. It is described in more detail in the section covering Paper II.

22 Palladium(II)-Catalyzed Coupling Reactions With A Chelating Vinyl Ether & Arylboronic Acids: A New Heck/Suzuki Domino Diarylation Reaction (Paper I)

Inspiration & Objectives Controlling the regio- and stereoselectivity of Heck couplings is essential in the case of many alkenes. Chelation-control has during the last two decades emerged as a successful tool in achieving this for Pd(0)-catalyzed Mizoroki- Heck reactions (Scheme 10).138–143

Scheme 10. Schematic illustrations of stereo- and regioselectivity in the Mizoroki- Heck reaction by nitrogen- and oxygen-based intramolecular chelation-control.

More recently, White and co-workers introduced a similar method for Pd(II)- catalyzed Heck reactions, in which a linear chelating alkene was successfully arylated in the terminal position with high regioselectivity (Scheme 11).52

Scheme 11. Terminal (β) regioselectivity in the oxidative Heck reaction by intramolecular oxygen- or sulfur-based chelation-control.52

Inspired by the work of White and colleagues, the prospect of chelation- controlled Heck couplings under Pd(II)-catalysis became intriguing, especially by using the linear chelating vinyl ether 1.1 that has been extensively studied by our department in the past for its chelation-controlling ability in Pd(0)-catalyzed Mizoroki-Heck reactions (Scheme 12).140,144–151

Scheme 12. Regioselectivity by chelation-control using the linear vinyl ether 1.1.

The target objective was thereby to use arylboronic acids as arylating agents and obtain high regio-control in two ways: 1) internal arylation of vinyl ether 1.1 by blocking the nitrogen auxiliary using an external bidentate ligand (Scheme 13, A); 2) terminal arylation of vinyl ether 1.1 through coordination of palladium by the chelating nitrogen auxiliary (Scheme 13, B).

Scheme 13. Internal (α) arylation with a bidentate ligand (A) or terminal (β) arylation by chelation control (B).

During the course of this investigation, a serendipituous finding led to a to- tally different main objective. It was found that the choice of palladium reoxidant dramatically changed the product outcome: when using p-BQ as the

24 reoxidant, a 1,2-diarylation of the vinyl ether double bond was observed (Scheme 14).

Scheme 14. Unexpected 1,2-diarylation product in the presence of p-BQ.

From then on, exploring the monoarylation reactions was not the main objective, but rather to improve, optimize and understand this serendipituously discovered diarylation reaction.

Results & Discussion

Internal α-Arylation The bidentate ligand diphenylphosphinopropane (dppp) has been proven to counteract the chelating ability of the dimethylamino auxiliary of 1.1 under Pd(0)-catalysis,145 which shifts the regioselectivity from terminal arylation on the β-carbon to the otherwise electronically controlled internal arylation on the α-carbon.14 Based on this knowledge, vinyl ether 1.1, p-tolylboronic acid 1.2a and Pd(CF3CO2)2 was mixed with dppp using 1,4-dioxane as solvent and stirred at 25 ºC with O2 (g) as the reoxidant. This provided the electronically controlled, internally arylated product 1.3a in high yield with high regioselectivity (Scheme 15).

Scheme 15. Internal (α) regioselectivity by blocking the chelating nitrogen-auxiliary with dppp. a Determined by GC-MS.

25 Terminal β-Arylation To achieve terminal β-arylation, dppp had to be removed from the mixture in order to allow the dimethylamino auxiliary to coordinate palladium. Only small amounts of the terminally arylated product 4a could be obtained however, which was also the case when using THF, toluene and chlorofom as solvents. The polar solvents MeCN, MeOH, DMSO and DMF were also tested, and it was found that using DMF and Pd(OAc)2 with an increased temperature improved the isolated yield. Thus, by mixing 1.1, 1.2, Pd(OAc)2 and DMF using O2 (g) as the reoxidant and stirring at 60 ºC, the terminally arylated products 1.4a-d were obtained in moderate to good yields (Table 1). The regioselectivity was excellent in this case, as no internally arylated products could be detected. The stereoselectivity was rather low for all but the p-methoxysubstituted arylboronic acid, however.

Table 1. Terminal (β) regioselectivity by chelation-control.

Aside from trying various solvents, catalysts and temperatures, different reoxidants were also investigated. While Cu(OAc)2 and AgOAc provided outcomes inferior to that of O2, p-BQ had an unexpected impact on the product outcome: a reaction performed with p-BQ produced a previously unseen compound as detected by GC-MS. The compound was isolated and characterized by 1D and 2D NMR-spectroscopy as structure 1.5a (Scheme 16).

Scheme 16. Formation of the 1,2-diarylation product 1.5 in the presence of p-BQ.

26 α/β-Diarylation Searching the literature revealed that β-hydride elimination, the catalytic step prior to formation of the Heck product (Heck product 1.4 in this case), can be prevented by certain ligands.152,153 Therefore, a likely scenario could be that the σ-alkyl palladium(II)-intermediate is stabilized by both the intramolecular dimethylamino auxiliary as well by p-BQ, which presumably acts as a weak π-acidic Pd-ligand. This palladacycle intermediate could then undergo a Suzuki-type transmetallation by another arylboronic acid and yield the diarylation product 1.5 after a reductive elimination in a Heck/Suzuki domino fashion (Scheme 17).

Scheme 17. Proposed key mechanistic step promoting the formation of 1.5.

Thus, the target objective of the investigation was shifted towards favouring the formation of 1.5a. The ratio of arylboronic acid 1.2a to vinyl ether 1.1 was increased to 3:1 and 1,4-dioxane was identified as the most productive solvent among the ones tested. Increased polarity such as with MeCN, DMSO and DMF favoured the terminal monoarylated product 1.4a, while toluene severely retarded the reaction rate. Pd(CF3CO2)2 was the superior catalyst as compared to Pd(OAc)2 and Pd(acac)2. The temperatures used for internal (25 ºC) and terminal arylation (60 ºC) reduced the reaction rate or increased the amount of monoarylated product 1.4a, respectively. A temperature of 40 ºC was found to be favourable for the domino 1,2-diarylation. These reaction conditions furnished 1.5a in high yield (82%) and the monoarylated product could not be observed (Table 2, entry 1). The reaction was then applied to a range of different arylboronic acids as depicted in Table 2. The yields and the selectivity for the 1,2-diarylated domino product 1.5 were moderate to excellent for electron-rich and electron-neutral arylboronic acids (Table 2, entries 1-8). Sterically congested o-substituted acids exhibited slightly lower yields than their m- and p-substituted homologues (Table 2, entries 1-5). Electron-poor arylboronic acids were not thoroughly investigated at this point, as a series of tests indicated very low reactivity. The p- bromosubstituted aryl substrate 1.2i exhibited good performance, providing a 66% yield of diarylation domino product 1.5i alongside only traces of 1.4i (Table 2, entry 9). The p-iodophenyl-substituted arylboronic acid, however, provided both a poor yield and poor chemoselectivity as high amounts of

27 monoarylated product 1.4j was observed (Table 2, entry 10). The poor performance could possibly be explained by the propensity of dehalogenation of this compound, as well as homocoupled biaryl product that could be detected by GC-MS. The thiophene heterocycle 1.2k provided a low yield of the desired product 1.5k, while also forming the monoarylated product 1.4k. This may be attributed to palladium coordination of the sulfur atom in 2-position,

Table 2. Scope of arylboronic acids in the domino 1,2-diarylation reaction.

outcompeting the chelating nitrogen for the free binding sites on palladium (Table 1, entry 11). With the sulfur atom in the 3-position in arylboronic acid 1.2l, the reaction provided a relatively higher yield for 1.5l with no detecta- ble amount of monoarylated side-product 1.4l (Table 1, entry 12). The vinylboronic acid 1.2m delightfully reacted to yield 1.5m with a 65% yield without producing the monoarylated 1.4m (Table 1, entry 13). With the scope of the reaction established, it was also interesting to inves- tigate the role of p-BQ in terms of providing the diarylation domino product.

