Discovery, Development and Study of Carbenoid Mediated Reactions from Olefin

Research Collection

Doctoral Thesis

Discovery, Development and Study of Carbenoid Mediated Reactions From Olefin

Author(s): Sarria Toro, Juan M.

Publication Date: 2014

Permanent Link: https://doi.org/10.3929/ethz-a-010350749

Rights / License: In Copyright - Non-Commercial Use Permitted

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ETH Library Diss. ETH No. 22272

Discovery, Development and Study of Carbenoid Mediated Reactions From Olefin Metathesis to Cyclopropanation

A thesis submitted to attain the degree of DOCTOR OF SCIENCES of ETH ZURICH (Dr. sc. ETH Zurich)

Presented by Juan Manuel Sarria Toro

M. Sc. – Chemistry, Universidad Nacional de Colombia

born on 24.08.1984 citizen of Colombia

Accepted on recommendation of

Prof. Dr. Peter Chen, examiner Prof. Dr. Antonio Togni, co-examiner

Zürich, 2014

“Es mejor ser rico que pobre” Antonio Cervantes - Kid Pambelé

Acknowledgments – Agradecimientos – Захвалница – Danksagung

First and foremost I would like to thank my supervisor Prof. Dr. Peter Chen for giving me the chance to join his research group. During my stay he managed to show me subtly the difference between impossible and just difficult. Thanks to his encouragement and trust I have discovered that more often than not, the limit of what is chemically possible is only imposed by our lack of understanding. For these years of personal and professional development I will be always in his debt.

I would also like to thank my co–examiner Prof. Dr. Antonio Togni for playing a crucial role in my connection to ETH. One could rightfully say that all of this is his fault.

I am very grateful to PD. Dr. Andreas Bach, for being always there to solve all my questions, it is very reassuring to know that there is always someone who knows what needs to be done.

Dr. Sebastian Torker had the great challenge of taking my rebel character and focus it in a productive direction, thanks for not giving up. It was then thanks to Dr. Tim den Hartog’s obsessive attention to detail and rigorousness that the best of this PhD was possible. For his partnership, friendship and delicious dinners, organized together with the endlessly cheerful Dr. Elena Melillo, I will always be grateful.

Dr. Eric Couzijn and Dr. Krista Lynn Vikse contributed with inspiring academic and non– academic conversations to the completeness of my PhD. Krista’s help with the proof reading of this document was invaluable.

My stay in the Chen group would have not been the same without the cheer, the musical taste and the fun of my lab mates Augustin Armand Senghor Tchawou Wandji and David Hans Ringger, best luck to you in your future career.

Former and present group members have cheerfully shaped my image of what research and life abroad are; I am very happy to have met so many different cultures and the points of view that come along with them. Merci beaucoup Dr. Marc-Etienne Moret for trusting me his hood, there is certainly magic happening there, Dr. Daniel Serra for explaining to me the true nature of the T–shaped intermediate, Dr. Déborah Mathis for patiently guiding me though my very first Ski slope and Dr. Laurent Batiste for being such a good travel partner. Díky moc Marek Bot for opening my eyes to the true facts of Charlie.

Acknowledgments – Agradecimientos – Захвалница – Danksagung

Mulţumesc mult Dr. Mihai Răducan for gains. 谢谢 Yanan Miao for enthusiastically taking over my workplace, I am sure you will make good use of it. Hvala puno Inesa Semić for keeping the Balkan beat going in the group.

Ich bin auch sehr dankbar meiner deutschsprachigen Schweizer Kollegen, die während den Winter und Sommer Ausflüge mir ein Teil ihrer wunderschönes Land gezeigt haben. Danke schön Joël Gubler, Raphael Oeschger, Lukas Fritsche, Stefan Jungen und Stefan Künzi (Viel Erfolg bei der Cyclopropanierung).

I am especially thankful to our secretarial team, which has been always ready to solve my day–to–day questions about Switzerland and its ways. Merci vielmal! Mirella Rutz, Barbara Loepfe and Anke Witten.

The technical help provided by the permanent ETH staff during those years is greatly acknowledged. Particularly from our always ready–to–help Armin Limacher and from Carmela Pansino at the HCI–shop.

Quisiera también agradecer de forma especial la sincera amistad de mis queridos amigos hispanoparlantes, quienes han constituido durante estos años mi familia en Europa. Gracias por ser ejemplo viviente de que el idioma en lugar de crear barreras se disfruta mejor reduciéndolas. Gracias por la ayuda, la compañía, las risas, las fiestas, los chistes, pero por sobre todo por ser ejemplo de excelencia. Muchas gracias a Dr. Esteban Mejía, Luisa Duque, Dr. Luis Ladino, Elisa Ladino, Dr. Rafael Rodriguez, Dr. Vanessa Landaeta, Dr. Gustavo Santiso, Nelli Sanne, Dr. Fernando Rascón, Dr. Fernando Cortés, Sofia Riaño, Mónica Angarita y Dr. David Plaza. Gracias a los locos que desde pequeño me aguantan y todavía se acuerdan de mí: Omar Avella, Nicolás López y Juan Esteban Forero.

Merecen un especial reconocimiento mis mentores en la Universidad Nacional de Colombia Prof. Dr. Marco Fidel Suarez Herrera y Prof. Dr. Luca Fadini. Por su confianza, su motivación y su entrega estaré siempre en deuda.

Изразито ми је драго да ми се пружила прилика да упознам много изванредних људи са којима имам пуно тога заједничког. Прелепо ме је изненадило откриће да невезано за удаљеност наших земаља или језичких разлика, свеједно делимо исте страхове, наде и циљеве. Хвала пуно Ивани Фуртули, Илији Кобилијанском (знаш да припадаш овде), Драгани и Штефану Хоесер, др. Селени Милићевић и др. Марку Септону, Петри и Марку Танасковић, Милици и Томасу Рајц, Бојани и Бошку Ступар, Драгани Аврамовић и ii

Acknowledgments – Agradecimientos – Захвалница – Danksagung

Вукашину Нешовићу, Ани Јокановић и Анђелији Вукић што сте поделили са мном оно што нас чини људима.

Не могу да изразим колико сам захвалан на прилици да упознам др. Марију Јовић током доктората. Само захваљујући њеној љубави, инспирацији и охрабривању мој ум је остао разуман све ове године. Хвала што си ме узела за руку и показала ми да постоји диван свет спреман да га заједно откријемо.

Finalmente quiero agradecer a mi familia, a mis padres Miguel Angel y Yolanda, por traerme a la vida en más de una ocasión y a mis hermanas Angela Yolanda y Martha Patricia por apoyarme en todas y cada una de mis locuras. Gracias a su fe ciega y apoyo incondicional he podido seguir mis sueños que hoy están aquí plasmados. Este trabajo es de ustedes. Muchas gracias.

iii iv

Published Parts of this thesis

Reviewed Articles

1. “A Palladium-Catalyzed Methylenation of Olefins Using Halomethylboronate Reagents” Tim den Hartog, Juan Manuel Sarria Toro, and Peter Chen Organic Letters, 2014, 16, 1100-1103

2. “A lithiomethyl trimethylammonium reagent as a methylene donor” Tim den Hartog, Juan M. Sarria Toro, Erik P. A. Couzijn and Peter Chen Chemical Communications, 2014, 50, 10604-10607

3. “Cyclopropanation of styrenes and stilbenes using lithiomethyl trimethylammonium triflate as methylene donor” Juan M. Sarria Toro, Tim den Hartog and Peter Chen Chemical Communications, 2014, 50, 10608-10610 Poster Presentations 1. “New metathesis catalysts based on asymmetric phosphinosulfonate bidentate ligands for the A-ROMP of cycloolefins”

Presented at the XXIVth International Conference on Organometallic Chemistry (ICOMC XXIV), Taipei, Taiwan, July 18-23 2010.

2. “Influence of the anchoring group of a bidentate ligand on the activity and selectivity of a ruthenium metathesis catalyst”

Presented at the Gordon Research Conference on Organometallic Chemistry, Salve Regina University, Newport, RI, USA, July 10-15, 2011.

3. “Gas phase study of transition metal complexes containing N-C ylides”

Presented at the International Symposium on Reactive Intermediates and Unusual Molecules (ISRIUM), Ascona, Switzerland, July 8-13, 2012.

Presented at the XXVth International Conference on Organometallic Chemistry (ICOMC XXV), Lisbon, Portugal, September 2-7, 2012.

Table of contents

Abstract ...... xi Zusammenfassung ...... xiii 1. Introduction ...... 1 1.1. Scope ...... 1 1.2. Olefin metathesis ...... 1 1.1.1 Discovery of olefin metathesis and mechanistic proposals ...... 1 1.1.2 Schrock’s high oxidaton state early transition metal alkylidene complexes. .. 4 1.1.3 Grubbs Ruthenium based catalysts...... 6 1.1.4 Heterogeneous systems ...... 8 1.1.5 Applications of olefin metathesis ...... 9 1.1.6 Stereoselective olefin metathesis ...... 11 1.3. Methylenation Reactions ...... 12 1.3.1. Three–membered rings ...... 12 1.3.2. Bonding in three–membered rings ...... 14 1.3.3. Carbene equivalents or carbenoids for the synthesis of three–membered rings ...... 15 1.1.7 Nucleophilic methylenation ...... 17 1.1.8 Electrophilic methylenation ...... 19 2. Ruthenium catalyzed alternating ring opening metathesis polymerization (A- ROMP) ...... 23 2.1. Introduction ...... 23 2.1.1. Studies on the mechanism of olefin metathesis ...... 23 2.1.2. Rationally designed A-ROMP catalysts ...... 29 2.1.3. Optimization of the catalysts for chemo and stereoselectivity ...... 30 2.2. Phosphinosulfonate system ...... 35 2.2.1. Synthesis of a ruthenium metathesis catalyst bearing an asymmetric phosphino sulfonate ligand ...... 35 2.2.2. Structural characterization of complex 17 ...... 36 2.2.3. Alternating ROMP catalyzed by complex 17 ...... 38 2.2.4. Calculation of the catalyst commitment ...... 40 2.2.5. Symmetrically substituted phosphino sulfonate complex ...... 43 2.2.6. Chloride replacement with bulky sulfonate anions ...... 44 2.2.7. Polymerization experiments with sulfonate complexes ...... 48 2.2.8. Attempts to enhance the chemoselectivity of the phosphino sulfonate systems...... 50 2.3. Discussion ...... 53 2.4. Conclusions ...... 56 3. Lithiomethyl trimethylammonium salts as methylene donors ...... 59 vii

Table of contents

3.1. Introduction ...... 59 3.1.1. Yildes: bonding and reactivity ...... 59 3.1.2. Nitrogen ylides ...... 60 3.2. Lithiomethyl trimethylammonium reagents as methylene donors...... 63 3.2.1. Soluble tetramethylammonium salts ...... 63 3.2.2. Bonding in the lithiomethyl trimethylammonium ion ...... 66 3.2.3. Reactivity of lithiomethyl trimethylammonium triflate with aldehydes, ketones and imines ...... 68 3.2.4. Reactivity of lithiomethyltrimethylammonium triflate with styrenes ...... 70 3.2.5. Reactivity of lithiomethyl trimethylammonium reagents with transition metals ...... 75 3.3. Discussion...... 81 3.4. Conclusions ...... 84 3.5. Acknowledgments ...... 85 4. Palladium catalyzed methylenation of olefins using halomethylboronate reagents ...... 87 4.1. Introduction ...... 87 4.1.1. Nucleofuge and electrofuge alternatives ...... 87 4.1.2. Palladium catalyzed olefin transformations ...... 89 4.1.3. Palladium–catalyzed cyclopropanation of olefins ...... 90 4.2. Cyclopropanation of olefins using halomethylboronates ...... 92 4.2.1. Our hypothesis ...... 92 4.2.2. Methylenation of norbornene ...... 92 4.2.3. Methylenation of other olefins ...... 95 4.3. Mechanistic considerations ...... 97 4.3.1. Preliminary mechanistic investigations ...... 99 4.4. Discussion...... 102 4.5. Conclusions ...... 104 4.6. Acknowledgments ...... 105 5. Conclusions and Outlook ...... 107 6. Experimental Part ...... 111 6.1. General Remarks ...... 111 6.2. Ruthenium Catalyzed Ring Opening Metathesis Polymerization (Chapter 2) .. 112 6.2.1. Polymerization experiments ...... 112 6.2.2. Synthesis of ligands and complexes ...... 113 6.3. Solution phase chemistry of lithiomethyl trimethylammon reagents (Chapter 3) 119 6.3.1. Tetramethylammonium salts ...... 119 6.3.2. Notes on the influence of transition metal contamination on the methylenation reactions ...... 121 viii

Table of contents

6.3.3. Methylenation of aldehydes, ketones and imines ...... 121 6.3.4. Cyclopropanation of styrenes and stilbenes ...... 124 6.3.5. Kinetic measurements ...... 127 6.3.6. Reaction of lithiomethyl trimethylammonium reagents with transition metal complexes ...... 131 6.4. Palladium catalyzed methylenation of olefins using halomethylboronates reagents (Chapter 4) ...... 132 6.4.1. Synthesis and characterization of products from our methylenation reaction ...... 132 6.4.2. Synthesis and characterization of authentic samples ...... 134 6.5. X-Ray crystallography ...... 136 7. Appendices ...... 139 7.1. Crystal structure of complex 21 ...... 139 7.2. Crystal structure of complex 23 ...... 139 7.3. NMR spectra of the isolated mixture of 24 and 25...... 140 7.4. Computational Details ...... 140 7.5. Evidence of formation of 4-fluoro-1-cyclopropylbenzene reaction mixture (71f) ...... 144 7.6. 1H spectrum of complex 81 ...... 146 7.7. Confirmation by 1H NMR of the formation of exo-tricyclo[3.2.1.02.4]octane (87) ...... 146 7.8. Confirmation by 1H NMR of the formation of cis-bicyclo[6.1.0]nonane (91a) .... 147 7.9. Confirmation by 1H NMR of the formation of (2-cyclopropylethyl)benzene (92a) ...... 147 7.10. Confirmation by 1H NMR of the formation of cyclopropylbenzene (71a) ...... 148 7.11. NMR spectra of (2-cyclopropylethyl)benzene (91b) ...... 148 8. Bibliography ...... 151 Curriculum Vitae ...... 163

Abstract

Carbenoids are versatile reagents in the synthetic organic chemist’s toolbox, capable of undergoing a wide range of transformations ranging from olefin cyclopropanation to transition metal–catalyzed olefin metathesis. This dissertation combines the work in the field of ruthenium–catalyzed alternating ring opening metathesis polymerization (A- ROMP) with the quest for new reactivity in the area of olefin cyclopropanation.

Chapter 2 deals with the structural modification of a ruthenium–catalyst framework that has previously been employed to obtain alternating norbornene–cyclooctene copolymers. Substitution of the original anchoring phenolate for a sulfonate group provided a new catalyst that showed increased activity, chemo– and stereoselectivity.

Substitution of the chloride anion for bulky sulfonates increased the stereoselectivity as expected, but also diminished the activity and, surprisingly, also the chemoselectivity. The effects of the new anchoring group could be explained in terms of geometric parameters derived from experimentally–obtained molecular structures, and the increased intrinsic reactivity could be rationalized by DFT–calculated “catalyst commitment”

Chapter 3 describes the synthesis, characterization and reactivity studies of soluble lithomethyltrimethylammonium reagents, obtained by simple deprotonation of a tetramethylammonium salt in which the anion provides solubility in organic solvents.

This class of reagents were first described by Wittig in 1947 but their insolubility limited their usability and made them difficult to study. The soluble variants reported here are

Abstract promising alternatives for the methylenation of aldehydes, ketones and imines, and for the unprecedented cyclopropanation of styrenes and stilbenes by nucleophilic reagents.

Chapter 4 describes the discovery and initial development of a palladium–catalyzed cyclopropanation of electron–rich olefins where the methylene donor is a commercially available, bench–stable halomethylboronate reagent.

Optimal conditions for the cyclopropanation of highly–strained norbornene were found using both Pd0 and PdII precatalysts. Other types of olefins could also be cyclopropanated, however lower conversions and the formation of –hydride elimination products were observed. Preliminary observations point towards a possible Pd0–PdII ‘diverted Heck’ mechanism for this methylenation. Further mechanistic work is underway to find ways to improve catalyst stability and selectivity.

xii

Zusammenfassung

Carbenoide sind vielseitige Reagenzien in dem organischen Synthesechemiker Werkzeugkasten, die eine grosse Auswahl Transformationen von Olefin- Cyclopropanierung bis zur übergangsmetall-katalysierten Olefin–Metathese durchführen können. Diese Doktorarbeit versucht die Ergebnisse zum Thema alternierend Ruthenium–katalysierten Ringsöffnungsmetathese–Polymerisation (A- ROMP) mit der Suche nach neuen Reaktivität im Bereich der Olefin-Cyclopropanierung zu verbinden.

Kapitel 2 befasst sich mit der strukturellen Modifikation der Grundstruktur des zuvor verwendeten Ruthenium-Katalysators, mit dem alternierenden Norbornen–Cycloocten Copolymere erhalten worden. Austausch der Befestigungsgruppe von ursprünglichen Phenolat mit einem Sulfonat, ergab einen neuen Katalysator, welcher erhöhte Aktivität, Chemo-und Stereoselektivität zeigte.

Ersetzung des Chlorids durch sterisch anspruchsvollen Sulfonate erhöhte, wie erwartet, die Stereoselektivität, jedoch abnahm die Aktivität und unerwarteterweise auch die Chemoselektivität. Die Eigenschaften des neuen Katalysators lassen sich durch den geometrischen Parameter der experimentell erhaltenen molekularen Strukturen erklären. Die erhöhte intrinsische Reaktivität wurde mit Hilfe von berechneten (DFT) „Katalysator Engagement“ verstanden werden.

Kapitel 3 beschreibt die Synthese, Charakterisierung und Reaktivitätsstudien eines löslichen Lithiummethyltrimethylammonium Reagenzes, erhalten durch die einfache Deprotonierung eines Tetramethylammoniumsalzes, bei welchem das Anion die Löslichkeit in organischen Lösungsmitteln bewirkt. Solche Reagenzien wurden zuerst von Wittig im Jahr 1947 beschrieben, obwohl ihre Unlöslichkeit die Nutzbarkeit einschränkte und dadurch die Untersuchungen erschwerte. Die in dieser Arbeit beschriebenen löslichen Varianten sind vielversprechend Alternativen für die

xiii

Zusammenfassung Methylenierung von Aldehyden, Ketonen und Iminen, sowie für die neuartige Cyclopropanierung von Styrolen und Stilbenen durch nucleophile Reagenzien.

Kapitel 4 beschreibt die Entdeckung und anfängliche Entwicklung einer Palladium– katalysierten Cyclopropanierung von elektronenreichen Olefinen, in der der Methylen- Donor ein kommerziell erhältliches, luftstabiles halomethylboronate Reagenz ist. Optimale Bedingungen für die Cyclopropanierung hochgespannter Norbornen wurden mit Pd0- und PdII- Katalysatoren gefunden.

Olefinen anderer Art wurden auch cyclopropaniert worden, jedoch sowohl niedrigere Ausbeute als auch die Bildung von -Hydrid-Eliminierungsprodukten wurden beobachtet. Erste Beobachtungen verweisen auf einen möglichen Pd0–PdII „umgeleiteten Heck“ Mechanismus für diese Methylenierung hin.

xiv

1. Introduction

1.1. Scope

This dissertation is divided in two main topics. First, in chapter 2, the development of a ruthenium metathesis catalysts bearing a phosphino–sulfonate ligand for the alternating ring opening metathesis polymerization (A-ROMP) of norbornene and cyclooctene will be discussed. The synthesis and structural characteristics of this type of catalysts and how they influence the obtained polymer will be described. The relative activity of the novel system will be compared to the previous phosphino–phenolate framework and explained by means of density functional calculations. Lastly, the attempts of controlling the stereoselectivity of the catalysts by replacement of the chloride anion with sterically demanding sulfonates will be reported.

In the second part of this dissertation, chapters 3 and 4, two novel approaches to the synthesis of three–membered rings will be discussed. The first one involves the generation of a soluble ‘nitrogen ylide’ derived from a tetramethylammonium salt possessing a solubilizing anion. This reagent can perform nucleophilic addition to aldehydes, ketones, imines and styrenes to yield epoxides, aziridines and cyclopropanes efficiently. The second approach uses the advantages of Pd catalysis to transfer a methylene unit from commercially available halomethylboronate salts to a number of different olefins generating cyclopropanes.

1.2. Olefin metathesis

The exchange of methylene termini of a pair of olefins mediated by a transition metal catalyst is known as olefin metathesis (Scheme 1.1).

Scheme 1.1 Prototypical olefin metathesis reaction

1.1.1 Discovery of olefin metathesis and mechanistic proposals

Started by Ziegler and Natta in the early 1950s, the studies on the polymerization of olefins with transition metals ultimately lead to the discovery of what we know today as olefin metathesis. Originally discovered in the late 1950s at the industrial laboratories of Du Pont, Standard Oil and Phillips Petroleum, the first reports of cycloolefin polymerization with supported molybdenum or titanium seem to deal with different reactions.1 Initially, the polymerization of norbornene with a Ziegler-Natta catalyst was 1

Discovery, Development and Study of Carbenoid Mediated Reactions thought to be a simple insertion polymerization.2 Eleuterio’s work on the disproportionation of propene to produce a mixture of ethylene and 2-butenes3 and the polymerization of cyclic olefins4 marked an early understanding of the unique nature of this transformation. It was later recognized by Calderon that these reactions were in essence equivalent.5 He was the first one to use the name of “Olefin Metathesis”. Early industrial applications used ill-defined systems commonly composed of combinations of tungsten and molybdenum sources and alkylaluminums to form homogenous catalysts. One of these systems was used for reaction injection molding (RIM) polymerization of endo-dicyclopentadiene producing a polymer with unprecedented strength and stiffness.6 Heterogeneous catalysts were also employed. Immobilized molybdenum based catalysts are at the core of the Shell Higher Olefin Process (SHOP)7 and the “Tri Olefin Process”.8 The latter being an example on how the equilibrating nature of metathesis can be exploited. Depending on market demands and available feedstock the process can operate to produce ethylene and 2-butene from propylene, as initially developed, or, in reverse, to synthesize propylene from other olefins.

Even though the metathesis reaction has been employed since its discovery and industrial applications quickly arose, the mechanism of metathesis took much longer to be understood. The mediation of several novel organometallic intermediates was proposed during the late 1960s and early 1970s by renowned investigators (Figure 1.1). However these proposals did not offer explanation for all of the observations encountered to that date. Most importantly they could not predict the actual thermodynamic ratios at equilibrium of the products formed in cross metathesis reactions.

Figure 1.1 Intermediates proposed for the olefin metathesis mechanism. (a) Calderon (1968),9 (b) Pettit (1971)10 and (c) Grubbs (1972).11

In 1971 Yves Chauvin together with his student Pan Hérisson proposed a mechanism which could account for the observed disproportionation, polymerization and telomerization (chain transfer) of olefins that were so far encountered12 (Scheme 1.2). Their proposal consisted of the coordination of an olefin to a metal-carbene complex, from which a rearrangement would form a metallacyclobutane intermediate. A further 2

1. Introduction rearrangement was proposed to form a new olefin and place a new carbene moiety on the metal center. As seen on the left-hand side of scheme 1.2, depending on the orientation of the olefin and the substituents on the metal-carbene, the metallacyclobutane intermediate can lead to products that are identical to the starting materials, this reaction, now known as degenerate metathesis, was first accounted for by Chauvin.

Scheme 1.2 Representation of Chauvin’s mechanism for the olefin metathesis.

Multiple experimental evidence fitting Chauvin’s mechanism quickly followed. For instance, Casey and Burkhardt13 reported the generation of diphenylethylene when a tungsten diphenylmethylidene complex was reacted with isobutylene. Later Grubbs and coworkers14 distinguished between the mechanisms proposed by Calderon, Grubbs and Chauvin based on the expected ratios of deuterium found in ethylene produced by reaction of a mixture of 1,7-octadiene and 1,7-octaniene-1,1,8,8-d4 with three different catalysts based on tungsten or molybdenum. Their observations clearly favored Chauvin’s mechanism even though the true active species could not be identified at that time.

The first advance towards a discrete, well-characterized system for olefin metathesis began in 1978 with Fred Tebbe. His studies on the structure and reactivity of a titanium- methylene-aluminum complex,15 now known as Tebbe’s reagent, demonstrated for the first time the ability of metal alkylidenes to perform degenerate olefin metathesis 3

Discovery, Development and Study of Carbenoid Mediated Reactions presumably via metallacyclobutane intermediates16 (Scheme 1.3, a). In this study an analogous four–membered ring, a metallacyclobutene, was isolated by reaction of Tebbe’s reagent with diphenylacetylene (Scheme 1.3, b). Shortly afterwards Grubbs reported the isolation of a true metallacyclobutane intermediate when Tebbe’s reagent reacted with neopentene in presence of a pyridine base17 (Scheme 1.3, c). Addition of

(CH3)2AlCl to this complex regenerated Tebbe’s reagent and the free olefin. On the other hand, when exposed to a different olefin the products of metathesis could be identified; confirming that this metallacyclobutane was as indeed an intermediate in the metathesis of olefins.

Scheme 1.3 (a) Degenerate metathesis catalyzed by Tebbe’s reagent. (b) Isolation of a metallacyclobutene. (c) Grubbs’ isolation of a metallacyclobutane complex.

1.1.2 Schrock’s high oxidaton state early transition metal alkylidene complexes.

Before Wilkinson’s report18 on the synthesis of stable metal-alkyl complexes, it was believed that such species could not be prepared and isolated due to the intrinsic instability of the metal-carbon bond. Nonetheless, Wilkinson demonstrated that the absence of -hydrogens in the alkyl chains enhanced the stability of those complexes driving the research efforts towards the preparation of new organometallic systems. Inspired by the work of Schmidbaur19 on the synthesis of pentaalkyl phosphorus and arsenic derivatives, Schrock started his studies on the preparation of pentaalkyl tantalum complexes.20 Methyl and benzyl derivatives were stable and isolable as predicted, however attempts to prepare penta(neopentyl) derivatives led to the isolation of the first non–heteroatom stabilized neutral alkylidene species (Scheme 1.4). The mechanism by which such complex was formed was later recognized as -hydrogen activation or sigma bond metathesis. At first, a strong interaction of the electron pair from the C-H bond and

1. Introduction the metal center, i.e. an agostic interaction,21 is favored by the increased steric crowding provided by the bulky alkyl groups. Ultimately, a nucleophilic carbon center, from one of the neopentyl ligands, performs an intramolecular deprotonation yielding neopentane and the observed alkylidene complex. The recognition of the generality of this reaction produced a family of similarly crowded, electron deficient, alkylidene complexes of tantalum and niobium.22

Scheme 1.4 Schrock’s synthesis of a tantalum alkylidene complex.

These new metal alkylidenes exhibited an electron poor character at the metallic center together with a nucleophilic carbene carbon resembling the reactivity of the well–known phosphorus ylide. These complexes rarely yielded metathesis products, in contrast, when reacted with olefins the resulting metallacyclobutane intermediates underwent rearrangement into tantalocyclopentanes as the result of the formation of a tantalum(III) complex which in turn reacted with two olefin molecules.23

The replacement of chlorides with alkoxy ligands in these complexes “turned on” metathesis activity.24 Judicious exploration led Schrock to develop his current framework of molybdenum, tantalum and tungsten complexes characterized by a bulky imido ligand to prevent bimolecular decomposition together with electron deficient alkoxy anions to direct the reactivity towards metathesis25 (Figure 1.2).

Modular optimization of all the substituents in this framework has provided tailor–made catalysts for all types of metathesis reactions. In figure 1.2, c, a recently developed catalyst for the enantioselective tandem ring–opening ring–closing metathesis is shown.26 The resulting family of catalysts is characterized by its very high activity, and as a result it has found its way into commercialization in recent times. However, the high oxophilicity of early transition metals reduces the tolerance of the related catalysts to molecules containing polar groups and limits the use of polar solvents as reaction media. The desire to expand the scope of olefin metathesis in a different set of conditions eventually led to the development of Grubb’s ruthenium based catalysts.

Discovery, Development and Study of Carbenoid Mediated Reactions

Figure 1.2 (a) Schrock’s framework for metathesis active alkylidene catalysts. (b) Early example. (c) Catalyst optimized for use in enantioselective ring closing metathesis.

1.1.3 Grubbs Ruthenium based catalysts.

In his personal account,27 SonBihn Nguyen relates one of the most frustrating aspects of the early days of research using Schrock’s metathesis catalysts: their synthesis. The required skill for their preparation and the sensitivity of the resulting complexes was a major driving force in the search for alternative, more robust catalytic systems. Having

28 noticed Natta’s report on the polymerization of cyclobutene by RuCl3 in protic media, Grubbs engaged in the search for ruthenium based molecular catalysts for olefin metathesis. Soon Grubbs reported the ring opening metathesis polymerization (ROMP) of norbornene derivatives in aqueous media under atmospheric conditions,29 an unprecedented feat that demonstrated not only the stability, but also the reactivity of the assumed organometallic intermediates in such conditions.

The first molecularly well–defined alkylidene ruthenium–based metathesis catalyst was reported by Grubbs in 1992 (Figure 1.3, a). This complex was synthesized by reaction of

30 (PPh3)3RuCl2 and diphenylcyclopropene. It showed a remarkable stability towards protic solvents and polar functional groups, however its activity was limited to the ROMP of highly strained olefins. Replacement of PPh3 ligands for the more bulky and more electron donating tricyclohexyl phosphine (PCy3) in the complex increased the reactivity dramatically and afforded catalysts capable of performing more demanding reactions like ROMP of low-strained olefins, cross metathesis and ring closing metathesis of functionalized dienes (Figure 1.3, b).31 Even though the applicability of these catalysts was quickly recognized, their synthesis, although much more convenient than for Schrock’s complexes, was not fully scalable. The focus on the use of more efficient alkylidene sources led to the synthesis of a benzylidene derivative of Grubbs’ complexes by reaction of the same ruthenium precursor with phenyldiazomethane at low temperature.32 This

1. Introduction complex, now known as the first generation Grubbs catalysts (Figure 1.3, c), could be obtained in kilogram scale, making its commercialization feasible. The availability of such robust catalysts triggered the application of olefin metathesis in all aspects of organic chemistry.

N N

P Ph P Ph P Cl Cl Cl Cl Ru Ph Ru Ph Ru Ph Ru Cl Cl Cl Cl Ph P P P P

(a) (b) (c) (d)

Figure 1.3 (a) First well-defined ruthenium metathesis catalyst, (b) variation with PCy3, (c) first generation and (d) second generation Grubbs catalysts.

Mechanistic studies by Grubbs33 and others34 suggested that the active species during olefin metathesis by ruthenium alkylidene complexes was a 14e- complex formed by dissociation of one phosphine ligand. Attempts to increase the effective concentration of this intermediate resulted in accelerated catalyst decomposition. The replacement of one phosphine ligand with an N-heterocyclic carbene35 (NHC) afforded catalysts showing dramatically increased activity and stability (Figure 1.3, d). At the time, it was argued that the NHC ligands, thought to be excellent sigma donor ligands with limited  accepting capabilities, would promote the dissociation of the phosphine trans to the NHC ligand, while the ligand’s large steric demand would prevent bimolecular decomposition by forcing the catalyst molecules to stay apart from one another. Mechanistic studies together with theoretical calculations later showed that this interpretation was wrong (see section 2.1.1)

Based on the established ruthenium framework many different variants have been developed. Hoveyda introduced in 1999 a catalyst with a chelating isopropoxy group attached to the benzylidene moiety36 (Figure 1.4, a), this substitution improved the stability of the first generation systems. Later, in 2000 the same concept was applied to the second generation systems37 (Figure 1.4, b). In 2002, Grela reported the inclusion of an electron withdrawing group in the para position with respect to the ether substituent38 (Figure 1.4, c), in this way the oxygen-ruthenium bond was destabilized facilitating the activation of the catalyst. In 2001, Grubbs replaced the remaining

Discovery, Development and Study of Carbenoid Mediated Reactions phosphine ligand with pyridines (Figure 1.4, d) which are more easily displaced by an olefin.39 This complex was found to initiate more than a million fold faster than the regular second generation Ru-catalyst. Given this leap in reactivity the catalyst received the name of third generation Grubbs catalyst.

Figure 1.4. (a) First generation and (b) second generation Hoveyda-Grubbs catalysts, (c) Grela’s complex and (d) Third generation Grubbs catalyst.

1.1.4 Heterogeneous systems

Convenient catalyst recovery and recyclability, and the possibility of incorporating static catalysts in flow reactors are just some of the benefits of using heterogeneous catalysts for organic transformations in the laboratory or in industrial processes.40 Ever since the discovery of olefin metathesis heterogeneous systems have played a crucial role. The

3-4 initial reports by Eleuterio used MoO3 or WO3 supported on silica or alumina. Important advances were made by British Petroleum with their Re3O7/Al2O3 system which can perform olefin metathesis at room temperature.41 Even though these kinds of systems have facilitated important industrial applications their actual molecular composition remains ill-defined. Contrary to the case of the well-defined molecular catalysts, rational design of heterogeneous systems is limited by the knowledge of the surface active sites. One approach that attempts to combine the advantages of heterogeneous systems with the abilities of the homogeneous catalysts consists of the immobilization of molecular catalysts on well-defined surfaces by covalent bonding with reactive sites. This methodology is known as surface organometallic chemistry (SOMC). Parallel with the development of the early transition metal molecular catalysts, the grafting of these

1. Introduction complexes on silica systems provided the earliest examples of supported, highly active heterogeneous systems.42 However, the limited tools available at the time restricted the understanding at the molecular level of catalysts produced. More recently, the incorporation of more capable techniques has allowed the complete characterization of silica-supported metal alkylidene complexes.43 The intrinsic modularity of the well- defined supported catalysts has allowed their continuous improvement, in a fashion reminiscent to their homogeneous counterparts44 (Figure 1.5).

