Polysubstituted Cyclopentadienes and Their Ferrocenes

Research Collection

Doctoral Thesis

Author(s): Lauber, Alex

Publication Date: 2018-12

Permanent Link: https://doi.org/10.3929/ethz-b-000307868

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ETH Library Diss. ETH NO. 25126

Polysubstituted Cyclopentadienes and Their Ferrocenes

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

presented by ALEX SANDRO LAUBER

MSc in Chemistry, ETHZ

born on 14.12.1988

citizen of T¨asch VS

accepted on the recommendation of

Prof. Dr. Antonio Togni, examiner Prof. Dr. Erick M. Carreira, co-examiner

2018

I could put my thumb up to a window and completely hide the Earth. I thought, ’everything I’ve ever known is behind my thumb’.

James Arthur Lovell Jr.

Danksagung

Ich hatte das Gluck¨ viele Leute w¨ahrend meiner Zeit an der ETH kennenzulernen, die mich in jeglichen Belangen unterstutzt¨ haben. Es ist mir daher eine Freude, hier meine Dankbarkeit ausdrucken¨ zu durfen.¨

Der grosste¨ Dank geht an meinen Doktorvater Antonio Togni, der mich uber¨ die Jahre geleitet und begleitet hat. Danke dir, Antonio, fur¨ deine Menschlichkeit und Freundlichkeit, dein Vertrauen und deine Unterstutzung,¨ sowie fur¨ deine Leidenschaft in der Lehre und Forschung. Durch dich habe ich das Gluck¨ eine ausserordentliche Ausbildung genossen zu haben.

Prof. Erick M. Carreira mochte¨ ich ganz herzlich fur¨ die Ubernahme¨ der Rolle des Koreferenten danken, sowie fur¨ die zahlreichen packenden und lehrreichenden Seminare w¨ahrend der Ausbildung.

Meine allerliebste Andrea Sachs: ein Danke ist keineswegs genug fur¨ die vielen Unterhal- tungen, die einem den Tag immer wieder erfrischt haben und die st¨andige Hilfe in allen moglichen¨ Angelegenheiten.

Fur¨ seine grosszugige¨ Hilfsbereitschaft mochte¨ ich mich bei Antonio Mezzetti bedanken denn, komme was wolle, ich konnte immer auf seine Unterstutzung¨ z¨ahlen.

Ein grosser Teil meiner Zeit durfte ich fern(er) vom Tageslicht im Keller verbringen. Dennoch freute ich mich (fast) jedes Mal wenn es hiess ”s’NMR goht nume”,¨ und ich alles Wissen, welches mir René Verel mit viel Geduld und Passion beigebracht hatte, zur Geltung bringen durfte. Danke dir, René fur¨ die zusätzliche Ausbildung welche ich in einer Umgebung geniessen durfte welche ich bereits vermisse.

Doch war es jemand anders der mir in letztere Welt den Eingang ermoglicht¨ hatte. Meine liebe Barbara Czarniecki: deine ansteckende Leidenschaft machten einem das Privileg der Aufgabe des NMR Assistenten noch klarer.

Den Bewohnern des H222, welche mir bei der Verfassung dieser Arbeit geholfen haben, mochte¨ ich ebenfalls meine Dankbarkeit hier zeigen: Fabian Bruning,¨ danke dir fur¨ deine lockere und gleichzeitig gewissenhafte Art, sowie fur¨ die Ubernahme¨ der Rolle des “Sicherheits-Salamanders”. Meiner lieben Mona Wagner muss ich vor allem fur¨ Ihre Fursorglichkeit¨ danken. Mit ihren lieben Gesten vermochte sie mich während dem Schreiben immer wieder aufzumuntern. Dem jungsten¨ Mitglied, Phil Liebig mochte¨ ich herzlich fur¨ seine - wie es der Name ankundigt¨ - liebe Art und fur¨ die hilfreichen Diskussionen danken. Ich hatte während den letzten Jahren das Privileg in der Lehre tätig sein zu durfen,¨ und das zum ersten Mal auch hinter der Kulisse. Ich hatte dabei das Gluck,¨ dass ich diese spannende und intensive Aufgabe mit einer sehr fähigen Person teilen durfte. Carl Philipp Rosenau: die unzähligen Stunden welche wir zusammen gekrampft haben gehoren¨ zu den besten Erinnerungen die ich mitnehme.

Unseren Kristallographen Lukas Sigrist und Mona Wagner bin ich unendlich dankbar fur¨ ihre Zeit und Arbeit welche mir noch so einige schone¨ Strukturen hingezaubert haben.

Bei meinen Studenten Christian Rueger,¨ Jonas Bosken,¨ Salome Heilig und Raphael Lengacher mochte¨ ich mich ganz herzlich fur¨ ihre Motivation bedanken, welche diese Arbeit weitreichend unterstutzt¨ und geformt hat. Ich h¨atte mir keine besseren Schuler¨ wunschen¨ konnen¨ und es war mir ein Freude, mit euch zu arbeiten und dabei zu lernen.

Ich hatte das Vergnugen¨ und die Ehre gleich zwei wurdige¨ NMR-Assistenten ausbilden zu durfen.¨ Ein grosses Danke an Matthew Baker und Pascal Tripet fur¨ Ihre Bereitschaft dieses Amt zu ubernehmen.¨

Jelier Benson mochte¨ ich fur¨ die vielen netten Worte und interessanten Diskussionen danken. Sein Engagement in der Gruppe und die vielen Aufgaben die er ubernommen¨ hat sorgen dafur,¨ dass doch so einiges rund l¨auft.

Einige faszinierende wissenschaftliche Werke w¨aren mir verneint geblieben wenn diese nicht durch Dmitry Katayev aus dem Russischen ubersetzt¨ worden w¨aren.

Allgemein, muss ich allen Mitgliedern der Togni und Mezzetti Gruppen danken fur¨ die Hilfe w¨ahrend den Jahren und den vielen Freizeitaktivit¨aten die wir unternommen haben.

Allen Angestellten des HCI-Shops und des MS-Services (vor allem Louis Bertschi) danke ich fur¨ ihre ausgezeichnete Arbeit ohne welche nicht viel von dieser Dissertation moglich¨ gewesen w¨are.