28 It was already known that of the reoxidants tested, only p-BQ exhibited this reactivity, while the absence of p-BQ solely provided the monoarylated product 1.4a. To confirm the importance of p-BQ further, a reaction was set up as in Table 2 but without p-BQ and with 100 mol% of Pd(CF3CO2)2, which also resulted in only the monoarylated product 1.4a. The importance of the chelating dimethylamino group was also confirmed by replacing 1.1 with the non-chelating vinyl ethers n-butyl vinyl ether and t-butyl vinyl ether, respectively. While these vinyl ethers were not fully consumed in the reaction, they only provided a mixture of the α- and β-monoarylated Heck products. Based on the findings at hand, a mechanism for the catalytic cycle was proposed to explain the formation of 1.5 in the Pd(II)-catalyzed oxidative Heck/Suzuki domino 1,2-diarylation (Scheme 18).

Scheme 18. Proposed catalytic cycle for the Heck/Suzuki domino 1,2-diarylation reaction.

After initial transmetallation of arylboronic acid 1.2, vinyl ether 1.1 binds to palladium with both a η2-interaction from the double bond and coordination with the dimethylamino auxiliary as in A. Rotation of the double bond moiety into the plane of palladium’s orbitals allows syn insertion which yields palladacycle B. With p-BQ coordinating palladium in this six-membered intermediate, B remains stable enough to avoid β-hydride elimination, which would have formed side-product 1.4. Following these Heck-type steps, a Suzuki-type transmetallation occurs to form complex C. The diarylated domino product 1.5 can then be released through a reductive elimination step, afterwhich the formed Pd(0) species can recycle back to Pd(II) utilizing either O2 or p-BQ as the reoxidant.

29 Conclusions An oxidative Heck or domino Heck/Suzuki 1,2-diarylation reaction using arylboronic acids as aryl substrates and an electron-rich chelating vinyl ether were developed. The regioselectivity can be controlled by the ligand being used (or not being used) to offer three outcomes: internal (α) arylation, terminal (β) arylation, or domino Heck/Suzuki 1,2-diarylation (Scheme 19). The reaction offers moderate to good yields with excellent regioselectivity depending on the regioselective outcome. A catalytic mechanism has been proposed to explain the unexpected domino Heck/Suzuki 1,2-diarylation.

NMe Ar B(OH) [PdII] O 2 + 2 +

dppp

L Ar + O + Ar Pd N P Pd

NMe2 P O

+ Ar O L + L Pd N Pd NMe2 P Ar P O

-BQ

O O O NMe NMe NMe 2 Ar 2 Ar 2 Ar Ar

-Arylation -Arylation / -Diarylation

P P = dppp – – L = solvent, OAc ,CF3CO2 or vacant site

Scheme 19. Summary of the internal (α), terminal (β) and domino 1,2-diarylation pathways.

30 Evaluation of a Nonresonant Microwave Applicator for Continuous-Flow Chemistry Applications (Paper II)

Inspiration & Objectives The benefits and drawbacks of conductive heating and microwave irradiation were discussed on pages 18-20. Continuous flow technology was mentioned as a potential candidate for providing precise, uniform heating while also dodging both practical and safety concerns in large scale synthesis. Before this project started, access was granted to use a novel, nonresonant microwave applicator instrument, purpose-built for continuous flow opera- tion. This benchtop instrument was built to allow rapid method optimization on a small scale, followed by an increase in the reaction scale without having to change the reaction conditions (scale-out). The challenge was to find out whether or not it is possible to harness the efficient heating properties of microwave irradatiation without being con- strained to small and limited reaction scales.

The Instrument The components were comprised of a microwave generator (Figure 6, A), an applicator that transfers the generated microwave energy to the reaction mixture (Figure 6, B), and a software control unit (not visible in Figure 6). A tubular microwave-transparent borosilicate reactor with Valco® fittings (Fig- ure 7) is housed inside the applicator, through which the reaction mixture passes. A two-channel syringe pump with a pressurised storage compartment contains the reaction mixtures which can be pumped through the system with a desired flow rate. The mixtures go through a static mixing chamber before entering the reactor. A 17 bar backpressure regulator was placed after the reactor to avoid boiling of the reaction mixtures. The entire setup is depicted in Figure 8 as a schematic diagram.

Figure 6. Microwave generator (A) and microwave applicator (B).

Figure 7. Tubular borosilicate reactor with standard Valco® fittings.

STOCK SOLUTION 1

COIL ANTENNA COIL 1

MIXER IR SENSORS 90 mm 2

STOCK 3 SOLUTION 2 4

5 MICROWAVE TUBULAR GENERATOR REACTOR

CRUDE 17 PRODUCT BAR

Figure 8. Schematic diagram of the continuous flow microwave setup.

The software allows regulation of power (0–150 W) and microwave frequency (2.40–2.50 GHz),154 and it receives input from one of the five Optris CT IR temperature sensors, as chosen by the chemist, that are placed alongside the tubular reactor. Four of the IR sensors are positioned within the heating zone and one IR sensor outside near the reactor outlet. The software can regulate the power output and microwave frequency automatically, so that a desired target temperature is reached and maintained as quickly as possible. The novelty lies in the microwave applicator. It uses a non-resonant structure that suppresses standing waves, which essentially avoids the formation of hot and cold spots. The microwave field is generated in a coil antenna surrounding the borosilicate reactor, which allows the field to be concentrat- ed axially inside the coil. The length and diameter of the borosilicate reactor can be changed as long as it fits inside the coil, which allows the chemist to modify the residence time and flow capacity. The tubular reactors used in this project were 200 mm in length, while the coil antenna was 90 mm in length. Although only a maximum of 90 mm of the tubular reactor is covered by the coil antenna, heating could occur beyond the coil (the heating zone was determined to be 100 mm in length,

33 based on FLIR experiments, see page 37). This is due to the dielectric com- ponent of the electromagnetic field, which radiates in the transverse direction along the heating zone (in this case towards the outlet of the reactor). The inner lumen of the reactors were 3 mm in diameter with a maximum outer diameter of 9 mm. With a heating zone of 100 mm in length and an inner lumen of 3 mm for the tubular reactors, the volume of reaction mixture within the heating zone was calculated to be 0.7 mL in volume.

Results & Discussion

Initial Studies of Instrument Performance To test the heating capability and robustness of the instrument, a set of solvents common in microwave chemistry were pumped through and heated by the system. The solvents were heated from room temperature to -20 ºC below the boiling point (bp), from room temperature to their bp, and finally from room temperature to +20 ºC above their bp. The goal was to be ac- quainted with their heating profiles and heating ramp times. The flow rate was set to 701 μL/min, corresponding to a 1 min residence time (i.e. the time during which reaction mixture is within the heating zone of the coil antenna). Of the four IR sensors inside the heating zone (sensors 1–4), sensor 2 showed the fastest temperature response, and was thus chosen as the temperature regulator with which the software set the desired temperature (see Fig- ure 8). Data from all four IR sensors were averaged to see how the mean temperature in the heating zone deviated from the temperature-setting sensor 2. Figure 9 depicts the results for each of the tested solvents when heated to -20 ºC below their boiling points, to their boiling points, and +20 ºC above their boiling points, respectively. A general observable trend is that the average temperature in the heating zone deviates from sensor 2 as the temperature increases from -20 ºC below the boiling point to 20 ºC above the boiling point. For acetone, MeCN, H2O and EtOH, sensor 2 is within a ±5 ºC range of the average temperature in the heating zone at -20 ºC and at the actual boiling points (Figure 9, top and middle), but a slightly larger deviation is observed at +20 ºC above their boiling points. For the other solvents, this deviation is observed at both low and high temperatures with respect to their boiling points. This could be the result the rapid change in viscosity as each solvent is quickly heated once entering the heating zone. As cold high- viscosity solvent enters the heating zone, which contains hot solvent with lower viscosity, turbulence in the fluid dynamics may occur. Whether or not this was the case was not investigated further.