Figure 1.5 (a) First, (b) second and (c) third generation of well-defined silica supported alkylidene complexes.

A wide variety of anchoring groups have been used to attach ruthenium based catalyst to solid supports. Covalent bonding of the phosphine or NHC ligand in first or second generation systems, attachment via anionic group or the incorporation of the benzylidene into the solid phase have been used to immobilize active catalysts in polymeric supports.45 More recently, using SOMC principles, second generation Grubbs systems have been incorporated into hybrid organic-silica materials.46

1.1.5 Applications of olefin metathesis

Large scale industrial applications of olefin metathesis are mainly focused on the production of small to medium sized commodity olefins. The unmatched global demand for propene has driven the reverse-operation Phillips “Tri Olefin Process”8 to convert a mixture of ethene and 2-butene into the more valuable propene. The process uses a mixture of WO3/SiO2 and MgO at high temperature, the latter being an olefin isomerization catalyst. As an alternative, the Meta-4 process was developed using

47 Re2O7/Al2O3 for the same reaction in a liquid phase at 35 °C and 60 bar. Medium sized linear internal olefins (C11-C14) are produced by olefin metathesis in the third step of the Shell higher olefin process. These olefins are further transformed into detergent alcohols or alkylates.7

Discovery, Development and Study of Carbenoid Mediated Reactions On a slightly smaller scale, industrial production of polymers via ring opening metathesis polymerization (ROMP) has been focus of intense research since the early days. The ready availability of the required monomers from petrochemical refining helped the commercial success of ROMP. On the contrary, acyclic diene metathesis (ADMET) has so far remained as an academic curiosity (Scheme 1.5).

Scheme 1.5 Top. Ring opening metathesis polymerization (ROMP). Bottom: Acyclic diene metathesis.

Polymers of cyclopentene (polypentenomer), cyclooctene (Vestamer®), norbornene (Nosorex®) and dicyclopentadiene (Metton®, Telene® and PentamTM) quickly became available. Although these polymers can be used by themselves or in combination with other polymers or via functionalization of their olefins, as for example by vulcanization into rubber, the high price associated with these processes sets these polymers apart in the niche of specialty materials. In that respect, olefin metathesis offers unusual possibilities. For instance, it enables the incorporation of end-groups after polymerization by use of chain transfer reagents producing telechelic polymers for specialized applications.48 Self-healing polymers in which a vesicle provides monomer after a crack reaches a critical point, take advantage of the living nature of ROMP to regenerate the structure.49 Furthermore, biocompatible polymers made by ROMP are strong candidates for corneal tissue engineering.50

In fine chemistry, the most widely used application of olefin metathesis is ring closing metathesis (RCM).51 The possibility to create rings ranging from 5 to 20 or more carbon atoms with evolving ethylene as driving force for product formation has made this technique a crucial part of many total syntheses of biologically relevant molecules.52 However, the synthesis of increasingly bigger cycles must be performed at higher dilutions, catalysts loadings and temperatures in order to avoid dimerization and to compensate for catalyst decomposition. The combination of RCM with other types of metathetic transformations like ROM or CM in one pot are elegant approaches for the construction of complex molecules from relatively simple precursors.

1. Introduction 1.1.6 Stereoselective olefin metathesis

The complexity generated by contemporary synthetic approaches gives rise to products which may contain pro-chiral groups. Enantiopure variants of both early transition metal and ruthenium based catalysts have been made in order to prepare enantiomerically enriched products. The rigidity of the framework offered by early transition metal catalysts was exploited by replacing the alkoxy ligands with chelating chiral bisalcoholates (see for example see figure 1.2, c). These complexes were first shown to perform very well for the catalytic kinetic resolution of dienes via ring closing metathesis.53 Development of more user-friendly chiral systems formed in situ by combination of a commercially available optically pure binaphthol ligands and a suitable metal alkylidene precursor has been reported.54 Ruthenium catalysts bearing bidentate NHC ligands have also been reported to perform asymmetric ROM/CM reactions55 (Figure 1.6, a). These catalysts benefit from the inherent robustness of the ruthenium alkylidenes allowing them to operate under normal atmospheric conditions.

Figure 1.6 Examples of (a) enantioselective and (b) and (c) Z-selective metathesis catalysts.

Although very important, enantioselectivity is not the only isomerism that can be influenced during the process of olefin metathesis. The resulting olefin is often a mixture of the Z and E geometric isomers. Formation of the thermodynamically more stable E isomer is favored in most of the cases. Nonetheless, many important synthetic targets require the formation of the more challenging Z isomer. The first advances in this area were achieved by tuning the steric demand on monoaryloxy W and Mo alkylidene complexes, these complexes showed high selectivity towards Z-olefin formation56 (Figure 1.6, b). In a similar way, steric arguments guided the development of ruthenium catalysts bearing bidentate phosphine ligands which displayed a high degree of chemoselectivity for the alternating ROMP of cycloolefins; these catalysts were also optimized to induce some degree of Z-selectivity.57 Catalysts with chelating NHC ligands

Discovery, Development and Study of Carbenoid Mediated Reactions have also been shown to influence the stereochemical outcome of different olefin metathesis processes58 (Figure 6, c). Replacement of one59 or two60 of the chlorides by sulfur ligands in traditional second generation Grubbs systems has also yielded highly Z- selective catalysts (Figure 1.7).

Figure 1.7 Most recent examples of Z-selective catalysts based on sulfur-containing ligands.

1.3. Methylenation Reactions

1.3.1. Three–membered rings

Among the cyclic molecular scaffolds, three–membered rings are of particular importance due to their reactivity and abundance in molecules with important biological activities. The smallest cyclic hydrocarbon, cyclopropane (figure 1.8, a), and its derivatives are found in many relevant molecules, both naturally occurring and synthetically prepared.61

Figure 1.8 Left: Simplest examples of chemically relevant three membered rings: (a) cyclopropane, (b) oxirane, (c) thiirane and (d) aziridine.

One of the first compounds derived from cyclopropane that have found their way into industrial production are the members of the pyrethroid family. In 1924, Staudinger and Ružička isolated and characterized esters of (+)-trans-chrysanthemic acid as the active component in the defense mechanism against insects of certain pyrethrum flowers62 (figure 1.8).

1. Introduction

Figure 1.9 Structures of naturally occurring (a) (+)-trans-chrysanthemic acid and synthethic (b) allethrin and (c) permethrin.

It was quickly recognized that the synthetic derivatives of chrysanthemic acid were more potent, less toxic and more resistant to UV radiation than the natural variants,63 turning this type of compound into the most common household insecticide to date,64 after DDT was banned in 1972 in the USA by the Environmental Protection Agency (EPA).65 It comes as no surprise that the synthesis of cyclopropanes,66 and their subsequent use as intermediates,67 has become an established and intensively active area of research.

Three–membered rings containing one oxygen atom, i.e. epoxides, (figure 1.8, b), are important molecules that are not only found in nature,68 but are also regularly used as intermediates in the synthesis of more elaborate functionalities. Their rich chemistry,69 particularly the versatile ring opening,70 makes epoxides a desirable target or intermediate in many synthetic routes.71

Figure 1.10 Naturally occurring (a) moth sex pheromone (–)-Posticlure72 from Orgyia postica and (b) antifungal ambuic acid73 from Pestalotiopsis microspora.

The smallest nitrogen–containing heterocycles, the aziridines, also constitute an important class of compounds. Many of the discovered naturally occurring aziridines show antitumor activity, making them important targets for total synthesis.74 The cleavage of the aziridine ring can afford amines, amino acids, amino alcohols and other relevant nitrogen–containing molecules.75 The stereoselective synthesis of aziridines has been recently reviewed.76

Discovery, Development and Study of Carbenoid Mediated Reactions

Figure 1.11 Natural aziridines (a) (2S,3S)-(+)-aziridine-dicarboxylic acid,77 an antibacterial isolated from Streptomyces MD398-A1 and (b) Mitomycin K,78 an antibacterial and anticancer agent.

1.3.2. Bonding in three–membered rings

While on the basis of geometric arguments one would expect the cyclopropane ring to be one of the most unstable molecules, its experimentally measured ring strain is just slightly larger than that of cyclobutane; 27.5 kcal/mol vs 26.5 kcal/mol respectively.79 Additionally, the chemical reactivity of cyclopropane resembles more closely that of ethylene than other cycloalkanes. In this respect both ethylene and cyclopropanes can: interact with neighboring -electron systems (resonance); form metal complexes; add strong acids, halogens and ozone; and engage in cycloadditions. Although ethylene normally reacts much faster, there are no fundamental differences in the reaction types these two functional groups can perform. Much work has been devoted to the study of the bonding situation in the cyclopropane subunit.80 Two independent, albeit mathematically equivalent, bonding models were developed in order to explain the particularities of the cyclopropane ring. In 1949, A. D. Walsh derived the molecular orbitals (MO) for cyclopropane by combining three independent methylene units, each with a sp2 hybrid orbital pointing towards the center of the ring and an independent p orbital differing only in their symmetry properties81 (Figure 1.12 top). This description is very similar to the common MO picture of a C=C double bond in which the interaction of two sp2 atomic orbitals (AO) generate a  MO and the two perpendicular p AOs form the  bonding MO (Figure 1.12 bottom).

The second description, based on the valence bond model, predicts the C–C bonds to result from the overlap of two sp5 orbitals at each C atom.82 The direction of these orbitals does not correspond with the direction of bonding (line connecting two carbon atoms) and thus gives the impression of bent bonds (Figure 1.13 top). It has been experimentally confirmed that electron density is the greatest off the C–C axis.83 The same construction can be applied to ethylene giving rise to two “banana”  bonds on each side of the C–C axis, and because of this it has sometimes been called the smallest cyclic hydrocarbon.84

1. Introduction

Figure 1.12 Top: Walsh MO description of cyclopropane. Bottom: common MO description of ethylene.

As a consequence of the increase in double bond character (p character) of the C–C bonds in cyclopropane, the C–H bonds are enriched in s character. The C–H bonds in cyclopropane are therefore stronger and shorter than in other alkanes; i.e. the bond strengths and distances are somewhere between those of the C–H bond of olefins and saturated hydrocarbons.

Figure 1.13 Valence bond model of cyclopropane (top) and ethylene (bottom).

The bonding description in the other three–membered rings; oxirane, thiirane and aziridines; can be extrapolated from the one in cyclopropane by replacing one methylidene unit with an oxygen, sulfur or nitrogen atom respectively.

1.3.3. Carbene equivalents or carbenoids for the synthesis of three–membered rings

As shown in scheme 1.6 left, one general approach to the synthesis of three–membered rings, especially of cyclopropanes, is the direct addition of a methylene carbene to an unsaturated substrate. For this purpose, the most efficient way to generate free carbenes in solution is the thermal85 or photolytic86 decomposition of diazomethane (scheme 1.6, right).

Scheme 1.6 Left: Prototypical methylene addition to unsaturated compounds. Right: Generation of methylene from diazomethane.

Discovery, Development and Study of Carbenoid Mediated Reactions Although this may seem like an optimal reaction, the handling of diazomethane is complicated by severe health and safety risks. Due to its high nitrogen content, and the production of thermodynamically stable molecular nitrogen upon decomposition, diazomethane is intrinsically explosive. Solutions of diazomethane have been reported to explode upon distillation, exposure to sharp edges, drying over sharp KOH pellets, and exposure to light.87 Additionally, diazomethane and the precursors from which it is prepared, are highly toxic.88 In fact, these compounds have been found to be potent carcinogenic agents.89 Despite these drawbacks, when necessary, diazomethane can be used safely in the laboratory with the appropriate equipment (diazald kit). In situ generation of diazomethane under phase–transfer conditions offers a method in which the concentration of diazomethane never builds up to dangerous levels.90

In order to avoid the use of diazomethane and its precursors, reagents known as carbenoids are more commonly employed. A carbenoid, as defined by Closs and Moss, is a species which shows reactivity ‘Qualitatively analogous to those of carbenes without necessarily being a free divalent carbon species’.91 A wide range of reagents can be covered by this term, see figure 1.14. Although operating by markedly different mechanisms, all the carbenoids shown can be used for the synthesis of one or more of the three–membered rings discussed before (figure 1.8).

Figure 1.14 Some common methylene donors for the synthesis of three membered cycles: (a) iodomethyllithium,92 (b) iodomethyzinc iodide,93 (c) bis(iodomethyl)mercury,94 (d) dimethylsulfoxonium methylide95 and (e) transition metal carbenoid compounds.

Carbenoids can be classified in two main groups on the basis of their dominant electronic character. Nucleophilic carbenoids like (a) and (d) predominantly add to unsaturated compounds, yielding intermediates from which intramolecular ring closure affords a cyclic product. On the other hand, electrophilic carbenoids like (b), (c) and (e) are normally subject to attack by -systems, forming the cyclic products in one concerted step. The mechanism of reaction for the most important representatives of these two families will be discussed in the following sections.

1. Introduction 1.1.7 Nucleophilic methylenation

All nucleophilic methylenation reactions follow the same general mechanism depicted in scheme 1.7. The carbenoids employed in this type of reaction are derived either from deprotonation or lithium–halogen exchange of a suitable starting material like dihalomethanes,92 trimethylsulfonium halides,95 ammonium salts96 or enolizable carbonyl compounds.97 In addition to the nucleophilic carbon of the carbenoid, a leaving group needs to be present to enable the intramolecular ring closure. The leaving group can be either incorporated into the carbenoid or be already present in the substrate. Due to the stepwise nature of this methylenation, this transformation is not stereospecific, nonetheless many stereoselective variants have been reported.

Scheme 1.7 General mechanism for the nucleophilic methylenation of unsaturated compounds. (M) denotes a metal which may or may not be necessary, depending on the nature of the carbenoid.

Sulfur ylides: Corey-Chaykovsky reagent

Following a 1961 report by Johnson,98 E. J. Corey and M. Chaykovsky developed in 1962 the use of dimethylsulfonium and dimethyl(oxo)sulfonium methylides for the synthesis of epoxides from aldehydes and ketones.95, 99 Over the years their methodology has become a routine protocol in organic chemistry.100

Scheme 1.8 Corey-Chaykovsky reaction.

Although mainly used for the synthesis of epoxides, sulfur ylides can also be applied in the synthesis of other three–membered rings. The additions of sulfur ylides to benzylaniline101 and to chiral sulfinimines102 to afford the corresponding aziridines, have been reported (Scheme 1.9). Despite these promising reports addition of ylides to imines remains underdeveloped. Unlike carbonyl compunds (for epoxidation) and ,- unsaturated compounds (for cyclopropanation), N-alkyl and N-aryl imines are rather unreactive towards nucleophilic attack by ylide agents.103

Discovery, Development and Study of Carbenoid Mediated Reactions

Scheme 1.9 Sulfur ylide mediated methylenation of Left: benzylaniline101 and Right: chiral sulfimines.102

Sulfur ylides readily add to ,–unsaturated carbonyls affording cyclopropanes in excellent yields.104 This methylenation reaction belongs to the more general class known as Michael–initiated ring closures (MIRC). This reaction is not limited to conjugated carbonyls; in principle, any olefin activated by an adjacent electron withdrawing group can be attacked by an ylide. Addition to ,–unsaturated esters, amides, imides, nitriles, conjugated nitroolefins and vinylsulfones has been reported.104 On longer conjugated systems 1,6 addition is preferred over 1,4 addition.

Scheme 1.10 Some examples of Michael-initiated methylenation with sulfur ylides.104 Left: Cyclopropanation of an ,,,-unsaturated conjugated ketone. Right: cyclopropanation of a conjugated nitrile.

Halomethyllithium carbenoids

Since their introduction as nucleophiles,105 halomethyllithium carbenoids have been used as an alternative to diazomethane and sulfur ylides in the homologation of aldehydes and the synthesis of epoxides and aziridines.92 These carbenoids are simply prepared by addition of an alkyllithium to a dihalomethane at very low temperatures (scheme 1.11, left). Although initially believed to be unstable above -110 °C, more recent studies point to a less prohibitive temperature restriction of -78°C.106 More practical procedures involving the in situ preparation of the carbenoid in the presence of the electrophile, allow for even higher operating temperatures of up to 0 °C.

1. Introduction

Scheme 1.11 Left: Preparation of halomethyllithium carbenoids. Right: Use of these carbenoids for (a) Synthesis of epoxides107 and (b) aziridines.108 1.1.8 Electrophilic methylenation

Electrophilic carbenoids are organometallic species in which the carbon atom has a net electropositive character, and therefore is susceptible to attack by a nucleophile: in the case of cyclopropanation reactions, an olefin. The mode of addition of these reagents is a concerted, asynchronous process in which the key transition step possesses a butterfly geometry (scheme 1.12).

Scheme 1.12 General electrophilic methylenation of olefins.

Halomethylzinc reagents: the Simmons-Smith reaction

Although synthesized 30 years earlier by G. Emschwiller,109 it was the discovery by Howard Ensign Simmons, Jr. and Ronald D. Smith at the Du Pont Central Research laboratories that iodomethylzinc iodide reacted with olefins producing cyclopropanes stereospecifically93 that marked the development of the currently most popular method for the synthesis of this class of compounds, particularly for large scale applications.

The original Simmons and Smith procedure involved the activation of Zn with Cu at high temperature in a hydrogen atmosphere. Since then, more convenient variants have emerged. The most commonly used activation procedures involve the treatment of Zn

110 111 112 powder with CuSO4, Cu(OAc)2 or CuCl. In all of these cases an ethereal solvent is required (Et2O, THF or DME). Nonetheless, solvent coordination reduces the electropositive character of the carbenoid impairing its reactivity. A major breakthrough was achieved by Furukawa who replaced metallic Zn by soluble diethylzinc.113 Iodomethane replaces one of the alkyl groups and generates a reactive species which

Discovery, Development and Study of Carbenoid Mediated Reactions performs cyclopropanation efficiently in a wide variety of non-coordinating solvents, e.g. hexane, dichloromethane, toluene and benzene. Replacement of one alkyl ligand in diethylzinc by an anionic oxygen ligand like carboxylate,114 trifluorosulfonate,115 phenolate116 or phosphate117 has been reported to generate very effective cyclopropanating reagents by withdrawing electron density from the metallic center, and consequently increasing the electrophilic character of the carbenoid. These zinc organometallics have been employed in countless synthetic procedures in organic chemistry.118

Scheme 1.13 Top: original Simmons-Smith cyclopropanating reagent. Variants by Middle: Furuwaka and Bottom: Charette.

Transition metal catalyzed decomposition of diazomethane

The inherent safety risks associated with the bulk thermal or photolytic decomposition of diazomethane to generate free methylene has encouraged the development of alternative and safer ways to transfer the methylene moiety from diazomethane to olefins. Transition metal catalyzed decomposition of diazomethane allows the use of lower concentrations of this hazardous chemical. Almost all metals have been reported to react with diazomethane yielding a variety of products including cyclopropanes when olefins are present.

Depending on the metal used, two main mechanisms have been proposed for the methylene transfer to olefins.66b, 119 A more traditional outer sphere mechanism,120 in which the olefin does not coordinate the metal center, in resemblance to the Simmons- Smith reaction, is proposed for reactions mediated by Fe, Ru, Rh, Cu and Co (Scheme1.12 left). In this mechanism, an initial attack by diazomethane on the metal complex produces a metal methylidene intermediate after nitrogen extrusion. This species can then engage in a [2+1] concerted addition with the olefin producing cyclopropane and regenerating the metal catalysts.

1. Introduction

Scheme 1.12 Proposed (left) outer and (right) inner sphere mechanism for the methylene transfer in transition metal catalyzed decomposition of diazomethane.

Alternatively, a stepwise inner sphere mechanism, in which the olefin coordinates the metal center, is proposed mainly for Pd catalysts.121 In this mechanism, an unsaturated metal complex is initially coordinated by the substrate. Subsequent attack by diazomethane generates a carbene complex which then can undergo [2+2] cycloaddition to form a metallacyclobutane intermediate. From this intermediate cyclopropane is formed by reductive elimination with concomitant regeneration the metal catalyst.

2. Ruthenium catalyzed alternating ring opening metathesis polymerization (A-ROMP)

2.1. Introduction

2.1.1. Studies on the mechanism of olefin metathesis

Since the mechanistic proposal by Hérrison and Chauvin for the olefin metathesis12 considerable research effort has been devoted to experimentally support this mechanism. As discussed in the introduction, it quickly became clear that metal– alkylidene complexes were the active catalysts.13, 15, 122 The intermediacy of metallacyclobutanes was also confirmed as a result of the isolation and characterization of several examples which mediated olefin metathesis to varying degrees.16-17, 123 Even though these initial findings provided strong support for Chauvin’s mechanism, the fine details of every step were the source of debate over the following years. In the case of ruthenium catalysts, Adlhart and Chen have studied all the possibilities within a set of constrains reasonable for a transition metal catalyzed metathesis reaction124 (scheme 2.1).

Scheme 2.1 Possible pathways for the ruthenium olefin metathesis. Taken from (Adlhart and Chen, 2004)124.

Scheme 2.1 summarizes all the reasonable pathways for ruthenium–catalyzed olefin metathesis. Starting from a well–defined 16e- complex (A), i.e. the first generation Grubbs

Discovery, Development and Study of Carbenoid Mediated Reactions catalyst31 where the benzylidene was simplified by a methylidene, olefin coordination can take place directly either cis or trans with respect to the methylidene to form intermediate (Ba)cis or (Ba)trans respectively. In a dissociative pathway, initial phosphine loss leads to 14e- intermediate (B), which can then be coordinated by the olefin to form one of the intermediates (C), (C1)cis or (C2)cis depending whether one of the chloride anions is in the trans or in one of the two possible cis configurations. Direct formation of a metallacyclobutane from this intermediates leads to structures (D), (D1)cis and (D2)cis respectively. Structure (Da)cis can be formed directly from (Ba)cis, and (Da)trans can be formed after phosphine recoordination to intermediate (C). Calculations from Adlhart and Chen predicted the minimum energy pathway to go through the structures (A), (B), (C) and (D). Over the years, different groups have provided experimental evidence also favoring this particular pathway.

Grubbs offered convincing evidence for an initial dissociative mechanism in his phosphine exchange studies.125 He showed that olefin coordination is preceded by phosphine dissociation to form a reactive 14e- intermediate. More importantly, it was recognized for the first time that second generation systems (where one phosphine has been replaced by an N-heterocyclic carbene) showed a lower rate of initiation, in contradiction to the common belief. The increased reactivity seemed to arise from their intrinsic reactivity after the initiation event. Isolable 14e- complex reported by Piers126 (Figure 2.1) showed almost no activation barrier as would be expected since there is no ligand loss needed to engage in productive metathesis steps.

Figure 2.1 Piers cationic fast-activating 14e- metathesis catalyst.126

Mechanistic studies in the gas phase by Adlhart and Chen aimed at elucidating the nature of the rate determining step for olefin metathesis.34c In this study a positively charged phosphine ligand allows for the generation of 14e- species 1 during electro-spray ionization in a modified TSQ 700 ESI-MS instrument (Scheme 2.2). Exposure of this species to different olefins in the gas phase produced complex 2 which was then mass selected and reacted with either 1-butene or norbornene in a subsequent reaction chamber to produce complex 3 or 4 respectively.

2. Ruthenium catalyzed A–ROMP

Scheme 2.2 Mechanistic studies in the gas phase by Adlhart and Chen.34c

Adlhart and Chen found an accelerating effect on the reaction of 2 with 1-butene when an electron-withdrawing substituent was added to the parent benzylidene. They also found evidence of an inverse isotope effect for the forward and the backward reaction (reaction of 3 with a styrene) of this nearly thermoneutral process. On the contrary, no evidence was found of a substituent or isotopic effect for the exothermic reaction of 2 with norbornene. At that moment these findings led to contradictory conclusions. On a theoretical potential energy surface for the reaction of 2 with 1-butene or norbornene (Scheme 2.3) two assumptions can be made. If the metallacyclobutane (MCB) structure is considered an intermediate (left) the energetic profile from olefin coordination (B to C and B' to C') to MCB formation (C to D and C' to D') are in essence the same for both 1- butene and norbornene since the ring-strain in norbornene is only released after cycloreversion. The exothermicity of the ring opening for norbornene stabilizes the product D' and at the same time lowers the energy of the corresponding cycloreversion transition state (D' to E') in accordance to the Hammond postulate (dashed line in the left potential energy surface). In this scenario both a substituent and isotopic effect should be measurable and of similar magnitude not only for the pseudodegenerate reaction with 1-butene but also for the norbornene case. On the other hand, if the MCB structure would be a transition state (Scheme 2.3, right), the exothermicity of the ring opening would lower the energy of transition state D' diminishing or eliminating the substituent and isotopic effects for the exothermic reaction. The experimental evidence favored the latter case, whereas computations predicted an intermediate for the MCB structure.

Discovery, Development and Study of Carbenoid Mediated Reactions

Scheme 2.3 Metallacyclobutane (MCB) as intermediate or transition state.

The explanation to this apparent conflict was put forth by Adlhart and Chen two years later. Using a QM/MM model it was possible to model the complete system including the bulky tricyclohexyl phosphine.127 It was discovered that the rate limiting step on degenerate metathesis in first generation systems (such as the ones studied by Adlhart and Chen) was a 60 ° phosphine rotation around its three-fold symmetry axis at the metallacyclobutane intermediate (Scheme 2.4). On the other hand, the stabilization of the intermediates after the cycloreversion step in exothermic reactions, i.e. reaction with strained olefins like norbornene, allows the ligand rotation to take place at lower energies at a later stage on the reaction coordinate. Such rotation is not necessary in second generation systems due to the two-fold symmetry of the NHC ligand. Phosphine rotation at intermediate D to yield D'' avoids the destabilizing steric interaction present in E but not in E''. More importantly, it was then recognized that the carbene moiety switches sides after each productive cycle. Although unimportant for traditional systems where the phosphine ligand is freely rotating, this switch is the cornerstone upon which the fully chemoselective alternating ROMP catalysts were designed (vide infra).

2. Ruthenium catalyzed A–ROMP

Scheme 2.4. Rate-limiting ligand rotation at metallacyclobutane structure.

Direct observation of metallacyclobutanes at low temperature in ruthenium-catalyzed metathesis was afterwards reported by Piers128 and Grubbs.129

As mentioned earlier, Grubbs' experiments in solution phase revealed that contrary to what was commonly accepted, second generation catalysts showed slower rates for initial phosphine dissociation. Therefore, their superior activity must come from an intrinsic higher reactivity of the 14e- intermediate. Evidence in the solution phase was obtained by Grubbs after reacting a second generation catalyst with ethyl vinyl ether; this class of substrates form an inactive alkylidene after one metathesis step.125b Grubbs found no rate dependence on the catalyst concentration over a wide range of concentrations, indicating a case of saturation kinetics. On the other hand, first generation systems were highly dependent on catalyst concentration. However, the intrinsic reactivity of these systems cannot be fully separated from the initial activation step in solution phase. Adlhart and Chen were able to study the metathesis reaction after the activation step by reacting tagged ruthenium catalysts in the gas phase with norbornene.130 Under the same conditions, the second generation catalyst added up to 4 monomer units, whereas the first generation catalyst reacted only once. Calculations gave a rationale to this behavior (figure 2.2).124 From this potential energy surface it can be concluded that the energy required to dissociate the phosphine ligand from the starting 16e- complex A' to form 14e- intermediate B' is higher in second generation (26.1 kcal mol-1) than in the first generation system (21.1 kcal mol-1). These results are in accordance with the solution-phase studies by Grubbs (27.0 and 23.6 kcal mol-1 for second and first generation systems respectively). More dramatic though is the difference in

Discovery, Development and Study of Carbenoid Mediated Reactions relative energy for the transition state connecting the -complex C' and the metallacyclobutane intermediate D' (energy of TSC'D'). For the second generation catalyst there is effectively no barrier, making the initial ligand dissociation rate determining. In contrast, first generation catalyst shows a barrier of 5.8 kcal mol-1 for the formation of the metallacyclobutane intermediate. In this case, TSC'D' is rate determining, taking into consideration that the phosphine dissociation event will most likely take place only once over the course of a catalytic reaction. The ratio between the barriers for propagation (C' to D') and pre-catalyst formation (C' to A') in a system is known as catalyst commitment. More committed catalysts show low barriers for productive steps and disfavor the formation of inactive forms. In this case the second generation Grubbs system shows a much higher commitment compared to first generation systems.

Figure 2.2 Calculated potential energy surfaces for the reaction of first (black) and second (grey) generation Grubbs catalysts with norbornene. Benzylidene moieties were simplified as methylidene, labels correspond to those in scheme 2.3 (Adlhart and Chen).124

The anionic ligands on the ruthenium center also play a crucial role in determining the relative activity of the catalyst. Straub calculated the influence of different anions on the active and inactive conformations of both the carbene moiety and the coordinated olefin.131 He found that in agreement with Grubbs’ experimentally observed trends,33b electron poor anions stabilize active conformations and thus lead to more active catalysts, for instance chloride and mesilate are better choices than electron rich alkoxide or thiolate anions. Straub found as well that strongly -donor ligands, e.g. the NHC carbene in second generation systems, should be positioned trans to the

2. Ruthenium catalyzed A–ROMP coordinated olefin in order to maximize the rate of metallacyclobutane intermediate formation and cycloreversion. A derivation of this concept was later found by Torker and Hoveyda132 to be of great importance for the high stereoselectivity shown by their dithiocatecholate–containing catalysts.60 In their case, strongly donating cis thiolate ligands force the metallacyclobutane to form cis to the NHC ligand, but trans to one of the thiolates, instead of the more normally found trans to NHC configuration. In this case the heterocyclic carbene enforces a big steric barrier that forces all substituents away from it, yielding highly Z-selective olefin metathesis.

2.1.2. Rationally designed A-ROMP catalysts

The mechanistic studies by Adlhart and Chen, discussed in the preceding sections, revealed that the rate-limiting transition state in a pseudo-degenerate metathesis reaction catalyzed by first generation Grubbs catalysts is the phosphine rotation in the metallacyclobutane intermediate. As a result, it was recognized that the carbene moiety flips between the two “sides” of the catalyst. Phosphine rotation in classical first generation systems ensures degeneracy between these two states. However, if rotation is inhibited, e.g. by chelation, and different substituents are placed on the phosphine, a catalyst stereogenic at both the phosphine and the ruthenium would be obtained. Inversion at ruthenium as a result from the swing of the carbene moiety after every metathesis step would switch between two different diastereoisomeric states, which by definition, are not degenerate. This concept was exploited by Bornand and Chen in the design of a catalyst capable of distinguishing two different olefins in order to produce alternating co-polymers.133

Bornand and Chen explained the observed chemoselectivity with the mechanism shown in scheme 2.4. In the first half of the cycle (A→B→C→D) the carbene moiety switches from a low energy diasteromeric state A, in which the interaction between the small phosphine substituent and the carbene is small, to a high energy state D, in which the big phosphine substituent exerts an increased steric interaction. The metathesis reaction only proceeds if the strain release provided by the monomer is enough to compensate for this energy increase. On the other hand, switching back from D to A is thermodynamically favored and can be performed by any olefin. When the copolymerization is performed using an excess of the low strain olefin an alternated polymerization sequence is favored. Although catalyst 5 (figure 2.3) showed the desired selectivity, the presence of one free tricyclohexyl phosphine promoted the formation of

Discovery, Development and Study of Carbenoid Mediated Reactions the starting first generation Grubbs system, which in turn lowered the selectivity of the copolymerization.

Scheme 2.4 Mechanism for the alternating ROMP of norbornene and cyclooctene catalyzed by asymmetric, rotation-locked first generation Grubbs catalysts (Bornand and Chen).133

2.1.3. Optimization of the catalysts for chemo and stereoselectivity

Subsequent optimization of the catalysts by Torker, Bornand and Chen allowed the preparation of a fully chemoselective, more robust system for the A-ROMP of norbornene and cyclooctene57b, 134 (figure 2.3). The use of a Hoveyda-type benzylidine avoided the formation of classic first generation systems and increased catalyst’s stability. Increasing the steric demand of one of the substituents on the phosphine produced more chemoselective catalysts, which in turn allowed the reaction to be performed at lower monomer ratios. For instance catalyst 6a produces a 72% content of alternating linkages with a norbornene to cyclooctene ratio of 1/200 whereas catalyst 6d achieves 97% of alternation using a monomer ratio of only 1/20.

2. Ruthenium catalyzed A–ROMP

Figure 2.3 Proof of concept catalyst 5. Optimization of the catalysts towards full alternation (6a to 6e) and chloride replacement with bulky sulfonates to induce Z selectivity (6f to 6j). TMP= 1,1,2,2-tetramethylpropyl.

Replacement of the chloride anion with bulky sulfonates increased the selectivity towards the formation of Z-arranged olefins without affecting the chemoselectivity.57a The effect on the stereoselectivity was explained on the basis of similar steric arguments, see scheme 2.5. At the metallacyclobutane intermediate the polymer chain and the olefin substituents can be arranged in opposite directions, leading to an E-olefin, or in the same direction to form a Z-olefin. The steric repulsion experienced in the metallacyclobutane structure favors the formation of E-olefins as evidenced by the 90% E-olefin content when using catalyst 6e. When bulky sulfonates are introduced, an additional, orthogonal steric interaction forces the arrangement of the polymer chain and olefin to form an all- cis metallacyclobutane intermediate, producing a Z-double bond. The balance between this two opposing interactions in the catalyst ultimately determines the extent of stereoselectivity of the polymerization.