Ein grosses Danke geht an einige, teils ehemalige, Veteranen der Gruppe: Rima Drissi, Lukas Sigrist, Remo Senn, Simon Foser, Peter Ludwig, Jan Welch, Barbara Czarniecki, Rino Schwenk und Harutake Kajita. Danke euch, fur¨ die vielen schonen¨ Zeiten die ich mit euch erleben durfte. Einfach gesagt, mein Leben w¨are niemals das Gleiche ohne euch.

Ein besonderer Dank geht an meine Eltern Anna und Clemente, sowie meinen Brudern¨ Anthony und Joel. Ohne eure Unterstutzung¨ w¨are ich nie so weit gekommen und es gibt keine Worte um meine Dankbarkeit euch gegenuber¨ entsprechend auszudrucken.¨

Contents

Abstract iv

Zusammenfassung vi

Introductory Remarks ix

1 General Introduction1 1.1 Cyclopentadiene: A Historical Note...... 1 1.2 Cyclopentadiene in Organometallic Chemistry...... 1 1.3 Syntheses of Pentamethylcyclopentadiene...... 2 1.4 Syntheses of Chiral Cyclopentadienes: The Advantage of Modularity...4 1.5 Aim of this Thesis...... 7

2 First Generation Approach for the Synthesis of Polysubstituted Cyclopen- tadienes9 2.1 Introduction...... 9 2.1.1 General Retrosynthetic Analysis...... 9 2.1.2 Model Ligand...... 11 2.2 Results and Discussion...... 12 2.2.1 Preparation of 1,2,3-Trimethylcyclopentadiene...... 12 2.2.1.1 Preparation of a Disubstituted Cyclopentadiene Model Compound...... 14 2.2.2 Cross Coupling Reactions...... 15 2.3 Summary and Conclusion...... 17 2.4 Outlook...... 18

3 Second Generation Approach for the Synthesis of Polysubstituted Cy- clopentadienes 19 3.1 Introduction...... 19 3.1.1 General Retrosynthetic Analysis...... 19 3.1.2 Conversion of Cyclopentenones to Cyclopentadienes: A Closer Look 21 3.1.2.1 Model Ligand and Retrosynthetic Analysis...... 21 3.2 Results and Discussion...... 23 3.2.1 Preparation of Cyclopentenones...... 23 3.2.2 Preparation of Cyclopentadienes...... 26 3.2.3 Attempted Reduction of the Cyano Group...... 28 3.2.4 Preparation of Methoxy-Substituted Cyanocyclopentadienes... 28 3.3 Summary and Conclusion...... 32 3.4 Outlook...... 33

i Table of Contents

4 Polysubstituted Ferrocenes 35 4.1 Introduction...... 35 4.1.1 Goals and Synthetic Planning...... 36 4.1.2 O-Substituted Ferrocenes...... 38 4.1.2.1 Preparation of Ferrocenol and Derivatives Thereof... 39 4.1.2.2 Alternative Preparations of Ferrocenols and Derivatives Thereof...... 40 4.1.2.3 Applications of Ferrocenols and Derivatives Thereof.. 41 4.1.3 Cyanoferrocenes...... 42 4.1.3.1 Single Step Preparations of Cyanoferrocenes from Fer- rocene...... 42 4.1.3.2 Multistep Transformations Yielding Cyanoferrocenes.. 42 4.1.3.3 Cyanoferrocenes from Cyanocyclopentadienes..... 43 4.1.3.4 Applications of Cyanoferrocenes...... 44 4.1.4 The Only Example of a 1-Alkoxy-2-Cyanoferrocene...... 44 4.1.5 Cyclopentadienyl Iron(II) Transfer Reagents for the Preparation of Heteroleptic Ferrocenes...... 45 4.1.5.1 Heteroleptic Ferrocenes from Cyclopentadienyl Arene Iron(II) Compounds...... 47 4.2 Results and Discussion...... 49 4.2.1 Synthesis of Homoleptic Ferrocenes...... 49 4.2.2 Heteroleptic Ferrocenes...... 50 4.2.2.1 Preparation of Cyclopentadienyl Arene Iron(II) Compounds 50 4.2.2.2 Synthesis of Heteroleptic Ferrocenes: Photolysis Protocol 51 4.2.2.3 Synthesis of Heteroleptic Ferrocenes: Thermal Protocol 52 4.2.2.4 Optimizations of Reaction Conditions for the Synthesis of Heteroleptic Ferrocenes...... 53 4.2.2.5 Structural Considerations of Heteroleptic Cyanoferrocenes 61 4.2.3 Investigations on the Reactivity of Heteroleptic Ferrocenes.... 66 4.3 Summary and Conclusion...... 68 4.4 Outlook...... 69

5 General Conclusion and Outlook 71 5.1 Summary...... 71 5.1.1 First Generation Synthesis...... 72 5.1.2 Second Generation Synthesis...... 73 5.1.3 Synthesis of Ferrocenes...... 74 5.2 Outlook and Concluding Remarks...... 76

6 Experimental 77 6.1 General remarks...... 77 6.1.1 Techniques...... 77 6.1.2 Chemicals...... 77 6.1.3 Analytics...... 78 6.2 Syntheses...... 79 6.2.1 First Approach...... 79 6.2.1.1 Kumada Coupling Experiments...... 81 6.2.2 Second Approach...... 82 6.2.2.1 Syntheses of Starting Materials...... 82

ii Table of Contents

6.2.2.2 Knoevenagel Condensations...... 85 6.2.2.3 Nazarov Cyclizations...... 87 6.2.2.4 Syntheses of Cyclopentadienes...... 89 6.2.2.5 Pinene-Derived Cyclopentadiene...... 95 6.2.3 Ferrocenes and Related Compounds...... 98 6.2.3.1 Cyclopentadienyl Arene Iron(II) Salts...... 98 6.2.3.2 Homoleptic Ferrocenes...... 100 6.2.3.3 Heteroleptic Ferrocenes...... 101 6.2.4 Deprotonation Experiments...... 105

A Monitoring the Oxidative Coupling of 2-Butanone 127

B Attempted Synthesis of Technetium Complexes 128

C Towards an Enantiopure Polysubstituted Cyclopentadiene 129

D Abbreviations and Acronyms 131

E Crystallographic Data 133

F Literature Crystal Structures 149

G List of Contributions 155

iii Abstract

The original goal of the thesis at hand was the development of synthetic strategies for the preparation of a new class of polysubstituted cyclopentadienyls of type 1 (Figure 1).