34 Sensor 2 versus Average Temperature in Heating Zone

Temp. (ºC) 182 200 Set temp., sensor 2 (bp - 20 °C) 169 Average of sensors 1-4 160 125 172,4 161,4 120 81 80 61 119,3 80 58 36 81,1 74,0 40 59,3 57,4 35,4 0 Dioxane Acetone MeCN Water DMF NMP DMSO EtOH (101 °C) (56 °C) (81 °C) (100 °C) (150 °C) (202 °C) (189 °C) (78 °C)

Temp. (ºC) 240 Set temp., sensor 2 (bp) 202,0 Average of sensors 1-4 189,0 200 150,0 160 189,9 179,2 101,0 100,0 120 81,0 142,3 78,0 80 56,0 93,5 99,8 40 77,0 76,3 54,0 0 Dioxane Acetone MeCN Water DMF NMP DMSO EtOH (101 °C) (56 °C) (81 °C) (100 °C) (150 °C) (202 °C) (189 °C) (78 °C)

Temp. (ºC) 260 Set temp., sensor 2 (bp + 20 °C) 222,0 Average of sensors 1-4 209,0 220 175,0

180 202,7 193,7 121,0 120,0 140 164,3 101,0 98,0 100 76,0 110,7 114,0 95,6 60 95,0 71,8 20 Dioxane Acetone MeCN Water DMF NMP DMSO EtOH (101 °C) (56 °C) (81 °C) (100 °C) (150 °C) (202 °C) (189 °C) (78 °C)

Figure 9. Microwave heating of common laboratory solvents to -20 ºC below (top), to (middle), and +20 ºC above their boiling points (bottom), using the microwave assisted continous flow instrument with a tubular borosilicate reactor with a 3 mm inner diameter at a flow rate of 701 μl/min (1 min RT).

35 The software and hardware exhibited stable temperature profiles with a nice transition from ramp-up to steady-state. Only a tiny fluctuation within a ±0.6 ºC range (at best) or ±3.7 ºC (at worst) of the desired temperature was observed, as exemplified by the heating of DMSO from room temperature to 20 ºC above its boiling point (Figure 10).

Temp (ºC) Ramp-Time & Stability of DMSO 250 Ramp Temperature stability within ±2.4 ºC of the set temperature (209 ºC) Time 200

150

100

0 00:00 00:30 01:00 01:30 02:00 02:30 03:00 03:30 04:00 Time (min) Figure 10. Temperature profile from heating DMSO from room temp. to 209 ºC.

The heating rates from room to boiling temperature was measured for the eight solvents as well. The tan δ values (at 25 ºC)155 of the tested solvents were in accordance with the observed heating rates except for MeCN, which deviated slightly (Figure 11).

6 1,0

5 0,9

4 0,7

3 (°C/s) Heating rate 0,5

2 0,3

1 0,2 tan δ 0 0,0 Dioxane Acetone MeCN Water DMF NMP DMSO EtOH (101 °C) (56 °C) (81 °C) (100 °C) (150 °C) (202 °C) (189 °C) (78 °C)

Figure 11. Measured heating rates versus literature tan δ values155 of common laboratory solvents.

36 While industry-standard batch applicators have an energy consumption of 300–1400 W, the continuous flow instrument has a maximum energy consumption of only 150 W. Nevertheless, it efficiently heats up common solvents above their boiling points. This is mainly due to variable-frequency functionality (2.40–2.50 GHz), which allows the frequency to be tuned during heating, thus compensating the reduction in tan δ at higher temperatures.154,155 To gain further insight into the heating pattern of the applicator and its coil antenna, one of the walls of the applicator was removed so that temperature recordings could be conducted with an FLIR camera (Figure 12, left). Model solvents as well as a DMF-based oxidative Heck reaction mixture (as in Table 3) were studied. As shown in Figure 12 (right), the coil antenna heats the actual reaction mixture while its own temperature remains low. The temperature is largely uniform along the heating zone.

Figure 12. Left: Microwave applicator with open wall, exposing the coil antenna and the tubular borosilicate reactor. Right: FLIR IR image of the applicator heating a DMF-based Heck reaction mixture (as in Table 3).

Model Reactions To see if the instrument is capable of serving as both a method optimization platform and a scale-out device, a series of model reactions were investigated using the instrument. The chosen reactions require different solvents (both weakly and strongly microwave absorbing), metal catalysts, temperatures as well as reaction times. All reactions were performed with 17 bars of backpressure to allow superheating. Before analytical samples were collect- ed, an entire void volume was discarded after the desired reaction conditions were reached to ensure homogenous conditions. Once high-yielding optimized conditions had been identified, prolonged collection of reaction mixture was carried out in order to determine the isolated yield and throughput

37 per hour. The throughputs per hour are extrapolations from collection peri- ods of 5–42 mins, depending on the cost of chemicals used, as well as accu- mulation of particles/clogging and tubing damage after prolonged run times.

Pd(II)-Catalyzed Oxidative Heck Vinylation of an Arylboronic Acid Batch microwave assisted styrene syntheses via Pd(II)-catalyzed oxidative Heck vinylations of aryl boronic acids using vinyl acetate was first reported by Lindh and co-workers, in which they obtained a high yielding protocol with a 30 min reaction time at 140 ºC.156 This was adapted to continuous flow using conventional heating by Odell et al., reporting a residence time of 2 min at 150 ºC.123 The latter conditions were used as a starting guide. The temperature was varied between 120 and 160 ºC with residence times ranging between 30 and 120 s. The concentration of phenylboronic acid 2.1 had to be reduced to 0.25 M to avoid clogging and precipitation, as compared to 0.5 M that was used by Odell and colleagues. The outcomes were evaluated using 4- methoxybenzonitrile as internal standard (IS) (Table 3). It was found that a temperature of 140 ºC with a residence time of 75 s provided the best outcome (Table 3, run 5). An isolated yield of 66% was obtained for the desired styrene product 2.3 (only slightly lower than the 68% obtained by Odell et al.) with a calculated throughput of 2.83 mmol/h (0.51 g/h) (Table 3, run 10).

Table 3. Optimization and scale-out of oxidative palladium(II)-catalyzed Heck vinylations.

38 Suzuki-Miyaura Cross-Coupling Batch microwave assisted variants of this Nobel prize winning reaction are many, as well as continuous flow examples with conventional heating, but examples combining both microwaves and continuous flow are limited.132,134,137 To test the compatibility of the reaction with the instrument, two stock solutions were prepared. The first contained the precatalyst Pd(PPh3)2Cl2 (0.150 mmol, 0.05 equiv, 0.005 M) dissolved in DMF. The second solution contained 4-bromobenzyl methyl ether 2.4 (3 mmol, 1.0 equiv), 4- methoxyphenylboronic acid 2.5 (3.0 equiv) and DBU (3.0 equiv), 157 all dissolved in DMF/H2O (95:5). The concentration of the second stock solution was 0.1 M with respect to the aryl halide. The two stock solutions were pumped into the reactor with the same flow rate while the temperature and residence time were varied between 130 to 160 ºC and 0.17 to 2.75 min, respectively (Table 4).

Table 4. Optimization and scale-out of the Suzuki-Miyarua reaction.

The best outcome was identified as when heating at 150 ºC with a 30 s residence time (Table 4, run 4), and these conditions were used to perform a scale-out. An isolated yield of 71% was obtained for the desired product 2.6, resulting in a calculated throughput of 3.0 mmol/h (0.69 g/h) (Table 4, run 11). It is noteworthy that all reactions were performed within 3 h of working time in the lab. It is also worth mentioning that the residence time was reduced to 30 s as compared to 8 and 4 min reported previously by Wilson132

39 and Comer,137 respectively, who both employed modified standard, single- mode microwave applicators in their continuous flow setups.

Oxathiazolone Synthesis 1,3,4-Oxathiazol–2-ones are investigated as intermediates in the synthesis of different five-membered heterocycles which carry a C=N-S fragment.158–161 Derivatives of these have been successfully employed as fungicides,162,163 and the oxathiazoline ring is included in compounds that are selective M. tuberculosis (Mtb) proteasome inhibitors.164 5-Substituted 1,3,4-oxathiazol– 2-ones have been synthesized from the parent amide and chorocarbonyl- sulfenyl chloride using classic reflux in toluene, as well as using microwave irradiation in 1,4-dioxane for 15 min at 100 ºC.164 Due to this class of structures being selective Mtb proteasome inhibitors, it was interesting to test the performance of the continuous flow microwave instrument in a “real-world” drug discovery scenario. Two stock solutions were prepared. One consisting of the parent amide 2.7 (0.25 M), and the other one being a 0.75 M solution of chlorocarbonyl- sulfenyl chloride, with 1,4-dioxane as the solvent in both stock solutions. The solutions were pumped through the reactor with the same flow rate, and the conditions were optimized by varying the temperature and residence time between 120 to 220 ºC and 40 s to 5 min, respectively (Table 5).