Discovery, Development and Study of Carbenoid Mediated Reactions

Scheme 2.5 Steric interactions governing stereoselectivity on Ru–catalyzed metathesis.

Increasing the steric demand of the sulfonates increased the content of Z-arranged double bonds in the copolymer from 13% using 6f to 51% for 6i, when using in situ prepared catalysts. Further increase of the steric bulk of the sulfonate caused a dramatic reduction in the stereoselectivity. Catalyst 6j induces only 19% Z-selectivity under the same conditions. When isolated catalysts were tested in copolymerization it became evident that anion dissociation was playing a detrimental role. Z-selectivity of catalyst 6i went down to 36% (from 51%) when an analytically pure sample was used. The increased steric bulk of the sulfonates, while beneficial for the stereoselectivity, weakens the oxygen-ruthenium bond making the more demanding sulfonate anions also more prone to dissociation.

It was then predicted by Jovic ́ and Chen that the more strongly donating thiosulfonates would bind better to the ruthenium center and show increased effect in the stereoselectivity135 (figure 2.4).

2. Ruthenium catalyzed A–ROMP

Figure 2.4 Ruthenium catalysts for A-ROMP bearing thiosulfonate (left) and thiolate (right) ligands (Jovic ́ and Chen).135

The thiosulfonate ligands showed an increased stereoselectivity achieving up to 41% Z- olefin content using isolated catalyst 8f. However, together with the increase in the steric bulk of the thiosulfonate there was a significant loss in activity. While catalyst 8b produces a modest 18% of Z-arranged double bonds, and 82% copolymer, 8f only produces 4% copolymer. It was proposed that an excess of both steric demand and electronic donating capability of the thiosulfonate complexes renders the resulting complexes much less active than their sulfonate analogs. In an attempt to bring the steric influence closer to the metal center, thiolate ligands were used. The resulting catalysts however showed basically no control on the stereoselectivity and reduced activities. It is likely that the extremely crowded space around the ruthenium atom forces the ligand to dissociate before any metathesis can take place. Being very good electron donors, thiolates are strongly bound to the metal, disfavoring ligand dissociation.

Carboxylate ligands, as well as other oxyanions, were also employed in an attempt to steer the stereoselectivity towards Z-olefins.136 It was noted however that an unexpected drop in chemoselectivity was consistent among the tested catalysts. Nitro complex 12a being the worst, yielding only 77% alternating linkages in the copolymer compared with its chloride analog 6e at 97%. The exhibited low chemoselectivity could be explained after crystal structures of the complexes showed that the oxyanions effectively chelate the metal center. The additional coordination reduces the energetic difference between the two possible diasteromeric carbene states, therefore restricting the catalyst’s ability to distinguish between the two substrates. 33

Discovery, Development and Study of Carbenoid Mediated Reactions

Figure 2.5 Catalysts for A-ROMP bearing oxyanions136 (left). Representation of catalyst 12a showing nitrate chelation.

The planar geometry of the carboxylate anions places their steric demand away from the ruthenium center as shown by X–ray structures. Consequently, increasing the steric bulk of the carboxylate anion (catalysts 12a to 12f) led to no appreciable effect in the stereoselectivity of the catalysts, showing that the family of oxyanions is not a viable option to obtain active, yet more selective, catalysts.

It was clear after these attempts that a different approach would be needed in order to achieve a breakthrough in catalyst stereoselectivity. The use of thiosulfonates proved that more strongly bound anions do indeed increase the stereoselectivity of the system, bringing the steric barrier closer to the ruthenium center. However, their increased electron donating capability reduced the activity of the resulting catalysts. Thiolates on the other hand, appear to be far too close, inhibiting olefin coordination without prior ligand dissociation. There is however still another way to influence the bond strength of a ligand, and that is by modifying the donating properties of the ligand trans to it. The - donating capability of this ligand mainly affects the energy of the ground state, i.e. trans influence. On the other hand, the kinetic trans effect results from the –accepting character of the opposing ligand.137 If the catalyst framework could be modified in a way to include a weaker donor and more –basic anchoring group, it could be expected that the resulting catalysts would be both more active, according to the electronic effects of the ligands, and bind the sulfonate ligands more strongly, leading to more stereoselective A-ROMP.

2. Ruthenium catalyzed A–ROMP 2.2. Phosphinosulfonate system

Originally conceived of as supporting ligands for the palladium–catalyzed copolymerization of ethylene and polar compounds138 triarylphosphines with one ortho– sulfonate group139 were thought to form the active catalysts in situ by chelation when mixed with appropriate palladium sources. Later, the group of Stefan Mecking reported the first crystal structure of such a complex showing that the ligand indeed forms a palladacycle by binding with both the phosphorus and an oxygen atom to the metal center.140 The intense research on the palladium-catalyzed insertion polymerization of olefins has led to the development of several new polymers.141 Our desire to explore less electron donating groups as anchoring groups for our ruthenium catalysts framework prompted us to investigate the application of phosphine sulfonate ligands in the A- ROMP of olefins.

2.2.1. Synthesis of a ruthenium metathesis catalyst bearing an asymmetric phosphino sulfonate ligand

Scheme 2.6 Synthesis of an asymmetric phosphino sulfonate ligand, its sodium salt and the corresponding ruthenium Hoveyda-type benzylidene complex. The asymmetric phosphino sulfonate ligand 13a was easily synthesized by reaction of the appropriate chlorophosphine with ortholithiated benzenesulfonic acid in a slight modification of the procedure reported by Hearley et al.142 (scheme 2.6). The sodium salt 14 was prepared by direct deprotonation with sodium hydroxide.

Treatment of complex 1536 with sodium salt 14 in dichloromethane at 80 °C produces a dark green solution of intermediate 16 (scheme 2.6). The structure shown for this intermediate is proposed based on the characteristics found in the NMR spectra shown in figure 2.6 and the crystal structure of an analogous complex synthesized at a later

Discovery, Development and Study of Carbenoid Mediated Reactions stage, see section 2.2.8. The benzylidene proton ( 18.71 ppm) shows two distinct couplings with phosphorus nuclei exhibiting JH,P values of 8.48 and 15.75 Hz. Both the chemical shift and the multiplicity of the signal for the secondary proton in the isopropoxy unit of the benzylidene unit suggest rupture of the chelate in the Hoveyda- type carbene ( 4.79, heptuplet, JH,H = 6.06 Hz). For comparison, the chemical shift of the free isopropoxy unit is  4.68 ppm,36 and is  5.28 ppm in precursor 15, where it also shows a higher multiplicity due to its coupling with the phosphorus nucleus. In the 31P spectrum, two different phosphines with a small (JP,P = 27 Hz) coupling are observed, such small coupling is very indicative of a relative cis arrangement. For example, trans bisphosphine

134 complex 5 shows a much higher coupling constant (JP,P = 196 Hz).

Figure 2.6 NMR spectra of intermediate 16. Proton (left) and phosphorus (right).

Unfortunately, intermediate 16 cannot be isolated. Crystallization attempts showed that 16 releases triphenylphosphine slowly to form complex 17 toghether with decomposition products. Treatment of 16 with an excess CuCl, as phosphine scavenger, produces the brown complex 17 cleanly. After purification by column chromatography under strict exclusion of air and moisture, pure 17 can be obtained. X-ray quality single crystals allowed the determination of the molecular structure of 17 (figure 2.7).

2.2.2. Structural characterization of complex 17

Comparison of the molecular structure of complex 17 with the phosphino–phenolate complex 6a reveals a series of distinct structural features resulting from the use of a sulfonate as anchoring group. Most evident is the occupation of the coordination site

2. Ruthenium catalyzed A–ROMP trans to the benzylidene carbon by one of the oxygen atoms of the sulfonate group, having a Ru1–O7 distance of only 2.3957(14) Å. It is generally accepted that this coordination site remains vacant on most active ruthenium metathesis catalysts, nonetheless, weak agostic interactions on this site have led to the observation of unexpected structures.134 Two main geometric differences arise from the bridging over two atoms of the sulfonate group in comparison to the single–atom bridge in the phenolate case: 1) the non–chelating phosphine substituents (i.e. tert-butyl and phenyl) are forced closer to the chloride anion as evidenced by the significant increase in the C9– P2–Ru1 angle from 100.46(11) ° in 6a to 111.19(6) ° in 17. Concomitantly, the angles C14–P2– Ru1 (6a 118.55(13) ° vs 17 117.55(6) °) and C18–P2–Ru1 (6a 114.36(12) ° vs 17 112.53(7) °) are reduced. As a consequence of the increased steric demand the chloride atom is forced away from the phosphine and closer to the iso-propoxy unit of the Hoveyda-type benzylidene. The angle P2–Ru1–Cl4 in 6a is widened from 98.31(3) ° to 102.394(18) ° in complex 17. 2) The phosphine is twisted around the Ru–P bond placing its non–chelating substituents in an eclipsed rather than staggered configuration with respect to the other ruthenium ligands. The torsion angle C24–Ru1–P2–C9 is increased from 92.60(16) ° in 6a to 127.81(9) ° in 17.

Another particular characteristic in the structure of complex 17 is the exceptionally long Ru–OiPr(benzylidene) bond (Ru1–O31 2.3261(14) Å). For comparison, distances ranging between 2.238 and 2.281 Å have been reported for several catalysts bearing an isopropoxy unit.143 Comparable distances have been only been observed when the alkoxy unit is modified with the more sterically demanding cyclohexyl group. For example, catalyst 6a has a Ru–O bond distance of 2.310(2) Å. A long ruthenium–oxygen bond is normally associated with a faster catalyst initiation.

The chemical shift of the carbenic proton on the benzylidene moiety is highly influenced by the electronic environment arround the ruthenium center. The chemical shift of the benzylidene proton in complex 17 is shifted downfield with respect to its phenolate analog 6a ( 17.06 vs  15.14 ppm) as a result of the reduced electronic donation from the anchoring sulfonate to the metal. As expected, the Cl–Ru bond is shortened, to some extent, from 2.3397(10) in 6a to 2.3387(5) Å in complex 17.

Discovery, Development and Study of Carbenoid Mediated Reactions Figure 2.7 Crystal structure of complex 17. ORTEP Plot, ellipsoids at 50% probability. Hydrogen atoms have been omitted for clarity. Selected bond distances (Å) and angles (°): Ru1–O5 2.1060(14), Ru1–O7 2.3957(14), Ru1–O31 2.3261(14), Ru1–P2 2.2593(2), Ru1–Cl4 2.3387(5), Ru1–C24 1.846(2), C24–Ru1–P2 92.75(6), C9–P2–Ru1 111.19(6), C14–P2–Ru1 117.55(6), C18–P2–Ru1 112.53(7), P2–Ru1–Cl4 102.394(18), C24–Ru1– P2–C9 127.81(9)

2.2.3. Alternating ROMP catalyzed by complex 17

Complex 17 was tested on the copolymerization of norbornene (NBE) and cis-cyclooctene (COE) in dichloromethane at various temperatures and olefin ratios. For comparison purposes complex 6a was also used (Table 2.1).

Table 2.1 Copolymerization of NBE and COE using complexes 17 and 6a.a

Entry Comp. mol ratio T t Yield Alternating Poly Poly Z COE/NBE (°C) (min) (%)b linkages NBE COE olefin (%)c (%)c (%)c (%)d 1 17 50 25 15 113.4 79.9 2.9 17.2 45.7 2 17 20 25 15 100.8 79.9 7.6 12.4 43.7 3 17 20 0 15 94.0 88.6 6.4 5.0 45.2 4 17 20 -13 15 51.1 90.5 8.2 1.4 45.2 5 17 20 -23 60 49.7 88.4 9.8 1.8 44.6 6 6a 50 25 30 45.2 46.7 52.5 0.7 30.7 7 6a 20 25 15 49.9 34.0 66.0 0.0 29.9 8 6a 20 0 30 43.1 20.8 78.5 0.8 25.6 a Performed normally with ca. 150 mg of NBE and the corresponding amount of COE in a total volume of 20 mL completed with dichloromethane. Catalyst to NBE ratio in all experiments was 1:1000. b The yields calculated as: Yield=((mass of polymer/(molar mass NBE + molar mass of COE)/(n mol of NBE))*100. Yields over 100% are consequence COE polymerization after NBE depletion. c Determined by 13C NMR integration, see figure 2.8. d Measured by integration on the 1H NMR spectra. Comparing the yields obtained at the same conditions, it is evident that complex 17 catalyzes the copolymerization of NBE and COE more efficiently than complex 6a. At a NBE/COE molar ratio of 1:50, complex 17 produces 113.5% polymer after just 15 minutes

2. Ruthenium catalyzed A–ROMP whereas 6a only reaches 45.2% after 30 minutes (table 2.1 entries 1 and 6). At this olefin ratio the chemoselectivity of 17 is almost twice that of 6a, reaching 79.9 % compared to 46.7 %. It must be noted that complex 17 is active enough to homopolymerize excess COE after alternating copolymerization has depleted the NBE monomer, giving rise to higher than 100% yields and an apparent reduced chemoselectivity. On the other hand, complex 6a affords a polymer showing alternating pairs and poly-NBE, as a result of a lower activity and a more modest selectivity. Complex 6a has been shown to reach its best chemoselectivity (76 %) at 0 °C when reacted with a 1:200 mixture of NBE and COE.134

Upon reduction of the olefin ratio to 1:20 complex 17 retains its overall chemoselectivity as a result of an increase of poly-NBE content together with a reduction of the amount of poly-COE (entry 2). Complex 6a shows a significantly reduced chemoselectivity of 34% (entry 7) when used in the same conditions. Lowering the reaction temperature to 0 °C has the beneficial effect of reducing the amount of homopolymers formed when using 17, affording the best overall result, achieving 94.0% yield with 88.6% alternating linkages where only 6.4 and 5.0 % of homo–NBE and homo–COE were present respectively (entry 3). A polymer with a high content of poly-NBE was produced by 6a under these conditions (entry 8). Further reduction in the temperature did not improve the results and led to reduced yields even at prolonged reaction times (entries 4 and 5). Figure 2.8 represents graphically the effects discussed above.

A surprising characteristic of the polymers obtained when catalyst 17 was used is theier high content of Z-olefin. In comparison, complex 6a produced only 30.7 % Z-olefin in the best case (entry 6) compared to 45.7 % for 17 (entry 1). The observed stereoselectivity is not only higher than that shown by 6a but also higher than that of complex 6c, a catalyst exhibiting essentially the same chemoselectivity on this copolymerization (89 %).57b Only complex 6i, the most stereoselective A-ROMP catalyst reported, produces a polymer with a higher Z-olefin content of 51%.57a

Both the observed increase in chemo– and stereoselectivity in complex 17 can be related to the geometric parameters observed in its molecular structure. The expanded bridging between the aryl substituent on the phosphine and the ruthenium center provided by the sulfonate group forces the other two substituents closer to the metal center, most likely increasing the energetic difference between the two diasteromeric carbene states. The repositioning of the substituents also forces the chloride anion away from the axial phosphine, increasing the steric demand just above the region where the decisive

Discovery, Development and Study of Carbenoid Mediated Reactions metallacyclobutane structure is formed. In accordance to the model proposed by Torker and Chen for the control of the stereoselectivity,57a an increase in the content of Z-olefin in the polymer is expected from the anion placement.

Figure 2.8 13C NMR spectra of the copolymers obtained using complexes 17 (left) and 6a (right).

2.2.4. Calculation of the catalyst commitment

In terms of activity, both complexes 17 and 6a are expected to activate with a relatively similar rates due to their comparable Ru–O(CH(CR)2Ar) bond distances. Nonetheless, complex 17 shows an overall higher activity, producing higher yields and even homopolymerizing cyclooctene, a monomer that is essentially unreactive when 6a is used. This difference must then arise from an intrinsically more reactive propagating species. As mentioned before, Grubbs125 and later Chen130 explained the difference in intrinsic reactivity between first and second generation catalysts in terms of catalyst commitment.144 On a potential energy surface low barriers for metallacyclobutane formation and high barriers for precatalyst formation, i.e. phosphine coordination, are characteristic of highly committed catalysts. In view of the marked difference in activity displayed by the two catalysts compared, a theoretical evaluation of their commitment was performed. For this purpose, density functional theory (DFT) was used to calculate the relative Gibbs–corrected energy (table 2.2) of the first 5 critical points of the reaction profile describing the energy change for going from precatalyst (A) to 14e- methylidene (B), olefin –complex (C) followed by the transition state (D) leading to the

2. Ruthenium catalyzed A–ROMP metallacyclobutane intermediate (E) (figure 2.9). The reaction profiles correspond to the metathesis of ethylene with a methylidene analog of complex 17 and 6a. Due to the asymmetric nature of the phosphine in these complexes, there are two possible starting geometries for the calculations, one where the carbene moiety is positioned under the phenyl substituent, and a second where it is located under the tert-butyl group. Both starting structures should lead to different energetic profiles. For the calculation of the commitment, the path starting with the lower energy structure, methylidene under the phenyl group, was chosen, since the resulting profile should be endothermic in character and therefore performance–limiting. In both the molecular structure of complex 17 and 6a the benzylidene moiety is found under the phenyl group, confirming the thermodynamic preference for this state. For comparison purposes, the energetic profile was also calculated for the first and second generation Grubbs catalysts (figure 2.9).

Figure 2.9 Calculated Gibbs–corrected energy surface for the first steps in the metathesis of ethylene with several ruthenium catalysts. Calculated at the level M06L/6-31G**(non metals)+SDD(ruthenium). Structures show the key intermediates, mass balances are not shown but have been taken into account. All curves are referenced to structure C.

Discovery, Development and Study of Carbenoid Mediated Reactions Table 2.2 Calculated Gibbs–corrected energies (at 273.15 K) for the structures figure 2.9

Entry Complex Gibbs free energy of Catalyst Ligand structures in figure 2.9 commitment dissociation (kcal/mol) B/D energy B-A A B D E (kcal/mol) 1 17 -18.0 3.0 3.1 -3.3 0.96 21.0 2 6a -15.0 4.1 10.3 0.2 0.39 19.1 1st gen. 3 -23.3 1.6 2.9 -5.9 0.54 24.9 Grubbs 2nd gen. 4 -22.3 5.0 1.2 -6.5 4.19 27.3 Grubbs Graphically presented in figure 2.9, the calculated Gibbs–corrected energy values at 298.15 K (table 2.2) for the metathesis of ethylene show clearly that the phosphino sulfonate ligand provides a more favorable ratio between the energies for metallacyclobutane formation (productive step) and ligand coordination (unproductive) than the phosphino phenolate system (catalyst commitment: 0.96 for 17 vs. 0.39 for 6a, entries 1 and 2). This result is in line with Straub’s calculations which predict a stabilization of the active carbene conformations when electron poor anionic ligands are used.131 The ligand dissociation energy calculated for complex 17 (19.1 kcal/mol) is very close to that of complex 6a (21.0 kcal/mol), and in very good agreement with the predictions based entirely on the Ru–O(CR2)(benzylidene) bond distances found in the molecular structures of these complexes. For comparison, the profiles for first and second generation Grubbs catalysts were also calculated (entries 3 and 4). The calculated catalyst commitment for these complexes (0.54 and 4.19 for first and second generation respectively) corresponds with the markedly higher intrinsic activity of the second generation systems. Moreover, the ligand dissociation energy for the first generation catalysts is calculated to be lower than for the second generation, 24.9 kcal/mol and 27.3 kcal/mol respectively, in accordance with the experimentally determined values.125 Although general agreement between this model and the experimentally determined rates is achieved, one must exercise caution to draw conclusion from the comparison of absolute energetic values. The main goal of the theoretical calculations here presented is to gain insight into the intrinsic reactivity differences between the complexes studied, and only the trends are accurate enough to be considered. If absolute values of activation parameters are desired, this level of calculation is by no means replacement for the solution phase kinetic measurements.

2. Ruthenium catalyzed A–ROMP 2.2.5. Symmetrically substituted phosphino sulfonate complex

As seen in the molecular structure of complex 17, the sulfonate anchoring group binds the ruthenium atom with two of its oxygen atoms. This chelating coordination introduces an additional strain not found on the phosphino phenolate system. As discussed previously, Adlhart and Chen found that the carbene moiety must switch sides after each productive metathesis step on ruthenium catalysts.127 In the case of the phosphino sulfonate system, after one metathesis step the carbene should end up in the coordination position initially occupied by the one of the sulfonate’s oxygen atoms (Scheme 2.7, transition from 18 to 19). If the rupture of the chelation introduces an additional energetic barrier the anchoring group itself would influence the catalyst’s chemoselectivity. On the other hand, if an isomerization pathway exists to regenerate the chelation on the side opposing the final carbene location no influence on the selectivity would be expected (scheme 2.7 structure 20).

Scheme 2.7 Inversion of sulfonate chelation and its effect on the energy of the two possible diasteromeric states of the carbene in phosphino sulfonate systems (left). Symmetrically substituted phosphino sulfonate complex 21 (right).

In order to test whether the sulfonate group influences the energy of the two possible diasteromeric states of the carbene the symmetrically substituted complex 21 was synthesized i and tested for the copolymerization of NBE and COE. Under the same conditions used for complex 17 (NBE/COE ratio 1:20, room temperature) a 54.4% yield of polymer is obtained. This polymer is composed mainly of polynorbornene, some polycyclooctene and a small fraction of alternating copolymer, see figure 2.10.

Although no formation of copolymer is reported for a symmetrical variant of complex 5133 this complex is also not a good catalyst for the homopolymerization of cyclooctene, contrary to what was found for the phosphino sulfonate complex 17. In light of this difference, the small amount of alternating copolymer produced by 21 is likely the result

i For details see experimental part, a molecular structure is available in the appendices. 43

Discovery, Development and Study of Carbenoid Mediated Reactions of a statistically possible insertion of cyclooctene in an otherwise typical polynorbornene chain. The composition of the polymer obtained using catalyst 21 strongly suggests that the chelate ring inverts during the metathesis reaction producing energetically equivalent carbene states, therefore not affecting the chemoselectivity induced by the catalyst.

Figure 2.10 13C NMR of the polymer obtained using complex 21.

2.2.6. Chloride replacement with bulky sulfonate anions

Following the methodology used by Torker and Chen57a a series of complexes was prepared in which the chloride anion of the base complex 17 was replaced by arylsulfonates of increasing steric demand.

Figure 2.11 Phosphino sulfonate complexes bearing arylsulfonate anions.

Single crystals of suitable quality for molecular structure determination by X-ray diffraction were obtained for complexes 22a, 22b and 22c, these structures are shown in figures 2.12 to 2.14. In table 2.3 selected geometric parameters for those structures are compared with the available structures of phosphino phenolate complexes 6f and 6i.57a

2. Ruthenium catalyzed A–ROMP As seen in the case of complex 17, the reduced electron donation provided by the sulfonate anchoring group causes a bond shortening of the anion trans to it. In the case of complexes 22a to 22c the arylsulfonates exhibit shorter Ru1–O6 bond lengths, the longest being 2.058(7) Å in 22a, compared to their phenolate analogs where the shortest measured Ru1–O6 distance is 2.070(5) Å. Although subtle in appearance, minor geometric differences have been already shown to yield catalysts capable of producing polymers with very different characteristics (vide supra). Contrary to what is observed in the phosphino phenolate complexes, addition of ortho substituents on the aryl sulfonate causes a shortening of the Ru1–O6 bond from 2.058(7) Å in 22a to 2.041(4) in 22b or 2.040(9) in 22c. In addition, a significant increase in the bond length Ru1–O6 is observed. Ligands 7b and 7c induce a larger trans influence than the simple tosylate, as a result of the increased electron density provided by the ortho alkyl groups. The lengthening of the Ru1–O6 could be therefore explained on the basis of the electronic character of the aryl sulfonates used. Complex 6i also exhibits an increase in this bond length compared to 6f, although the corresponding anion is not closer to the metal center. It appears as if the Ru1–O6 bond length differences in the phosphino phenolate systems arise mainly because of the steric requirement of the aryl sulfonates rather than their electronic character.

Table 2.3 Selected bond lengths (Å) and angles (°) from the molecular structures of complexes 22a, 22b, 22c, 6f and 6i.

Entry 1 2 3 4 5

Complex 22a 22b 22c 6f 6i

Ru1–O6 2.107(6) 2.122(4) 2.127(8) 1.975(5) 1.986(2)

Ru1–O13 2.058(7) 2.041(4) 2.040(9) 2.070(5) 2.076(2)

Ru1–O5 2.441(7) 2.387(4) 2.478 - -

Ru1–O7 2.285(7) 2.294(4) 2.294(8) 2.242(6) 2.250(2)

Ru1–P9–C10 112.6(3) 111.36(19) 111.1(4) 99.6(3) 100.32(11)

Ru1–O13–S4 131.0(4) 132.7(2) 128.2(5) 136.0(4) 128.91(13)

C8–Ru1–P9–C10 122.0(4) 124.7(2) 109.2(5) 89.3(4) 94.4

Discovery, Development and Study of Carbenoid Mediated Reactions Figure 2.12 Crystal structure of complex 22a. ORTEP plot, ellipsoids at 30% probability. Hydrogen atoms have been omitted for clarity. For selected bond lengths and angles see table 2.3, entry 1.

Figure 2.13 Crystal structure of complex 22b. ORTEP plot, ellipsoids at 30% probability. Hydrogen atoms have been omitted for clarity. For selected bond lengths and angles see table 2.3, entry 2.

2. Ruthenium catalyzed A–ROMP Figure 2.14 Crystal structure of complex 22c. ORTEP plot, ellipsoids at 30% probability. Hydrogen atoms have been omitted for clarity. For selected bond lengths and angles see table 2.3, entry 3.

Both the series of complexes 22a to 22c, and 6f and 6i have shorter Ru1–07 distances compared to the corresponding distances in the chloride parent complexes 17 and 6a. It could be predicted that the presence of aryl sulfonates as ligands in this type of complexes may cause a reduction in the initiation rate of the catalysts. One of the main differences between the phosphino sulfonate and phenolate systems is the ability of the former to force the phosphine’s non–chelating substituents (i.e. tert-butyl and phenyl) closer to the metal center. The indicative Ru1–P9–C10 angle is first increased in complex 22a (112.6(2) ° vs 11.19(6) ° in 17) but then it decreases along the series in 22b and 22c. As a result of this structural changes an effect on the chemoselectivity of the complexes is expected.

Table 2.4 Chemical shifts for the benzylidene proton on phosphino sulfonate and phenolate57a complexes.

Entry Complex benzylidene proton chemical shift 1H NMR ( in ppm) CD2Cl2 C6D6 1 17 17.14 17.13 2 22a 17.63 17.86 3 22b 17.70 17.84 4 22c 17.70 17.82 5 22d 17.65 17.75

Discovery, Development and Study of Carbenoid Mediated Reactions

6 6a 15.65 N.A. 7 6f 16.29 N.A. 8 6i 16.34 N.A.

The chemical shifts for the benzylidene proton in CD2Cl2 and C6D6 on complexes 22a to 22d (table 2.4 entries 2 to 5) are shifted downfield with respect to complex 17 (entry 1) as expected from a more electron poor metal center. However, in CD2Cl2, as observed in the phosphino phenolate case, the presence of ortho alkyl groups causes a further downfield shift opposing what would be expected from the increased electron density in ligands 7b to 7d and particularly contrasting to the bond lengths observed in the solid state. In

C6D6, a less polar solvent, the increase in electron donating capability of the ligands is reflected in a progressive upfield shift. It has been observed that the use of a less polar solvent benefits the stereoselectivity of the catalyst most likely by disfavoring ligand dissociation.145 The marked difference in trend for the benzylidene chemical shift in

CD2Cl2 and C6D6 strongly supports this hypothesis, i.e. it suggests different states of association in the two solvents.

2.2.7. Polymerization experiments with sulfonate complexes

Complexes 22a to 22d were tested for the copolymerization of norbornene and cyclooctene in dichloromethane solution at an olefin ratio of 1:20. 1H and 13C NMR spectra of the obtained copolymers are shown in figure 2.15. Upon replacement of the chloride (complex 17) for tosylate (complex 22a) the content of Z-olefins increases from 43.7 to 47.2 % (table 2.5, entries 1 and 2). Further increase in the steric demand of the sulfonate anions produces an additional increase in Z-olefin content of the polymer, reaching 49.3, 58.8 and 57.1 % for complexes 22b, 22c and 22d respectively (entries 3 to 5). Although the stereoselectivity observed for complex 22c is the highest ever achieved in the alternating ROMP of norbornene and cyclooctene, analysis of the carbon NMR spectra of the polymers and the obtained yields reveal that it was accomplished at the expense of the catalyst’s chemoselectivity and activity.

2. Ruthenium catalyzed A–ROMP

Figure 2.15 1H and 13C NMR of the copolymers obtained using the all the prepared phosphino sulfonate complexes.

The most stereoselective complex 22c also shows a modest activity, producing only 38.8% copolymer over a period of 60 minutes. At the same time, chemoselectivity drops significantly to only a 44.5% of alternating dyads. It is then not surprising that the bulky arylsulfonates reduce the overall activity of the complexes, but it is not straightforward to explain why these catalysts become less chemoselective. When strongly bound thiosulfonates were used in the classical phenolate framework (vide supra) a drop in activity was observed and explained in terms of an electronic deactivation and steric shielding imposed by the ligands on the catalysts. However, no detrimental effect on the chemoselectivity was observed. In the case explored here, the catalyst’s steric shielding could account for the lower activity of the complexes bearing larger ligands, but not the drop in chemoselectivity. From the molecular structures of complexes 22a, 22b and 22c it was noted that the larger ligands force the phosphine non–chelating substituents away from the metal center (decreasing Ru1–P9–C10 angle, see table 2.3). Reducing this angle also reduces the influence of these phosphine substituents on the two diasteromeric carbene states, which ultimately determine the catalyst’s ability to energetically distinguish between the two monomers. The use of a sulfonate as an anchoring group also gives the backbone an increased flexibility not present, in the phenolate case, allowing the anionic ligand to influence not only the stereoselectivity in a direct way but also the chemoselectivity indirectly.

Discovery, Development and Study of Carbenoid Mediated Reactions Table 2.5 Copolymerization of NBE and COE using complexes 17, 22a, 22b, 22c and 22d.a

Entry Complex T t Yield Alternating Poly Poly Z (°C) (min) (%)b linkages NBE COE olefin (%)c (%)c (%)c (%)d 1 17 25 15 100.8 79.9 7.6 12.4 43.7 2 22a 25 30 76.9 80.5 18.3 1.2 47.2 3 22b 25 60 74.0 78.3 19.5 2.2 49.3 4 22c 25 60 38.8 44.5 55.5 0.0 58.8 5 22d 25 60 21.5 40.3 59.7 0.0 57.1 a Performed normally with ca. 150 mg of NBE and the corresponding amount of COE in a total volume of 20 mL completed with dichloromethane. Catalyst to NBE ratio in all experiments was 1:1000. b The yields calculated as: Yield=((mass of polymer/(molar mass NBE + molar mass of COE)/(n mol of NBE))*100. Yields over 100% are consequence COE polymerization after NBE depletion. c Determined by 13C NMR integration. d Measured by integration on the 1H NMR spectra. 2.2.8. Attempts to enhance the chemoselectivity of the phosphino sulfonate systems.

The marked drop in activity of the complexes bearing the most sterically demanding sulfonates suggest that the phosphino sulfonate framework is at the limit where a further increase in the steric demand would just lead to inactive complexes. Nonetheless, if, as in the case of the phosphino phenolate system, the phosphine substituents could be optimized to achieve perfect alternation, possibly a better compromise between activity, chemoselectivity and stereoselectivity would be achieved.

With this goal in mind, the synthesis of two complexes analogous to 17 was attempted (figure 2.16). The asymmetrically substituted phosphines (13c and 13d, see experimental part) necessary for the preparation of complexes 23 and 25 are easily obtained following a procedure analogous to the one for the synthesis of phosphine 13a. Reaction of 13c with 15, followed by phosphine removal with CuCl affords complex 23. The molecular structure of complex 23 could be determined by X-ray diffraction of a single crystal, see section 6.2. The structures of complexes 23 and 17 resemble one another with only minor, but still significant differences. As a result of the presence of the adamantyl substituent the phosphorus–ruthenium bond gets elongated from 2.2593(2) Å in 17 to 2.2711(10) in 23. As a consequence, the angle Ru1–P2–C13 in 23 is reduced to 109.57(13) ° from 111.19(6) ° in 17. As could be expected from the increased distance between the phosphine substituents and the metal center, the chloride anion can be placed further away from the chelating isopropoxy unit. The angle Cl4–Ru1–P2 is widened from 102.394(18) ° in 17 to 109.57(13) ° in 23. Perhaps more interesting is the reduction in the torsion angle C36– Ru1–P2–C13 which only reaches 109.57(13) ° in 23 compared to 127.81(9) ° in 17. The

2. Ruthenium catalyzed A–ROMP increased steric demand of the adamantyl moiety together with the flexibility of the sulfonate anchor allows the ligand to flex in a way such that to reduce the steric interaction it places the phosphine away from the metallic center.

Figure 2.16 Complexes with phosphines bearing adamantyl (23) and neopentyl (24+25) substituents.