PGO

R* F M O N F NR* PG

Figure 1: Target cyclopentadienyl ligand 1 and envisaged coordination compounds.

Corresponding transition-metal complexes of 1 were intended to be used as chiral Lewis acids promoting asymmetric hydrofluorinations. A first attempt towards ligand class 1 relied on the scission of the aryloxy and aminoethyl fragments from the main 1,2,3-trimethylcyclopentadiene scaffold. Synthesis of the latter compound according to published procedures could not be accomplished and this strategy was thus discarded early on in favor of an improved one. The second synthetic procedure relied on the early installation of the aryl and nitrogen moieties and this strategy was examined with the preparation of model compound 13-OMe (Scheme 1).

O O O OMe OMe Ph CN OH CN CN CHO NMe2 Ph Ph Ph OMe

11 19 14 13-OMe

Scheme 1: Second generation approach towards model compound 13-OMe

Tiglic acid was converted on a 50 g-scale to β-oxo nitrile 11 which served as substrate for a subsequent Knoevenagel condensation. The so afforded diene underwent a clean Nazarov cyclization to cyclopentenone 19 which was O-methylated and enolized to yield cyclopentadiene 14. Unfortunately, the subsequent envisaged reduction of the cyano functionality could not be accomplished which was required to continue towards the initially intended structures derived from 1. The direction of this thesis took a turn at this point since an interesting new class of cyclopentadienes had been obtained with compound 14. The corresponding homoleptic ferrocenes were thus prepared like their heteroleptic congeners which could be obtained efficiently by improving published protocols. Corresponding homo- and heteroleptic ferrocenes were also successfully

iv Abstract prepared with other, similarly polysubstituted ligands which were obtained analogously to 14 (Scheme 2).

1 1 1 R R Fe - R CN CN R2 PF6 CN OMe FeBr 2 OMe 2 CN R Fe + Fe Fe OMe R1 CN R2=OMe CN OMe 1 1 R R iPr 1 R =Me, Ph R2=OMe, R1=Me, Ph, , R2=H, R1=Ph iPr iPr

Scheme 2: Polysubstituted ferrocenes of this work.

These ferrocenes are the first of their kind being extensively investigated in the liquid and solid state alike. This revealed, for example, the hindered rotation of the larger aryl groups in heteroleptic ferrocenes which results in structures which are bent up to 9.86° (Figure 2).

Figure 2: Some crystal structures of obtained heteroleptic ferrocenes.

In an attempt at deprotonating the unsubstituted cyclopentadienyl of heteroleptic ferrocene 49 a surprising reactivity was observed as the methyl group adjacent to the methoxy moiety had selectively reacted (Scheme 3).

Mes 1) tBuLi Mes CN CN KOtBu OMe OMe Fe Fe D 2) CD3OD

Scheme 3: Observed deprotonation of methyl group in heteroleptic ferrocene 49.

v Zusammenfassung

Das ursprungliche¨ Ziel dieser Dissertation war die Entwicklung synthetischer Strategien fur¨ die Herstellung einer neuen Klasse von polysubstituierten Cyclopentadienyle des Typs 1 (Abbildung1).

PGO

R* F M O N F NR* PG

Abbildung 1: Zielstruktur 1 und deren Komplexe.

Die von 1 abgeleiteten Ubergangsmetallkomplexe¨ sollten dabei als chirale Lewis-S¨auren eingesetzt werden um asymmetrische Hydrofluorierungen zu katalysieren. Ein erster Versuch, um die Liganden-Klasse 1 herzustellen, beruhte auf die Einfuhrung¨ der Aryl- und Aminoethyl-Fragmente in die grundlegende Trimethylcyclopentadien-Struktur. Da die Synthese dieser Kernstruktur anhand von publizierten Vorschriften nicht hergestellt werden konnte, wurde diese Strategie zugunsten einer verbesserten fruhzeitig¨ abgesetzt. Eine zweite synthetische Sequenz sah die fruhe¨ Installation der Aryl- und Stickstoff-Fragmente vor und diese Idee wurde mit der Herstellung eines Abkommlings¨ von 1 gepruft¨ (Schema 1).

O O O OMe OMe Ph CN OH CN CN CHO NMe2 Ph Ph Ph OMe

11 19 14 13-OMe

Schema 1: Synthese zweiter Generation fur¨ die Herstellung von 13-OMe.

Ausgehend von Tiglins¨aure wurde Nitril 11 in bis zu 50 g-Mengen erhalten, welches als Substrat fur¨ die folgende Knoevenagel-Kondensation diente. Das so erhaltene Dien zyklisierte unter sauren Bedingungen zum entsprechenden Cyclopentenon 19 welches folglich durch O-methylierung und Enolisierung zu Cyclopentadien 14 reagiert wurde. Unglucklicherweise¨ war es nicht moglich¨ die Cyano-Gruppe zu reduzieren was fur¨ die weiteren Schritte in Richtung Varianten der ursprunglichen¨ Zielstrukturen 1 notig¨ war. Das Ziel dieser Arbeit wurde daraufhin angepasst, haupts¨achlich weil eine neue und interessante Art von Cyclopentadien (14) hergestellt wurde. Deshalb wurden erstens die entsprechenden homoleptischen Ferrocene synthetisiert und an zweiter Stelle, nach

vi Zusammenfassung

Verbesserung von publizierten Vorschriften, auch entsprechende heteroleptische Komplexe. Diese Reaktionen konnten auch mit weiteren Varianten von Cyclopentadien 14 ausgefuhrt¨ werden, welche auf gleichem Wege erhalten wurden (Schema2).

1 1 1 R R Fe - R CN CN R2 PF6 CN OMe FeBr 2 OMe 2 CN R Fe + Fe Fe OMe R1 CN R2=OMe CN OMe 1 1 R R iPr 1 R =Me, Ph R2=OMe, R1=Me, Ph, , R2=H, R1=Ph iPr iPr

Schema 2: Polysubstituierte Ferrocene in dieser Arbeit.