Table 5. Optimization and scale-out of an oxathiazolone synthesis.

40 The optimized conditions, 200 ºC and 1 min residence time, provided the product 2.8 with an isolated yield of 62% and a calculated throughput of 3.3 mmol/h (0.58 g/h) (Table 5, run 12).

Fischer Indole Synthesis Both a batch microwave165 and continuous flow protocol employing a micro- reactor166 for the synthesis of Fischer indoles has been published. Even a continuous flow protocol combined with single-mode microwave heating has been reported by Bagley and co-workers,135 as well as a scale-out experiment with promising results.167 To test the instrument against the already formidable reports in the literature, a reaction mixture was prepared with pure acetic acid as the solvent, which resulted in clogging and precipitation in the tubing and after the tubular reactor. Using a 3:1 mixture of acetic acid and 2-propanol instead cir- cumvented this problem. Two stock solutions were prepared, one with phe- nylhydrazine 2.9 (1 M, 30 mmol) and the other with cyclohexanone 2.10 (1.1 M, 33 mmol), and then evaluated with the reaction conditions depicted in Table 6.

Table 6. Optimization and scale-out of the Fischer indole synthesis.

While all entries seemed to provide similarly high conversions, entry 7 was chosen for scale-out due to the low residence time (Table 6, entry 8).

41 The product indole 2.11 was isolated in 90% yield with a calculated throughput of 57.2 mmol/h (9.8 g/h).

Claisen Rearrangement The first batch microwave assisted Claisen rearrangement was performed and reported in 1986 by microwave pioneers Giguere and Majetich.103 The high temperatures and reaction times required under conventional heating makes the Claisen rearrangement an interesting subject both in the explora- tion of microwave techniques,168–170 and continuous flow applications.121,167 In testing the instrument, 4-allyloxyanisole 2.12 was chosen as the model substrate, as p-substituents are known to increase the reaction rate.171 As polar solvents with high boiling points are suitable for Claisen rearrangements,172 NMP was chosen as the solvent. 2.12 was diluted in NMP (2 M) and pumped through the reactor. The temperature was varied between 225 to 270 ºC and the residence time between 1 to 5 min (Table 7, runs 1-12).

Table 7. Optimization and scale-out of the Claisen rearrangement.

42 The optimized conditions of 270 ºC and 5 min residence time were subjected to scale-out (Table 7, run 12) to yield product 2.13 in 79% isolated yield with a calculated throughput of 13.6 mmol/h (2.23 g/h). Similar conditions using a continuous flow system with conductive heating have been reported by Razzaq et al., in which a residence time of 4 min at 249 ºC was required.167 Another reaction was set up without any NMP, in which neat 2.12 was pumped through the system (Table 7, runs 13-20). The best conditions were identified as a 15 min residence time at 260 ºC, to yield 2.13 in 85% isolated yield with a calculated throughput of 15.0 mmol/h (2.46 g/h) (Table 7, run 20). The longer residence time required is likely due to the absence of a polar solvent suitable for microwave irradiation.

Diels-Alder Reaction Long reaction times of 15–60 min and high temperatures of 160–180 ºC are common in previously reported microwave assisted protocols concering the Diels-Alder reaction.173–175 A continuous flow method with a short residence time of 2 min has been reported, although with a relatively high recorded temperature of 330 ºC.125 Diene 2.14 and dienophile 1,4-naphthoquinone 2.15 were used as the model substrates for the evaluation, with MeCN as solvent. 1,4- Naphthoquinone has previously been reported as a good dienophile in Diels- Alder reactions.176 Temperatures between 125 and 190 ºC and residence times between 1 and 5 min were explored. The best conversion was obtained using a 5 min residence time at 190 ºC, albeit the reaction did not go to completion (73% conversion). Increasing the temperature was not possible, however, as boiling occurred despite the presence of a 17 bar backpressure regulator. High boiling point solvents were explored instead, including acetic acid, DMF and DMSO, all of which are known as good solvents in the Diels- Alder reaction.177 NMP was also included although it is known to be not fully efficient for this purpose.178 The reactions were first tested in a standard single-mode microwave applicator at 150 and 190 ºC for 5 min. DMF had to be excluded as byproducts formed above 200 ºC, probably due to the thermal decomposition of DMF.179 NMP, exhibiting a better byproduct profile, was chosen instead. While >95% conversion was observed, the reaction only provided a 52% isolated yield of 2.16 after cumbersome preparative purifica- tion using HPLC (Scheme 20). A throughput of 4.72 mmol/h (1.07 g/h) was achieved.

Scheme 20. Scale-out of the Diels-Alder reaction.

Conclusions A microwave heating source with novel nonresonant applicator technology, purpose-built for continuous flow applications, has been evaluated and applied in various classic, medicinal and organometallic organic reactions. The microwave applicator achieved uniform heating of the reaction zone according to measurements with IR sensors and a FLIR camera. The variable 2.4- 2.5 GHz microwave frequency could be automatically tuned to successfully match the temperature-dependent tan δ of the solvents and reaction mixtures, allowing rapid heating to high temperatures. This technology, in tandem with a continuous flow setup, allowed fast optimization of reaction conditions and direct scale-out without the need of re-optimization, allowing throughputs up to 57 mmol/h.

44 Palladium(II)-Catalyzed Decarboxylative Heck Arylations of Acyclic Electron-Rich Olefins With Internal Selectivity (Paper III)

Inspiration & Objectives High internal regioselectivity for classic Heck arylations of electron-rich olefins has been extensively demonstrated in the past,180 but decarboxylative counterparts are limited. These include internal decarboxylative arylation of electron-rich cyclic olefins,181 indoles,182 and one low-yielding example involving an acyclic olefin with no substrate variability.183 With these limitations in mind, an investigation to enable Pd(II)-catalyzed decarboxylative internal arylations of electron-rich acyclic olefins was undertaken. The starting point for the project was inspired by Lindh et al. and Svenson et al., who reported a bidentate ligand-modulated system for the decarboxylative addition of benzoic acids to nitriles to form aryl ketones under Pd(II)-catalysis.96,184

Results & Discussion

Preparative Chemistry & Scope A mixture of 2,6-dimethoxybenzoic acid 3.1a, the electron-rich enamide 3.2a, Pd(CF3CO2)2 and 6-methyl–2,2’-bipyridine (6MBP), with p-BQ as the reoxidant and DMF as the solvent, delightfully yielded the internal Heck product 3.3a in 77% isolated yield after 24 h at 120 ºC (Table 8). No traces of the terminal Heck product, unreacted benzoic acid 3.1a or the protodecar- boxylation by-product 1,3-dimethoxybenzene could be deteced by neither 1H-NMR, LC-MS or GC-MS, respectively. The scope of the method was investigated by reacting a variety of o- substituted carboxylic acids with enamide 3.2a (Table 8).

45 Table 8. Scope of arylcarboxylic acids for the oxidative decarboxylative Heck reaction.

O 2 mol% Pd(CF3CO2)2 O 2.4 mol% 6MBP Ar COOH + N Ar N 1.2 equiv -BQ, 1 mL DMF 24-48 h, 120 C 1 mmol 2 equiv

Ar COOH Time Isolated Yield Ar COOH Time Isolated Yield

MeO OMe 24 , 77% 24 , 23% OMe MeO

EtO N 24 , 68% 48 ,n.d. OEt

MeO S 48 , 53% 48 , 39% Br OMe

MeO S a 48 , tracesa 48 , traces O2N OMe

MeO O 48 ,n.d. 48 , 41% NH2

Regioselectivities confirmed by 1H-NMR. n.d. = Not detected by GC-MS. Product was hydrolized and isolated as its corresponding ketone due to competing hydrolization.