In contrast with complex 23, complex 25 could not be isolated in a pure from. After reaction of the phosphine precursor 13d with 15 only a mixture of the intermediate 24 and the desired complex 25 could be obtained. Addition of excess of CuCl was not effective in removing PPh3. During purification attempts it was noted that in solution the predominant form was that of 25 plus free PPh3, however, upon evaporation of the solvent 24 was formed. The solid state structure of 24 can be seen in figure 2.17. As expected from the weak donor character of the sulfonate group, the ligand trans to the sulfonate, in this case tryphenylphosphine, is strongly bound. The ruthenium– phosphorus(PPh3) bond is actually shorter than that of the bidentate phosphine (2.2916(8) vs 2.3818(8) Å respectively), although the longer distance could also be attributable to the more donating chloride trans to the bidentate phosphine. The presence of tryphenylphosphine makes difficult the comparison of the geometric parameters of the intermediate with complexes 17 and 23. Nonetheless, the expected configuration of the chelating phosphine around the ruthenium atom is similar to that of the analogous complexes. Although the neopentyl substituent is considered sterically more demanding than t-butyl or adamantyl, the lack of two substitutions at the  carbon provides room for the PPh3 to remain bound. Such effects were not observed in the original phosphino phenolate complexes.

Discovery, Development and Study of Carbenoid Mediated Reactions

Figure 2.17 Molecular structure of intermediate 24. Ortep plot, ellipsoids at 30% probability. Hydrogens are omitted for clarity. Selected bond distances (Å) and angles (°). Ru1–O2 2.377(2), Ru1–O3 2.242(2), Ru1–P3 2.2916(8), Ru1–Cl1 2.3831(8), Ru1–C101 1.873(3), Ru1–P2 2.3818(8), Ru1–P2–C50 110.58 (11), C101–Ru1–P2–C50 113.87(13).

Complex 23 as well as the mixture of 24 and 25 were tested in the copolymerization of NBE and COE under the standard conditions. Complex 23 is even more active than 17, producing 116.5% of copolymer (table 2.6, entry 2). The composition of the polymer reveals that homopolymerization of COE is the cause for the increased yield. There is a reduction on the poly-NBE content of the polymer, which indicates an increase in the specific chemoselectivity of the complex, later spoiled partially by the poly-COE component. The stereoselectivity is somewhat reduced, down to 42.6% from 43.7 % in 17, as could be expected from the reduced steric demand on top of the chloride, that has more room to position itself away from the metallacyclobutane formed during polymerization. The mixture of 24 and 25 shows a reduced activity, 80.6% polymer produced (entry 3), under the same conditions. The observed chemoselectivity is mostly on par with that of 17 with an increase of poly-NBE. Most interesting is the reduction in stereoselectivity, 31.2 % Z vs 43.7% for 17. Most likely, the same effect that allows the PPh3 to stay in place allows the chloride to be pushed away from the reaction center, reducing its influence on the relative orientation of the substituents at the metallacyclobutane intermediate. A reduction of reaction temperature diminished to some extent the formation of poly-COE at the expense of some reactivity (entry 4).

2. Ruthenium catalyzed A–ROMP Table 2.6 Copolymerization of NBE and COE using complexes 23 and a mixture of 24 and 25.a The result obtained with complex 17 is shown for comparison.

Entry Complex T t Yield Alternating Poly Poly Z (°C) (min) (%)b linkages NBE COE olefin (%)c (%)c (%)c (%)d 1 17 25 15 100.8 79.9 7.6 12.4 43.7 2 23 25 15 116.5 75.4 4.6 20.0 42.6 3 24+25 25 15 90.2 80.6 13.0 6.4 31.2 4 24+25 0 15 81.9 82.1 16.0 2.0 32.2 a Performed normally with ca. 150 mg of NBE and the corresponding amount of COE in a total volume of 20 mL completed with dichloromethane. Catalyst to NBE ratio in all experiments was 1:1000. b The yields calculated as: Yield=((mass of polymer/(molar mass NBE + molar mass of COE)/(n mol of NBE))*100. Yields over 100% are consequence COE polymerization after NBE depletion. c Determined by 13C NMR integration, see figure. d Measured by integration on the 1H NMR spectra. It is possible that the most selective substituent in the case of the phosphino phenolate system (1,1,2,2-tetramethylpropyl = TMP) would have also contributed to a better chemoselectivity in the new framework. However, the subsequent substitution of the halide by bulky sulfonates would have most likely led to rather inactive complexes due to overcrowding of the catalyst. In this regard, the sulfonate as anchoring group accomplished its task, allowing the bulky arylsulfonate to be strongly bound to the ruthenium center. Nonetheless, this structurally beneficial effect caused a negative effect on the general activity of the prepared complexes. Contemporary approaches for the control of stereoselectivity in olefin metathesis promise an alternative that could be exploited to make fully chemoselective, fully stereoselective catalysts. Those approaches will be discussed in the following section.

2.3. Discussion

The first reports of alternating ROMP date back to 2002. The first strategies did not involve any modification of the catalyst itself. Coughlin obtained a high degree of alternation in special cases when the balance between the steric demand and ring strain of the two monomers was correctly adjusted.146 Grubbs prepared alternating polymers by insertion of a diacrylate into an already formed homopolymer chain.147 Following similar monomer based interactions, the group of Sanda produced alternating copolymers of an amino acid-derived norbornene unit in a system where acid-base interactions led to a preferential sequence of monomer consumption.148 More recently, Sampson reported a new case where two monomers were found to copolymerize in a sequential manner, despite the fact that neither of them would generate a

Discovery, Development and Study of Carbenoid Mediated Reactions homopolymer.149 Apart from our own system, catalyst controlled alternating ROMP has only been reported, by Blechert and Buchmeiser using unsymmetrical, chiral or achiral monodentate NHC carbenes in ruthenium catalysts.150 In this case, the high degree of alternation was explained by an enhanced cyclooctene insertion rate on a norbornene derived terminus and vice versa. The reason behind this selectivity was proposed to be purely steric. After a norbornene insertion the catalyst would become too sterically crowded to allow an additional norbornene molecule to insert, favoring the cyclooctene insertion, after which the more reactive norbornene would outcompete the low strain olefin producing an alternating copolymer. This type of sequence control, where the last inserted monomer determines the next, is called chain-end control. A key requirement for this proposed mechanism is the free rotation of the NHC ligand around the Ru–C bond. Rotation makes distinction between the two carbene states on each ‘side’ of the catalyst impossible and therefore rules out a diasteromeric site control mechanism (vide infra). However, if rotation of the NHC ligand were to be prevented by the steric bulk of the growing polymer chain during catalytic conditions, differentiation between the two sides of the catalyst would become possible and the mechanism of alternation would probably resemble the one operative in the phosphino–phenolate and sulfonate catalysts. In fact, thermally switchable latent ruthenium catalysts exhibiting a cis– dichloro arrangement effectively prevent the rotation of the NHC (IMes-H2) ligand at room temperature; rapid rotation around the Ru–C(carbene) bond is only observed at elevated temperatures.151

Scheme 2.8 Explanation proposed by Blechert and Buchmeiser for their alternating copolymerization of NBE and COE.150

Contrary to Blechert and Buchmeiser’s our catalyst framework allows the distinction between the two possible diasteromeric carbene states formed after each productive step. The sequence control in which the catalyst determines the next monomer to be

2. Ruthenium catalyzed A–ROMP inserted is known as diasteromeric site control. Our proposed mechanism bears close resemblance to that of the stereospecific polymerization of propylene catalyzed by chiral metallocenes.152 In ethylene-bridged ansa zirconocenes the relative orientation of the growing polymer chain and the incoming monomer is a result of the steric influence of the ligand.

The replacement of the phenolate by a sulfonate group as anchoring group in the described catalytic systems seems to not have modified the controlling mechanism of the copolymerization. Even though the sulfonate group clearly shows a chelating interaction with the metal center, as seen in the molecular structures of complexes 17, 22a, 22b and 22c, the same does not negatively affect the differentiating ability of the catalysts. Symmetrically substituted complex 21 shows no preference for the alternating copolymerization, strongly supporting the diasteromeric site control as the operating mechanism in this new catalyst framework.

Figure 2.16 Traditional (left) vs contemporary (right) approach to stereoselectivity on ruthenium catalyzed olefin metathesis.

The pursuit of stereoselectivity on metathesis catalysts has also received attention in the past. As discussed in the introduction, the more common approaches involve the utilization of bulky anionic ligands for ruthenium as well as molybdenum and tungsten complexes. These complexes place the bulky anions cis to the strongest donor ligand, i.e. the phosphine, NHC or imido ligand, in order to maximize the steric influence on the metallacyclobutane intermediate. The complexes described in this chapter follow the same guidelines in order to influence the Z-olefin content on the produced copolymer. More recently, a series of complexes where the chloride anions have been replaced by dithiocatecholates have shown extremely high selectivity towards the Z-arranged olefin.60 In those complexes the donating capabilities of the thiolate anions combined with their forced cis arrangement favors the metallacyclobutane formation cis to the NHC ligand, contrary to traditional systems.

Discovery, Development and Study of Carbenoid Mediated Reactions 2.4. Conclusions

The reduced electron-donating capability of a sulfonate group as compared to a phenolate group prompted us to use it as an anchoring group in our alternating ROMP catalyst framework. It was predicted that the reduced trans influence of a sulfonate chelating group would reduce the extent of ligand dissociation which limites the achievable Z-selectivity of catalysts bearing bulky sulfonates. The base complex 17 shows an enhanced chemo– and stereoselectivity, both of which could be explained in terms of the geometric characteristics imposed by the sulfonate as anchoring group. In this regard comparison of its molecular structure with that of previously reported phosphino phenolate complexes was crucial to determine which parameters are directly responsible for the resulting polymer properties.

Complex 17 was also found to be significantly more active than its phenolate analog 6a. The difference in intrinsic activity was explained in terms of a more favorable ratio between the energies for product and pre-catalyst formation, as revealed by DFT calculations. In this sense, phosphino sulfonate catalysts exhibit a higher commitment than the original phenolate catalysts, just as second generation Grubbs systems are better propagating than the first generation.

Replacement of the chloride anion with sulfonate ligands of increasing steric demand yielded complexes that showed increased stereoselectivity, reaching a maximum of 58.8% Z–olefin content. Unfortunately, the increased steric demand rendered the catalysts less active, most likely by steric overcrowding, and less chemoselective, by forcing the phosphine away from the metal center. The latter effect is also a result of the increased flexibility of the ligand backbone, which is not present in the original phenolate ligands.

The molecular structures of catalysts 22a, 22b and 22c indicate that their aryl sulfonate ligands are in fact more strongly bound than in the case of phosphino phenolate complexes, supporting our original hypothesis that weaker donor ligands in trans position promote stronger binding of the bulky sulfonates.

Even though these systems represent a new step towards fully stereoselective catalysts, it also seems that the use of more complex, more flexible backbones also brings drawbacks like the interconnection of chemoselectivity and stereoselectivity, which were perfectly orthogonal in the original catalysts. These unforeseen consequences remind us of the complexity and difficulty of designing highly active and selective catalysts. 56

3. Lithiomethyl trimethylammonium salts as methylene donors

3.1. Introduction

3.1.1. Yildes: bonding and reactivity

Ever since the pioneering work by Nobel laureate George Wittig in the 1950s, ylides have become one of the most important tools in synthetic organic chemistry.153 Ylides are in essence carbanionic nucleophiles, but at that, a particular set of them. Best described by A. W. Johnson “an ylid can be defined as a substance in which a carbanion is attached directly to a heteroatom carrying a high degree of positive charge”.154 Ylides can be represented with two extreme resonance structures (scheme 3.1). On the left, a zwitterion or ‘ylide’, and on the right one without formal charges, an ‘ylene’.

Scheme 3.1 Ylide and ylene representations of (Ph)3PCH2, a common olefination reagent.

The precise contribution to the actual structure from these two extremes depends on how strong the stabilizing interaction between the onium group (positively charged heteroatom) and the carbanion is. Cheng studied the acidity constants of various ylides in DMSO and found that the stabilizing capability of the onium fragment followed the order N < P < S.155 In this work, the stabilization mechanism was explained by the combination of two main components: 1) a simple electrostatic interaction between the positive and negative charges, which in turn depends on the C-X bond distance and the onium group polarizability, and 2) a resonance stabilization. The nature of the resonance stabilization in ylides, particularly the well-studied phosphorus ylides, has been source of intense debate. Involvement of the phosphorus 3d orbitals in a d–p bonding scheme (valence shell expansion) was proposed in early works.156 More recently, accurate calculations have shown that the phosphorus d orbitals act as polarization functions but are not directly involved in bonding.157 The currently accepted model involves a combination of negative hyperconjugation and polarization effects.158 The details of this stabilization will be discussed in comparison to the nitrogen ylides in section 3.2.2. The body of evidence nonetheless points towards more stabilized, more ylidene-like structures for the S and P ylides,159 whereas the N ylides, uncapable of resonance stabilization, exhibit a structure more in line with the ylide representation.160

Discovery, Development and Study of Carbenoid Mediated Reactions Ylides can undergo three main types of reactions: olefination, cyclization to three– membered rings and rearrangement.103, 161 The differences in reactivity are dictated by the central heteroatom and a) its influence on the nucleophilicity of the adjacent carbanion and b) the leaving group ability of the onium fragment.162 The stabilization provided by the onium fragment affects directly the nucleophilicity of the carbon atom, however, the barriers of addition to different electrophiles are generally very low and therefore are usually not rate determining. On the contrary, departure of the onium fragment constitutes the highest barrier and determines the outcome of the reaction. The order of leaving group ability has been calculated to follow the order O > S > N > P. 162 In fact, the calculated energy for phosphine displacement is so high that the alternative formation of oxaphosphetanes becomes competitive, ultimately leading to the extrusion of phosphine oxide and the formation of an olefin, i.e. the useful Wittig reaction.163 For the sulfur and nitrogen ylides similar reactivities have been so far described, albeit under different conditions. The ease by which sulfides are displaced from the product of addition of sulfur ylides together with their great stability, have certainly helped the wide spread adoption of the Corey-Chaykovsky reaction104 for the formation of three– membered rings.

3.1.2. Nitrogen ylides

Nitrogen ylides have been mostly used in relation with their participation in rearrangements, of which Stevens164 and Sommelet-Hauser165 are the most prominent examples (scheme 3.2).

Scheme 3.2 Stevens (left) and Sommelet-Hauser (right) rearrangements.

The rare use of nitrogen ylides, in comparison with their sulfur and phosphorus analogs, is in sharp contrast with the fact that N-ylides were, in fact, discovered first. The first report of proton removal from a pyridinium salt dates back to 1935. Krohnke and coworkers described the deprotonation of N-phenacylpyridinium bromide,166 marking the start of their research on pyridinium ylides and related substances.

3. Lithiomethyl trimethylammonium salts as methylene donors

Scheme 3.3 Preparation of an pyridinium ylide by Krohnke in 1935.166

After 12 years, in 1947, Wittig and Wetterling, during an attempt to prepare pentavalent nitrogen compounds, reported the deprotonation of tetramethylammonium bromide with phenyllithium in ethereal suspension.167 The product of which was rationalized as the LiBr adduct of trimethylammoniummethylide (scheme 3.4).

Scheme 3.4 Wittig and Wetterling synthesis of lithium coordinated ammonium ylide.167 ‘N-Ylide’ 27 is shown as originally proposed by Wittig.

The reactivity shown by 27 was that expected of a typical nucleophile (scheme 3.5). It produced tetramethylammonium hydroxide when reacted with water, the product of addition 32 in presence of benzophenone (30), and ethyltrimethylammonium iodide (33) in reaction with methyl iodide. However, the almost complete insolubility of both the starting ammonium salt and the ‘ylide’ product in ethereal solvents forced extremely long reaction times (deprotonation and subsequent reaction) and reduced the general applicability of this reagent.

Scheme 3.5 Reactivity of nitrogen ‘ylide’ 27 with diverse electrophiles.

Studies by Wittig and Polster confirmed the importance of lithium coordination by studying the decay behavior of 27.168 Deprotonation of 26 with phenyllithium in ether over a period of 90 hours produced 20% of triethylamine and 12% of polymethylene, the

Discovery, Development and Study of Carbenoid Mediated Reactions latter supposedly formed by polymerization of the resulting free methylene formed in the decomposition of the ylide into the amine and the carbene. In presence of more coordinating solvents like dimethylether and ethylene glycol, the polymethylene yield increased to 74%. This increase was related to the higher ability of these solvents to coordinate the lithium cation removing it from the ‘ylide’ 27 promoting its decay. Although proposed as the key intermediate in this polymerization, the formation of free methylene under this conditions is highly unlikely.

Scheme 3.6 Wittig’s proposed decay pathway of 27 in presence of coordinating solvents.168

The possibility of free carbenes being formed from the decomposition of 27 was explored in relation with their cyclopropanating ability. In 1960, Franzen and Wittig reported the cyclopropanation of cyclohexene with 27 in variable but low yields (between 5 and 18%).169

Scheme 3.7 Franzen and Wittig’s reported cyclopropanation of cyclohexene.169

Later attempts to reproduce this reaction by Krauss and Wittig were however unsuccessful.170 They could nonetheless cyclopropanate cyclohexene with the ‘ylides’ obtained by deprotonation of alkoxy–substituted ammonium salts. A mixture of endo and exo isomers resulted as expected from the asymmetry of the expected methylene.

The study of the chemistry of ‘ylide’ 27 and other non-stabilized ylides by Wittig171 and others172 continued over the years, however the results pointed to a reactivity parallel to the one of traditional carbanionic nucleophiles. No special “ylide” behavior was found in contrast to what was discovered for the sulfur and phosphorus analogs.

3. Lithiomethyl trimethylammonium salts as methylene donors

Scheme 3.8 Cyclopropanation of cyclohexene with ‘N-ylides’ derived from alkoxy- substituted ammonium salts.170

Only very recently, nitrogen ylides stabilized with electron withdrawing groups at the carbanionic atom have been considered for the synthesis of three–membered rings.173 Initial reports by Jończyk and coworkers of the stoichiometric use of cyano-stablized ylides for the synthesis of epoxides, aziridines and cyclopropanes with electrophilic olefins174 were soon followed by the discovery by the group of Gaunt that nitrogen ylides could be used in catalytic conditions for the cyclopropanation of Michael acceptors.175 These reports marked the start of a revitalized interest in the nitrogen ylides as nucleophilic substrates, providing an alternative to the well stablished sulfur ylide methodologies.

3.2. Lithiomethyl trimethylammonium reagents as methylene donors

Even though great advances haven been made on the synthetic use of nitrogen ylides, the structure and more detailed reactivity of the simplest nitrogen ‘ylide’ 27 remain unclear. Earlier attempts to study 27 have been limited to Wittig’s own work and O’Hair’s gas–phase studies.176 Our interest in simple nitrogen ylides as potential methylene donors motivated us to gain further understanding of these reagents in solution.

3.2.1. Soluble tetramethylammonium salts

The acidity constant of the tetramethylammonium ion has been estimated

177 178 experimentally and computationally to be close to 42 pKa(DMSO) units. Therefore, common organolithium compounds like phenyl and butyl lithium (the conjugated acid

179 of CH3Li, CH4 has a pKa(DMSO) ≈ 56 ) should be efficient bases for proton removal from an ammonium salt like 26. Nonetheless, extremely long deprotonation times, of up to two days, have been characteristic in previous reports. It was rationalized that these very long reaction times are consequence of the almost negligible solubility of the parent ammonium salt rather than a low intrinsic acidity.

Discovery, Development and Study of Carbenoid Mediated Reactions Replacement of the halide in tetramethylammonium iodide 43 with the weakly

F coordinating anion tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (BAr ) produced NMe4 BArF 45, which was found to be fully soluble in ether and THF (Scheme 3.9, top). Reaction of 45 in THF at -78 °C with 1 equivalent of nBuLi in a closed vessel generated the nitrogen ‘ylide’ 47 in only 5 minutes (scheme 3.9 bottom). Addition of a second equivalent of nBuLi formed the ‘diylide’ 48, however this latter species is basic enough to deprotonate the BArF anion regenerating 47.

F Scheme 3.9 Top: Synthesis of NMe4 BAr 45. Bottom: Reaction of 45 with nBuLi to generate nitrogen ‘ylide’ 47 and ‘diylide’ 48.

For the first time, the structure of the simplest nitrogen ‘ylide’ 47 could be assesed by NMR spectroscopy. 1H, 1H-6Li HMBC and 1H-15N HMCB experiments were performed to confirm the structure of 47 in solution (figure 3.1). ‘Ylide’ 47 shows two distinct signals on the 1H NMR spectrum at  2.27 and 2.95 ppm with an integral ratio of 2 to 9. The upfield shift observed for both the three methyl and one methylidene groups is expected as removing one proton increases the electron density of the molecule compared with the parent tetramethylammonium ion. Comparison of the chemical shifts of other similar products of deprotonation with those of ‘ylide’ 47 is shown in table 3.1.

Heteronuclear multiple-bond correlation experiments allowed the connectivity on 47 to be established. As seen in the 1H,6Li HMBC spectrum (figure 3.1), there is only one correlation between lithium and the deprotonated methyl group ( 2.27 ppm) in 47. On the other hand, the 1H,15N HMBC shows two correlations, one with the three methyl groups ( 2.95 ppm) left in the ammonium ion, and a second one with the methylene group correlating with lithium. These results strongly support a structure where a

3. Lithiomethyl trimethylammonium salts as methylene donors specific methyl group is deprotonated generating a carbanion stabilized by bonding with lithium, reminiscent of the structure of neopentyllithium 55.

Figure 3.1 1H, 1H,6Li HMBC and 1H,15N HMCB NMR spectra of 47.

Table 3.1 Chemical shifts for some deprotonated species and their parent compounds

entry Parent  /ppm Derivate (CH3) /ppm (CH2) /ppm

1 2.47180 1.38181 -0.7181

50 (DCCl3) 51 (N/A)

2 3.86182 3.13183 1.7183 (DMSO) (Dioxane) 52 53

3 0.902184 1.13185 -0.67185 54 (CCl4) 55 (Benzene)

4 3.17 2.96 2.27 46 (THF) 47 (THF)

In order to test experimentally whether lithium is essential for the stability of 47, like in the case of organolithium compounds and unlike P and S ylides, the stability of 47 in a closed NMR tube at -30 °C in THF-d8 was monitored in the absence and in the presence of 12-crown-4, a strong lithium-coordinating agent. As it can be seen in figure 3.2, in a closed NMR tube 47 is rather stable, showing no major changes in concentration over a period of 70 minutes. In the blank experiment addition of a portion of solvent under

Discovery, Development and Study of Carbenoid Mediated Reactions argon counterflow causes some degradation of 47 but once the NMR tube is closed and cooled down the remaining 47 shows the same stability as before. On the contrary, addition of 12-crown-4 causes a higher fraction of 47 to decay and increases the rate of decomposition irrespective of the closure or the cooling of the NMR tube.

0.050

0.045

0.040 [47]blank = -1.94E-05t + 2.98E-02

(M) 0.035 R² = 9.87E-01

47 0.030

0.025

0.020

0.015 [47]12-crown-4 = -5.75E-05t + 2.54E-02 Concentration 0.010 R² = 9.91E-01

0.005 12‐crown‐4 experiment blank experiment

0.000 0 50 100 150 200 t (min)

Figure 3.2 Stability of 47 in THF solution at -30 °C in absence (white circles) and in presence of 12-crown-4 (black circles).

Based on the evidence obtained so far, it seems clear that the lithium cation is essential for the stability of 47, in contrast to what is observed for P and S ylides, which can be isolated “salt free”.183, 186 The former designation of 47 as “trimethylammonium methylide” wrongly describes the nature of this species, therefore the term “lithiomethyl trimethylammonium”, which relates to the actual structure of 47 in solution, is recommended over the former name.

3.2.2. Bonding in the lithiomethyl trimethylammonium ion

In order to gain a better understanding of the bonding situation in 47, and how it compares with its closest P analog, trimethylphosphonium methylide (50), a series of DFT calculations were performed.187

The calculated thermochemistry for the isodesmic188 reaction shown in table 3.2, reveals that the lithium cation stabilizes structure 47b by 8.1 kcal/mol more than 51b in vacuo, and by 3.6 kcal/mol in solution.

3. Lithiomethyl trimethylammonium salts as methylene donors Table 3.2 Stabilization of ylides by lithium cation

Environment Reaction Energy (kcal/mol)

In vacuo -8.1a

Solution -3.6b a M06L/aug-cc-pVTZ yero point corrected energies. b M06L/aug-cc-pVTZ/SMD(THF) Gibbs-corrected energies (298.15 K) with two explicit THF molecules. Moreover, extended transition state analysis of the structures shown above187 reveal that the number of stabilizing orbital interactions and steric repulsion remain relatively constant irrespective of whether lithium is present or not in the nitrogen ‘ylide’ (structures 47a and 47b). On the other hand, the presence of lithium in 51b reduces the amount of stabilizing orbital interactions and increases the steric repulsions compared to 51a, resulting in a net destabilizing effect. More illustrative perhaps is the effect of these interactions on the corresponding optimized geometries (figure 3.3).

In the lithium-free nitrogen ylide 47a the methylide moiety adopts a tetrahedral geometry, whereas in the P-ylide 51a the geometry is closer to trigonal planar (X-C-H angle widens from 114.1 ° in 47a to 148.3 ° in 51a). Lithium-coordinated ylides 47b and 51b exhibit both a tetrahedral geometry in their lithiomethyl moieties. Similar structural differences have been calculated for oxygen and sulfur ylides.189 Another differentiating characteristic can be observed in the heteroatom-carbon bond distances on the two ylides. In lithum-free phosphorus ylide 51a the P-methylene bond is shortened and the P- Me(1) bond is elongated compared to the P-Me bonds in tetramethyphosphonium ion 50a. In the lithium-coordinated structure 51b these bonds are affected in the same manner albeit to a smaller degree. On the other hand, both lithium-free (47a) and lithium-coordinated (47b) nitrogen ylides have slightly longer N-CH2(Li) and N-Me(1) bonds than the parent tetramethylammonium cation (46a).

Discovery, Development and Study of Carbenoid Mediated Reactions

+ Figure 3.3 Selected bond lengths and angles for a) N(CH3)4 (46a), b) N(CH3)3CH2 (47a), c) + + + N(CH3)3CH2Li (47b), d) P(CH3)4 (50a), e) P(CH3)3CH2 (51a) and f) P(CH3)3CH2Li (51b).

In summary, the removal of the lithium cation from 47b causes a localized electron density to accumulate at the methylene carbon of 47a, whereas in the phosphorus case, after removal of lithium from 51b the excess electron density is delocalized over the rest of the molecule in 51a. This redistribution is possible due to 1) an enhanced p,*(P-C) negative hyperconjugation; 2) enhanced electron dispersion towards P due to the lower polarization of P-C bonds as compared to N-C bonds; and 3) enhanced overlap of the methylene orbitals with the diffuse 3p orbitals of phosphorus. Both the experimental and the theoretical evidence agree that lithium coordination is essential for the stabilization of lithiomethyl trimethylammonium reagent 47b.

3.2.3. Reactivity of lithiomethyl trimethylammonium triflate with aldehydes, ketones and imines

Having, for the first time, a soluble version of the simplest nitrogen ‘ylide’ at hand, our next goal was set to test its reactivity towards the most representative electrophiles, however a more convenient source of a soluble ‘ylide’ was desirable. During our studies it was discovered that other anions could also enhance the solubility of the precursor salts or the resulting lithiomethyl species in THF (figure 3.4). Even though tetramethylammonium salts of pivalate (56) and triflate (57) anions show only marginal solubility in THF, their corresponding ‘ylides’ are fully soluble. In particular, from the salts prepared, tetramethylammonium triflate (57) could be easily prepared and purified, showed no hygroscopic character and was easy to handle (free flowing solid).

3. Lithiomethyl trimethylammonium salts as methylene donors

Figure 3.4 Precursors of soluble nitrogen ‘ylides’ in THF: tetramethylammonium BArF (45), pivalate (56), triflate (57) and triflimide (58).

The ‘ylide’ derived by deprotonation of 57 was tested in methylenation of aldehydes, ketones, imines and epoxides. The corresponding products were obtained in reasonable to excellent yields (table 3.3)

Table 3.3 Methylenation of aldehydes, ketones, imines and epoxidesa

Entry Substrate R1 R2 Product Yieldb

1 59a Ph Ph 60a 67%

2 59b Ph nPr 60b 73%

3 59c nBu nBu 60c 84%

4 59d cPr p-(OMe)Ph 60d 68%c

5 61a Ph Ph 62a 46%

6 61b Ph tBu 62b 73%

7 63 Ph - 64 58%

8 60a Ph Ph 65 70%

a For details see experimental part. b Isolated yields after column chromatography. c Crude Yield.

Discovery, Development and Study of Carbenoid Mediated Reactions Using 57 bis-aryl (table 3.3, entry 1), alkyl-aryl (entries 2 and 4), and bis-alkyl (entry 3) ketones can be transformed into their corresponding epoxides efficiently. The mechanism for this methylenation most likely involves the consecutive 1,2-addition of lithiomethyl trimethylammonium triflate (66) to the ketones 59 and intramolecular cyclization with concomitant release of trymethylamine (34), see scheme 3.10.

Scheme 3.10 Proposed mechanism for the methylenation of carbonyl compounds.

The formation of aziridines from imines (entries 5 and 6) proceeds reasonably well under the same reaction conditions, however, the reaction with the less electron rich aldehyde 63 (entry 7) requires heating to force closure. Methylenation of epoxide 60a (entry 8) yields allylic alcohol 65 in reasonable yield.

In all of these cases the reactivity of the soluble nitrogen ‘ylide’ matches exactly the one of sulfur ylides in the Corey-Chaykovsky reaction. However, the nature of the soluble nitrogen ‘ylides’ was proven to resemble more closely that of an organolithium reagent than the traditional P and S ylides. Organolithium reagents are more powerful nucleophiles, being capable of addition to a wider range of substrates, among them certain olefins, e.g. styrenes. If reagent 66 could perform addition to styrenes, it would open the possibility to a very facile synthesis of cyclopropanes; relevant molecules for which an alternative method of preparation is still very desirable, vide supra.

3.2.4. Reactivity of lithiomethyltrimethylammonium triflate with styrenes

Carbolithiathion, the nucleophilic addition of organolithium reagents to styrenes, has been extensively studied since its discovery190 for diverse applications,191 including the formation of heterocycles192 and the stereoselective formation of cyclopropane derivatives.193 However, the formation of cyclopropanes via carbolithiation was limited to substrates incorporating a leaving group. Potentially, a bigger substrate scope for the cyclopropanation could be obtained when nucleophilic reagents possessing a leaving group, like the lithiomethyl reagent 66, are used.

3. Lithiomethyl trimethylammonium salts as methylene donors

Scheme 3.11 Top: Previously reported cyclopropanation of styrenes using carbolithiation.193 Bottom: Cyclopropanation of styrenes and stilbenes with 66.

Table 3.4 Effect of the solubilizing anion on the cyclopropanation of styrene.a

Entry Precursor Anion Yield of 71ab Remaining 69ab

1 45 -BArF 24% 76%

- 2 56 OOC(CH3)3 30% 70%

- 3 57 OSO2CF3 60% 40%

- 4 58 N(SO2CF3)2 19% 81%

a 0.3 mmol scale. b Determined by GC-FID, see experimental part for details.

Lithiated ammonium salts with all the available counterions (figure 3.4) were tested for the cyclopropanation of styrene in THF. Deprotonation of the tetramethylammonium salts at 0 °C for 30 min, followed by addition of styrene (69a), produced cyclopropylbenzene (71a) in all cases. THF-soluble salts tetramethylammonium BArF (45) and triflimide (56) afforded 70a in 24% and 19% yield respectively (Table 3.4, entries 1 and 2). Ammonium salts with triflate (57) and pivalate (58) and anions were also evaluated. Higher yields of 60% and 30% were obtained when 57 and 58 were used respectively (entries 3 and 4). The strong dependence of the reaction yield on the anion might correlate to the ability of the anion to coordinate the lithium cation, i.e. this coordination could influence the rate of ring closure from intermediate 70 (vide supra).

Discovery, Development and Study of Carbenoid Mediated Reactions Table 3.5 Cyclopropanation of olefins at 1.2 mmol scale with lithiomethyl trimethylammonium triflate.

Entry Substrate R1 R2 Product Yielda

1 69a Ph H 71a 71%

2 69b 4-CH3Ph H 71b 88%

3 69c 4-C(CH3)3Ph H 71c 80%

4 69d 4-OCH3Ph H 71d 88%

5 69e 3-OCH3Ph H 71e 77%

6 69f 4-FPh H 71f 17%b

c 7 69g 4-NO2Ph H 71g 0%

8 69h Ph E-Ph trans-71h 92%

9 69i Ph Z-Ph trans-71h 98%

10 69j 4-OCH3Ph E-Ph trans-71j 73%

11 39 cyclohexene 40 0%d

a Isolated yields after purification unless otherwise stated, see experimental part for details. b Estimated from GC data. c Exclusively polymeric products were obtained. d Unreacted starting material was recovered.