Diese Ferrocene sind die ersten ihrer Art die ausfuhrlich¨ in der flussigen,¨ sowie festen Phase untersucht wurden. Somit wurde, zum Beispiel, die erschwerte Rotation grosserer¨ Aryl-Reste festgestellt welche die Strukturen bis zu 9.86° verbiegen (Abbildung2).

Abbildung 2: Einige Kristallstrukturen der erhaltenen heteroleptischen Ferrocenen.

Zuletzt wurde versucht, den unsubstituierten Liganden in Ferrocen 49 zu deprotonieren, was uberraschenderweise¨ jedoch zu einer selektiven Reaktion der Methyl-Gruppe in der N¨ahe des Methoxy-Substituenten fuhrte¨ (Schema3).

Mes 1) tBuLi Mes CN CN KOtBu OMe OMe Fe Fe D 2) CD3OD

Schema 3: Beobachtete Deprotonierung von Ferrocen 49.

vii

Introductory Remarks

This thesis describes the synthesis of substituted cyclopentadienes which possess two enantiotopic sides and their ferrocenes. Depending whether a homoleptic (containing two equal ligands) or heteroleptic metallocene (two different cyclopentadienyls are bound to iron) is formed, differing numbers of stereoisomers are expected. To clarify and define the terminology describing these circumstances, the following thesis makes use of the one presented by Halterman and Schlogl¨ (Scheme 4).[1,2]

pair of enantiomers pair of enantiomers achiral meso-diastereomer

2 CN NC OMe CN NC CN 1 OMe MeO OMe MeO OMe Fe Fe CN Fe Fe + Fe OMe MeO CN σ CN NC OMe

(Sp) (Rp) (Sp,Sp) (Rp,Rp) (Sp,Rp)

Scheme 4: Representation of cyclopentadienyls of this work and their ferrocenes.

The case where heteroleptic ferrocenes are synthesized is reminiscent of the situation which would be encountered with any other half-sandwich complex. Due to the two enantiofaces of the cyclopentadienyl ligand, a mixture of two enantiomers is afforded. When homoleptic ferrocenes are prepared with such a ligand will result in the formation of three stereoisomers: a pair of enantiomers and an achiral meso-diastereomer. When referring specifically to planar chirality in metallocenes, the stereodescriptors willbe followed by the subscript P.

This work cites a number of results and investigations from publications which are not available in digital format. However, these accounts have been collected and reviewed in the excellent and comprehensive Gmelin Handbook of Inorganic and Organometallic Chemistry series. In the following, the corresponding volumes will be cited where appropriate.

Chapter 1

General Introduction

In this introductory chapter the underlaying key aspects and motivations of this thesis are presented.

1.1 Cyclopentadiene: A Historical Note

It was 1885 when Sir Henry E. Roscoe stated that he had received a ”camphor-like substance from Mr. W. W. Staveley from West Bromwich...obtained by him from the most volatile portions of the hydrocarbons, resulting from the decomposition of crude phenol at a red heat”.[3] The narration continues with Mr. Staveley’s observation about this substance he submitted to Roscoe: ”after standing for some weeks the greater portion of the volatile bodies, boiling from 20 ◦C to 40 ◦C, was changed by absorption of atmospheric oxygen into bodies boiling between 160 ◦C and 170 ◦C. After distilling off the lighter portion from the oxidised mixture, the residue in the retort, on cooling, solidified to a, white crystalline mass”. Roscoe analyzed this solid compound and determined its molecular formula as C10H12, thus disproving the assumption of Staveley that an oxidation was taking place. He then continued his investigations and eventually deduced that this species must be the result of a dimerization of the aforementioned volatile compound: ”Whether, as seems not unlikely, the new crystalline hydrocarbon is derived from a hydrocarbon, C5H6, an isomeride of valylene, must at present remain doubtful, as the search for this body proved unsuccessful”. A decade later, in 1896, Kraemer and Spilker managed to elucidate the structures of Roscoe’s compounds as cyclopentadiene [4] (C5H6) and its dimer dicyclopentadiene (C10H12). Just a few years later, in 1901 in Munich, Johannes Thiele reacted cyclopentadiene with potassium in benzene and collected a white to yellow solid: the first cyclopentadienyl-metal compound.[5]

1.2 Cyclopentadiene in Organometallic Chemistry

It is no understatement that the discovery of ferrocene in 1951 has abruptly changed the chemistry of metal complexes for times to come.[6,7] Indeed, it was not for long before researchers replicated the η5-binding mode of the cyclopentadienyl ligand with other metals and, as a result, nowadays one may easily feel overwhelmed by the masses of reports on cyclopentadienyl complexes and their applications.[8–11] The common feature shared by the plethora of these coordination compounds, the cyclopentadienyl ligand, has received considerable attention also before the advent of metallocenes (see above).[12] In

1 Chapter 1 most cases, however, it is a rather neglected part the of chemistry involving metallocenes since the sought after interactions take place at the metal core or other ancillary sites. Thus, cyclopentadienyls are mainly regarded as spectators, strongly bound to the metal and influencing the characteristics of complexes from behind the scenes.

1.3 Syntheses of Pentamethylcyclopentadiene

Any deviation form the standard C5H5 formula will have effects on the overall features of a coordination compound and systematic investigations on substituted cyclopentadienes began soon after the discovery of ferrocene. The earliest one was published in 1959 by Wilkinson et al. as they compared the effects of exchanging cyclopentadiene for methylcyclopentadiene in organometallic complexes.[13] As time progressed, researchers had introduced virtually every possible functionality in cyclopentadienyl ligands and investigated the effects that such entail.[14, 15] Further comprehensive studies eventually allowed the parametrization of the influence that cyclopentadienyl-substituents exert in metallocenes, as for example, on the rates of aromatic substitution or the redox behavior in ferrocenes.[16, 17] An evolution of this area was provided by the study of polysubstituted cyclopentadienes since the steric and electronic effects of a substituent are amplified up to five times.The most important example of such a ligand is pentamethylcyclopentadiene which allowed the isolation and characterization of new and important structures due to its electron-richness and bulkiness.[8, 18, 19] The first complex containing this ligand was published byRoth et al. in 1962 as the product of the reaction of unsaturated hydrocarbons with TiCl4 under vigorous conditions (Scheme 1.1).[20]