As expected, the di-ortho-substituted electron-rich carboxylic acids 3.1a and 3.1b provided the highest isolated yields of 77% and 68%, respectively. The less electron-rich bromo-substituted 3.1c provided a lower isolated yield of 53% of the desired Heck product. Only traces of the Heck products were observed for the nitro- and amino-substutited 3.1d and 3.1e, presumably due to the drop in electron density and coordination of the amino group to palla- diu, respectively. The mono-ortho-substituted acid 3.1f provided a lower yield than its di-ortho-substituted counterpart 3.1a, also as expected. For the pyridine-based heterocyclic acid 3.1g, nitrogen coordination to palladium was again the likely reason for not obtaining the desired Heck product 3.3g. The thiophene-based acids 3.1h and 3.1i exhibited a noteworthy pattern: while a 39% isolated yield was achieved for the 3-methylthiophene acid 3.1h, its benzothiophene counterpart 3.1j provided only traces of its corresponding Heck product 3.3j. The low to moderate range of yields is a limitation of the reported method, although the excellent regioselectivity observed for all of the reactions is a strength, as no corresponding terminal regioiso- mer could be observed.

46 To expand the scope of the method further, a variety of linear electron-rich olefins were reacted with arylcarboxylic acid 3.1a and the less electron-rich bromo-bearing 3.1c. The results are shown in Table 9.

Table 9. Scope of electron-rich olefins for the oxidative decarboxylative Heck reaction.

The reduced electron density of 3.1c resulted in lower reactivity with all of the tested olefins, as was expected according to previous reports,78,80,185,186 but the high regioselectivity remained unaffected. The vinyl ethers 3.2b and 3.2c and enamide 3.2f were the most successful. The outcome for enamide 3.2f was similar to its homologue 3.2a. Enamides 3.2d and 3.2e exhibited surprising behaviors, however: while the nitrogen in enamide 3.2e is expected to coordinate palladium and hamper the reaction more than for 3.2d, the corresponding Heck product 3.4g was isolated in a higher yield than Heck product 3.4e. The so far exclusive preference for internal regioselectivity for the tested electron-rich olefins, prompted the use of a less electronically biased olefin. Allyl alcohol 3.2g was thus investigated, and a regioselectivity of 17:1 (determined by 1H-NMR) in favor of the internal position was observed (Scheme 21).

Scheme 21. Oxidative decarboxylative Heck arylation of allyl alcohol.

This strong preference for the internal position, despite the use of a relatively electronically non-biased olefin, suggests that a cationic mechanism may be at play.14 It is noteworthy that the regioisomers 3.4m and 3.4m’ were isolated as their corresponding saturated aldehydes. This in situ isomerization has been previously reported,187 and the controlling factors investigated,188–190 but high regioselectivity has only been observed for terminally arylated corresponding aldehydes. This observation may be the result of a palladium hydride reverse addition-elimination, but further studies must be conducted to confirm this.

Mechanistic Investigation by ESI-MS Oxidative decarboxylative Heck reactions were first studied by Myers and colleagues, providing kinetic data and experimental evidence of the captured aryl-palladium intermediate that suggested extrusion of CO2 to be rate- determining.186 These findings were computationally confirmed by Zhang et al.,185 The chemistry presented in this project employs a bidentate ligand and electron-rich olefins, in contrast to monodentate ligands and electron-poor olefins employed in the aforementioned mechanistic studies. Thus, a mechanistic investigation of the present catalytic system was undertaken. Soft ionization which results in few fragmentation products have rendered electrospray ionization mass spectroscopy (ESI-MS) a valuable tool in eluci- dating key intermediates in palladium-catalyzed reactions,35,156,191–195 and was the tool of choice in this study. An array of 10 identical reactions with the same conditions as in Table 8, using 3.1a and 3.2a, were set up in order to be sampled at 10 different heating times. Since pressure builds up during the reaction due to CO2 release, this strategy avoids collecting 10 samples from a single reaction vessel, which would result in severe pressure drops and thus alter the reaction conditions. An ESI-MS(+) spectrum was recorded for each sample within an hour by scanning the last quadropole (Q3) of a QTrap instrument in linear ion trap mode. The highest prevalence of cationic organopalladium complexes (106Pd and 108Pd) were observed for the sample taken prior to heating (heating time 0 min) as depicted in Figure 13. This was unexpected since formation of Heck product 3.3a is not observeable on GC-MS or LC-MS until at least 2 h of heating. Their structures were assigned based on MS/MS analyses and given the letters A-D, based on their plausible role in the catalytic cycle.

Figure 13. Detected organopalladium intermediates at heating time 0 min.

The prevalence of the detected organopalladium mediates at the 10 different reaction times are shown in Table 10.

Table 10. Prevalence of organopalladium intermediates at various heating times.

+ + + N N N N N N + + N N N N Pd Pd Pd Pd Pd O O O R R Ar Ar CF Ar Ar O 3 O O

Structures based on MS/MS 0 5 10 15 20 25 30 45 60 120

+ Heating time (minutes) [(N N)-Pd-(CF3CO2)] ( ) 389 / 391 [(N N)-Pd-(OOCAr)]+ ( ) 457 / 459 [(N N)-Pd-(OOCAr)( 2-Olefin)]+ ( ) 568 / 570 [(N N)-Pd-(Ar)]+ ( ) 413 / 415 [(N N)-Pd-(Ar)( 2-Olefin)]+ ( ) 524 / 526 [(N N)-Pd-( - )]+ ( ) 522 / 524

The color intensities represent approximated relative abundance between detected Pd complexes in the mother spectra for each heating time. Complexes with unknown roles omitted for clarity. N N, Ar and R = as in Figure X.

While the detected, and by MS/MS identified, structures were to be expected based on previous findings,80,185,186,196 three observations are worth mentioning: 1) Complex B, which precedes decarboxylation, is formed at room tem-

49 perature and unobservable already after 5 min of heating. This may indicate a fast decarboxylation step and is contradictory to previous findings;185,186 2) The decarboxylated aryl-palladium intermediate C, and its olefin- coordinating counterpart D that preludes aryl-insertion, are also formed at room temperature; 3) An unexpected ionic species 3.5 starts to form after 5 min of heating and remains present throughout the rest of reaction time. This indicates a highly stable complex that may disturb the catalytic cycle. MS/MS analysis of 3.5 revealed an aryl, olefin, palladium and ligand moiety, but not enough information to deduce its structure in detail. In order to see if 3.5 could be isolated, 3.1a and 3.2a were reacted according to Scheme 22 with 100 mol% of the palladium(II) catalyst instead of p-BQ [the reaction was diluted in order to avoid formation of Pd(0)]. Both complex 3.5 and the Heck product 3.3a could be detected on LC-MS as discrete compounds.

Scheme 22. The oxidative decarboxylative Heck reaction with stoichiometric loadings of Pd(II) salt.

Next, Heck product 3.3a was mixed with Pd(CF3CO2)2 and 6MBP in DMF (Scheme 23), in order to establish whether complex 3.5 is formed within or outside of the catalytic cycle. Surprisingly, LC-MS revealed the formation of 3.5 within 30 min of stirring at room temperature, although with 3.3a still present in the solution. Nevertheless, this suggests that complex 3.5 is indeed formed outside of the catalytic cycle, i.e. after the Heck cycle is complete and the Heck product 3.3a has been formed.

Scheme 23. Direct formation of palladium(II)-complex 3.5a from the oxidative decarboxylative Heck product 3.3a.

After a total of 2 h of stirring at room temperature, a slight increase in the amount of complex 3.5 relative to Heck product 3.3a was observed on LC- MS, and the outcome remained unchanged after a total of 24 h of stirring. Heating of the solution at 120 ºC for yet another 24 h did not indicate decomposition or any observable change in the ratio between 3.3a and 3.5.

50 Addition of diethyl ether to the solution precipitated 3.5 which could be isolated by filtration, after which its structure could be characterized (Figure 14, 19 – left). Fluorine was detected by F-NMR and the CF3CO2 anion could be detected on TOF-MS(-), but the anion could not be detected by 13C-NMR, however. Attempts at obtaining suitable crystals for X-ray analysis failed at this point, despite trying different crystallization methods and exchanging – Pd(CF3CO2)2 with other palladium salts consisting of anions such as Cl and – BF4 . The experimentally deduced structure of 3.5 was in accordance with the lowest energy conformation found for 3.5 by means of DFT calculations (Figure 14, right). How palladacycle 3.5 is formed remains unknown at this point.