At a 1.2 mmol scale styrene could be methylenated by 66 to produce phenylcyclopropane 71a in 71% isolated yield (Table 3.5, entry 1). In a similar fashion, p-methyl substituted (69b) and p-tBu substituted (69c) styrenes afforded their corresponding cyclopropanes 71b and 71c in 88% and 80% yields, respectively (entries 2 and 3). Styrenes bearing methoxy substituents in the para-position (69d) as electron-donating group (= -0.268), or in the meta-position (69e) as electron-withdrawing group ( = +0.115), can be methylenated to afford cyclopropanes 71d and 71e in 88% and 77% yield (entries 4 and 5). Substitution with electron withdrawing groups in the para position leads either to a lower yield (p-F, entry

6) or to no traces of cyclopropane (p-NO2, entry 7). In both of these cases the formation of polymers was observed, for p-NO2 styrene 69g the polymer was the only product. Methylenation of stilbenes 69h, 69i and 69j afforded trans-1,2-bissubstituted

3. Lithiomethyl trimethylammonium salts as methylene donors cyclopropanes194 71h and 71j exclusively, in 92, 98 and 73% yields respectively (entries 8 to 10). Kinetic experiments have shown that Z-4-methoxystilbene racemises to E-4- methoxystilbene before carbolithiation occurs in the presence of 66. Finally, reaction of 66 with the aliphatic olefin cyclohexene (39), the original substrate in Franzen and Wittig’s report,169 did not give the corresponding cyclopropane; instead, unreacted starting material could be recovered after workup (entry 11). This is in agreement with the required forcing reaction conditions reported in literature for the nucleophilic addition of carbanions to nonactivated olefins.195

0.03 Cyclopropane 71c formation -2 A0=2.3(±0.1)x10 M -3 -1 0.03 k1=1.1(±0.1)x10 s

0.02

0.01 Concentration [M] 'N-C Ylide‘ 66 consumption -2 A0=2.8(±0.2)x10 M -4 -1 0.01 k1=7.5(±1.0)x10 s

0.00 0 500 1000 1500 2000 2500 3000 3500 4000 time (s)

Figure 3.5 Typical plot of the absolute concentrations of 66 (white circles) and 71c (black circles) over time. Also shown are the average fitting parameters obtained after three different measurements.

The irreversible nature of carbolithiations, and the irreversible formation of trimethylamine gas in the second step of our mechanism, allows the straightforward kinetic study of this reaction. Monitoring the reaction of 66 with excess of styrene 69c using a combination of GC and ESI-MS analysis (see experimental part) showed first order kinetics for the consumption of 66 and the formation of cyclopropane 71c. The pre- exponential factors and kinetic constants found for both curves are statistically very similar (figure 3.5). Assuming the model of two consecutive, irreversible reactions (A → B → C) a kinetic model can be deduced.196 In case the first reaction is much slower than the second, i.e. k1 << k2 (scheme 3.11, bottom), the analytic solution simplifies to:

; 1 . Our kinetic data strongly support that the 73

Discovery, Development and Study of Carbenoid Mediated Reactions carbolithiation is much slower than the ring-closure, since the concentration of both product and reagent display an apparent first order regime with similar pre-exponential factors and rate constants, see fitting parameters in figure 3.5.

Figure 3.6 Hammett Plot for the methylenation of styrenes with 66. Sigma Hammett parameters are shown in brackets.197

Competitive kinetic measurements198 showed a marked decrease in reaction rate when electron-donating substituents on the aromatic ring are present (Figure 3.6). As expected, nucleophilic attack on the olefin is strongly disfavored when its electron density is increased, and styrenes bearing electron-withdrawing substituents exhibit a modest increase in methylenation reactivity. Substitution with an electron-withdrawing substituent at the meta position influences the olefin inductively but has a minor effect on the resonance stability of intermediate 70, and therefore only modestly affects the rate of ring closure. For an electron-withdrawing group in the para position a much greater influence can be observed; in fact, disappearance of ‘N-C ylide’ 66 when reacted with styrene 69h is instantaneous at 0 °C, however no cyclopropane product is formed. It is likely that the stabilization of the benzylic carbanion 70h by the electron- withdrawing group slows down the ring closure enough to kinetically favor polymerization over cyclopropane formation.199 The opposing effects of the substituents on the two steps of this mechanism should result in a change of rate limiting step. For electron rich styrenes, addition is rate limiting, whereas for electron poor styrenes, ring

3. Lithiomethyl trimethylammonium salts as methylene donors closure should be rate limiting. Such changes are normally associated with curved Hammett plots.200 The measured plot for this system (Figure 3.6) deviates from linearity as expected; however, the observed polymerization does not allow the study of methylenation reactions that are kinetically dominated by rate limiting ring closure.

During our experiments, we found that trace amounts of (transition) metals degrade the lithiomethyl trimethylammonium reagent to ethylene and trimethylamine, reducing the efficiency of this methylenation. Consequently, thorough cleaning of all glassware (see experimental part), the use of glass stir bars, and purification of the ammonium salts to ensure sub-ppm concentration of metal impurities (as assessed by ICP-MS) is necessary to achieve high and reproducible yields. We also noted that reagent 66 is more stable in closed vessels but quickly decays when open to a dry argon atmosphere. This curious phenomenon motivated us to study the interaction of 66 with several transition metals in order to gain some insight into its decomposition mechanism.

3.2.5. Reactivity of lithiomethyl trimethylammonium reagents with transition metals

Organolithium species are very well known alkylating agents of transition metals complexes.201 Additionally, P ylides have been reported to add to transition metals forming stable metal–ylide complexes.202 Hence, it is very likely that 66 could perform a transmetallation to a spurious transition metal contamination to form a transition metal–stabilized ‘ylide’ complex. These type of ‘ylide’ complexes have been also shown to generate metal methylidenes upon release of the onium fragment; in turn, these carbenoids have been trapped with olefins to make cyclopropanes.203 However, metal carbenoids can engage in nonproductive homocoupling reactions that produce ethylene and reduce the methylene transfer efficiency of these complexes.204 If one considers these literature precedents, it is possible to formulate a mechanism which could lead to the catalytic transfer of methylene from ‘N–ylide’ 66 to an olefin mediated by a transition metal (scheme 3.12), as well as a side reaction which could explain the production of the observed ethylene and trimethylamine. It was our next goal to test the feasibility of such proposal.

Discovery, Development and Study of Carbenoid Mediated Reactions

Scheme 3.12 Possible mechanism for a catalytic methylenene transfer from lithiomethyl ammonium reagents to olefins mediated by transition metals. Precedents of individual steps: a) Ylide coordination to a metal complex,202 b) formation of methylene from a metal–ylide complex,203 c) homocoupling of methylidene complexes generating ethylene, a possible side reaction,204 and d) transfer of methylene from a metal complex to an olefin.205

We chose electrospray ionization mass spectrometry (ESI-MS) as our analytical tool for the analysis of the reaction of lithiomethyl reagents with a series of neutral transition metal complexes. If a transmetallation reaction would occur its product most likely will bear a positive charge, making them ideal analytes for the ESI-MS technique.

Scheme 3.13 Reaction of copper complexes 72 with lithiomethyl reagent 47.

Lithiomethyl reagent 47 was reacted with copper complexes 72 in THF at -30 °C. A sample of the reaction mixture was then diluted appropriately under strict exclusion of oxygen and water for subsequent ESI-MS analysis. In all cases, the product of transmetallation 73 could be observed and characterized by comparison of the measured and predicted (red bars superimposed to measured curves) isotope patterns. After mass selection, the

3. Lithiomethyl trimethylammonium salts as methylene donors adducts 73 were activated by collision induced dissociation206 and the fragmentation products characterized by tandem MS.

Figure 3.7 CID experiment on ion 73a. Main channel is dissociation of neutral ylide 47a. Parameters: Spray voltage = 4500 V, Capillary temperature: 180 °C, Collision Offset: 5 V, Tube Lens: 20 V, Collision gas pressure: 0.1 mTorr, Collision Energy: 10 V.

As can be observed in the figures 3.7 to 3.9 the products of CID strongly depend on the nature of the supporting ligand. Strongly donating Johnphos, in complex 73a, favors the dissociation of the neutral nitrogen ylide 47a, producing the monoligated Cu complex 74a. The strong donor ability of the bisalkyl–phosphine weakens the Cu-C bond favoring the dissociation of the ylide. On the other hand, weakly donating tris-o-tolylphosphite binds more weakly to the copper center in ion 73b so that after activation by CID the main fragmentation pathway involves loss of the ligand. The daughter ion corresponds in this case to the Cu stabilized nitrogen ‘ylide’ 74b. In these two cases no rupture of the N–C bond was observed. Nonetheless, if a weakly donor ligand would bind strong enough to enable more energetic reactions without dissociation, there would be a chance of generating a Cu–carbenoid in the gas phase. When using the ligand tris(3,5-bis- (iPr)pyrazoyl)methane, the resulting Cu–ylide ion 73c was able to release neutral trimethylamine to form complex 74c (m/z = 543). We expect the complex 74c to be Cu– methylidene based on its isotope pattern and additional CID experiments where the fragmentation shows no loss of single CH2. Subsequently, the reactivity of 74c towards olefins was tested. After conditions for production of 74c during spray were found, a CID experiment using styrene as collision gas was performed (figure 3.10). 77

Discovery, Development and Study of Carbenoid Mediated Reactions

Figure 3.8 CID experiment on ion 73b. Main channel is dissociation of tristolylphosphite 75. Parameters: Spray voltage = 4500 V, Capillary temperature: 180 °C, Collision Offset: 5 V, Tube Lens: 20 V, Collision gas pressure: 0.1 mTorr, Collision Energy: 10 V.

Figure 3.9 CID experiment on ion 73c. Main channel is dissociation of NMe3 (34). Parameters: Spray voltage = 5000 V, Capillary temperature: 170 °C, Collision Offset: 35 V, Tube Lens: 100 V, Source CID= 20 V, Collision gas pressure: 0.5 mTorr, Collision Energy: 10 V.

The adduct 75c was formed upon collision of 74c with styrene in the gas phase. Although the collision parameters were varied on a wide range, no cyclopropanation reaction was observed. The transfer of the methylene in 74c to the styrene would have led to the

3. Lithiomethyl trimethylammonium salts as methylene donors formation of neutral cyclopropylbenzene and a cationic Cu complex at m/z = 529. This species was not observed.

Figure 3.10 CID of 74c using styrene as collision gas. Parameters: Spray voltage = 4500 V, SG = 5 A.U., Capillary temperature: 170 °C, Collision Offset: 50 V, Tube Lens: 225 V, Collision gas pressure: 10 mTorr, Collision Energy: 3 V.

The lack of reactivity in the gas phase paralleled the results in solution where no transition metal–catalyzed cyclopropanation was observed with any of the complexes studied in the gas phase. The requirement of a fairly complex supporting ligand for the possible formation of a methylidene intermediate in the Cu complexes does not support our initial hypothesis of a bimolecular decomposition pathway (scheme 3.2 c). Nonetheless, the complexes bearing simple ligands catalyze the formation of ethylene and trimethylamine from any of the soluble nitrogen ‘ylides’ very efficiently. Therefore, another mechanism for this decay must be in operation. An insight was obtained when the NHC–Cu complex 76 was reacted with a 4–fold excess of nitrogen ‘ylide’ 47 at -30 °C.

Scheme 3.14 Proposed formation of 78 via nucleophilic attack of 47 into 77 in solution.

Discovery, Development and Study of Carbenoid Mediated Reactions

Figure 3.11 CID experiment on ion 78a. Main channel is release of trimethylamine and ethylene. Shown is the proposed mechanism for ethylene and trimethylamine formation. Spray voltage = 5000 V, Capillary temperature: 170 °C, Collision Offset: 50 V, Tube Lens: 100 V, Collision gas pressure: 0.5 mTorr, Collision Energy: 20 V.

ESI-MS analysis of the resulting mixture showed the formation of what could be rationalized as the product of nucleophilic attack of excess nitrogen ‘ylide’ 47 into the initial transmetallation product 77 (scheme 3.14). Subsequent CID experiment on the ion 78a showed the loss of a neutral fragment whose mass is exactly the combined mass of trimethylamine and ethylene. The NHC–Cu complex 79a is the only observable cationic species. A possible mechanism for the concerted formation of ethylene and trimethylamine from 78a is shown in figure 3.11. However, an initial release of a zwitterionic species followed by rearrangement to form ethylene and amine is also possible.

Results from Ringger and Chen have shown that gold–based sulfone complexes can be

207 used for the cyclopropanation of olefins. In this system a SO2–imidazolium moiety behaves as a leaving group, generating a gold carbenoid which then is trapped by an olefin. The resemblance of this step with the release of trimethylamine to form a metal

3. Lithiomethyl trimethylammonium salts as methylene donors methylidene required in a possible catalytic methylene transfer from our nitrogen ‘ylide’ to an olefin prompted us to evaluate the reactivity of gold complexes in our system.

In sharp contrast to all the other transition metal complexes studied, NHC–Au complex 80 reacted with 66 to form the stable complex 81. Even though the gold stabilized ‘ylide’ is expected to be the least reactive of the series due to the very similar electronegativity of gold and carbon,201b the inertness of 81 towards weak proton sources like methanol is remarkable. Complex 81 could be isolated and characterized by NMR. The great stability of 81 was evidenced both in solution and in the gas phase. Heating dichloromethane solutions of 81 up to 150 °C for 14 hours in a closed vessel in presence of olefins showed no cyclopropanation products nor decomposition of the gold complex. In the gas phase, CID experiments showed that 81 required quite forcing conditions to fragment, and in those conditions, it was the supporting ligand which fragmented and not the C–N bond.

Scheme 3.15 Formation of a gold stabilized nitrogen ‘ylide’.

Even though the stability of complex 81 is intriguing, especially contrasted to all the other transition metal complexes studied, its inability of engaging in any productive reactions discouraged us to further explore its properties.

3.3. Discussion

The importance of ylides in organic chemistry can hardly be overstated. In fact, two Nobel Prize laureates have contributed greatly to the development of useful transformations mediated by ylides. The importance of the formation of olefins from carbonyl compounds by reaction with phosphorus ylides,163 developed by Prof. Dr. Georg Wittig was recognized in 1979 with the Nobel prize in chemistry.208 Prof. Dr. E. J. Corey (Nobel laureate in 1990)209 is well–known for the his seminal contribution to the use of sulfur ylides in the synthesis of three–membered rings as epoxides, aziridines and cyclopropanes, all variations of the now known as Corey-Chaykovsky reaction.104 It is therefore puzzling to find that the related nitrogen ylides, which in fact were discovered

Discovery, Development and Study of Carbenoid Mediated Reactions years before,160 are only very recently receiving attention as potential synthetically useful reagents.173 The experimental difficulties (long deprotonation times and chemical instability) reported by Wittig167-169, 210 and others176, 211 on the preparation of ylides derived from simple tetramethylammonium salts, which are in sharp contrast to the ease of preparation of ylides from tetramethylphosphonium181 and trimethylsulfonium183 salts, seem to be the main deterrent against the more widespread use of these reagents.

The replacement of the counter ion in simple tetramethylammonium salts with the weakly coordinating anion212 -BArF afforded the substrate salt 45 which was found to be fully soluble in common organic solvents. The increased solubility allowed for a fast deprotonation time, 5 minutes instead of two days, and the possibility of characterizing the resulting ‘ylide’ 47 by means of conventional condensed phase techniques as NMR. The spectroscopic evidence, together with DFT calculations confirmed that lithium coordination is essential to the stability of the nitrogen ‘ylide’ 47. Contrary to S and P ylides, which delocalize the negative charge of the carbanion center by a combination of negative hyperconjugation and polarization effects,158 nitrogen ‘ylide’ 47 concentrates the negative charge on the carbon atom, requiring the cation coordination to ensure stability, closely resembling organolithium compounds. ‘Ylide’ 47 is stable in solution when protected from oxygen and water, however, unlike S and P ylides it cannot be isolated “salt free”.183, 186 Due to this requirement, the more correct ‘lithiomethyl trimethylammonium’ name is recommended over the previously used ‘trimethylammonium methylide’ designation.

The nucleophilic reactivity of the described lithiomethyl trimethylammonium reagents parallels that of the sulfur ylides. Epoxides can be obtained from ketones and aldehydes, as well as aziridines from appropriate imines. The more forcing conditions required for the formation of the epoxide when primary aldehydes are used can be justified by considering the leaving group ability of the trimethylamine moiety. Aggarwal has calculated the leaving group ability of the ylides to follow the order O > S > N > P.162 This order correlates perfectly with the necessary conditions to obtain epoxides from aldehydes. Sulfur ylides can methylenate aldehydes at cryogenic temperatures,213 whereas nitrogen ylides required prolonged heating, at the other end of this reactivity continuum are P ylides, in which the P–C bond is not directly cleaved and therefore do not cyclize, instead P ylides favor the alternative olefination reaction.

3. Lithiomethyl trimethylammonium salts as methylene donors

177- Although the estimated pKa(DMSO) of the tetramethylammonium ion is close to 42 units, 178 lithiomethyl reagent 66 did not deprotonate ketones possessing –hydrogens, whose

214 acidity constants have been reported to be around 27 pKa(DMSO) units. An even more dramatic reduction in basicity is exhibited by the gold–stabilized ‘N–Ylide’ 81, which was found to be stable in methanol solution. The apparent discrepancy in basicity arises from the treatment of the anions as free ions in DMSO solution, in this solvent ion association interaction is minimized increasing the generality of the DMSO acidity scale.179 However, in THF, the interaction of the ‘N–Ylide’ with a cation provides stabilization and modulation of the basicity. In the case of lithium, a good balance between the basicity and the reactivity of the deprotonation product is observed, whereas the extreme stabilization offered by gold renders complex 81 inert towards any useful transformation.

Additionally to the modulation exerted by the cation, the inability of the onium group in nitrogen ‘ylide’ 47 to stabilize the negative charge in the carbon atom reduces its general stability, but also increases its nucleophilic character. S and P ylides do not add to olefins whereas lithiomethyl trimethylammonium reagents were able to add to a series of styrenes, just as organolithiums do.190-193 The presence of a leaving group allowed a subsequent intramolecular cyclization that afforded cyclopropanes. Our kinetic data strongly favor the proposed nucleophilic addition–ring closure mechanism. This is the first report of a nucleophilic reagent capable of cyclopropanating olefins which do not possess electron withdrawing activating substituents, i.e. does not fall under the Michael–initiated ring closure scope.

The observed decomposition of lithiomethyl trimethylammonium reagents observed during our initial experiments when only standard glassware cleaning was performed prompted us to investigate the reactivity of 47 with transition metals. Contrary our original hypothesis, ESI-MS experiments showed that the generation of metal methylidenes from the transition metal–stabilized nitrogen ‘ylides’ required an elaborated supporting ligand and was most likely not the pathway of the decomposition observed. Instead, the detection of an ethylammonium species, which could be explained as the result of nucleophilic attack of excess lithiomethyl reagent on the transmetallated complex, offered a plausible explanation for the efficient decomposition of 47 exhibited by several simple metal complexes.

Discovery, Development and Study of Carbenoid Mediated Reactions Curiously, gold forms stable, isolable complexes with the nitrogen ‘ylide’ which do not undergo any productive reaction even when heated at 150 °C for prolonged period of time. The stability of this complex is extraordinary when compared to the reactivity presented by all the other transition metal complexes studied.

3.4. Conclusions

A simple anion exchange allowed the synthesis of a soluble tetramethylammonium salt which in turn allowed the rapid formation of a soluble lithiomethyl trimethylammonium reagent. The increased solubility allowed us to fully characterize this compound in solution by NMR spectroscopy. For the first time, more than 60 years after the initial report by Wittig the structure of the simplest nitrogen ‘ylide’ could be determined. NMR and DFT calculations showed that lithium coordination is essential to the stability of this molecule, more akin to organolithium reagents than to regular S and P ylides.

The reactivity of soluble lithiomethyl trimethylammonium reagents parallels that of sulfur ylides when reacted with aldehydes, ketones and imines. However, the increased nucleophilicity due to the lack of delocalozation allowed the cyclopropanation of styrenes and stilbenes via a nucleophilic addition–ring closure mechanism. A feat no traditional ylide can achieve when non–activated olefins are used as substrates.

This new cyclopropanation reaction offers an alternative to other well established methodologies, like the Simmon–Smith reaction, or the transition metal–catalyzed decomposition of diazomethane, which although effective, still possesses risks associated with the production of toxic byproducts or the utilization of toxic and explosive raw materials.

The transition metal–catalyzed methylene transfer from soluble lithiomethyl trimethylammonium reagents was hypothesized as a result of the quick degradation of the nitrogen ‘ylides’ in presence of metal complexes. Even though the transmetallation of the nitrogen ‘ylide’ to a transition metal was observed by ESI-MS, the formation of a methylidene required an elaborate supporting ligand and therefore is highly unlikely to happen in solution. It was clear from these experiments that the C–N bond is simply too strong to allow easy dissociation of trimethylamine in these metallomethyl trimethylammonium complexes. We envisioned that another leaving group, instead of trimethylamine, was necessary for the successful design of a catalytic methylenation. This ultimately led us to employ commercially available halomethyl trifluoroborate

3. Lithiomethyl trimethylammonium salts as methylene donors reagents together with palladium catalysts for the cyclopropanation of electron rich olefins. The results and mechanistic proposals will be discussed in chapter 4.

3.5. Acknowledgments

Dr. Tim den Hartog and Dr. Erik P. A. Couzijn are greatly acknowledged for their work in the discovery and characterization (NMR and DFT) of the soluble lithiomethyl trimethylammonium reagents (sections 3.2.1 and 3.2.2) which opened the way to the development of the synthetic protocols discussed in sections 3.2.3 and 3.2.4. Mr. Joël Gubler is acknowledged for the kinetic experiments that revealed the isomerization of cis–4-methoxystilbene in presence of ‘N-ylide’ 66.

4. Palladium catalyzed methylenation of olefins using halomethylboronate reagents

4.1. Introduction

As discussed in section 3.2.5., reaction of lithiomethyl trimethylammonium reagents with transition metal complexes led to the formation ethylene and trimethylamine. Although metallomethyl trimethylammonium complexes 73 could be detected in the gas phase, simple transition metal complexes could not catalyze the transfer the methylene unit from the ‘ylide’ to an olefin. Experimentally we found that the formation of methylidene complexes was challenging, due to a very strong C–N bond. On the contrary, nucleophilic attack of excess nitrogen ‘ylide’ on the metallomethyl trimethylammonium complexes seemed to be the preferred pathway for ‘ylide’ decomposition. We then rationalized that a different leaving group is necessary to achieve catalytic methylene transfer to an olefin.

4.1.1. Nucleofuge and electrofuge alternatives

Molecules like the lithiomethyl trimethylammonium are members of a more general family characterized by possessing two distinctly different functional groups attached to a central methylene unit. On one side a nucleofuge,215 which retains an electron pair upon displacement, and on the other, an electrofuge,216 that leaves an electron pair after dissociation (Figure 4.1, left). Although the use of the terms nucleofuge and electrofuge is rare in contemporary scientific literature, it is our opinion that they describe accurately the nature and reactivity of the two different types of functional groups discussed here.

Figure 4.1 Left: Examples of nucleofuges and electrofuges that can be attached to a central methylidene unit. Right: Commercially available halomethyl trifluoroboronates (82) and halomethyl pinacolboranes (83).

From the possible combination of nucleofuges and electrofuges shown above, some are well–known carbenoids. For example, (I)CH2(ZnI) is the proposed intermediate in the 87

Discovery, Development and Study of Carbenoid Mediated Reactions

118 217 Simmons–Smith reaction, and (I)CH2(MgCl) is a known methylenation reagent, albeit not for cyclopropanation. All the species whose electrofuge is a metal, including our lithiomethyl trimethylammonium reagents, are highly basic and difficult to handle, therefore these reagents are commonly prepared in situ prior use. However, when boranes or boronates are used as electrofuges instead, isolable molecules can be prepared; some of them are even commercially available (figure 4.1 right).

The development of synthetic routes and commercial availability of many different organoboranes is a direct consequence of the widespread adoption of the Suzuki– Miyaura palladium–catalyzed cross coupling, in which these reagents play a central role.218 The Suzuki–Miyaura reaction belongs to the group of palladium catalyzed cross couplings of aryl or alkyl electrophiles with organometallic nucleophiles (scheme 4.1, left). These couplings share a general mechanism characterized by three main steps219 (scheme 4.1, right): 1) oxidative addition of the carbon–halide electrophile to a Pd0 species; 2) transmetallation of the nucleophilic organometallic species to the transition metal center to form a disubstituted palladium intermediate; finally 3) reductive elimination to form a carbon–carbon bond between the two substrates and regeneration of the starting palladium catalyst. Unlike the Negishi,220 Kumada221 and Stille222 couplings, the Suzuki–Miyaura223 and Hiyama224 reactions require the addition of an activator, mainly hydroxide or fluoride anions, to promote the transmetallation step. The antagonistic role of the anionic bases in the Suzuki–Miyaura coupling has been recently reviewed.225

Scheme 4.1 Left: palladium catalyzed cross coupling reactions Right: General mechanism.

The operational simplicity, environmentally benign nature, and thermal stability of the most common transmetallating partners, have made the Suzuki–Miyaura reaction the most used method for the preparation of bisaryl molecules. Even though many boronic

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates acids, and esters are commercially available and readily used in cross coupling reactions, these molecules are difficult to handle since they are oils or waxy solids, sensitive to air and moisture and very difficult to further functionalize due to the inherent reactivity of the boron moiety. To overcome this limitations, the group of Molander developed cross coupling methodologies employing bench–stable, trifluoroborate salts as transmetallating partners.226 The commercially available halomethyltrifluoroborate reagents 82 were developed to be the starting point for more complex coupling reagents227 (Scheme 4.2). Salts 82 can undergo nucleophilic substitution with a wide variety of reagents at the halomethyl fragment to form products that can be directly used in Suzuki–Miyaura couplings or even further functionalized.

Scheme 4.2 Left: Synthesis of halomethyltrifluoroborates 82 and their functionalization via nucleophilic substitution. Right: Some examples of coupling partners for Suzuki– Miyaura reaction prepared using the procedure described by Molander.

4.1.2. Palladium catalyzed olefin transformations

The rich cross coupling chemistry of palladium catalysts is not limited to reactions involving organometallic nucleophile substrates. Mizoroki228 and Heck229 pioneered the use of olefins as cross coupling partners in the early 1970s. Although it took around 15 years for the first practical application of this transformation to be developed by Hans– Ulrich Blaser at Ciba-Geigy,230 today the Mizoroki–Heck coupling plays a central role in the industrial production of specialty chemicals, ranging from pharmaceuticals231 to optoelectronic materials.232 The mechanism of the arylation of olefins diverges from the general mechanism discussed previously (scheme 4.3 left). After the oxidative addition of the aryl–halide, coordination of the olefin followed by insertion and subsequent – hydride elimination generates the product.233 A base is necessary to abstract the resulting hydride from the palladium center and regenerate the catalyst.

Discovery, Development and Study of Carbenoid Mediated Reactions

Scheme 4.3 General mechanisms of: Mizoroki–Heck coupling (left) and Pd–catalyzed ethylene polymerization (right).

Palladium olefin insertion chemistry has also been used for the Ziegler–Natta type polymerization of olefins by cationic complexes. Maurice Brookhart contributed to the start of the post–metallocene era with the introduction of his catalytic systems based on late transition metals (nickel and palladium) and bulky diimine ligands.234 These systems perform olefin polymerization via the insertion mechanism shown in scheme 4.3 right. Since in cationic palladium systems –hydride elimination is kinetically competitive, the diimine systems are prone to produce branched polymers. The extent of branching is dependent on the steric bulk of the diimine ligand, with the more demanding ligands favoring insertion over branching. In this way, the same catalytic system can be rationally tuned to produce polymers ranging from high density linear to low density highly branched polyethylene.235 Hinderling and Chen have studied the propagation and selectivity of palladium diimine complexes in the gas phase, reporting a high– throughput methodology for the discovery and assessment of the performance of new cationic catalysts for which –hydride elimination was used as an integral part of the screen.236

4.1.3. Palladium–catalyzed cyclopropanation of olefins

Other than couplings and polymerization, palladium catalysts have also been used for the cyclopropanation of olefins. As discussed in the introduction section 1.1.8, the palladium–catalyzed decomposition of diazomethane constitutes a well–established methodology for the methylenation of a wide variety of olefins. Nonetheless, alternatives employing other reagents have also been developed. Continuing his studies on the palladium catalyzed [3+2] cycloaddition to five–membered rings using

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates trimethylenemethane,237 Barry Trost reported a unique reactivity when a mono–oxa variant was used instead of the full carbon analogue. In this case, reaction with norbornene exhibited selective formation of methylketylcyclopropanes238 (scheme 4.4). Even though the reaction outcome was markedly different, the same type of trimethylenemethanepalladium (oxa––allyl) complex was proposed as intermediate.239

Scheme 4.4 Trost’s methylketylcyclopropanation of norbornene.

Mechanistically related cyclopropanations of norbornene have been reported employing ketone –carbonates,240 5-methylene-1,3-dioxolan-2-ones,241 -(tributylstannyl)alkenyl acetates242 and 3-trimethylsilylallyl acetates.243 More recently, vinyl halides244 and propiolates245 have also been shown to cyclopropanate norbornene in presence of palladium catalysts. In these examples the simple transfer of a methylene unit to the olefin is precluded by the complex nature of the substrates required.

The only example of methylenation of norbornene catalyzed by palladium not using diazomethane was reported by Eric Fillion and Nicholas Taylor in 2003.246 In their study an elaborate iodomethylstannate reacted with Pd0 to form a gem-dimetallic species which showed carbenoid character (Scheme 4.5). In a sealed NMR tube ethylene, iodomethylstannate and formaldehyde (from reaction of the carbenoid with spurious

O2) were detected. Trapping of the carbenoid with norbornene produced the expected methylenation product. However the reaction proved to be of limited practical use since high catalyst loadings (up to 25 mol %) and long reaction times (several days) were needed. Interestingly, the same reactivity was found when Pd(II) complexes were reacted with the bisstannatomethane Me3SnCH2Sn(CH2CH2CH2)3N, strongly suggesting that transmetallation onto a Pd(II) species could also lead to the reactive carbenoid intermediate.

Discovery, Development and Study of Carbenoid Mediated Reactions

Scheme 4.5 Carbenoid character of the product of oxidative addition of iodomethylstannates to palladium zero complexes.

4.2. Cyclopropanation of olefins using halomethylboronates

4.2.1. Our hypothesis

Considering the precedents discussed in the previous sections, we anticipate that the use of halomethylboron reagents such as 82 or 83, together with a palladium–based catalyst would allow us to replace diazomethane or the zinc carbenoids in the methylenation of nucleophilic olefins. Several possible mechanisms for this transformation are deemed possible, however all the functionalities present in both the substrate and the reagent would play a specific role (scheme 4.6). 1) The alkylboron fragment is capable of transferring its alkyl moiety by either intra– or intermolecular247 transmetallation to a PdII species; 2) the halide could act as a leaving group, facilitating a ring closure or the formation of a carbenoid intermediate, or the C–X bond could oxidatively add248 to a Pd0 complex; 3) The olefin can perform a migratory insertion249 or react with a palladium carbenoid, depending on whether an inner121 or an outer120 sphere mechanism is operative.

Scheme 4.6 Proposed cyclopropanation of olefins using halomethylboronate reagents and palladium–based catalysts.

4.2.2. Methylenation of norbornene

Norbornene was chosen as the initial substrate due to the strong metal bonding properties of its strained double bond, and because the single syn –H available after a possible migratory insertion cannot eliminate due to Bredt’s rule.250 Commercially

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates available potassium iodomethyltrifluoroborate was selected as methylene donor due to the high reactivity of the C–I bond towards nucleophilic substitution and oxidative addition.248 Suzuki–Miyaura–type conditions consisting of a combination of water and base in a polar solvent were employed for the in situ activation of the trifluoroborate fragment towards transmetallation.251

Table 4.1 Screening of catalysts for the methylenation of norbornene.a

Entry Catalyst Yieldb Remainingb 86

1 none 0 % 80 %

2 Pd(PPh3)4 6 % 71 %

c 3 Pd(dba)2 + IPr 2 % 81 %

4 Pd(IPr)2 37 % 45 %

5 Pd(P(tBu)3)2 (88) 85 % 15 %

6 PdII-Herrmann (89) 98 % 0 %

7 Pd(IPr)Cl2-dimer (90) 88 % 4 % a Scale: 0.0117 mmnol of 86 at 0.06 M concentration. b Determined by standardized GC-FID. c 0 Pd (dba)2 (5 m0l %) and IPr ligand (6 mol %) were used.

Without a catalyst reaction of 86 with 82c, base and DMF/H2O did not produce the expected exo-tricyclo[3.2.1.0-2,4]octane (87) while most of the starting material could be recovered (Table 4.1, entry 1). The use of zerovalent Pd(PPh3)4 complex or the combination of Pd(dba)2 with 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) ligand yielded 6 and 2% of cyclopropane 87 respectively (entries 2 and 3). An encouragingly better result

252 was observed when the preformed complex Pd(IPr)2 was used, affording 37% of the expected cyclopropane (entry 4). Finally, when the Pd0 complex 88253 bearing two bulky and electron–rich tris(tert-butyl)phosphines was used, a good yield of 85% for 87 as a single isomer was observed (entry 5). Interestingly, the use of two PdII complexes, the

Discovery, Development and Study of Carbenoid Mediated Reactions

254 255 Herrmann catalyst (89) and the Pd(IPr)Cl2-dimer (90), also afforded cyclopropane 87 efficiently, in 98 and 88% yields respectively (entries 6 and 7). It must be noted that in all the reactions presented in table 4.1 extensive formation of palladium black was observed.