Mixture of unsaturated MX Cl Cl hydrocarbons 3 M M TiCl Ti Cl 4 Cl Cl 30-60 atm Cl 300 °C Cl

M=Rh, Ir Roth 1962 Maitlis 1968

Scheme 1.1: First synthesis of a pentamethylcyclopentadienyl complex according to Roth[20] and conversion of dewar hexamethylbenzene to the corresponding rhodium and iridium pentamethylcyclopentadienyl dimers.[21]

A similarly serendipitous and elegant reaction worth mentioning was discovered by Maitlis et al. as they isolated rhodium an iridium pentamethylcyclopentadienyl complexes from reactions of the respective chlorides and dewar hexamethylbenzene.[21–24] The first organic synthesis of this important ligand actually precedes the work by Rothand Maitlis. In 1960, deVries published a five step sequence of pentamethylcyclopentadiene,[25] which allowed chemists to produce enough quantities of this ligand to synthesize congeners of the multitude of metallocenes which were published at the time.[18, 19] Although this might be the simplest known polysubstituted cyclopentadiene, the original synthesis of deVries has been revisited multiple times since it was deemed as too expensive and inefficient (Scheme 1.2).

2 Chapter 1

deVries 1960 Burger 1974 Whitesides 1976

O O O

H OH

O O COMe O

46% yield 8% yield 31% yield 34% yield over 5 steps over 4 steps over 2 steps over 3 steps

Scheme 1.2: Selection of syntheses of pentamethylcyclopentadiene.

Following the publication of deVries,[25] Burger et al. developed a simpler synthetic sequence to corroborate their findings that dewar hexamethylbenzene formed pentamethylcyclopentadiene as well after oxidation with peracids and treatment under acidic conditions.[26] Due to the demand of pentamethylcyclopentadiene in the organometallic community, Whitesides and collaborators optimized the synthetic sequence of Burger and achieved a higher yield in fewer steps.[27] Eventually, Jutzi and Marks again optimized Burgers protocol to render the synthesis of pentamethylcyclopentadiene more economical by further elaborating the synthetic operations. This resulted in an entry in the renowned Inorganic Syntheses collection.[28, 29] However, the most useful and economical synthesis of pentamethylcyclopentadiene was published by Bercaw et al. in 1977 (who also optimized deVries’s protocol[30]) as it provides a distinct advantage: libraries of pentasubstituted cyclopentadienes can readily be prepared by choosing the appropriate starting material (Scheme 1.3).[31]

overall yields R=Me 75% HO R R O R=Et 65% Li + H n R= Pr 51% R OEt n R= Bu 54% R=Ph 29%

Scheme 1.3: Bercaw’s synthesis of pentasubstituted cyclopentadienes.[31]

This synthetic strategy subsequently proved to be very useful for the synthesis of a number of polysubstituted cyclopentadienes.

3 Chapter 1

1.4 Syntheses of Chiral Cyclopentadienes: The Ad- vantage of Modularity

The five membered cyclopentadiene ring is a versatile scaffold which, by meansof corresponding synthetic efforts, can be decorated with virtually every possible substituent. An important story of cyclopentadiene-design is told by the numerous accounts on the integration of stereogenic residues in this framework. The most important examples, along with their syntheses are discussed in the excellent reviews by Halterman who was also active in this area.[1,8] Chiral metallocenes were known by the late 1960ies but the first synthesis of a free cyclopentadiene ligand bearing stereogenic residues was provided in 1974 by Tirouflet and coworkers (Scheme 1.4).[32]

Ph Ph

Ph 1) LiAlH4 Cl Cl Ti + Ti 2) TiCl4 Cl Cl

Ph Ph (S,S) and (R,R) (S,R) racemate meso-diastereomer

Scheme 1.4: The first synthesis of a cyclopentadienyl ligand bearing a chiral residue and corresponding titanocenes.[32]

Although the ligand was prepared as a racemate, Tirouflet et al. accurately described the mixture of diastereomers formed by their corresponding titanocenes. Further developments in this area followed and gave rise to a number of cyclopentadienes bearing stereogenic substituents. In doing so, the first pentasubstituted, chiral cyclopentadiene followed in 1983 (Scheme 1.5).[33]

Ph Ph Et Li 1) nBuLi Et 1) 2 2) TiCl3 Cl EtO C Et Ti 2 2) H+ Cl 3) (C5Me5)Li 4) HCl, H2O

Scheme 1.5: Synthesis of the first pentasubstituted cyclopentadiene containing a stereogenic moiety and its corresponding titanocene.[33]

By applying Bercaw’s synthesis of pentaalkylcyclopentadienes,[31] Moise and collaborators reacted a chiral ester with two equivalents of 2-butenyllithium yielding the corresponding pentasubstituted cyclopentadiene in excellent 90 % yield. Bercaw’s strategy reemerged again in 1990 when Erker et al. prepared a camphor-derived, C 2-symmetric ligand which allowed the synthesis of chiral zirconium complexes.[34–36]

4 Chapter 1

1) HCO2Et (0.5 equiv.) 1) nBuLi

2) H+ O Li 2) ZrCl4 TiCl3 cat.

O OH OH OH CO2Et (5 equiv.) CO2Et cat. (5 mol%) H2O (27 mol%) CH2Cl2 56% yield 84% ee

Scheme 1.6: Synthesis of a camphor-derived cyclopentadiene and its corresponding zirconium complex. The latter was further employed in the addition of pyruvate esters to naphtols.[34–36]

These complexes where then investigated by the same group as chiral Lewis acids and were used in addition-reactions of 1-naphtol with pyruvate esters.