N N H Pd H O MeO N

OMe

Figure 14. Proposed structure of 3.5 based on spectroscopic characterization (left) and lowest energy conformation found using DFT calculations (right). Computa- tional parameters as on page 54.

It is plausible that complex 3.5 is more readily formed than the desired Heck product 3.3a, as it quickly forms in room temperature and can withstand 120 ºC of heat. This points to that both the Pd(II)-catalyst and 3.3a are consumed in the formation of 3.5 (or in equilibrium but shifted towards 3.5), resulting in lower amounts of catalytically active palladium available for the Heck cycle, possibly leading to a less efficient catalytic cycle. Since enamides 3.2a and 3.2d-f are similar in structure, their corresponding Heck products 3.4e, 3.4g and 3.4i were reacted with stoichiometric amounts of Pd(CF3CO2)2 and 6MBP, which provided their corresponding palladacycles 3.6, 3.7 and 3.8 (Scheme 24).

51 + + + NN NN NN Pd Pd Pd H 1 equiv Pd(CF CO ) H O 3 2 2 H O 1.2 equiv 6MBP O or or 3.4e, 3.4g or 3.4i Ar N N Ar N 0.3 mmol 2 mL DMF, 2 h, rt Ar H

3.6 3.7 3.8 Isolated yield: Isolated yield: Isolated yield: 22% 24% 29%

Scheme 24. Formation of palladium(II)-complexes 3.6-3.8 with enamide Heck products.

Their structures were confirmed experimentally, again without being able to neither detected their anions by 13C NMR nor obtaining crystals for X-ray analysis. Their lowest energy conformations could be confirmed by DFT calculations, however, which were in accordance with the experimentally deduced structures (Figure 15).

3.6 3.7 3.8

Figure 15. Lowest energy conformation found for Pd(II)-complexes 3.6-3.8.

The corresponding palladacycle of Heck product 3.4a, which lacks the enamide moiety, was unable to form, indicating the importance of the enamide’s palladium-coordinating carbonyl oxygen for the stability of complexes 3.5-3.8. Based on complexes A-D and 3.5, as observed in the ESI-MS investigation, a reaction mechanism is proposed (Scheme 25).

Scheme 25. Proposed catalytic cycle for the oxidative decarboxylative Heck reaction using electron-rich non-cyclic olefins.

The following key steps are depicted: 1) Ligand exchange by the arylcarboxylate with intermediate A to give complex B, which in turn is in equilibrium with B’ given the excess of olefin; 2) Decarboxylation of B to generate the aryl-palladium intermediate C; 3) olefin double bond coordination in a π- fashion to give D; 4) Insertion of the aryl to the double bond followed by internal rotation to provide complex E; 5) β-Hydride elimination and the release of Heck product 3.3, which gives complex F; 6) Recycling of Pd(0) back to Pd(II), mediated by p-BQ as the reoxidant, to generate the starting catalyst A, which can then either reinitiate the catalytic cycle or 7) undergo a reaction with the corresponding Heck products of olefins 3.2a and 3.2d-f to yield 3.5-3.8, respectively.

Conclusions An oxidative decarboxylative Heck reaction with excellent regioselectivity for the internal position was developed. The method allows internal arylation of electron-rich enamides, vinyl ethers and allyl alcohol, using ortho- substituted arylcarboxylic acids, including heterocycles. Key organopalladium intermediates were detected by ESI-MS experiments which were the basis for a proposed catalytic mechanism. The mechanistic investigation also revealed the formation of highly stable palladium(II) intermediates that seem to intercept the desired Heck products as well as the Pd(II) precatalyst. The complexes were characterized by spectroscopy and their structures were confirmed by means of DFT calculations.

53 Theoretical Mechanistic Investigation of a Decarboxylative Heck Reaction With an Electron-Rich Olefin and Possible Catalyst Entrapment by the Heck Product (Paper IV)

Inspiration & Objectives The mechanism of oxidative decarboxylative Heck reactions has previously been studied computationally, but for non-chelating electron-poor olefins,80,185 in contrast to the electron-rich olefins studied in Paper III. With regards to the proposed structure of complex 3.5, the enamide oxygen’s coordination to palladium suggests that the same moiety in olefin 3.2a may exhibit unexpected effects on the Heck mechanism, rendering olefin 3.2a as a peculiarly interesting olefin. Also, the ESI-MS investigation and its ac- companying preparative experiments were somewhat contradictory: complex 3.5 was readily formed in room temperature by consuming the Pd(II)- catalyst and Heck product 3.3a, although the Heck reaction proceeds to give a 77% isolated yield of Heck product 3.3a. It was thus interesting to study the mechanism when using a chelating electron-rich olefin such as 3.2a, by means of DFT calculations, and probe whether or not complex 3.5 acts as a catalyst trap.

Results & Discussion

Computational Details DFT calculations were carried out with Jaguar197 version 7.9 using the B3LYP hybrid functional.198–200 The LACVP** basis set, which uses an effective core potential for Pd and 6-31G** for elements H–Ar,201 was used for geometry optimizations and vibrational analyses, whereas LACVP**+ was used for single point solution phase energy calculations. The B3LYP functional has been successfully used in combination with the 6-31G basis set for investigating free energy profiles of Pd(II)-catalyzed decarboxylation and carbopalladation.185,202,203

54 All complexes were optimized in the gas phase and subjected to single-point energy calculations using the PBF solvation model with default settings in Jaguar for DMF.204,205 Dispersion correction was calculated using the DFT- D3 program.183 Frequencies and thermodynamic contribution to the free energy were calculated for the optimized geometries in the gas phase at 393.15 ºK. The reported free energies were calculated by adding the thermodynamic correction (including zero-point energy) and the dispersion correction to the single-point solution phase energy. The transition states (TSs) presented herein were verified to have no more than one imaginary frequency and were verified to be connected to their respective preceding and suc- ceeding energy minima using QRC calculations.206 All stationary minima were verified to have no imaginary frequencies.

Mechanistic Pathway The DFT calculations were based on the reaction pathway deduced from the ESI-MS investigation and the reactants used therein: Pd(CF3CO2)2 as the palladium source, DMF as the solvent, 3.1a and 3.2a as reactants, 6MBP as ligand and p-BQ as reoxidant and/or ligand. Only complexes in which 6MBP operates in a bidentate fashion were considered. Reaction pathways without investigated connections are represented by dashed lines.

Decarboxylation

Figure 16. Free energy profile of the decarboxylation step.

55 Figure 16 depicts the relative free energies of the decarboxylation process. The diligated trifluoroacetate Pd(II) complex CP1 was set as the starting point. Replacement of one trifluoroacetate anion with the carboxylate of 3.1a lowered the free energy by -5.3 kcal mol–1, giving CP2. Replacing the remaining trifluoroacetate anion by the other oxygen of the already ligated carboxylate anion gave CP3, further lowering the free energy by another - 6.4 kcal mol–1. CP3 was the lowest energy minimum found prior to decarboxylation, and and all other reported energies are relative to the energy of CP3. Arrangement of the carboxylate anion with the aryl’s ipso-carbon coordinating to Pd gave CP4, which is connected to TS1. The aryl group of the carboxylate of 3.1a is oriented trans to the methyl-substituted pyridine ring in 6MBP (its cis-oriented counterpart is +4.1 kcal mol–1 higher in energy and was thus discarded (see the Supporting Information of Paper IV for more information). The free energy requirement from CP3 to TS1 is +17.3 kcal –1 mol . From here, CO2 is extruded to give the Ar-Pd intermediate CP5 and lowering the energy by -6.3 kcal mol–1. The carbon dioxide ligand in CP5 is then replaced by olefin 3.2a to give CP6, lowering the energy by another - 14.1 kcal mol–1, which gives a total free energy release of -20.4 kcal mol–1 from TS1. The decarboxylation pathway is in accordance with previous findings.80,184–186

Carbopalladation

Figure 17. Free energy profile of the carbopalladation step.