Table 4.2 Optimization norbornene methylenation using Pd(P(tBu)3)2 (88) and Hermann (89) catalysts.a

b b Entry Cat. XCH2’B’ Base DMF/H2O Yield Rem. 87

1 89 ICH2BF3K (82c) K2CO3 1/0 25% 56%

2 88 ICH2BF3K (82c) K2CO3 1/0 47% 42%

3 89 ICH2BF3K (82c) None 8/1 24% 54%

4 88 ICH2BF3K (82c) None 8/1 35% 52%

5 89 ICH2BF3K (82c) None 1/0 1% 73%

6 88 ICH2BF3K (82c) None 1/0 87% 7%

c 7 89 ICH2BF3K (82c) K2CO3 8/1 38% 37%

c 8 88 ICH2BF3K (82c) K2CO3 8/1 66% 17%

9 88 BrCH2BF3K (82b) None 1/0 7% 73%

d 10 88 ICH2B(pin) (83c) CsF 1/0 70% 16%

d 11 88 ICH2B(pin) (83c) K2CO3 + CsF 8/1 92% 8% a Scale: 0.0117 mmnol of 86 at 0.06 M concentration. b Determined by standardized GC-FID. c 82c was preactivated with base at 90 °C for 30 min before addition of 86 and catalyst. d 3.0 eqv. of CsF were used. In order to minimize the formation of palladium black, methylenation attempts were conducted under the exclusion of water and/or base. Alternative halomethylboronate reagents were also studied. Contrary to the combined use of water and base (table 4.1, entries 5 and 6), the omission of base or water afforded a significantly lower methylenation yield when both PdII-Herrmann (89) (Table 4.2, entries 1 and 3) and

Pd(P(tBu)3)2 (88) (entries 2 and 4) catalysts were used. Interestingly, when both water and base were excluded, PdII catalyst 89 produced just 1% of 87 (entry 5), while Pd0 catalyst 88 methylenated norbornene 86 efficiently, reaching 87% yield (entry 6). In both cases a very

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates small amount of palladium black was formed. Preactivation of iodomethyltrifluoroborate 82c with K2CO3 and water at 90°C for 30 min prior addition of norbornene and catalyst reduced the yield of 87 drastically (37%) when using catalyst 89 (entry 7) or moderately (66%) when catalyst 88 was used (entry 8). Accordingly, an optimum must exist between the rate of in situ activation of 82c and the hydroxide/fluoride mediated decomposition of catalysts 88 and 89. When bromide was used as nucleofuge (82b), catalyst 88 was able to produce some 87 (7%) in the absence of base and water (entry 9). Finally, when the electrofuge was replaced with a pinacolborane fragment (83c) activation with 3 eqv. of CsF under anhydrous conditions yielded 70% of 87 using catalyst 88 (entry 10) and 92% of 87 when a combination of 1.5 eqv. K2CO3 and 3.0 eqv. CsF were used in presence of water and catalyst 88 (entry 11).

During the optimization experiments it was noted that the results were in general more variable when Pd–black formation was observed, i.e. when base and water were used. The subtle differences between experiments could influence the speed at which this inactive form of Pd is formed and therefore also affect the efficiency of the reaction. For the norbornene substrate the total exclusion of water and base when using catalyst 88 provided both the highest yields as well as the highest reproducibility.

4.2.3. Methylenation of other olefins

After further optimization the methylenation of other electron–rich olefins was deemed possible. Using a combination of 5 mol % of PdII–Herrmann catalyst 89 and an additional 7.5 mol % of tris(o-tolyl)phosphine (93) it was possible to methylenate Z-cyclooctene 90a in 31% yield, with concomitant formation of the exocyclic olefin methylenecyclooctene 92a in 7% at 90 °C (Table 4.3, entry 1). The latter product may arise from a –hydride elimination from one of the possible PdII intermediates (vide infra). Reduction of the catalyst loading to 2 mol % combined with 3 mol % of extra ligand at 65 °C afforded the desired cyclopropane 91a in a slightly increased yield of 36%. More importantly though, the formation of the side product 92a was reduced to just 3% (entry 2). Lower temperatures (45 °C) however failed to produce any significant 91a (entry 3), while catalyst deactivation could be still observed. For instance, when a reaction mixture was left for a prolonged time at room temperature and then heated to 90 °C no product of cyclopropanation was observed. Clearly, catalyst decomposition is operative even at room temperature, while the productive reactions require temperatures of at least 65 °C.

Discovery, Development and Study of Carbenoid Mediated Reactions Reaction of 4-phenyl-1-butene (90b) at 90°C produced a mixture of the desired cyclopropane 91b and the –elimination product 92b in 15 and 20% yields respectively (entry 4). Styrene (69a) could be also methylenated at 90 °C in 21.2% yield. In this case all the possible isomers of the –hydride product could be detected (entry 5). As might be anticipated by the presence of base and a protic solvent in all the reactions reported in table 4.3, extensive formation of Pd–black was observed.

Table 4.3 Methylenation of several electron rich olefins using Hermann catalyst 89.a

Entry Olefin Cyclopropaneb –elimination productsb Rem. (T/°C) 90b

1 58% (90)

2c 61% (65)

3c 97% (45)

4 43% (90)

5 30% (90) 69a a Scale: 0.0117 mmnol of 90 at 0.06 M concentration. b Determined by standardized GC-FID. c 2 mol % of 89 + 3 mol % of 93 were used. The formation of cyclopropanes from different classes of olefins, shown in table 4.3, evidences the generality of this methylenation reaction, however, the low yields and the presence of –elimination products indicates that further catalyst optimization is needed. In order to be able to rationally improve the catalytic system a better

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates mechanistic understanding is required. In the following sections the plausible mechanisms will be discussed and the first evidence gathered so far will be presented.

4.3. Mechanistic considerations

The variety of mechanisms potentially operative for the Pd–catalyzed methylenation of olefins with halomethylboronate reagents have been heuristically classified in figure 4.2. The mechanisms have been arranged according to 1) whether there is an initial olefin coordination or an initial methylene transfer (out of plane axis), 2) whether transmetallation occurs before oxidative addition (PdII catalysis) or vice versa (vertical axis), and 3) whether the reaction proceeds via an outer or inner sphere mechanism (horizontal axis).

Figure 4.2 Heuristic classification of mechanisms for the Pd–catalyzed olefin methylenation.

Several mechanisms are consistent with the methylenation reaction developed (for a list of all mechanisms see reference 256). However, mechanism number V is currently favored (scheme 4.7). This ‘diverted Heck’ mechanism features an initial oxidative addition248 of halomethylboronate reagent 82 to a Pd0 complex 93 to form PdII intermediate 94. Olefin 90 would then coordinate and perform migratory insertion249 to yield intermediate 95, from which intramolecular transmetallation leads to metallacyclobutane 97.257 It is likely that due to the intramolecular character of the transmetallation step, no activation of the BF3 moiety is required (vide supra). Reductive 97

Discovery, Development and Study of Carbenoid Mediated Reactions elimination from 97 produces cyclopropane 91 and regenerates catalyst 93. At least two possible side reactions leading to 92 from intermediates in mechanism V are plausible. –hydride elimination product from 95 followed by allylic protodeboration258 from 96 would produce 92. The second possibility involves –hydride elimination from metallacyclobutane 97 followed by reductive elimination.

Additionally, several pathways for the formation of Pd0 catalysts from PdII precursors have been reported.259 Therefore, the activity of Herrmann catalyst 89 does not necessarily require a mechanism based on PdII catalysis, nor can PdII be ruled out just

0 based on the activity of (tBu3P)2Pd catalyst 88. The complexity of the system and the apparent not linearity of the trends observed so far call for a more detailed mechanistic investigation which could lead to a better understanding of the underlying pathways. Only upon acquisition of this basic knowledge can a rationally design catalyst be proposed.

Scheme 4.7 Proposed mechanism V for the methylenation of olefins catalyzed by Pd0 complexes.

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates 4.3.1. Preliminary mechanistic investigations

Oxidative addition step

In order to experimentally test whether potassium iodomethyltrifluoroborate 82c could

0 0 perform oxidative addition on a Pd complex, (tBu3P)2Pd catalysts 88 was reacted with 82c in anhydrous THF for 1h at 90 °C. The resulting mixture was then diluted with a 1:1 THF:DCM mixture and analyzed by ESI–MS. In the negative ion mode full spectra (figure 4.3) products of oxidative addition are clearly visible. In one case (94b, m/z = 517.0) the ion corresponds directly to the expected product, whereas the peak at m/z = 424.6 (94a) is the result of subsequent exchange of iodide for chloride. Even though there was no explicit chloride source during the reaction, it is possible that HCl traces present in DCM are sufficient to perform such halogen exchange under ESI conditions.

Activation of the most abundant species 94a by CID causes the initial loss of phosphine at lower collision energies (10 V), followed by extrusion of neutral BF3 at higher collision energies (40 V) (Figure 4.4). The ability of the complex 99 to release BF3 in the gas phase without the need of any additional activator, albeit in rather harsh conditions, allows the consideration of a possible intramolecular transmetallation requiring no activation, in solution phase.

Figure 4.3 Full Scan in the negative ion mode showing products of oxidative addition 94a and 94b of 82c in complex 88. Parameters: Spray voltage = -4500 V, Capillary temperature: 170 °C, Collision offset: -50 V, Tube lens: -50 V.

Discovery, Development and Study of Carbenoid Mediated Reactions

Figure 4.4 CID experiment on ion 425. Parameters: Spray voltage = -4500 V, Capillary temperature: 170 °C, Collision Offset: -50 V, Tube Lens: -50 V, Collision gas pressure: 0.5 mTorr, Collision Energy: 10 V (gray spectra, back), 40 V (black spectra, front).

Catalyst decomposition

Aggregation of Pd0 species leading to macroscopic precipitation of Pd–black is a well– known deactivation pathway in most catalytic processes involving Pd catalysis.260 In general, the loss of stabilizing ligands during the catalytic cycle due to simple ligand dissociation or chemical decomposition causes the bare Pd0 atoms to form aggregates which ultimately separate from the reactive phase, effectively removing catalyst from the system.261 In our methylenation reaction, the required conditions to cyclopropanate olefins other than norbornene always lead to the formation of Pd–black. We presume that in these cases catalyst decomposition outcompetes olefin methylenation and this is the reason for the lower conversions obtained with less reactive substrates like cyclooctene. The first hint of the possible fate of the ligands in our system came from a report by Srivastava, who reacted a bisphosphine Pt0 complex (analogous to catalyst 88) with two equivalents of methyliodide in benzene solution262 (scheme 4.8). The product of oxidative addition was found in solution as the dimer 103. Concomitant formation of tris(tert-butyl)methylphosphonium iodide 104 as white solid was also observed. Reductive elimination, forming a phosphonium cation in this case, introduces another pathway for ligand depletion. Formation of phosphonium salts is detrimental for the stability in solution of Pd0 species, because in the absence of stabilizing ligands Pd atoms

100

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates naturally tend to form aggregates. We therefore decided to test whether a process similar to the one observed by Srivastava is operative under our catalytic conditions.

Scheme 4.8 Srivastava’s reaction of (tBu3P)2Pt with CH3I resulting in the formation of phosphonium salt 104.262

In a closed NMR tube, methylenation of norbornene (86) was performed with potassium

0 iodomethyltrifuoroborate (82c) catalyzed by 20 mol % of Pd catalyst 88 in DMF-d7 (figure 4.5). The 1H and 31P NMR spectra of the reaction mixture measured immediately after mixing show signals corresponding only to the starting compounds. After heating the mixture for 1h at 65 °C palladium black formation was clearly observed. The 1H NMR spectrum evidences the formation of the cyclopropanation product 87 (multiplet signals around 0 ppm); while the fate of the catalyst is apparent in the 31P NMR spectrum. The sole signal detected after 1 h of reaction corresponds to phosphonium salt 104, while nothing of the starting phosphine complex was left in solution. Curiously, even though there was no added protic solvent, the moisture present in the NMR solvent is enough to hydrolyze the C–BF3 bond leading to the observed methylphosphonium salt.

Formation of the observed phosphonium salt could occur via two main mechanisms, direct alkylation or metal catalyzed phosphonium salt formation. Simple dissociation of the ligand upon oxidative addition, forming complex 94 as observed in the gas phase, would allow direct alkylation of the phosphine with iodomethyltrifluoroborate 82c. An independent experiment where tris(tert-butyl)phosphine was reacted with excess 82c in DMF showed total conversion into 104 after prolonged heating (overnight). However, under catalytic conditions, formation of phosphonium salt 104 was observed after just 1h, indicating a clear participation of the palladium catalyst in this transformation. Scrambling of aryl groups between Pd and P in cross-coupling reactions is a known source of side products. Aryl-aryl exchange has been reported to proceed via a phosphonium intermediate: the product of reductive elimination of the phosphine with an additional aryl moiety.263 Aryl phosphines bearing electron donating groups were reported to facilitate the scramble by stabilizing the phosphonium intermediate. In fact, Charette has shown that the Pd–catalyzed formation of phosphonium salts can be used in a preparative manner.264 Although little is known about the behavior of alkyl

101

Discovery, Development and Study of Carbenoid Mediated Reactions phosphines in such reactions, it is likely that their increased donor capabilities favor the formation of more stable phosphonium salts. Similarly, a recent report found that reductive elimination of carbene (NHC) ligands with alkyl substituents from PdII complexes is a low energy deactivation pathway for this kind of complexes.265

Figure 4.5 NMR evidence for the formation of phosphonium salt 104 under catalytic conditions. Bottom: spectra measured right after mixing. Top: After 1h heating at 65 °C. The 1H NMR section showing 87 formation has been magnified compared to the rest of the spectrum.

4.4. Discussion

The importance of the Pd–catalyzed C–C bond formation has been recognized with the 2010 Nobel prize in chemistry awarded to professors Richard Heck, Ei-ichi Negishi and Akira Suzuki for the development of the cross coupling reactions that today bear their names266 (section 4.1.2). Although immensely useful, Pd–catalyzed C–C bond formation does not limit itself to cross coupling reactions. As we have seen, Pd catalysis can also be used to prepare precisely–controlled polyethylene, with the post–metallocene Brookhart catalysts. On the other hand, excluding the well–documented decomposition of diazocompounds,267 including diazomethane,268 there are relatively few examples of cyclopropane synthesis catalyzed by Pd. In most cases,237-245 the intermediacy of a (oxo)––allyl species is proposed, which in turn rules out the possibility of transferring a

102

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates simple methylene unit (scheme 4.4). Only Fillion’s halomethylstannates have been reported to methylenate norbornene to some extent.246

The methylenation reported herein seems to diverge mechanistically from the previously reported instances, bearing some resemblance only to Fillion’s example. Initial ESI-MS evidence confirms that oxidative addition of halomethylboronate reagents 82 and 83 to

0 Pd complex 88 is possible, furthermore the release of neutral BF3 upon CID activation was also observed in the gas phase. These observations support two of the critical steps involved in the preferred mechanism V (scheme 4.7); specifically, oxidative addition248 of the halomethylboronate reagent to a Pd0 complex and intramolecular transmetallation. All of the research on Pd–catalyzed polymerization of olefins supports a possible

249 migratory insertion of the coordinated olefin into the Pd–CH2’B’ bond. Finally, reductive elimination is the productive step in many of the known cross coupling methodologies, and has been also proposed as the last step in the cyclopropanation of olefins with diazomethane occurring via an inner sphere mechanism (see section 1.1.8).

Although the yields for cyclopropanation of olefins other than norbornene by our method are low to moderate, and the concomitant formation of byproducts is significant, it must be noted this is the first time a Pd catalyzed methylenation not employing diazomethane has been observed for substrates other than highly strained olefins. The higher reactivity of norbornene can be explained by two factors. First, the strained nature of the double bond makes this olefin a particularly good ligand, which in turn could also stabilize Pd0 in solution, for example complexes of the type

0 269 (norbornene)3Pd have been isolated. Second, norbornene avoids the formation of byproducts altogether due to the fact that the only syn –hydrogen available after migratory insertion is configurationally inaccessible (vide infra) and cannot be eliminated due to Bredt’s rule.250 This favorable combination of characteristics makes norbornene the perfect substrate for reaction discovery, and could explain its prevalence in all previous reports. However, norbornene also masks the inherent problems associated with olefins which are neither strong donors nor inert towards –hydride elimination.

Less configurationally hindered substrates, particularly –olefins, can locate thier – hydrogen in the necessary coplanar conformation for –hydride abstraction.270 Even though the syn configuration characteristic of migratory insertions271 forms an intermediate that should favor the subsequent intramolecular transmetallation where

103

Discovery, Development and Study of Carbenoid Mediated Reactions the –hydrogen is not in plane with the free coordination site on the metal, the reaction conditions, e.g. elevated temperatures, enable conformational changes in the system that could bring –hydrogens close to the metal and result in the formation of byproducts (scheme 4.9). As seen from the results on the cyclopropanation of cyclooctene (Table 4.3 entry 2 vs entry 1) the selectivity of the developed methylenation can be controlled to a certain degree by reduction of the reaction temperature.

Scheme 4.9 Conformational arguments on proposed intermediates favoring –hydride elimination under forcing conditions.

Even though attempts to perform this methylenation at lower temperatures were made, the minimum temperature at which cyclopropanation was observed was 65 °C. Lower temperatures only produced catalyst decomposition, which was found to be still operative at room temperature. The delicate balance of processes acting simultaneously require a better understanding of their reaction mechanisms in order to rationally propose an improved catalytic system. Of particular importance is the study of catalyst decomposition pathways and their prevention.

4.5. Conclusions

Taking advantage of the versatile Pd catalysis a new cyclopropanation method for electron rich olefins has been developed. Commercially available halomethylboronate reagents replace explosive diazomethane or the potentially toxic zinc carbenoids and provide an alternative for this important transformation. Conditions for the efficient methylenation of norbornene were found. Curiously, both Pd0 and PdII complexes can catalyze this transformation. Preliminary evidence favors a mechanism mediated by an initial Pd0 species which follows a ‘Diverted Heck’ mechanism in which after oxidative addition of the halomethylboronate substrate, olefin coordination and subsequent

104

4. Palladium catalyzed cyclopropanation of olefins using halomethyborates migratory insertion lead to a Pd––boronate intermediate. This species could then undergo an intramolecular transmetallation to form a palladacyclobutane from which reductive elimination forms the desired cyclopropane and regenerates the starting Pd0 catalyst. The formation of a Pd0 species from PdII precatalysts is a common phenomenon in homogeneous catalysis, and could explain the activity of the PdII-Herrmann catalyst when a protic solvent and base are present.

Methylenation of different olefins was found to be feasible after further optimization, however the concomitant formation of –hydride elimination products was also observed. Less rigid olefins can perform conformational changes when sufficient energy is available in the system thus positioning the –hydrogen atom close to the Pd center. After this configuration is reached, the thermodynamics of -hydride elimination favor the formation of side products. The competition between transmetallation and – hydride elimination determines the ratio of product to byproduct obtained. Temperature control allows certain control over the outcome of the reaction, but limited reactivity at lower temperatures becomes problematic.

Chemical decomposition of the supporting ligand was found under catalytic conditions and it is likely the major reason for the catalyst decomposition observed, i.e. aggregation of Pd0 species into inactive Pd–black. Formation of phosphonium salts by reductive elimination of phosphines and an alkyl group in palladium is a known process.

Better mechanistic understanding of this transformation is the best strategy to optimize the catalytic system towards higher conversions and better selectivities.

4.6. Acknowledgments

Dr. Tim den Hartog contributed equally to the development of the chemistry described in this chapter.

105

106

5. Conclusions and Outlook

In the first part of this dissertation (chapter 2) the use of a sulfonate as the chelating– anchoring group of a bidentate phosphine in ruthenium benzylidene complexes used as catalysts for the alternating ring opening metathesis polymerization of norbornene and cyclooctene was evaluated. It was found that the sulfonate group led to a more active, as well as more chemo– and stereoselective catalyst in comparison to the analogous catalyst containing a phenolate as anchoring group. The effects on chemo– and stereoselectivity could be accounted for by close examination of the solid–state molecular structures determined by X-Ray crystallography. Complementarily, computational calculation of the catalyst commitment by DFT methods aided the understanding of the greatly increased reactivity of the sulfonate–bearing catalyst. On the basis of the reduced trans influence of the sulfonate group, compared to a phenolate, it was expected that bulky anions would form stronger bonds with the more electron deficient ruthenium center and higher stereoselectivities could be attained. Indeed, both polymerization results and solid–state molecular structures obtained with catalysts in which the chloride anion was replaced by a bulky arylsulfonate supported our hypothesis. However, even though the stereoselectivity was enhanced, a concomitant detriment in activity and chemoselectivity was also observed. It appears as if a limit in the possible optimization of the current catalyst framework has been reached. If total control of stereoselectivity of the produced polymer is required, recently reported catalysts based on a chelating dithiocatecholates can be employed.60 Structural modifications of those base structures, like the incorporation of an asymmetrically substituted NHC ligand, could potentially lead to the induction of chemoselectivity150 on the already highly stereoselective systems.

Figure 5.1 Concept for a potentially highly Z-selective catalyst for A-ROMP.

In the second part of this dissertation (chapters 3 and 4) novel approaches for methylene transfer were studied. The use of solubilizing anions like BArF and trifluoromethylsulfonate in tetramethylammonium salts allowed the straightforward and reliable synthesis of lithiomethyltrimethylammonium reagents in THF solution. For

107

Discovery, Development and Study of Carbenoid Mediated Reactions the first time traditional solution–phase NMR could be used for the structural characterization of this species. It was determined that lithium coordination was essential to stabilize the resulting highly–localized carbanion which more closely resembles an organolithium than a traditional ylide. Soluble lithiomethyltrimethylammonium reagents were shown to nucleophilically add to aldehydes, kenotes and imines followed by intramolecular ring closure to form epoxides and aziridines respectively, in analogy to sulfur ylides, i.e. the Corey–Chaykovsky reagent. Interestingly the soluble ‘N-C–ylide’ can also add to styrenes and stilbenes which after closure yield cyclopropanes. Competition experiments supported our proposed carbolithiation–ring closure mechanism. Even though several electron rich styrenes and stilbenes could be successfully cyclopropanated, fully non–activated olefins like cyclohexene were unreactive in this reaction. In fact, carbolithiation of olefins other than styrene or styrene derivatives is an unknown process. However, recent advances on alkene activation by coordinatively unsaturated lithium cations in toluene solution points at the possibility of organolithium addition of simple olefins as in the case of anionic polymerization of isobutylene initiated by nBuLi. ii If this concept could be extrapolated to the addition of our ‘N–C ylide’ reagent the nucleophilic cyclopropanation of non–activated olefins could be envisioned.

Scheme 5.1 Proposed nucleophilic cyclopropanation of simple olefins catalyzed by Li+.

In chapter 4, a mechanistically novel cyclopropanation mediated by Pd catalysts is described. In this case, commercially available potassium halomethyltrifluoroborate and halomethyl pinacolboranes are used as methylene sources. After optimization of the reaction using norbornene as substrate it was found that PdII catalysts required activation with water/methanol and an external base, while Pd0 complexes could catalyze the methylenation without the need of activators. This evidence, together with the gas–phase observation of the product of oxidative addition of the halomethyltrifluoroborate on a Pd0 complex, favors a diverted Heck mechanism involving a Pd0–PdII cycle. Methylenation attempts of less strained olefins capable of -

ii As described by Prof. Dr. Josef Michl on a private communication to Prof. Dr. Peter Chen. 108

5. Conclusions and Outlook hydride elimination gave rise to the formation of byproducts that lowered the efficiency of this reaction. Additionally, when these olefins were used, competitive catalyst decomposition became an issue. It was noted that reductive elimination of phosphonium salts effectively removed the supporting ligand from the solution promoting the formation of palladium black. A ligand system with the appropriate balance between electronic donor strength, to favor the oxidative addition of the alkyl halide, and steric hindrance, to avoid its reductive elimination to phosphonium salts, is therefore required. Diligent efforts on this regard are underway in our group. Alternatively, based on Fillion’s stoichiometric cyclopropanation of norbornene with mixed bisstannates246 a mechanism based on a two sequential transmetallation steps followed by reductive elimination, coupled with an external oxidant could provide an alternative that avoids the need for very electron rich phosphines.

Scheme 5.2 Proposed cyclopropanation of olefins with a bisboronate reagent272 mediated by Pd using a stoichiometric oxidant.

Continuous evaluation of alternative mechanistic concepts is an essential part of the research culture at the Chen group, one that has led to significant advances in the understanding of established processes as well as the discovery of new reactivity. It is expected that the continuation of this tradition will overcome the present difficulties generating concepts and processes of great value to all the scientific community.

109

110

6. Experimental Part

6.1. General Remarks

Unless otherwise stated, all the manipulations were carried out under argon atmosphere on a vacuum line using standard Schlenk techniques or under a nitrogen atmosphere inside a BRAUN drybox. The solvents were dried by distillation from the appropriate drying agents prior use273 and were transferred under nitrogen. NMR measurements were performed either on a Varian Gemini 300 MHz (1H 300, 13C 75, 31P 121 MHz), Bruker Advance 400 MHz (1H 400, 13C 100, 31P 160, 19F 376 MHz), Varian DRX500 500 MHz (1H 500, 13C 126, 15N 50 MHz), Bruker Advance 500 MHz (1H 500, 6Li 73.62 MHz) or Bruker Advance 600 MHz (1H 600, 13C 150 MHz) instruments. Chemical shifts (δ values) are reported in ppm referenced to tetramethylsilane and calibrated with respect to the residual solvent

1 13 signal for H and C NMR (CD2Cl2: 5.32 and 53.80 ppm; CDCl3: 7.26 and 77.00 ppm, THF-d8:

31 19 15 6 3.58 and 67.57 ppm, CD3OD: 3.31 and 49.00 ppm) or uncorrected for P, F, N and Li NMR. Coupling constants are reported in Hz. 13C and 31P NMR spectra were proton broadband decoupled. The multiplicities of the peaks are denoted as follows: (s) singlet, (d) doublet, (t) triplet, (q) quadruplet and (m) multiplet. Elemental analyses were performed by the Mikroelementaranalytisches Laboratorium der ETHZ. Melting points were measured on a Büchi melting point apparatus and are uncorrected. GC analysis was performed on a Finnigan Focus CG with a Zebron ZB-5MS, 30m*0.25 mm column using a flame ionization detector. GC-MS was performed on a Thermo-Finnigan Trace GC [SN17479]- MS[SN20015483] equipped with a Zebron ZB-5MS, 30m*0.25mm column using electron impact ionization (70 eV). Electrospray ionization (ESI) MS analysis was performed on a Thermo Finnigan TSQ Quantum.

Compunds tert-butylphenylphosphorus chloride,274 (1-adamantyl)phenylphosphorus

57b 57b 36 chloride, neopentylphenylphosphorus chloride, [PPh3Ru(=CH(o-O-i-Pr)Ph)Cl] (15), silver salts of sulfonate ligands 7b, 7c and 7d,57a sodium tetrakis(3,5- bis(trifluoromethyl)phenyl)borate (NaBArF),275 copper complexes 72a,276 72b277 and 72c,278

0 252 0 253 Pd (IPr)2, Pd (P(tBu)3)2 (88), di--acetatobis[2-(di-o-

II 279 tolylphosphino)benzyl]dipalladium(II) (Pd -Herrmann catalyst 89), Pd(IPr)Cl2-dimer (90),255 were prepared according to reported procedures. Silver p-toluenesulfonate 7a, diisopropylethylamine, cis-cyclooctene, undecane, phenethylbromide, cyclooctene (90a), styrene (69a) were purchased from Fluka and used without further purification. nBuLi

(1.6M), ClPCy2, norbornene, NMe4I, benzophenone, butyrophenone, 5-nonanone,

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Discovery, Development and Study of Carbenoid Mediated Reactions benzylideneaniline, benzylidene-tert-butylamine, 12-crown-4, 1,3-bis(2,6- diisopropylphenyl)imidazol-2-ylidene(Acetonitrile)gold(I) tetrafluoroborate (80), authentic cyclopropylbenzene (71a), authentic prop-1-en-2-ylbenzene (92ca), authentic (E)-prop-1-en-1-ylbenzene (92cc), tetramethylethylenediamine (TMEDA), magnesium

0 chips, K2CO3, norbornene (86), 4-phenyl-1-butene (90b), Pd (dba)2 were purchased from

Aldrich and used as received. NMe4Cl, allylbenzene (92cd), allylbromide (stabilized), CsF,

0 Pd (PPh3)4, tri-(o-tolyl)phosphine (93) were purchased from Acros Organics. Cyclopropyl- 4-mehoxyphenyl ketone was purchased from ABCR chemicals and used without further purification. 3-phenylpropionaldehyde, authentic (Z)-prop-1-en-1-ylbenzene (92cb), potassium iodomethyltrifluoroborate (82c), potassium bromomethyltrifluoroborate (82b), 1,3-bis(2,6-diisopropylphenyl)imidazol-2-ylidene (IPr) ligand were purchased from TCI-Deutschland and used without further purification. 1-Bromomethylcyclopropane was purchased from Maybridge and used as received. 2-(iodomethyl)-4,4,5,5,- tetramethyl-1,3,2-dioxaborolane (83c) was purchased from Combi–Blocks Inc. and used without further purification.

6.2. Ruthenium Catalyzed Ring Opening Metathesis Polymerization (Chapter 2)

6.2.1. Polymerization experiments

Norbornene (NBE) (approximately 150 mg, 1.59 mmol) was placed in a Schlenk flask along with 20 or 50 equivalents of cyclooctene (COE) and the volume completed to 20 mL with anhydrous dichloromethane (DCM), the catalyst was added then as a DCM solution to achieve a NBE/catalyst ratio of 1:1000. For the experiments carried out at temperatures other than room temperature, the flasks were placed in cooling baths whose temperature was adjusted accordingly and stirred for 10 minutes prior to the addition of the catalyst. The polymerizations were stopped by precipitation of the polymer with methanol. After 5 minutes of stirring the polymer was filtered and washed with methanol. After a minimum of 2 hours of drying on the high vacuum, a sample of around

40 mg of polymer was dissolved in CDCl3 and analyzed by NMR spectroscopy.

112

6. Experimental Part 6.2.2. Synthesis of ligands and complexes

2-(tert-Butylphenylphosphino)benzenesulfonic Acid (13a): Anhydrous benzenosulfonic acid (7.79 g, 45 mmol) was dissolved in anhydrous tetrahydrofuran (THF) (50 ml). nBuLi (53 mL, 90.6 mmol, ~1,71 M in hexane) was added over at 0 °C and the reaction stirred overnight, during this time the mixture reached room temperature. A white precipitate was formed during the reaction. A solution of tert-butylphenylphosphorus chloride in THF (9.10 g, 45 mmol) was then added dropwise at room temperature to the reaction mixture, during the addition the white precipitate dissolved and a dark brown solution was obtained. After 30 min stirring the solvent was removed in vacuo. Degassed water (80 mL) was used to dissolve the residual dark oil, then degassed DCM (60 mL) was added and the mixture was acidified with concentrated HCl until it became acidic as checked with tornasol paper. The organic layer was then separated and the aqueous phase was washed with DCM (2x50 mL). The DCM washings were collected and concentrated to an approximate volume of 50 mL and then cooled down to 0 °C to induce crystallization. The white crystals obtained in this way were washed with a minimal amount of ice-cold DCM and then dried on the high vacuum. Yield = 9.52 g (61.6 %). 1H

NMR (400 MHz, CD2Cl2) δ 8.34 – 8.27 (m, 1H), 7.99 – 7.90 (m, 3H), 7.80 (dd, JH,H = 14.6, 7.0

3 13 Hz, 2H), 7.71 – 7.63 (m, 3H), 1.56 (d, JH,P = 18.5 Hz, 9H). C NMR (100 MHz, CD2Cl2) δ

152.91 (s, 1C), 134.60 (d, 2C, JC,P = 10.3 Hz), 133.59 (d, 2C, JC,P = 8.8 Hz), 132.24 (d, 1C, JC,P = 7.4

Hz), 130.16 (d, 2C, JC,P = 12.5 Hz), 129.55 (d, 1C, JC,P = 11.3 Hz), 128.95 (d, 1C, JC,P = 7.8 Hz), 116.63

31 (d, 1C, JC,P = 77.6 Hz), 113.70 (d, 1C, JC,P = 82.3 Hz), 32.96 (d, 1C, JC,P = 41.4 Hz), 26.39 (s, 3C). P

NMR (162 MHz, CD2Cl2) δ 19.09 (s).