The above described examples of structurally complicated cyclopentadienes, show the importance of synthetic strategies which allow for easy alteration of substituents. In the presented cases this was possible thanks to Bercaw’s modular protocol.[31] An analogous situation has evolved from the work of Halterman et al., who in 1989 prepared binaphtyl-containing cyclopentadienes via a bisalkylation-rearrangement sequence.[37, 38]

R NaCp PhMe R 220 °C

R=Br, OMs

Scheme 1.7: Synthesis of a binaphtyl-containing cyclopentadiene by Halterman and coworkers.[37, 38]

With the same method, a corresponding pentasubstituted variant was also prepared by employing a pre-functionalized cyclopentadiene as starting material (Scheme 1.8).[1,8]

Br PhMe

Br NaH 220 °C

Scheme 1.8: Extension of Halterman’s synthesis of binaphtyl-containing cyclopentadienes to a corresponding pentasubstituted variant.[1,8]

A more recent evolution of Halterman’s strategy has been applied with success since 2012 by the Cramer group (Scheme 1.9).[39]

5 Chapter 1

Ph OMe OR

1) BuSLi 1) BuSLi 2) RX 2) Tf2O, NEt3 3) Pd(PPh3)4 Ph PhB(OH)2 OMe OR PhMe PhMe PhMe 220 °C 220 °C 220 °C

Ph OMe OR

Ph OMe OR R=iPr, TIPS, TBDPS

Scheme 1.9: Modification of Halterman’s strategy to prepare binaphtyl-containing cyclopentadienes by Cramer et al.[39]

Incorporation of O-substituents on the binaphtyl scaffold allowed for a facile modification of the latter and thus for the synthesis of vast cyclopentadienyl-libraries. In doing so, they subsequently prepared an equal number of transition metal complexes containing these ligands. This allowed for easy and fast identifications of suitable catalysts for specific transformations (an optimized example is depicted in Scheme 1.10).[39–42]

OTIPS MeO C O OMe O cat. (5 mol%) N OMe (BzO)2 (5 mol%) H Ph N Rh(C2H4)2 H CH2Cl2, -20 °C MeO OTIPS cat. 80% yield, e.r. 96.5:3.5

Scheme 1.10: Example of a rhodium-catalyzed reaction by Cramer et al. employing one of their binaphtyl-based cyclopentadienes (optimized conditions).[39]

Recently, they modified this proven strategy further by installing a third substituent in modular fashion.[43]

OMe OMe OMe Acetone or R cyclohexanone RLi or

pyrrolidine LiAlH4

OMe OMe OMe from acetone from cyclohexanone R=H, Me, Ph R=Me, nBu

Scheme 1.11: Further modification of binaphtyl-derived cyclopentadienes by the Cramer group .[43]

6 Chapter 1

Simple condensation of the binaphtyl-containing cyclopentadienes with ketones provided corresponding fulvenes which were then treated with nucleophiles to yield libraries of trisubstituted ligands. In this last case, two additional degrees of freedom were thus introduced in the ligand structure by the judicious choice of synthetic transformations. This concept of synthetic modularity has played an important role during the development of this thesis.

1.5 Aim of this Thesis

Our goal was the synthesis of polysubstituted and chiral cyclopentadienyl-ligands of type 1 (Scheme 1.12).

X NR PGO Li X M O X O N R M X NR PG

1 (RP,R) diastereomer (SP,R) diastereomer favored disfavored

Scheme 1.12: Target ligand 1 and proposed stereoselective coordination to group 5 or 6 transition-metal halides (PG=protecting group).

We envisaged to coordinate ligand 1, after removal of the protecting groups from the heteroatom functionalities, to group 5 and 6 metal halides in oxidation state +V. Since the two sides of the cyclopentadienyl 1 are enantiotopic, we proposed to control the stereospecificity of the coordination process with the two tethered groups. More precisely, the steric clash of the stereogenic aminoethyl moiety with the flanking aryl substituent was anticipated to favor one possible diastereomer over the other. Concerning the use of such complexes, we proposed their employment as chiral Lewis acids for the nucleophilic fluorination of suitably electrophilic substrates (Scheme 1.13).

7 Chapter 1

F F HO M F F N R O H

X O HF F F HO M M F F N X NR R H

F F F HO M F HN R O HF

Scheme 1.13: Proposed application of envisaged complexes containing ligand 1 in hydrofluo- rination reactions of acrylic compounds.

The Togni group has already worked in the past in this general area,[44–48] and we wanted to expand on these previous transformations by using the proposed transition-metal complexes as catalysts in asymmetric hydrofluorinations (a possible catalytic cycle is depicted in Scheme 1.13). We propose that upon treatment of the initially formed complex with HF, the amido- and phenoxo-metal bonds should be easily broken and the heteroatoms protonated. Linkage of the latter to the cyclopentadienyl scaffold would keep them relatively close to the metal center and in doing so, we anticipated that intramolecular hydrogen bonds could be formed.[49] Such interactions could thus preserve the overall structure of the complex by preventing the cyclopentadienyl ligand from rotating. Furthermore, the hydrogen bonds could prove beneficial in removing the fluorides from the Lewis acidic metal. We expected that the synthesis of pentasubstituted ligand 1 would pose a considerable challenge and that it might be required to exchange specific cyclopentadienyl-substituents for a successful synthesis and employment of complexes containing 1. However, we also saw this as an opportunity to develop new strategies to obtain such complicated cyclopentadienes. The following work in this thesis describes our approaches towards a modular synthesis of ligands 1 (Chapter 2 and 3) and although we did not achieve our goal, we eventually managed to synthesize a number of new and interesting polysubstituted cyclopentadienes as well as their ferrocenes (Chapter 4). In each chapter, a dedicated and more detailed introduction is presented.

8 Chapter 2

First Generation Approach for the Synthesis of Polysubstituted Cyclopentadienes

2.1 Introduction

This chapter presents our initial endeavors towards the preparation of the targeted cyclopentadienyl ligand class 1. A retrosynthesis for this compound is presented alongside with an adaptation for a simplified analogon (2 presented on page 11). The latter was formulated to test the strategy and protocols. However, we discontinued this pathway due to the unsatisfactory performance of the synthetic transformations and limited flexibility concerning the variability of residues offered by the strategy.

2.1.1 General Retrosynthetic Analysis As described in the general introduction, our main goal consisted in preparing cyclopentadienyl ligands of type 1. We thus formulated an initial retrosynthesis relying on the asymmetric generation of the stereogenic center by virtue of a remote chiral auxiliary (R∗) and the disconnections of the two heteroatom-bearing residues (aryloxy and amino fragments) from the cyclopentadienyl base structure (Scheme 2.1).

formamide cross coupling condensation PGO Li PGO PGO X OPG + R* N N Cy PG PG R*

1 1-I 1-II 3 1-III

Scheme 2.1: Retrosynthesis of 1 leading to three main synthons: a formamide bearing a chiral auxiliary, a phenolate substrate and the basic cyclopentadienyl scaffold ∗(R =stereogenic residue, PG=protecting group, X=halogen or pseudo-halogen).