Figure 17 shows the carbopalladation step. First, olefin 3.2a in CP6 rotates so that its π-bond is in the same plane as the Pd center to give CP7, which

56 then inserts the olefin into the Ar-Pd bond via the four-membered cyclic transition state of TS2. The free energy requirement from CP6 to TS2 is –1 +13.1 kcal mol . After the insertion, CP8 rotates around the Cα–Cβ bond of the now saturated olefin, so that the enamide oxygen coordinates the metal center, which gives CP9. The free energy release from TS2 to CP9 is -20.3 kcal mol–1. Regarding alternatives to palladacycle CP9, the lowest energy minimum found was that of CP8-ArCOO, which is +12 kcal mol–1 higher, thus suggesting that CP9 is the lowest point prior to the following β-hydride elimination. Terminal arylation of 3.2a was not studied, as no traces of the terminal Heck arylation product could be observed in the preparative study.

β-Hydride Elimination and Catalyst Regeneration The β-hydride elimination is depicted in Figure 18.

MeN

Pd N MeN

H R Ar Pd N Ar R H +9.4

+5.5 -1.6

MeN

-10.3 O Pd N

Ar H MeN O Pd N Ar O O N N No O-Pd coordination

Figure 18. Free energy profile for the β-hydride elimination step.

Rotation around the Cα–Cβ bond in CP9 yields a vacant site on Pd, with which the β-hydrogen can align, giving TS3 with a free energy requirement of +19.7 kcal mol–1. This high free energy requirement is due to breaking the favorable carbonyl oxygen O–Pd coordination of CP9. Following elimination of the β-hydrogen, CP10 is formed, in which Heck product 3.3a inter- acts with Pd in a η2 fashion, perpendicular to the plane of the Pd orbitals. Based on previous studies,61 and the fact that the reaction only proceeds in the presence of p-BQ, it is assumed that p-BQ regenerates the catalyst through electron-transfer from Pd(0). Pd(0) can be formed through a reductive elimination process starting with CP11, in which the Heck product 3.3a

57 has been released and replaced by the carboxylate of 3.1a, giving the neutral Pd(II)-hydride complex. As depicted in Figure 19, the palladium hydride CP11 can undergo reductive elimination through TS4, which yields the Pd(0) intermediate CP12. The free energy requirement from CP9 to TS4 is +25.8 kcal mol–1. The newly formed carboxylic acid 3.1a in CP12 is then displaced by p-BQ, resulting in CP13 with a free energy release of -41.1 kcal mol–1, which makes this reaction step effectively irreversible. Reoxidation of Pd(0) back to Pd(II) occurs via protonation of the p-BQ oxygen, followed by rearrangement,61 resulting in the Pd(II)-hydroquinone complex CP14. Once hydroquinone is released from the Pd center, the starting point CP3 is regenerated.

MeN

O Pd N Ar H O +13.6

+15.5 MeN

O Pd N Ar OH -1.6

MeN MeN

O Pd N O Pd N

Ar H OOCAr O

HO -16.2 -23.3 -27.5 O MeN N O Pd N Pd NMe O Ar O

Figure 19. Free energy profile for the reductive elimination and catalyst regeneration steps.

Interestingly, CP13 has a lower free energy than starting point CP3. Thus, the relative energies of the following catalytic cycles must be calculated with regards to CP13 as the reference point. This effectively increases the free energy requirement for the decarboxylation step from the previous +17.3 kcal mol–1 to +21.5 kcal mol–1. An overview of the β-hydride and catalyst regeneration steps is shown in Figure 20, and based on the findings herein, the reductive elimination process (CP9 to TS4, +25.8 kcal mol–1 free energy requirement) is suggested to be rate-determining. The breaking of the stable, chelating O–Pd bond in the six-membered palladacycle CP9 rationalizes this suggestion. This differs

58 from the previously reported computational study, in which the decarboxylation step has been identified as rate-determining.185 Albeit, the olefins used in the mentioned study could not form chelates corresponding to CP9, and the aryl source was experimentally unproductive benzoic acid.

Figure 20. Overview of the β-hydride elimination, reductive elimination and catalyst regeneration pathways.

It is worth mentioning that other pathways for catalyst regeneration and reductive elimination are known and thus possible in this case. Proton abstraction by molecular oxygen is one example,61,207,208 One can also speculate on the possibility of a non-ligated base abstracting the hydrogen instead of the ligated arylcarboxylate in TS4, followed by p-BQ coordination to give CP13. The role of p-BQ was elucidated by running the reaction in Table 8 using 3.1a, but without p-BQ, which produced only traces of Heck product 3.3a according to GC-MS. This indicates that p-BQ is involved in the catalyst regeneration process, since 3.3a can be formed with a stoichiometric amount of Pd(II) without the addition of p-BQ (Scheme 22). Nevertheless, the observed stabilizing effect of the O–Pd bond in CP9 results in the following consequences: 1) The free energy requirement for β-hydride elimination will increase. An analogous low energy chelate was observed when allylic esters were reacted with arylboronic acids under oxidative Heck conditions.143 2) Regarding the β-hydride elimination and reductive elimination steps, the reverse reaction is likely to be favored (CP12 back to CP9), since the proceeding complexes after TS3 are higher in energy than CP9. Thus, the free energy requirement for the reductive elimination must be calculated from CP9. The difference between the required free energy for decarboxylation and reductive elimination is -4.3 kcal mol–1, which ought to be compared to the decrease of -8.2 kcal mol–1 in free energy when forming the chelate CP9 from the carbopalladation product CP8. Therefore, when employing an olefin without chelating properties that avoids the low energy complex CP9, to instead form a complex similar to CP8-ArCOO, decarboxylation would possibly be the process with the highest free energy requirement.

59 Palladium Complex 3.5

Characterization by X-Ray Crystallography During the course of the DFT studies, parallell preparative work with palladium(II)-complex 3.5 resulted in suitable crystals and the possibility to con- duct an X-ray analysis (Figure 21).

Figure 21. X-ray structure of 3.5 (solvent molecules, anions and one instance of 3.5 ommited for clarity). Thermal ellipsoids are drawn at 50% probability level.

The obtained crystal structure reveals a dimer consisting of two cationic palladium complexes with the two Pd centers aligned along their dz2 orbitals. Two trifluoroacetate counter ions and three chloroform molecules (remnants from the crystallization process) are present as well. The complexes were used as starting points for DFT optimizations, which resulted in similar geometry and free energy (within 0.3 kcal mol–1) as the calculated lowest energy minimum found (Figure 14, right).

Calculations by DFT Palladium(II)-complex 3.5 is likely formed after completion of the first catalytic cycle, as Heck product 3.3a and a Pd(II) species has been shown to form 3.5. A summary of the calculated free energy profile for the entire reaction is thus depicted in Figure 22, together with the relative free energy of complex 3.5, which is -4.6 kcal mol–1 lower in free energy than the regenerated catalyst CP3. The relative free energy requirement for the formation of 3.5 is unknown, but the pathway for its formation is currently under investigation. Since the Heck arylation product 3.3a reacts with Pd(CF3CO2)2 and 6MBP to form complex 3.5 in room temperature, however, the pathway leading to 3.5 has probably a lower free energy requirement than the pathway leading to Heck product 3.3a.

60 Relative Free Energy in DMF (kcal/mol)

MeN

O Pd N MeN Ar MeN O Pd N TS1 Pd N +17.3 Ar H R R TS2 Ar TS3 CP3 +10.0 +9.4 0.0 CP6 -3.1 MeN MeN O Pd N CP9 -10.3 to CP11... O Pd N Ar R Ar MeN Pd N Ar O N

Decarboxylation Carbopalladation -Hydride Elim. G‡‡‡+17.3 G +13.1 G +19.7

Reaction Coordinate

MeN

O Pd N Ar H O ... from TS3 TS4 +15.5

MeN CP11 -1.6 O Pd N

MeN MeN Ar O O Pd N O Pd N TS1 -6.0 Ar H OOCAr O

HO CP14 CP3 -16.2 -23.3 CP13 4 -27.5 -27.9 O N MeN Pd O Pd N N Me O N

Reductive Elim. Catalyst Decarboxylation ( G‡ +21.5) G‡ +25.8 Regeneration or formation of 4

Reaction Coordinate, continued

Figure 22. Free energy profile summary of key reaction steps in the investigated oxidative decarboxylative Heck reaction.