Sodium 2-(tert-Butylphenylphosphino)benzenesulfonate (14): Reaction of NaOH (0.132 g, 3.30 mmol) with 13a (1.016 g, 3.15 mmol) in methanol afforded the corresponding sodium benzenosulfonic salt in quantitative yield. After solvent removal the product was dried overnight P

31 on the high vacuum. P NMR (121 MHz, CD2Cl2): δ 6.31 (s). SO3Na

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Discovery, Development and Study of Carbenoid Mediated Reactions

[rac-(tBuPhP(o-SO3Ph))Ru(=CH(o-O-i-Pr)Ph)Cl] (17): In a tube shaped Schlenk bomb, solutions of 15 (51.68 mg, 0.088 mmol) and 14 (34.49 mg, 0.100 mmol) in approximately 20 mL of DCM where mixed. After closing the bomb, the mixture was heated to 50 °C for 8 hours, after this time the solution became dark green. Anhydrous CuCl

(17.6 mg, 0.18 mmol) was added in order to scavenge the PPh3 that should be released from the precursor complex, the reaction mixture was then stirred and heated at 40 °C for 14 h, the color of the solution changed to dark brown. The mixture was filtered to remove the excess CuCl, then the solvent was evaporated at reduced pressure and the mixture redissolved in a 1:1 mixture

Acetone/Hexane. In this way, a white precipitate of Cu(PPh3)n complexes was separated by filtration. Finally, the complex was passed through a short column of activated silica using a mixture 80:20 DCM/diethylether as eluent. X-Ray quality crystals were grown by

1 diffusion of diethylether into a DCM solution of the complex. H NMR (600 MHz, CD2Cl2)

δ 17.06 (d, JH,P = 8.0 Hz, 1H(Ru=CHAr)), 8.10 – 8.07 (m, 1H(Ph)), 7.71 – 7.67 (m, 1H(Ph)), 7.63 – 7.54 (m, 5H(Ph)), 7.52 – 7.48 (m, 2H(Ph)), 7.46 – 7.42 (m, 1H(Ph)), 7.23 (dd, J = 7.6, 1.7 Hz, 1H(Ph)), 7.20 (d, J = 8.5 Hz, 1H(Ph)), 7.05 (td, J = 7.4, 0.8 Hz, 1H(Ph)), 5.44 – 5.37 (m,

1H((CH3)2CHOAr)), 1.94 (d, JH,H = 6.4 Hz, 3H((CH3)2CHOAr)), 1.73 (d, JH,H = 6.3 Hz,

13 3H((CH3)2CHOAr)), 1.59 (d, JH,P = 15.3 Hz, 9H(t-BuP)). C NMR (151 MHz, CD2Cl2) δ 310.21 (s, 1C

(Ru=C)), 155.83 (d, JC,P = 1.5 Hz, 1C (Ph)), 145.19 (d, JC,P = 10.6 Hz, 1C (Ph)), 143.94 (s, 1C (Ph)),

136.07 (s, 1C (Ph)), 133.04 (d, JC,P = 8.0 Hz, 2C (Ph)), 132.22 (d, JC,P = 44.6 Hz, 1C (Ph)), 131.42 (s,

1C (Ph)), 130.70 (d, JC,P = 2.0 Hz, 1C (Ph)), 130.58 (d, JC,P = 5.8 Hz, 1C (Ph)), 130.15 (d, JC,P = 2.6 Hz,

1C (Ph)), 128.38 (d, JC,P = 9.7 Hz, 2C (Ph)), 128.02 (d, JC,P = 38.3 Hz, 1C (Ph)), 126.69 (d, JC,P = 6.6

Hz, 1C (Ph)), 123.84 (s, 1C (Ph)), 122.43 (s, 1C (Ph)), 113.47 (s, 1C (Ph)), 77.54 (s, 1C ((CH3)2CHO)),

37.61 (d, JC,P = 26.7 Hz, 1C (CH3)3CP)), 28.94 (d, JC,P = 3.8 Hz, 3C ((CH3)3CP)), 21.40 (s, 1C

31 ((CH3)2CHO)), 21.25 (s, 1C ((CH3)2CHO)). P NMR (121 MHz, CD2Cl2) δ 66.79 (s). Elemental analysis: calc. (%) for C26H30O4PSClRu (606.08 g/mol) C 51.53, H 4.99, P 5.11, found C 51.30, H 5.04, P 5.13. High resolution MALDI-MS: (M+Na)+, expected 571.0646, found 571.0648.

114

6. Experimental Part 2-(dicyclohexylphosphino)benzenesulfonic acid (13b):

Was synthesized analogously to 13a, from benzenesulfonic (378.5 mg, 2.39 mmol), nBuLi (2.82 mL, 1.69 M, 4.78 mmol) and chlorodicyclohexylphosphine (500 mg, 2.15 mmol). Yield: 750 mg

1 (98%) of a white powder. H NMR (400 MHz, CD2Cl2) δ 8.15 (s, 1H, Ph),

7.81 (s, 1H, Ph), 7.62 – 7.47 (m, 2H, Cy2P), 2.26 (s, 2H, Cy2P), 1.96 – 1.60

31 (m, 9H, Cy2P), 1.59 – 0.93 (m, 12H, Cy2P). P NMR (162 MHz, CD2Cl2) δ 51.85, 19.92. These two signals are associated to an equilibrium between the phosphonium and the free acid form of the phosphine.

2-(1-adamantyl(phenyl)phosphino)benzenesulfonic acid (13c):

Was synthesized analogously to 13a, from benzenesulfonic (170.55 mg, 1.08 mmol), nBuLi (1.34 mL, 1.6 M, 2.14 mmol) and (1- adamantyl)phenylphosphorus chloride (301.55 mg, 1.08 mmol). Yield: 89.7 mg (21%) of a white powder. 1H NMR (300 MHz, DMSO) δ 8.20 (t, J = 8.7 Hz, 1H, Ph), 8.07 – 7.92 (m, 3H, Ph), 7.78 – 7.57 (m, 5H, Ph), 2.10 – 1.89 (m, 9H, Adm), 1.76 – 1.60 (m, 6H, Adm). 31P NMR (122 MHz, DMSO) δ 12.87.

2-(neopentyl(phenyl)phosphino)benzenesulfonic acid (13d):

Was synthesized analogously to 13a, from benzenesulfonic (1.4974 g, 9.47 mmol), nBuLi (11.72 mL, 1.6 M, 18.75 mmol) and (neopentyl)phenylphosphorus chloride (1.6109 g, 7.50 mmol). Yield: 608.3 mg (24%) of a white powder. 31P NMR (121 MHz, DMSO) δ 20.53.

General procedure for anion exchange on parent complex 17

Complex 17 (3 mg, 5 mol) was dissolved in 1 mL DCM. The silver salt of a sulfonate ligand (1.1 eqv. 5.5 mol) was dissolved in 1 mL DCM and added over the reaction mixture in the dark. After 2 hour stirring the mixture was filtered through a small plug of celite and the solvent evaporated. The complexes were then recrystallized by slow diffusion of diethylether into a saturated DCM solution.

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Discovery, Development and Study of Carbenoid Mediated Reactions Complex 22a:

1 H NMR (600 MHz, CD2Cl2) δ 17.63 (apparentdd, JH,P = 7.8, J =0.8 Hz, 1H (Ru=CHAr)), 8.03 (dddd, J = 7.8, 3.6, 1.5, 0.4 Hz, 1H (Ph)), 7.67 (dddd, J = 8.5, 7.3, 1.7, 0.6 Hz, 1H (Ph)), 7.65 – 7.62 (m, 1H (Ph)), 7.59 (tt, J = 7.7, 1.4 Hz, 1H (Ph)), 7.56 – 7.47 (m, 5H (Ph)), 7.41 – 7.37 (m, 1H (Ph)), 7.32 (dd, J = 7.6, 1.7 Hz, 1H (Ph)), 7.25 (dt, J = 8.0, 0.4 Hz, 1H (Ph)), 7.11 (td, J = 7.4, 0.8 Hz, 1H (Ph)), 7.06 – 7.04 (m, 1H (Ph)), 7.04 – 7.02 (m, 2H (Ph)), 5.06 – 5.01 (m, 1H

((CH3)CHO)), 2.32 (s, 3H (CH3Ar)), 1.96 (d, JH,H = 6.3 Hz, 3H ((CH3)CHO)), 1.60 (d, JH,H = 6.2 Hz,

13 3H ((CH3)CHO)), 1.42 (d, JH,P = 15.2 Hz, 9H (t-BuP)). C NMR (151 MHz, CD2Cl2) δ <310 (s, 1C

(Ru=C)), 158.25 (d, JC,P = 1.5 Hz 1C (Ph)), 145.24 (d, JC,P = 10.4 Hz 1C (Ph)), 145.03 (s, 1C (Ph)),

141.55 (s, 1C (Ph)), 139.91 (s, 1C (Ph)), 136.76 (s, 1C (Ph)), 133.91 (d, JC,P = 8.2 Hz, 2C (Ph)), 133.26

(s, 1C (Ph)), 131.85 (d, JC,P = 6.0 Hz, 1C (Ph)), 131.65 (s, 1C (Ph)), 131.35 (seen as half a doublet, it overlaps with next signal, 1C (Ph)) , 131.19 (d, JC,P = 2.7 Hz, 1C (Ph)), 129.41 (d, JC,P = 9.9 Hz, 2C

(Ph)), 129.09 (s, 2C (Ph)), 128.59 (d, JC,P = 39.9 Hz, 1C (Ph)), 127.57 (d, JC,P = 6.6 Hz, 1C (Ph)), 126.71 (s, 2C (Ph)), 125.00 (s, 1C (Ph)), 123.25 (s, 1C (Ph)), 113.79 (s, 1C (Ph)), 78.55 (s, 1C

((CH3)2CHO)), 37.05 (d, JC,P = 25.7 Hz, 1C ((CH3)3CP)), 29.41 (d, JC,P = 3.8 Hz, 3C ((CH3)3CP)), 21.61

31 (s, 2C (CH3)2CHO), 21.57 (s, 1C (CH3Ar)). P NMR (122 MHz, CD2Cl2) δ 62.53.

Complex 22b:

1 H NMR (600 MHz, CD2Cl2) δ 17.70 (apparentdd, JH,P = 8.1, J = 0.8 Hz, 1H (Ru=CHAr), 8.06 – 8.03 (m, 1H (Ph)), 7.66 – 7.63 (m, 1H (Ph)), 7.62 – 7.57 (m, 2H (Ph)), 7.54 – 7.50 (m, 1H (Ph)), 7.50 – 7.43 (m, 5H (Ph)), 7.38 – 7.33 (m, 2H (Ph)), 7.13 – 7.09 (m, 2H (Ph)), 6.73

(dd, J = 1.2, 0.7 Hz, 2H (Ph)), 5.17 – 5.11 (m, 1H ((CH3)2CHO)), 2.32

(s, 6H (ortho(CH3)2Ar)), 2.20 (s, 3H (paraCH3Ar)), 1.94 (d, J = 6.4 Hz,

13 3H ((CH3)CHO)), 1.57 (d, J = 6.3 Hz, 3H ((CH3)2CHO)), 1.30 (d, J = 15.3 Hz, 9H (t-BuP)). C NMR

(151 MHz, CD2Cl2) δ 324.56 (apparentt, JC,P = 13.3 Hz (Ru=CHAr)), 157.60 (s, 1C (Ph)), 145.56 (d, JC,P = 10.5 Hz, 1C (Ph)), 145.19 (s, 1C (Ph)), 140.17 (s, 1C (Ph)), 138.62 (s, 1C (Ph)), 137.35 (s, 1C (Ph)),

136.66 (s, 1C (Ph)), 133.74 (d, JC,P = 8.0 Hz, 2C (Ph)), 132.96 (s, 1C (Ph)), 132.23 (d, JC,P = 45.7 Hz,

1C (Ph)), 131.75 (d, JC,P = 12.9 Hz, 1C (Ph)), 131.69 (d, JC,P = 2.9 Hz, 1C (Ph)), 131.60 (d, JC,P = 10.8

Hz, 1C (Ph)), 131.11 (s, 2C (Ph)), 129.38 (d, JC,P = 9.7 Hz, 2C (Ph)), 128.74 (d, JC,P = 39.9 Hz, 1C (Ph)),

127.69 (d, JC,P = 6.6 Hz, 1C (Ph)), 124.91 (s, 1C (Ph)), 123.37 (s, 1C (Ph)), 114.46 (s, 1C (Ph)), 78.63

(s, 1C ((CH3)2CHO)), 36.18 (d, JC,P = 25.6 Hz, 1C ((CH3)3CP)), 29.06 (d, JC,P = 3.9 Hz, 3C ((CH3)3CP)),

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6. Experimental Part

23.02 (s, 2C (ortho(CH3)2Ar)) , 21.67 (s, 1C ((CH3)CHO))), 21.49 (s, 1C ((CH3)CHO))), 21.05 (s, 1C

31 (paraCH3Ar)). P NMR (121 MHz, C6D6) δ 64.86.

Complex 22c:

1 H NMR (600 MHz, CD2Cl2) δ 17.70 (apparentdd, JH,P = 8.0, J = 0.8 Hz, 1H), 8.05 – 8.01 (m, 1H (Ph)), 7.68 (dddd, J = 8.4, 7.3, 1.7, 0.6 Hz, 1H (Ph)), 7.62 – 7.56 (m, 2H (Ph)), 7.53 – 7.43 (m, 5H (Ph)), 7.38 (dd, J = 7.6, 1.7 Hz, 1H (Ph)), 7.36 – 7.32 (m, 1H (Ph)), 7.18 (dd, J = 8.3, 0.9 Hz, 1H (Ph)), 7.14 (td, J = 7.4, 0.8 Hz, 1H (Ph)),

7.00 (d, J = 0.5 Hz, 2H (Ph)), 5.28 – 5.20 (m, 1H ((CH3)2CHO)),

3.99 (hept, J = 6.8 Hz, 2H (ortho(CH3)2CHAr)), 2.88 – 2.78 (m, 1H (para(CH3)2CHAr)), 1.89 (d, J =

6.4 Hz, 3H ((CH3)2CHO)), 1.60 (d, J = 6.3 Hz, 3H ((CH3)2CHO)), 1.31 (d, J = 15.2 Hz, 9H (t-BuP)),

1.20 (d, J = 6.9 Hz, 6H ((CH3)2CHAr)), 1.11 (d, J = 6.8 Hz, 6H ((CH3)2CHAr)), 1.09 (d, J = 6.8 Hz,

13 6H ((CH3)2CHAr)). C NMR (151 MHz, CD2Cl2) δ 324.75 (apparentt, JC,P = 13.5 Hz, 1C (Ru=CHAr),

157.73 (s, 1C (Ph)), 151.07 (s, 1C (Ph)), 148.33 (s, 2C (Ph)), 145.39 (d, JC,P = 10.4 Hz, 1C (Ph)), 145.08

(s, 1C (Ph)), 137.33 (s, 1C (Ph)), 136.66 (s, 1C (Ph)), 133.78 (d, JC,P = 8.0 Hz, 2C (Ph)), 133.06 (s, 1C

(Ph)), 132.14 (d, JC,P = 45.4 Hz, 1C (Ph)), 131.84 – 131.56 (m, 2C (Ph)), 131.17 (d, JC,P = 2.7 Hz, 1C

(Ph)), 129.40 (d, JC,P = 9.8 Hz, 2C (Ph)), 128.82 (d, JC,P = 39.9 Hz, 1C (Ph)), 127.57 (d, J = 6.6 Hz, 1C (Ph)), 125.05 (s, 1C (Ph)), 123.28 (s, 1C (Ph)), 123.10 (s, 2C (Ph)), 114.32 (s, 1C (Ph)), 78.53 (s, 1C

((CH3)2CHO)), 36.20 (d, JC,P = 25.6 Hz, 1C ((CH3)3CP)), 34.62 (s, 1C (para(CH3)2CHAr)), 29.52 (s, 2C

(ortho(CH3)2CHAr)), 29.17 (d, JC,P = 3.9 Hz, 3C ((CH3)3CP)), 25.02 (s, 2C (para(CH3)2CHAr)), 24.94 (s,

2C para(CH3)2CHAr)), 24.05 (s, 1C (ortho(CH3)2CHAr)), 24.03 (s, 1C (ortho(CH3)2CHAr)), 21.61 (s, 1C

31 ((CH3)2CHO)), 21.01 (s, 1C ((CH3)2CHO)). P NMR (121 MHz, C6D6) δ 65.09.

Complex 22d:

1 H NMR (300 MHz, CD2Cl2) δ 17.65 (d, J = 7.9 Hz, 1H (Ru=CHAr)), 8.01 (ddd, J = 7.7, 3.6, 1.5 Hz, 1H (Ph)), 7.67 (td, J = 7.9, 1.7 Hz, 1H (Ph)), 7.63 – 7.52 (m, 3H (Ph)), 7.52 – 7.45 (m, 4H (Ph)), 7.38 – 7.31 (m, 2H (Ph)), 7.14 (t, J = 7.6 Hz, 2H

(Ph)), 6.96 (s, 2H (Ph)), 5.24 – 5.09 (m, 1H ((CH3)2CHO)),

3.59 – 3.47 (m, 2H (ortoCyAr)), 2.50 – 2.36 (m, 1H (paraCyAr)),

1.87 (d, J = 6.4 Hz, 3H ((CH3)2CHO)), 1.84 – 1.58 (m, 17H

(CyAr)), 1.54 (d, J = 6.2 Hz, 3H ((CH3)2CHO)), 1.33 (d, J = 15.3 Hz, 9H (t-BuP)), 1.48 – 1.14 (m, 13H

31 (CyAr)). P NMR (121 MHz, CD2Cl2) δ 64.62.

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Discovery, Development and Study of Carbenoid Mediated Reactions

Symmetrically substituted complex [(Cy2P(o-SO3Ph))Ru(=CH(o-O-i-Pr)Ph)Cl] (21):

The complex was synthesized by a slight modification of the procedure to prepare complex 17. Instead of using the sodium salt of ligand 13b the anionic form was prepared in situ by addition of 1.0 eqv. of diisopropylethylamine with respect to the ligand 13b to

1 the reaction mixture. H NMR (300 MHz, CD2Cl2) δ 18.33 (d, JH,P = 6.0 Hz, 1H (Ru=CHAr)), 8.04 (ddd, J = 7.7, 3.1, 1.3 Hz, 1H (Ph)), 7.77 (t, J = 7.9 Hz, 2H (Ph)), 7.72 –

7.55 (m, 3H (Ph)), 7.29 – 7.16 (m, 2H(Ph)), 5.48 – 5.36 (m, 1H ((CH3)2CHO)), 3.09 (td, J = 12.0,

9.0 Hz, 1H (CyP)), 2.81 – 2.63 (m, 1H (CyP)), 1.89 (d, JH,P = 6.4 Hz, 3H ((CH3)2CHO)), 2.00 – 1.57

31 (m, 10H (CyP)), 1.71 (d, J = 6.3 Hz, 3H ((CH3)2CHO)), 1.51 – 1.06 (m, 10H (CyP)). P NMR (122

MHz, CD2Cl2) δ 51.79.

Complex [((1-adamantyl)PhP(o-SO3Ph))Ru(=CH(o-O-i-Pr)Ph)Cl] (23):

Was synthesized in analogy to complex 21.

1 H NMR (600 MHz, CD2Cl2) δ 17.13 (apparentdd, JH,P = 7.6, J = 0.9 Hz, 1H (Ru=CHAr)), 8.06 (dddd, J = 7.8, 3.6, 1.5, 0.4 Hz, 1H (Ph)), 7.69 – 7.63 (m, 3H (Ph)), 7.63 – 7.59 (m, 1H (Ph)), 7.55 (tdd, J = 7.4, 1.4, 0.8 Hz, 2H (Ph)), 7.49 – 7.41 (m, 3H (Ph)), 7.25 (dd, J = 7.6, 1.7 Hz, 1H (Ph)), 7.17 (dt, J = 8.4, 0.7 Hz, 1H (Ph)), 7.04 (td, J = 7.5, 0.8 Hz, 1H (Ph)), 5.41 – 5.34 (m,

1H ((CH3)2CHO)), 2.52 – 2.43 (m, 3H (AdmP)), 2.37 – 2.29 (m, 3H (AdmP)), 2.05 (h, J = 3.3 Hz,

3H (AdmP)), 1.92 (d, JH,H = 6.3 Hz, 3H ((CH3)2CHO)), 1.78 – 1.68 (m, 6H (AdmP)), 1.72 (d, J = 6.2

13 Hz, 3H ((CH3)2CHO)). C NMR (151 MHz, CD2Cl2) δ 309.88 (apparentt, JC,P = 12.3 Hz 1C), 156.31 (d,

JC,P = 1.6 Hz, 1C (Ph)), 146.80 (d, JC,P = 10.7 Hz, 1C (Ph)), 144.72 (s, 1C (Ph)), 137.25 (s, 1C (Ph)),

134.39 (d, JC,P = 7.8 Hz, 2C (Ph)), 132.18 (s, 1C (Ph)), 132.10 (d, JC,P = 43.5, 1C (Ph)), 131.61 (d, JC,P =

2.1 Hz, 1C (Ph)), 130.86 (d, JC,P = 2.7 Hz, 1C (Ph)), 130.80 (d, JC,P = 5.8 Hz, 1C (Ph)), 129.04 (d, JC,P

= 9.6 Hz, 2C (Ph)), 128.04 (d, JC,P = 6.8 Hz, 1C (Ph)), 126.53 (d, JC,P = 38.8 Hz, 1C (Ph)), 124.43 (s,

1C (Ph)), 123.34 (s, 1C (Ph)), 114.29 (s, 1C (Ph)), 78.10 (s, 1C ((CH3)2CHO)), 43.28 (d, JC,P = 24.0 Hz,

1C (AdmCP)), 39.26 (s, 3C (AdmP)), 36.82 (d, JC,P = 1.8 Hz, 3C (AdmP)), 29.46 (d, JC,P = 9.9 Hz,

31 3C (AdmP)), 22.35 (s, 1C ((CH3)2CHO)) , 22.12 (s, 1C ((CH3)2CHO)). P NMR (121 MHz, CD2Cl2) δ 60.13.

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6. Experimental Part

Attempt to synthesize complex [((neopentyl)PhP(o-SO3Ph))Ru(=CH(o-O-i-Pr)Ph)Cl] (25):

The procedure used for the synthesis of 21 and 23 was followed. Despite efforts to isolate the product only a mixture of intermediate 24 and complex 25 could be obtained. For an NMR of the mixture see section 6.3.

6.3. Solution phase chemistry of lithiomethyl trimethylammon reagents (Chapter 3)

The synthesis, characterization and decay experiments of soluble lithiomethyl trimethylammonium BArF reagent 47 and dilithiomethyl trimethylammonium BArF 48 were performed by Dr. Tim den Hartog. Details of these experiments can be found in reference 187. For completeness the synthesis of the starting tetramethylammonium BArF will be included in this dissertation.

6.3.1. Tetramethylammonium salts

Tetramethylammonium tetrakis(3,5-bis(trifluoromethyl)phenyl)borate (45):

In a round bottom flask equipped with stir bar and open to air, NaBArF (1 equiv., wet, open to air for a week)

F was dissolved in CH2Cl2 (40 mL/mmol NaBAr ). Tetramethylammonium iodide (1.25 equiv.) was added. After stirring for 1 h the reaction was filtered over a glass filter. The CH2Cl2 was evaporated and the resulting powder was dissolved in Et2O and filtered (removing excess NMe4I). The Et2O was evaporated and the resulting powder was recrystallized from CH2Cl2 yielding the pure product. The product was then dried overnight under high vacuum. Mp 249-250 °C

1 (from CH2Cl2); H NMR (400 MHz, THF-D8) δ 7.80 (s, 8H), 7.59 (s, 4H), 3.31 – 3.14 (m, 12H);

13 2 C NMR (101 MHz, THF-D8) δ 162.99 (dd, 1JC,B = 49.8 Hz, C), 135.78 (CH), 130.22 (qq, JC,F =

3 1 3 19 31.5 Hz, JC,B = 2.8 Hz, C), 125.71 (q, JC,F = 272.2 Hz, C), 118.38 (m, CH), 55.90 (t, JC,N = 4.0 Hz);. F

NMR (376 MHz, CD3OD) δ -64.32. Elemental analysis: calc. (%) for C36H24BF24N (937.35 g/mol): C, 46.13; H, 2.58; N, 1.49; found: C, 45.88; H, 2.56; N, 1.49.

Tetramethylammonium pivalate (56):

The salt was synthesized in analogy to tetramethylammonium benzoate.280 A mixture of 4 mL of tetramethylammonium hydroxide 25% solution in methanol (10.96 mmol) and 1.12 g of pivalic acid (10.96 mmol) were stirred with 25 mL of methanol in a round bottom flask at 40 °C overnight.

119

Discovery, Development and Study of Carbenoid Mediated Reactions After reaction the solvent was removed on a rotary evaporator. The white solid obtained was sonicated three times with portions of 20 mL of diethylether followed by decantation. The solid was then dried overnight on the high vacuum (1x10-3 mbar). Yield: 1.81 g (94%) 1H NMR (400 MHz, MeOD) δ 3.20 – 3.19 (m, 12H), 1.13 (s, 9H); 13C NMR (101 MHz,

1 MeOD) δ 187.30 (s, 1C, COO), 55.86 (t, J(C-N) = 4 Hz), 40.79 (s, 1C, C(CH3)3), 28.89 (s, 3C, C(CH3)3).

Elemental analysis (highly hygroscopic solid): Calc. (%) for C9H21NO2 (175.26 g/mol): C, 61.68; H, 12.08; N, 7.99. Found: C, 59.79; H, 12.11; N, 7.23.

Tetramethylammonium trifluoromethanesulfonate (57):

Was prepared according to the procedure reported by Martin281 or alternatively by simple anion metathesis between tetramethylammonium chloride and silver trifluoromethanesulfonate. The latter method generally afforded higher yields and circumvents the requirement of an inert atmosphere. A typical batch was synthesized as follows: Tetramethylammonium chloride (2.2020 g, 20.09 mmol) was dissolved in 100 mL methanol in a 250 mL round bottom flask. Silver trifluoromethanesulfonate (5.1622 g, 20.09 mmol) was dissolved in 50 mL methanol and added over the ammonium salt solution with constant stirring. After 10 minutes of stirring the mixture was filtered and the solvent evaporated under reduced pressure. The crude salt was then recrystallized from distilled isopropanol requiring approximately 60 mL of solvent per gram of salt. After cooling down to -20 °C for 20 hours the crystals were filtered and rinsed with a small amount of cold isopropanol. Drying on the high vacuum (5x10-2 mbar) afforded

1 19 3.7824 g (84%) of pure material. H NMR (300 MHz, CD3OD) 3.19 (s, 12H). F NMR (282

MHz, CD3OD) -80.14. Elemental analysis: calc. (%) for C5H12NO3F3S (223.22 g/mol) C 26,90, H 5.42, N 6.27, O 21.50, F 25.53, S 14.37. Found: C 26.95, H 5.33, N 6.22, F 25.72, S 14.29.

Tetramethylammonium triflimide (58):

The salt was prepared following a reported procedure.282 The salt was recrystallised twice from CH2Cl2 and dried under high vacuum before use. 1H NMR (400 MHz, MeOD) δ 4.78 – 4.72 (m, 12H). 13C NMR (101 MHz,

1 1 19 MeOD) δ 121.21 (q, J(C-F) = 320 Hz), 55.88 (t, J(C-N) = 4 Hz). F NMR (376 MHz, MeOD) δ -80.70.

Elemental Analysis: Calc. (%) for C6H12F6N2O4S2 (): C, 20.34; H, 3.41; N, 7.91. Found: C, 20.39; H, 3.41; N, 7.92.

120

6. Experimental Part 6.3.2. Notes on the influence of transition metal contamination on the methylenation reactions

In early methylenation attempts low and variable yields were obtained. After careful examination of the possible causes it was noted that even traces (ppm level) of transition metals in the reaction mixture degraded the lithiomethyl trimethylammonium reagent, with concomitant formation of ethylene and trimethylamine, therefore reducing the efficiency of the methylenation. As a preventive measure all the materials were thoroughly purified and all the glassware was cleaned rigorously (see below). It was noted that commercially available stir bars, coated with Teflon, are susceptible to corrosion by the used cleaning methods, and were an important source of contamination. It was then decided to construct glass coated stir bars which allowed for a very rigorous exclusion of metals in our system. All the tetramethylammonium salts can be easily prepared and/or purified by recrystallisation from distilled solvents to achieve sub-ppm levels of metals, as measured by ICP-MS. A self-made nBuLi solution (see procedure below) was also used to guarantee that all possible sources of trace metals were controlled. It was later recognized that the minimal trace metals present in commercial nBuLi (Aldrich) were not detrimental for the methylenation. All the experiments reported in this disseration were performed using commercial nBuLi.

Glassware cleaning

All glassware in which cyclopropanation reactions were performed, or substrates were synthesized, including the self-made glass stir-bars were cleaned consecutively in a base bath to remove all organics and then with aqua regia to ensure that no traces of transition metals were present. Finally, rinsing of the glassware was performed with HPLC grade deionised water.

6.3.3. Methylenation of aldehydes, ketones and imines

General procedure from methylenation of ketones and imines: A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with NMe4 OTf (390 mg, 1.74 mmol). The salt was suspended in anhydrous THF (20 mL) and the flask was cooled down to 0 °C in an ice-water bath. nBuLi (1.00 mL, 1.6 M, 1.60 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at 0 °C. Then under an Ar counterflow at 0 °C, the ketone or imine substrate was added (1.45 mmol) either neat, or alternatively if 121

Discovery, Development and Study of Carbenoid Mediated Reactions the substrate is solid, dissolved in 2 mL of anhydrous THF. The flask was then again fully closed and the stirring was continued for 16 h during which the temperature was allowed to slowly reach room temperature. Then the reaction mixture was diluted with 30 mL of

H2O and transferred to a separation funnel. 20 mL of pentane was used to rinse the Schlenk flask and perform the first extraction of the aqueous phase. The aqueous phase was extracted using pentane (2x 10 mL). The combined organic extracts were washed with H2O (4x 10 mL) and brine (10 mL), dried using MgSO4, filtered and the solvent was concentrated under reduced pressure. The crude material was then purified by column chromatography on neutral aluminium oxide (epoxides), or basic aluminium oxide (aziridines).

2,2-diphenyloxirane (60a):

Benzophenone was used as substrate. 60a was purified using column chromatography (neutral aluminium oxide) with a mixture of pentane/Et2O (85/15) as eluent. 190 mg of 60a (67 % yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 283.

2-phenyl-2-propyloxirane (60b):

Butyrophenone was used as substrate. 60b was purified using column chromatography (neutral aluminium oxide) with a mixture of pentane/Et2O (95/5) as eluent. 173 mg of 60b (73 % yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 284.

2,2-dibutyloxirane (60c):

Nonanone was used as substrate. 60c was purified using column chromatography (neutral aluminium oxide) with a mixture of pentane/Et2O (96/4) as eluent. 190 mg of 60c (84 % yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 285.

2-cyclopropyl-2-(4-methoxyphenyl)oxirane (60d):

Cyclopropyl-4-mehoxyphenyl ketone was used as substrate. All attempts to purify 60d by traditional methods caused 60d to decompose, therefore the crude product was characterized, the impurity consists of the ring-opened epoxide product: 2-cyclopropyl-2-(4-methoxyphenyl)acetaldehyde. 199 mg

122

6. Experimental Part of a mixture of approximately 94% 60d (corresponding to 68 % yield of 60d) and 6% 2- cyclopropyl-2-(4-methoxyphenyl)acetaldehyde was obtained as a colorless oil.

1 Characterization: H NMR (300 MHz, CDCl3) δ 7.42 – 7.35 (m, 2H), 6.91 – 6.85 (m, 2H), 3.81 (s, 3H), 2.86 (d, J = 5.4 Hz, 1H), 2.76 (d, J = 5.4 Hz, 1H), 1.50 (tt, J = 8.3, 5.2 Hz, 1H), 0.59 – 0.52 (m, 2H), 0.44 – 0.37 (m, 2H). 13C NMR (75 MHz, CDCl3) δ 159.18, 132.91, 127.44, 113.74, 69.97, 55.42, 54.60, 14.44, 2.42, 1.94. MS(EI(+)) m/z 190.2 (M+, 6), 161.2 (100), 145.9 (18), 130.9 (14), 91 (32), 77.0 (14), 62.9 (5).

1,2-diphenylaziridine (62a):

Benzylideneaniline was used as substrate. 62a was purified using column chromatography (basic aluminium oxide) with a mixture of pentane/ NEt3 (95/5) as eluent. 135 mg of 62a (46 % yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 286.

1-tert-butyl-2-diphenylaziridine (62b):

Benzylidene-tert-butylamine was used as substrate. 20b was purified using column chromatography (basic aluminium oxide) with a mixture of pentane/NEt3 (98/2) as eluent. 185 mg of 20b (73 % yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 287.

2-phenethyloxirane (64):

A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with NMe4 OTf (390 mg, 1.74 mmol). The salt was suspended in anhydrous THF (20 mL) and the flask was cooled down to 0 °C in an ice-water bath. nBuLi (1.00 mL, 1.6 M, 1.60 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at 0 °C. Then under an Ar counterflow at 0 °C, 3-phenylpropionaldehyde (192 L, 1.45 mmol) was added neat. The flask was then again fully closed and the stirring was continued for 30 min. The flask was then opened to the Ar line and the reaction mixture was stirred for 5 h at 65 °C. Then the reaction mixture was allowed to cool to room temperature with 30 mL of H2O and transferred to a separation funnel. 20 mL of pentane was used to rinse the Schlenk flask and perform the first extraction of the aqueous phase. The aqueous phase was extracted

123

Discovery, Development and Study of Carbenoid Mediated Reactions using pentane (2x 10 mL). The combined organic extracts were washed with H2O (4x 10 mL) and brine (10 mL), dried using MgSO4, filtered and the solvent was concentrated under reduced pressure. The crude material was then purified by distillation under reduced pressure in a Kugelrohr apparatus. 125 mg of 64 (58 % yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 288.

1,1-diphenylprop-2-en-1-ol (65):

A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with NMe4 OTf (382 mg, 1.71 mmol). The salt was suspended in anhydrous THF (20 mL) and the flask was cooled down to 0 °C in an ice-water bath. nBuLi (1.00 mL, 1.6 M, 1.60 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at 0 °C. Then under an Ar counterflow at 0 °C, 2,2-diphenyloxirane (160 mg, 0.82 mmol) dissolved in 2 mL of anhydrous THF was added. The flask was then again fully closed and the stirring was continued for 18 h during which the temperature was allowed to slowly reach room temperature. Then the reaction mixture was diluted with 30 mL of H2O and transferred to a separation funnel. 20 mL of pentane was used to rinse the Schlenk flask and perform the first extraction of the aqueous phase. The aqueous phase was extracted using pentane (2x 10 mL). The combined organic extracts were washed with H2O (4x 10 mL) and brine (10 mL), dried using MgSO4, filtered and the solvent was concentrated under reduced pressure. The crude material was then purified by column chromatography (silica gel) with a mixture of pentane/EtOAc (90/10) as eluent. 120 mg of 65 (70 % yield) was obtained as a colorless oil. The oil solidified slowly.