We wanted to create the stereogenic center between cyclopentadienyl and amine by a conjugate addition of a methyl anion to the corresponding fulvene compound 1-I. This protocol had been established in our group and performed well albeit it was only tested

9 Chapter 2 with unsubstituted cyclopentadiene and tertiary amines.[50] The diastereoselectivity of this addition would be biased by a more distant chiral component (R∗). The therefore required fulvene compound 1-I could be obtained via condensation of a tetrasubstituted cyclopentadiene scaffold 1-II and a separately prepared formamide (1-IV in Scheme 2.2) bearing the required stereogenic component. This would allow us to use commercially available chiral amines, which, after formylation and activation by O-methylation, could be used for the condensation (see Scheme 2.2 for more details). We initially planned to employ a chiral auxiliary derived from cyclohexyl ethyl amine since it had performed well in the previous work in our group.[50] Advantageously, this fragment should be readily altered by using different chiral amines in case that the diastereoselectivity of the methyl addition were insufficient or the afforded diastereomers not easily separable by common techniques. A matter to be addressed concerns the protecting groups, which we would have liked to be of silyl type due to their easy removal by fluorides.[51, 52] Considering the aryloxy residue this should not pose any synthetic challenge since such a silyl ether is very likely to survive the various preparatory steps.[51] A silyl group on the nitrogen is more problematic, since they are usually cleaved off easily.[52] The latter will not survive the nucleophilic and electrophilic reagents required to prepare and install the amino moiety and thus calls for a more specific consideration. For this purpose, we envisaged a protecting groupfor nitrogen to be applied during the formamide synthesis (Scheme 2.2).

CHO N N N R H nBuLi Ts CHO 1) Me2SO4 MeLi N N Ts R or N N R* R* 2) NaCp HCO2H R* R* DCC R=H R=Ts 1-IV 1) Mg TsCl 2) TMSCl R=Ts R=TMS

Scheme 2.2: Planned preparation of formamide I-IV bearing a chiral auxiliary with the nitrogen initially protected by a tosyl group. The latter could be exchanged for a less stable silyl group after the formamide has been condensed with a cyclopentadiene (R∗=stereogenic residue, DCC=N,N′-dicyclohexylcarbodiimide, Ts=tosyl, TMS=trimethylsilyl).

To our advantage, similar formamides have been prepared by sequential tosylation and then formylation using a variety of reagents.[53–57] The tosyl group is expected to protect the amine from methylation during the activation of the substrate prior to reaction with a cyclopentadienyl anion to afford the fulvene. After the generation of the new stereogenic center, the tosyl group could be removed under reductive conditions (e.g. with Mg) and then replaced by a silyl group.[52] Regarding the introduction of the aryloxy moiety, we planned on using a Kumada cross coupling (Scheme 2.1). Thus, we would generate the cyclopentadienyl anion of 3 and couple it with a protected, halofunctionalized aryloxy substrate 1-III. However, only few accounts report on the cross coupling of cyclopentadienes with aryl substrates. Thereby, the majority of the literature makes use of metallocenes as the cyclopentadienyl source (Scheme 2.3).

10 Chapter 2

1) ArX Pd cat. [M] Arn + 2) H3O

Scheme 2.3: General depiction of reported cross couplings of cyclopentadienyls with haloarenes (see text below for details of employed metallocenes, X=halogen, Ar=aryl).

[58, 59] [60–63] Thus, [Cu(Cp)(PBu3)] and [Cu(Cp)(SMe2)] can be reacted with iodoarenes to afford the corresponding coupling products. Vollhardt et al. have also shown that other metallocenes like [Mn(C5H4I)(CO)3] can be reacted with stannylcyclopentadiene in palladium-catalyzed reactions.[64] Further accounts on couplings with haloarenes are also given using [Zr(Cp)2Cl2], [Ti(Cp)2Cl2] or nickelocene as cyclopentadienyl-releasing agents.[65] In the latter case, it was found that also free cyclopentadiene can undergo cross couplings.[66, 67] This protocol has recently been used for the per-arylation of cyclopentadiene.[68, 69] The lack of literature on such reactions could temptingly be attributed to the dreaded likelihood of cyclopentadienyls forming inert complexes with transition-metal catalysts, thus inhibiting any productive reactions. Hence, we were intrigued and wanted to explore these transformations further, especially to assess how well they could be performed with our envisaged cyclopentadienes (Scheme 2.4).

1) Base PGO 2) Pd or Ni cat. X OPG

3 1-III 1-II

Scheme 2.4: Planned coupling between cyclopentadiene 3 and aryloxy substrates 1-III using palladium or nickel catalysts (X=halogen, PG=protecting group).

Deprotonation of cyclopentadiene 3 should allow the formation of an organometallic compound which could undergo oxidative addition of haloarene 1-III. As stated, the danger of the formation of a catalytically inactive species inherently remains, but we expected to be able to control this behavior by the appropriate choice of ancillary ligands and reaction conditions. In the end, the decomposition of 1 into three main synthons leads finally to the base trimethylcyclopentadiene 3, the preparation of which is described in the literature and outlined in the next section.[70] Before starting with the preparation of ligand class 1, we intended to test the strategy and protocols with a model compound.

2.1.2 Model Ligand Due to the many steps, and the inherent uncertainty of their performance, we decided to test the proposed synthetic sequence with a simplified model compound (2, Figure 2.1).

11 Chapter 2

PGO Li MeO Li

N Cy NMe2 PG

1 2

Figure 2.1: Target compound 1 and simplified model compound 2 (PG=protecting group).

In a first instance, we changed the oxygen and nitrogen protecting groups withmore inert methyl residues.[51, 52] These should not interfere with the required transformations towards the final compound and at the same time reflect to some extent the electronic and steric bias introduced by other groups. Also, we chose to initially not integrate the chiral auxiliary and replaced it with a methyl group to delineate the structure provided in 1. This would also allow to use dimethylformamide (DMF) as substrate and thus preserve resources for the main transformations. With these modifications in mind, the retrosynthesis of 1 was adapted for 2 (Scheme 2.5).

aldol and formamide (DMF) cross coupling oxidative coupling condensation dehydration MeO Li MeO MeO O * NMe2 NMe2 O

2 3 4

Scheme 2.5: Retrosynthesis of model ligand 2 adapted from the one outlined for 1 and depiction of the preparation of trimethylcyclopentadiene 3.