61 Due to the low energy difference between the starting catalyst CP3 and complex 3.5, it is difficult to conclude from the computed free energies whether 3.5 is a dead end in the catalytic cycle or not. The low energy difference, combined with the fact that the Heck cycle provides sufficient turn- overs to yield 77% of the desired Heck product 3.3a, in fact suggests that instead of being a dead end, complex 3.5 might function as a reservoir of active Pd(II) catalyst. To test this hypothesis, a preparative experiment was set up in which complex 3.5 was the sole Pd source (Scheme 26).

Scheme 26. Palladium(II)-complex 3.5 as catalyst in the oxidative decarboxylative Heck reaction.

An isolated yield of 11% for Heck product 3.3a suggests that 3.5 is either a very poor catalyst, or alternatively, it decomposes to form an active Pd(II) species able to catalyze the reaction to a minor extent. The low isolated yield indicates therefore that once complex 3.5 is formed, the reaction is severely hindered, thus rendering complex 3.5 as a catalyst trap. The isolated yield of 77% for Heck product 3.3a (Table 8) remains contradictory, however. Two possible explanations may shed light on this issue: 1) p-BQ, which is present in the conditions used in Table 8 but not in the experiment in Scheme 26, retards the formation of complex 3.5 to a sufficient degree so that the Heck cycle can proceed without hindrance; 2) Com- plex 3.5 has only been isolated when stoichiometric amounts of Pd(II) have been used, whereas catalytic amounts of Pd(II) has been used when 3.5 has been detected in the ESI-MS studies. While the reaction order for the formation of 3.5 in Scheme 23 is unknown, its propensity to form may vary depending on the amounts of Pd(II) and p-BQ present.

Introducing Steric Bulk on The Pd Ligand In CP9 and complex 3.5, the bipyridine methyl group is oriented away from the enamide oxygen and olefin hydrogen, respectively. Therefore, introducing steric bulk on the non-substituted pyridine ring was tested as a means of destabilizing both CP9 and 3.5, relative to TS2 and CP3, respectively, while still having the potential to form Heck product 3.3a. The dimethyl substituted bidentate nitrogen ligand 2,9-dimethyl–1,10-phenanthroline (dmphen) was chosen, as it is known to be productive in Pd(II)-catalyzed decarboxylation reactions.96 First, Heck product 3.3a was mixed with dmphen and

62 Pd(CF3CO2)2 to see if 3.5’, the corresponding complex to 3.5, could form (Scheme 27).

Scheme 27. Synthesis of complex 3.5’, with dmphen as the ligand.

Unfortunately complex 3.5’ was readily formed and isolated. Replacing 6MBP with dmphen in the oxidative decarboxylative Heck reaction showed no major differences in terms of the isolated yield either (Scheme 28).

Scheme 28. The decarboxylative oxidative Heck reaction with dmphen as the ligand.

The relative free energies of the reaction pathway with dmphen were slightly higher than that of 6MBP, as shown in Table 11. The attempt to destabilize complex 3.5’ with increased steric bulk failed, as there was a free energy release of -1.3 kcal mol–1 from CP3 to 3.5’, rather than an increase (although a lower release than from CP3 to 3.5).

Table 11. Free energy requirements using 6MBP and dmphen as the ligand.

63 Conclusions Understanding the factors by means of DFT calculations and increasing the rate of the oxidative decarboxylative Heck reaction based on the results has proven to be difficult. Based on the findings herein, the carbonyl oxygen of the enamide in 3.2a appears to play an important role, as it coordinates the Pd center in the low energy complex CP9, as well as in 3.5 (and 3.5’), which can act as a catalyst trap. The mechanism behind the formation of complex 3.5 (and 3.5’) must be elucidated, however, in order to gain a fuller understanding of the catalytic cycle. Attempting to destabilize CP9 and 3.5 by using the more sterically hindered dmphen ligand was unsuccessful. The reductive elimination step was identified as rate-determining, mainly as a result of the low energy chelate CP9. Alternative mechanisms may be at play in this step, however, such as proton abstraction by molecular oxygen or a non-ligated base. If these alternative mechanisms would exhibit a suffi- ciently lower free energy requirement, one must look at decarboxylation. With a free energy requirement of +21.5 kcal mol–1 (as calculated from CP13 to TS1), the decarboxylation process has the second highest free energy requirement, which could be the de facto rate-determining step. This is especially the case for olefins that can avoid forming low-energy chelates such as CP9. The decarboxylation process may in turn be improved by exchanging p-BQ for another Pd(0) reoxidant, in order to avoid the formation of the low-energy complex CP13. This would be a futile strategy for olefin 3.2a, however, as Heck product 3.3a would still be able to form complex 3.5, resulting in a low energy complex prior to decarboxylation.

64 Acknowledgements

Hereby I would hereby like to express my deepest gratitude to my colleagues, as this thesis would not have been in existence if it weren’t for the following individuals:

My supervisor Professor Mats Larhed; for introducing me, very inspiringly so, to the world of organometallic chemistry. Your support and confidence in my work, and your many leaps of faith in my tendency to jump aboard different projects (some successful, some not, that’s the way it is), have been invaluable beyond words.

My co-supervisors Associate Professor Luke Odell and Associate Professor Christian Sköld; for inspiring me many times and always being resourceful when I’ve been stuck. Thanks for the many fruitful discussions and a-ha moments. I couldn’t have asked for better co-supervisors.

Dr. Alejandro Trejos, my friend and former room-mate; for being my first contact, master’s degree supervisor and source of inspiration in the world of chemical research. Without your guidance, wisdom and teaching, I wouldn’t have been here.

Professor Anja Sandström, Dr. Ulrika Rosenström and Dr. Charlotta Wall- inder; for believing in my teaching capabilities. Thank you for the confidence in me, letting me explore teaching methods and styles which has allowed me to improve my teaching skills beyond what I could’ve imagined.

Gunilla Eriksson; for being an amazing colleague, problem-solver, organiz- er, administrator, and extraordinary person in general. A colleague like you is hard to find. It’s been an honor.

Dr. Per J. Sjöberg; for being the king of ESI-MS. Laying mechanistic puz- zles with data gathered from ESI-MS has been one of the most exciting things I’ve done as a researcher.

My co-authors at the department, Dr. Jonas Lindh, Dr. Peter Nilsson, Dr. Prasad Wakchaure and Dr. Per Öhrngren; for your great contributions and for great collaborations.

65 Dr. Francesco Russo, co-author and friend; for the fun, the laughs and exciting times behind the continuous flow equipment. Your way of challenging the status quo in science and everything else has been very inspirational and meaningful to me!

Sorin Srbu; for being a great sysadmin and colleague and for keeping all the computers alive. Thanks for the admin privileges, saved me approximately 3981 hours in all of my computer related tasks during these 5 years :)

WaveCraft AB, Dr. Jon-Sverre Schanche, Magnus Fagrell and Ingemar Orsén; for being great colleagues, and for introducing me to continuous flow chemistry and lending out your microwave technology to our lab.

Fredrik Svensson, co-author and colleague; for all the great help with computational chemistry. You’re a great teacher and inspiring chemist. Thanks for your help and contributions!

Dr. Jonas Sävmarker; for amazing discussions and a-ha moments (probably more for me than for you) when discussing organometallic chemistry. Your expertise and amazing arsenal of knowledge has been extremely valuable.

Dr. Peter Brandt, Martin Lindh and Hiba Alogheli; for being fun and helpful colleagues to have around when I did my computational project in your labs.

Dr. Ulf Bremberg, former lab-mate; for being an inspiring chemist and for great discussions about life science and business.

Birgitta Hellsing; for being a great administrator and colleague, and for great discussions about gourmet food and cooking :)

Matyás Wejdemar; for being a great collague and master’s degree project student.

Dr. Mounir Andaloussi; thanks for being a motivating and helpful colleague during my master thesis and summer projects!

Dr. Gopal Datta; for being my supervisor during SOFOSKO.

Fifth floor extraordinaires: Sara Bergman, Karin Engen, Rebecka Isaksson, Dr. Patrik Nordeman, Jonas Rydfjord (my amazing office/cubicle-mate), Bobo Skillinghaug, Marc Stevens, Dr. Puspesh Upadhyay, thanks for being such great and fun colleagues to be around everyday!

Thank you.

66 References

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Acta Universitatis Upsaliensis Digital Comprehensive Summaries of Uppsala Dissertations from the Faculty of Pharmacy 194 Editor: The Dean of the Faculty of Pharmacy

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