All experimental data was in agreement with data in reference 289.

6.3.4. Cyclopropanation of styrenes and stilbenes

Preliminary attempts to cyclopropanate olefins with soluble lithiomethyl trimethylammonium reagents derived from several tetramethylammonium salts.

A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with a tetramethylammonium salt (0.35 mmol of 45, 56, 57 or 58). The salt was suspended in anhydrous THF (10 mL) and undecane (50 L) was added as internal standard. The flask was cooled down to 0 °C in an ice-water bath. nBuLi (0.20

124

6. Experimental Part mL, 1.6 M, 0.33 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at 0 °C. Then under an Ar counterflow at 0 °C, neat styrene 69a was added (34 L, 0.30 mmol). The flask was then again fully closed and the stirring was continued for 5 h during which the temperature was allowed to slowly reach room temperature. A sample of 0.50 mL of reaction mixture was diluted with 1.00 mL pentane and filtered through a small amount of silica. The filtrate was then directly analyzed by GC-FID. The concentration of the starting material and product are obtained by interpolation in previously measured calibration curves.

General procedure for the cyclopropanation of olefins with 66.

A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with NMe4 OTf (390 mg, 1.74 mmol). The salt was suspended in anhydrous THF (20 mL) and the flask was cooled down to 0 °C in an ice-water bath. nBuLi (1.00 mL, 1.6 M, 1.60 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at 0 °C. Then under an Ar counterflow at 0 °C, the olefin substrate was added (between 1.16 and 1.45 mmol, for 1.4 to 1.1 eqv. ylide to olefin ratios) either neat, or alternatively if the substrate is solid, dissolved in 2 mL of anhydrous THF. The flask was then again fully closed and the stirring was continued for 16 h during which the temperature was allowed to slowly reach room temperature. Then the reaction mixture was diluted with 30 mL of H2O and transferred to a separation funnel. 20 mL of pentane was used to rinse the Schlenk flask and perform the first extraction of the aqueous phase. The aqueous phase was further extracted using pentane (2x 20 mL). The combined organic extracts were washed with H2O (4x 20 mL) and brine (10 mL), dried using MgSO4, filtered and the solvent was concentrated under reduced pressure. The crude material was then purified by column chromatography on silica gel.

Cyclopropylbenzene (71a):

Styrene (170 L, 1.48 mmol) (69a) was used as substrate. 71a was purified by column chromatography using pentane as eluent. 147.8 mg of 71a (71% yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 115.

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Discovery, Development and Study of Carbenoid Mediated Reactions 1-cyclopropyl-4-methylbenzene (71b):

4-methylstyrene (192 L, 1.45 mmol) (69b) was used as substrate. 71b was purified by column chromatography using pentane as eluent. 179.7 mg of 71b (93% yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 290.

1-(tert-butyl)-4-cyclopropylbenzene (71c):

4-tert-butylstyrene (263 L, 1.45 mmol) (69c) was used as substrate. 71c was purified by column chromatography using pentane as eluent. 202.8 mg of 71c (80% yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 290.

1-cyclopropyl-4-methoxybenzene (71d)

4-methoxystyrene (197 L, 1.45 mmol) (69d) was used as substrate. 71d was purified by column chromatography using pentane as eluent. 189.5 mg of 71d (88% yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 291.

1-cyclopropyl-3-methoxybenzene (71e):

3-methoxystyrene (157 L, 1.16 mmol) (69e) was used as substrate. 71e was purified by column chromatography using pentane as eluent. 132.8 mg of 71e (77% yield) was obtained as a colorless oil.

All experimental data was in agreement with data in reference 292.

4-fluoro-1-cyclopropyl-benzene (71f):

4-fluorostyrene (139 L, 1.16 mmol) (69f) was used as substrate. During workup a polymer precipitated. Initial GC analysis of the soluble organics showed a complex mixture consisting of approximately 37% of the desired product and several other compounds. The product was identified by GC-MS and NMR293 spectroscopy of the mixture (See the spectra and GC traces in section 6.6). Isolation of this compound was not attempted. The mass of the obtained product mixture after workup was 70.9 mg. Yield of the product can be estimated as 26.2 mg (16% yield).

126

6. Experimental Part Attempted cyclopropanation of 4-nitrostyrene (69g)

4-nitrostyrene (174 L, 1.16 mmol) (69g) was used as substrate. During workup a polymer precipitated. SEC analysis of this material confirmed its polymeric nature. No remaining material was found in the organic phase after extraction. trans-1,2-diphenylcyclopropane (trans-71h):

Trans-stilbene (210 mg, 1.16 mmol) (69h) was used as substrate. trans- 71h was purified by column chromatography using pentane/ethyl acetate 95/5 as eluent. 207.2 mg of trans-71h (92% yield) was obtained as an off-white solid.

All experimental data was in agreement with data in reference 294.

Alternatively, reaction of cis-stilbene (207 L, 1.16 mmol) (69i) affords 221.3 mg of trans- 71h (98% yield). trans-1-(4-methoxyphenyl)-2-phenylcyclopropane (trans-71j):

4-methoxy-trans-stilbene (245 mg, 1.16 mmol) (69j) was used as substrate. trans-71j was purified by column chromatography using pentane/ethyl acetate 90/10 as eluent. 190.6 mg of trans-71j (73% yield) was obtained as a white solid.

All experimental data was in agreement with data in reference 295.

Attempted cyclopropanation of cyclohexene (69k)

Cyclohexene (118 L, 1.16 mmol) (69k) was used as substrate. NMR analysis of the crude product after workup showed unreacted starting material and no sign of norcarene (71k).

6.3.5. Kinetic measurements

Monitoring of the reaction of reagent 66 with styrene 69c.

127

Discovery, Development and Study of Carbenoid Mediated Reactions Method

A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with NMe4 OTf (196 mg, 0.88 mmol). The salt was suspended in anhydrous THF (20 mL) and 100 L of undecane was added as internal standard. The flask was then cooled down to 0 °C in an ice-water bath. nBuLi (0.50 mL, 1.6 M, 0.81 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at 0 °C. The first sample was now taken (see sampling procedure). Then under an Ar counterflow at 0 °C, the styrene substrate 69c was added (1.48 mL, 8.14 mmol, 10 equivalents) as quickly as possible (t=0). The reaction mixture was sampled over time following the sampling procedure described below.

Sampling procedure

Under Ar counterflow an aliquot of approximately 200 L of reaction mixture was taken and poured quickly over 0.7 mL of D2O. Pentane (2 mL) was added to the quenched sample and the vial was shaken vigorously for 30 seconds. The organic phase was separated in a GC vial and analyzed by GC-FID. A small portion of the aqueous phase was diluted approximately 200 times with methanol for analysis by ESI-MS.

The absolute concentration of the neutral organic materials in the organic phase was determined by extrapolation in previously measured calibration curves using authentic materials with undecane as internal standard.

Under the assumption that there were no sources of acidic protons under the described

+ reaction conditions all N(CH3)4 (m/z = 74) ions must have come from the excess of 57 employed in the reaction, i.e. tetramethylammonium salt that was not deprotonated by nBuLi, and therefore can be used as self-reference since its concentration should not change during the course of the experiment. After quenching the reaction mixture with

D2O the part of the ammonium that was deprotonated (lithium coordinated N-C ‘ylide’

+ 66) and still has not reacted is deuterated N(CH3)3(CH2D) (m/z = 75, 57-d1). Using ESI-MS it is possible to determine the isotopic composition of the ammonium ions for all of the samples. Using the first measurement, done before the substrate is added, as calibration it is possible to assess the concentration of reagent 66 at the time of quenching by simple interpolation.

128

6. Experimental Part The intensity of the peak at m/z = 74 is measured as the area under the peak. The intensity of the peak at m/z = 75 is the area under the peak minus 4.9% of the area of peak m/z 74 accounting for the natural abundance of deuterium.

t1=0 t2>t1 t3>t2

73 74 75 76 77 73 74 75 76 77 73 74 75 76 77

m/z m/z m/z Figure 5.1 Typical isotope patterns recorded from quenched samples at different times, normalized for intensity of peak at m/z = 74.

Data analysis

The absolute concentration of 66 and 71c can be plotted against time to produce graphs like figure 3.5. Using the least squares method, the decay of 66 and the formation of 71c

are fitted to the equations and 1 respectively. The confidence intervals for the fitted parameters A0 and k1 were determined using the Bootstrap method296 of iterative resampling and refitting for 1000 times. The real value for the fitted parameter is considered to lie between +/- 2 standard deviations () (approximately 95% confidence) from the mean of the produced set of values.

Table 5.1 Fit parameters for the reaction of 66 with 4-tert-butylstyrene 69c

Rep. Formation of cyclopropane 71c Consumption of 66

-1 -1 A'0 (M) 2 k'1 (s ) 2 A0 (M) 2 k1 (s ) 2 1 2.22E-02 1.90E-03 1.23E-03 2.79E-04 2.44E-02 3.77E-03 8.12E-04 2.29E-04 2 2.37E-02 1.87E-03 1.11E-03 2.24E-04 2.76E-02 4.54E-03 7.78E-04 1.89E-04 3 2.44E-02 1.77E-03 1.04E-03 1.88E-04 3.08E-02 1.98E-03 6.67E-04 6.29E-05

129

Discovery, Development and Study of Carbenoid Mediated Reactions Competition Experiments

Following the method described by Harper et al.198 a series of competition experiments were performed. In order to avoid interferences with the stabilizers added to the styrenes all of the substrates were dried over CaH2 and distilled under reduced pressure. A stock solution was prepared containing the substrates styrene 5a (100 L, 0.869 mmol), 3- methoxystyrene 5e (100 L, 0.739 mmol), 4-methoxystyrene 5d (450 L, 3.34 mmol) and 4-tert-butylstyrene 5c (600 L, 3.32 mmol) as well as undecane (100 L, 0.474 mmol) as internal standard in 4 mL anhydrous THF.

A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with NMe4 OTf (80 mg, 0.36 mmol). The salt was suspended in anhydrous THF (10 mL). The flask was then cooled down to 0 °C in an ice-water bath. nBuLi (0.20 mL, 1.6 M, 0.33 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 20 minutes at 0 °C. Under Ar counterflow 1.00 mL of the stock solution is quickly added to the reaction mixture and the flask is closed again. After 20 minutes stirring at 0 °C the reaction is quenched by addition of 0.20 mL of methanol. A sample of 0.50 mL is taken and diluted with 1.0 mL of pentane. The sample is filtered through celite to remove the precipitated ammonium salt. The filtrate is analyzed by GC-FID.

The absolute concentrations of the styrenes before and after reaction (with respect to undecane) are obtained by extrapolation in previously measured calibration curves. Following equation (5.1) one can obtain the ratio of the rates as function of the ratio of the concentrations.

, (5.1) ,

Table 5.2 Concentration in mmol of styrenes per mmol of undecane before and after reaction.

Substrate Beforea Rep. 1 Rep. 2 Rep. 3 4-H 69a 1.98 1.53 1.49 1.46 3-MeO 69e 1.81 1.23 1.21 1.18 130

6. Experimental Part

4-MeO 69d 7.32 7.22 7.24 7.26 4-tBu 69c 7.28 6.74 6.76 6.79 a All reactions were performed using the same stock solution over a period of less than 24 hours. All experiments are referenced to this initial composition.

Table 5.3 Values of kX/kH obtained from data in table 5.2 using equation (5.1)

Hammet Substrate parameter197 Rep. 1 Rep. 2 Rep. 3 Average 2a 4-H 69a 0 0.00 0.00 0.00 0.00 0.00 3-MeO 69g 0.115 0.18 0.14 0.15 0.16 0.02 4-MeO 69f -0.268 -1.29 -1.41 -1.57 -1.42 0.14 4-tBu 69c -0.197 -0.52 -0.58 -0.63 -0.58 0.06 a Standard deviation. 6.3.6. Reaction of lithiomethyl trimethylammonium reagents with transition metal complexes

General procedure for the reaction of 47 with transition metal complexes

F In a tube shaped Schlenk bomb equipped with a glass coated stir bar, NMe4 BAr (5.9 mg, 6.29 mol) was suspended in 1 mL of anhydrous THF and cooled down to -30 °C. Under argon counterflow nBuLi (3.88 L, 1.6 M, 6.21 mol) was added to the suspension and the flask was completely closed to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at -30 °C. Under Ar counterflow a solution of the transition metal complex 72a, 72b, 72c, 76 or 80 (0.5 eqv., 3.10 mol) in 1.00 mL THF was quickly added to the reaction mixture and the flask is closed again. After 20 minutes stirring at -30 °C the flask is transferred to the glovebox where a sample of 0.1 mL of the reaction mixture is diluted with 2 mL of a 1:1 mixture of THF and DCM. This solution is then immediately analyzed in the mass spectrometer.

131

Discovery, Development and Study of Carbenoid Mediated Reactions Synthesis of complex 81

A dried 50 mL Schlenk flask equipped with a glass coated stir bar and a glass stopper under Ar, was charged with NMe4 OTf (80 mg, 0.36 mmol). The salt was suspended in anhydrous THF (10 mL). The flask was then cooled down to 0 °C in an ice-water bath. nBuLi (0.20 mL, 1.6 M, 0.33 mmol) was added to the suspension and the flask was completely closed using the glass stopper and the Schlenk tap to prevent any gas exchange. The reaction mixture was stirred for 30 minutes at 0 °C. Under Ar counterflow complex 80 (50 mg, 0.07 mmol) is added as a THF (1.00 mL) solution and the flask is closed again. After 60 minutes stirring at 0 °C the reaction is quenched by addition of 0.20 mL of methanol. The solvent is then removed in a rotary evaporator and the crude complex is extracted with 1,2-dichloroethane. After filtration and removal of the solvent complex 81 is obtained as a white solid. 1H NMR (300

MHz, CD2Cl2) δ 8.16 (dd, J = 1.5, 0.7 Hz, 1H, HC=CH(NHC)), 7.57 (td, J = 7.9, 4.7 Hz, 2H, 4- H(Ph)(NHC)), 7.38 (d, J = 5.6 Hz, 2H, 3-H(Ph)(NHC)), 7.35 (d, J = 5.7 Hz, 2H, 3-H(Ph)(NHC)),

6.93 (dd, J = 1.5, 0.7 Hz, 1H HC=CH(NHC)), 3.21 (s, 2H, AuCH2N(CH3)3), 2.83 (s, 9H,

AuCH2N(CH3)3), 2.61 – 2.47 (m, 4H, (CH3)2CH(Ph)(NHC)), 1.37 (d, J = 6.8 Hz, 6H,

(CH3)2CH(Ph)(NHC)), 1.28 (d, J = 6.9 Hz, 6H, (CH3)2CH(Ph)(NHC)), 1.18 (d, J = 4.8 Hz, 6H,

(CH3)2CH(Ph)(NHC)), 1.16 (d, J = 4.9 Hz, 6H, (CH3)2CH(Ph)(NHC)). (see spectrum in section 6.7)

6.4. Palladium catalyzed methylenation of olefins using halomethylboronates reagents (Chapter 4)

6.4.1. Synthesis and characterization of products from our methylenation reaction

General procedure for the methylenation of norbornenes

In the glove box, a 5 mL Young Schlenk (approximately 10 mL total volume) equipped with a glass coated stir bar, was charged with Pd-catalyst (5 mol% Pd) and K2CO3 (1.5 equiv). Subsequently, a solution of the norbornene (1 eqv., 0.117 mmol scale) in anhydrous DMF (4.3 mL/mmol substrate), a solution of the boron reagent (1.5 equiv) in anhydrous DMF (8.5 mL/mmol substrate), anhydrous DMF (4.3 mL/mmol substrate), and degassed water (2.1 mL/mmol substrate) were added. The Schlenk was transferred outside the glovebox and the reaction mixture was heated to 90 °C in a preheated oil bath and

132

6. Experimental Part stirred for 6 h. Then the reaction mixture was rapidly cooled to 0 °C in an ice bath and a work-up was conducted.

General procedure for the methylenation of several olefins

In the glove box, a 5 mL Young Schlenk (approximately 10 mL total volume) equipped with a glass coated stir bar, was charged with the Herrmann-catalyst 4 (5 mol% Pd), K2CO3 (1.1 eqv.), and the boron reagent (1.1 eqv.). Subsequently, anhydrous DMA (4.3 mL/mmol substrate), the olefin (1 eqv., approximately 0.11 mmol scale), anhydrous MeOH (2.1 mL/mmol substrate), and anhydrous DMA (12.8 mL/mmol substrate) were added. The Schlenk was shaken and allowed to stand 15-25 minutes at room temperature before it was transferred outside the glovebox and the reaction mixture was heated to 90 °C in a preheated oil bath and stirred for 24 h. Then the reaction mixture was rapidly cooled to 0 °C in an ice bath and a work-up was conducted.

Work-up procedure

The internal standard undecane (10 L, around 0.40 eqv. for 0.117 mmol scale of olefin) was added to the Schlenk with the reaction mixture, followed by Et2O (45 mL/mmol substrate). The solution was transferred to a 15 mL glass vial. The Schlenk was rinsed with

H2O (45 mL/mmol substrate), and this aqueous layer was transferred to the 15 mL glass vial, the layers were separated, and the organic layer was decanted and transferred to another 15 mL glass vial. The Schlenk was rinsed with Et2O (45 mL/mmol substrate) and the solution was used to extract the aqueous phase, and decanted to the second 15 mL glass vial. The combined organic phases were washed with brine (45 mL/mmol substrate), dried over MgSO4, and filtered over celite. The resulting solution was analyzed by GC and GC-MS (the latter for reactions with >30% yield of cyclopropane).

Analysis of the conversion, yield and remaining substrate for volatile substrates (norbornene (86), cyclooctene (90a), 4-phenyl-1-butene (90b), styrene (69a)) and products (exo-tricyclo[3.2.1.0-2,4]octane (87), cis-bicyclo[6.1.0]nonane (91a), methylenecyclooctane (92a), (2-cyclopropylethyl)benzene (91b), 5-phenyl-1-pentene (92b), cyclopropylbenzene (71a), prop-1-en-2-ylbenzene (92ca), E-prop-1-en-1-ylbenzene (92cc), Z-prop-1-en-1-ylbenzene (92cb), allylbenzene (92cd)) was performed by GC using undecane as internal standard. The chromatograms were compared to chromatograms from authentic cyclopropanes and authentic -H elimination products. For the reactions giving more than 30% yield of volatile cyclopropane products (exo-tricyclo[3.2.1.0-

133

Discovery, Development and Study of Carbenoid Mediated Reactions 2,4]octane (87), cis-bicyclo[6.1.0]nonane (91a)) the fragmentation patterns obtained by GC-MS were compared to GC-MS fragmentation patterns of authentic samples to exclude possible impurities under the GC-FID peak. Furthermore, the GC samples were carefully concentrated and 1H NMR spectra of those samples were recorded. The NMR spectra of the reaction mixtures were compared to the 1H NMR spectra of the authentic cyclopropanes to confirm the presence of the cyclopropanes (see sections 6.6 to 6.9).

6.4.2. Synthesis and characterization of authentic samples exo-tricyclo[3.2.1.0-2,4]octane (87) was prepared analogous to a reported

297 procedure (procedure A, 16 h reaction time) using norbornene (1) as substrate. Data for 87 were in accordance to those given in reference 298. cis-bicyclo[6.1.0]nonane (91a) was prepared analogous to a reported

297 procedure (procedure A, 16 h reaction ime) using Z-cyclooctene (90a) as substrate. Data for 91a were in accordance to those given in reference 297.

Methylenecyclooctane (92a) was prepared analogous to a reported procedure299 (Methylenetriphenylphosphorane for methylenecyclohexane

(general procedure)) using cyclooctanone as substrate. Data for 92a were in accordance to those given in reference 300 (1H) and reference 301 (13C).

(2-cyclopropylethyl)benzene (91b):

A 50 mL Schlenk equipped with stir bar and septum under an Ar atmosphere, was charged with 10 mL toluene (excess) and 1.10 mL TMEDA (0.853 g, 7.34 mmol). The reaction mixture was cooled to 0 °C. Then 3.53 mL nBuLi (1.6 M in hexanes, 5.64 mmol) was added drop wise to the reaction mixture. The mixture was stirred consecutively for 30 min at 0 °C, for 15 min at room temperature and for 30 min at 90 °C. The reaction mixture acquired a deep red color during this time.

In a 50 mL Schlenk equipped with stir bar and septum under an Ar atmosphere, 0.762 g of (bromomethyl)cyclopropane (5.64 mmol) was dissolved in 20 mL anhydrous Et2O. This reaction mixture was cooled to -78 °C in an acetone-dry ice bath. Then the benzyl lithium solution was cooled down to 0°C and was added drop wise via cannula to the cyclopropane solution. After the addition was completed the mixture was stirred for 16 h (-78 °C to room temperature). The mixture was then added to 25 mL of a saturated aqueous ammonium chloride solution. The water phase was extracted twice with 25 mL of n-pentane and the combined organic extracts were washed with brine (3x 25 mL). The

134

6. Experimental Part organic phase was dried over MgSO4 and was concentrated under reduced pressure. The compound was purified by distillation under reduced pressure to give a colorless oil in 54.7% yield (0.452 g, 3.09 mmol). 1H NMR δ 7.32–7.23 (m, 2H), 7.23–7.13 (m, 3H), 2.76–2.68 (m, 3H), 1.52 (dt, J = 9.4 Hz, 7.1 Hz, 3H), 0.79–0.64 (m, 1H), 0.43 (ddd, J = 8.0 Hz, 5.6 Hz, 4.1 Hz, 2H), 0.09–0.00 (m, 2H); 13C NMR δ 142.8, 128.6, 128.4, 125.7, 36.9, 36.2, 10.9, 4.7.; MS(E.I.)

+ + + + + + m/z 146 (M , 20), 117 (C9H9 , 44), 104 (C8H8 ,42), 91 (C5H5CH2 , 100), 77 (C6H5 ,21), 65 (C5H5 ,56).

5-phenyl-1-pentene (92b):

A 100 mL 3-necked flask, equipped with dropping funnel, cooler, stir bar and septum under an Ar atmosphere, was charged with Mg (0.401 g, 16.5 mmol). In the glassware, the Mg was activated by heating with a heat gun under vacuum. After allowing the glassware to cool to room temperature, anhydrous THF (20 mL) was added to the Mg. In the dropping funnel phenethylbromide (2.2 mL, 16.1 mmol) was mixed with anhydrous THF (10 mL). 1 mL of the phenethylbromide/THF solution was added to the Mg, and the Mg-reaction mixture was heated to reflux temperature by a heat gun. Further addition of the phenethylbromide/THF solution allowed the reaction mixture to gently reflux. After the addition was completed the reaction mixture was stirred at 70 °C for 1 h.

After allowing the reaction mixture to cool down to room temperature, in the dropping funnel allylbromide (1.73 mL, g, mmol) was mixed with anhydrous THF (10 mL). Then, the allylbromide/THF solution was added drop wise to the reaction mixture (exothermic reaction). After the addition was completed the reaction mixture was stirred at 70 °C for 3 h, and consecutively 16 h at room temperature.

Then 5 mL H2O was added drop wise to the reaction mixture (exothermic reaction), and the solution was transferred to a separation funnel, the vial was rinsed with Et2O (40 mL) and H2O (35 mL). The water phase was extracted twice with 40 mL of Et2O and the combined organic extracts were washed with brine (2x 25 mL). The organic phase was dried over MgSO4 and was concentrated under reduced pressure. The compound was purified by distillation under reduced pressure (73 °C at 17 mbar) to give a colorless oil in 18% yield (0.4245 g, 2.90 mmol). Data for 92b were in accordance to those given in reference 302.

135

Discovery, Development and Study of Carbenoid Mediated Reactions 6.5. X-Ray crystallography

Relevant details about structure refinements are given in the following tables. Geometrical parameters are included in the captions of the corresponding figures. Data collection was performed on a Bruker Nonius, KappaCCD (graphite monochromator, Mo Kα radiation λ = 0.71073). Program used to solve structures was SIR97303 and program(s) used to refine structures was SHELXL-97304.

136

Table 5.1 Crystallographic data and structure refinement parameters substance identification 17 21 22a 22b 22c 23 25

empirical formula C26H30ClO4PRuS C28H39ClO4PRuS C72H80O14P2Ru2S4 C36H43Cl2O7PRuS2 C41H53O7PRuS2 C69H84Cl4O9P2Ru2S2 C48H53ClO5P2RuS Mr [g/mol] 606.083 639.14 1561.762 854.811 854.040 1527.450 940.482 T [K] 123 100 100 100 100 100 100 crystal system Triclinic Monoclinic Triclinic Monoclinic Monoclinic Monoclinic Triclinic space group P¯1 P 1 21/c 1 P1 P2 1/n P 21/c C 2/c P¯1 a [Å] 9.0758 (2) 10.3720(9) 11.12190 (10) 19.7717(3) 22.496(2) 31.9573(6) 13.6608(2) b [Å] 12.0029 (2) 18.4781(14) 12.6755 (2) 14.9687(2) 15.9710(12) 10.1420(2) 19.2253(4) c [Å] 13.2659 (2) 14.6866(15) 12.8151 (2) 25.7127(4) 11.4937(7) 20.9224(5) 19.4725(4) α [°] 65.5584 (8) 90.00 85.6456 (6) 90.00 90.00 90.00 94.1677(11) β [°] 76.1567 (7) 95.556(7) 76.7148 (6) 100.1742(10) 100.198(2) 103.0096(9) 110.0928(12) γ [°] 75.7071 (8) 90.00 78.1998 (7) 90.00 90.00 90.00 109.2592(8) V [Å3] 1259.41 (4) 2801.5(4) 1720.32 (4) 7490.2(2) 4064.3(5) 6607.1(2) 4433.18(14) Z 2 4 1 8 4 4 4 1.598 1.515 1.508 1.516 1.396 1.536 1.409 density (calcd) [Mg m-3] μ [mm-1] 0.906 6.903 0.672 0.762 0.575 0.788 0.579 F(000) 620.0 1324 806.0 3520.0 1784 3152.0 1952.0 crystal size (mm3) 0.24*0.18*0.15 0.04*0.01*0.01 0.3*0.27*.012 0.48*0.255*0.066 0.24*0.255*0.066 0.255*0.084*0.021 0.36*0.18*0.15  range for 2.753—27.485 3.86–65.04 2.910 – 27.485 2.910 – 27.485 2.910 – 27.485 2.753 – 27.485 2.910 – 27.485 data collection [°] reflections collected 21244 16379 31417 36123 15181 30062 44222 independent reflections 5758 4631 14414 15997 6665 7525 18156 data / restraints /parameters 5758/0/312 4631/4/345 14414/3/797 15997/0/898 6665/0/455 7525/0/412 18156/0/1468 GOF on F2 0.896 1.211 1.218 1.645 2.521 1.151 0.912 final R1 0.0286 0.0809 0.0589 0.0744 0.1475 0.0575 0.0422

wR2 [I > 2(I)] 0.1006 0.1767 0.1574 0.2197 0.3522 0.1621 0.1164 largest diff. peak and hole [eÅ- 0.468 and 1.149 and 1.933 and 1.250 and 9.103 and 1.539 and 0.628 and 3] -1.060 -1.509 -1.709 -1.639 -1.707 -1.874 -1.004

137

138

7. Appendices

7.1. Crystal structure of complex 21

Ortep plot, ellipsoids at 30% probability. Hydrogens are omitted for clarity. The structure was resolved with two possible iPrO conformations, only one is shown. Selected bond distances (Å) and angles (°). Ru1–O1 2.396(7), Ru1–O2 2.142(7), Ru1–O4a 2.333(19), Ru1–Cl1 2.307(3), Ru1–C27 1.837(10), Ru1–P1 2.252(3), Ru1–P1–C2 111.6(3), C27–Ru1–P1– C2 140.6(5).

7.2. Crystal structure of complex 23

Ortep plot, ellipsoids at 30% probability. Hydrogens are omitted for clarity. The structure was resolved with two possible iPrO conformations, only one is shown. Selected bond distances (Å) and angles (°). Ru1–O5 2.402, Ru1–O6 2.120(3), Ru1–O37 2.311(3), Ru1–Cl4 2.3380(11), Ru1–C36 1.847(5), Ru1–P2 2.2711(10), Ru1–P1–C13 109.57(13), C27–Ru1–P1–C2 118.6(2).

139

Discovery, Development and Study of Carbenoid Mediated Reactions 7.3. NMR spectra of the isolated mixture of 24 and 25.

The proton NMR can account for the aromatic protons of the complex and the additional triphenylphosphine. The benzylidene proton shows two signals, one for the free complex, and a broad singlet for the dynamic PPh3-bound complex. In the phosphorus NMR one singlet is observed along with two broad signals corresponding most likely to the bisphosphine intermediate.

7.4. Computational Details

Calculations were performed at the M06L/6-31G**+SDD level of theory as implemented in the Gaussian09305 software package. Both minima and transition state optimizations were checked by frequency analysis where minima are characterized by zero imaginary frequencies, and transitions by only one imaginary frequency. Relaxed potential energy surface scan calculations performed from a well-characterized intermediate where bond length or dihedral angle was scanned progressively provided very close approximations to the actual transition state geometries. Full optimization of the transition states was started from these guesses.

140

7. Appendixes Table 6.1 Potential and Gibbs free energies for structures in figure 2.9 (T=298.15 K) in hartrees.

Series Structure A B C D E

-3148.9674401 -2101.8075899 -2180.4039483 -2180.3988853 -2180.4165706 Grubbs EM06L

1st gen. F. Gibbs -3148.046078 -2101.349530 -2179.895699 -2179.891016 -2179.905148

-3027.1885928 -1980.0220397 -2058.6230172 -2058.6225945 -2058.6425047 Grubbs EM06L

2nd gen. F. Gibbs -3026.337049 -1979.636412 -2058.187954 -2058.186067 -2058.198387

-2446.4551236 -1631.5396695 -1710.1391533 -1710.1230701 -1710.1437872 Complex EM06L

6a F. Gibbs -2445.782461 -1631.26363 -1709.81376 -1709.797313 -1709.813451

-2604.3201571 -2180.1015481 -2258.7013774 -2258.6945867 -2258.7086636 Complex EM06L

17 F. Gibbs -2603.875736 -2179.816864 -2258.365239 -2258.360305 -2258.370462

-78.5736935 -1047.0955078 -893.4503646 EM06L Ethylene PCy3

F. Gibbs -78.543634 -1046.657244 -893.032064

-502.7533579 EM06L

-502.56915 F. Gibbs

141

Discovery, Development and Study of Carbenoid Mediated Reactions

Calculated structures for 1st generation Grubbs catalyst

A B C

D E

Calculated structures for 2nd generation Grubbs catalyst

A B C

D E

142

7. Appendixes

Calculated structures for complex 6a

A B C

D E

Calculated structures for complex 17

A B C

D E

143

Discovery, Development and Study of Carbenoid Mediated Reactions 7.5. Evidence of formation of 4-fluoro-1-cyclopropylbenzene reaction mixture (71f)

1H NMR of the mixture obtained after workup

CG-FID trace of the mixture obtained after workup

144

7. Appendixes

CG-MS trace of the mixture obtained after workup

145

Discovery, Development and Study of Carbenoid Mediated Reactions 7.6. 1H spectrum of complex 81

7.7. Confirmation by 1H NMR of the formation of exo-tricyclo[3.2.1.02.4]octane (87)

146

7. Appendixes 7.8. Confirmation by 1H NMR of the formation of cis-bicyclo[6.1.0]nonane (91a)

7.9. Confirmation by 1H NMR of the formation of (2-cyclopropylethyl)benzene (92a)

147

Discovery, Development and Study of Carbenoid Mediated Reactions 7.10. Confirmation by 1H NMR of the formation of cyclopropylbenzene (71a)

7.11. NMR spectra of (2-cyclopropylethyl)benzene (91b)

148

7. Appendixes

149

150

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Curriculum Vitae

Full name Juan Manuel Sarria Toro Nationality Colombia Date of birth 24.08.1984 Place of birth Bogotá, Colombia

Education

Dates 2009–2014 Title awarded Doctor of Sciences Thesis supervisor Prof. Dr. Peter Chen Institution ETH Zürich Vladimir–Prelog–Weg 2, 8093, Zürich, CH

Dates 2007–2008 Title awarded Master of Science – Chemistry Thesis supervisor Prof. Dr. Luca Fadini Institution Universidad Nacional de Colombia Calle 45 No. 30-02, Bogotá, Colombia

Dates 2002–2006 Title awarded Bachelor in Chemistry Thesis supervisor Prof. Dr. Phill. Marco Fidel Suarez Herrera Institution Universidad Nacional de Colombia Calle 45 No. 30-02, Bogotá, Colombia

Experience

Dates 2009–2013 Assignment Teaching Assistant. Organic Chemistry Practical Course Institution ETH Zürich

Dates 08.2008–09.2008 Assignment Research Internship. Group Prof. Dr. Antonio Togni Institution ETH Zürich

Dates 2007–2008 Assignment Teaching Assistant. Analytical Chemistry Courses Institution Universidad Nacional de Colombia

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