As described above, this first generation approach to ligand 1 and its proposed model variant 2 utilize cyclopentadiene 3 as base structure. The latter can be obtained from an intramolecular aldol condensation of 1,4-diketone 4 which in turn is afforded by the oxidative coupling of 2-butanone.[70] With these plans in hand, we set out to attempt the preparation of the model system 2.

2.2 Results and Discussion

2.2.1 Preparation of 1,2,3-Trimethylcyclopentadiene The first step towards trimethylcyclopentadiene 3 involved the preparation of diketone 4 which, as described in the literature,[70] can be obtained via oxidative coupling of [71, 72] 2-butanone using PbO2 as oxidant (Scheme 2.6).

O O O O PbO2 + + 100-120 °C O O O 4 4a 4b

Scheme 2.6: PbO2 promoted oxidative coupling of 2-butanone to 1,4-diketone 4 and possible side products 4a and 4b.

12 Chapter 2

The authors simply heated a suspension of the oxidant in 2-butanone and obtained after distillation product 4 in 33 % yield.1 In doing so, and to our surprise, we only detected traces of the target compound 4 when following the reported procedures.[70–72] We did not investigate further the high molecular weight compounds obtained after fractional distillation of the crude product. This result could be attributed to successive oxidative couplings of 4 and/or its isomers (4a, 4b) affording oligomers. However, reasons for this outcome remain elusive. Anyways, the above used literature actually cites a more efficient way to prepare diketone 4. In fact, when using a Soxhlet extractor, with the [74, 75] PbO2 loaded in the cartridge, overreaction of the target compound can be avoided. Although, discrepancies between the literature and our observations are manifested again. While in the latter case the authors report 61 % yield of 4 within 24 h, we found the reaction to proceed at a tenth of this rate: after 80 h the concentrations of product 4 and of byproducts 4a and 4b, were still linearly increasing (see appendix on page 127). Interruption of the reaction after this time afforded only 15 % of the desired material (4). Thus the conversion was drastically slower in our hands. Due to these drawbacks we looked for alternative procedures for the oxidative coupling of 2-butanone. We opted to use FeCl3 as oxidant to couple the corresponding enolates; a method which has been used with a wide variety of substrates and which, at first glance, [76, 77] seemed to be more efficient than the2 PbO procedure (Scheme 2.7).

1) NaH O THF, r.t. O

2) FeCl3 DMF O -78 °C-r.t. 4

Scheme 2.7: Oxidative coupling of the 2-butanone using FeCl3 as oxidant.

The thermodynamically favored enolate of 2-butanone was formed with NaH at room temperature and the resulting mixture subsequently treated with a DMF solution of FeCl3 at low temperature. Though substantial amounts of 4 were detected by GC-MS after work-up, we were not able to isolate it due to a multitude of byproducts. This fact rendered this procedure unattractive as well. In the end, we were not able to produce the required diketone 4 in satisfying fashion but decided to go on with the synthesis since we had enough material in our hands for first experiments. The next step involved the intramolecular aldol condensation of 4 to afford cyclopentenones 5 (Scheme 2.8).[70]

O O O O NaOH + + H2O, 100 °C O 80% yield 4 5a cis/trans-5b 5c

Scheme 2.8: Intramolecular aldol condensation of 4 delivering cyclopentenones 5 as a mixture of four isomers.

Addition of 1,4-diketones 4 to a boiling solution of NaOH in H2O afforded after distillation a mixture of four isomers of 5 in good yield (80 %). Spectroscopic analysis of the obtained

1This old protocol has recently been investigated in greater detail.[73]

13 Chapter 2 products by NMR was cumbersome as the resonances were not resolved but we could detect four species bearing the expected mass to charge ratio of 5 by GC-MS. We continued with the reduction of the carbonyl functionality (Scheme 2.9).

O O O OH OH OH LiAlH4 + + + + Et2O 0 °C-r.t. 5a cis/trans-5b 5c 6a 6b 6c

Scheme 2.9: Reduction of isomer mixture of 5 to afford the corresponding alcohols 6.

Treatment of 5 with LiAlH4 followed by aqueous work-up converted the starting materials to the corresponding alcohols of type 6. Again, analysis of the mixture was complicated by the multitude of afforded isomers (see Scheme 2.9). The presence of the target compound was thus assessed by GC-MS analysis. Finally, we dehydrated 6 under acidic conditions to afford cyclopentadiene 3, which had to be performed swiftly due to possible Diels-Alder dimerization. (Scheme 2.10).[70]

OH OH OH HCl + + + Et2O, H2O r.t. 6a 6b 6c 3

Scheme 2.10: Dehydration of alcohols 6 to afford cyclopentadiene 3 which already dimerized to the corresponding dicyclopentadiene during the reaction.

Mixing 6 in an acidic emulsion of H2O and Et2O at room temperature triggered the elimination to afford the unsaturated product 3. However, by following the published procedure we couldn’t isolate product 3 since the corresponding dimer already started to form during the reaction. Due to the unexpected difficulties encountered during the production of 3, the little amounts we had obtained and forecasted challenges involving its functionalization, we decided to prepare a more easily accessible model substrate mimicking the substituted cyclopentadiene scaffold before we would revisit an optimized synthesis towards 3.

2.2.1.1 Preparation of a Disubstituted Cyclopentadiene Model Compound To prepare a polysubstituted cyclopentadiene delineating the structure of 3, we decided to employ commercially available dihydrojasmone 7 and transform it into the corresponding cyclopentadiene 8 (Scheme 2.11).

O n-C H 1) LiAlH4, Et2O, 0 °C n-C H 5 11 5 11 + 2 structurally not elucidated isomers 2) HCl, Et2O, H2O, r.t.

7 8

Scheme 2.11: Preparation of cyclopentadiene 8 from dihydrojasmone 7 by reduction and consecutive dehydration.

14 Chapter 2

[78] Reduction with LiAlH4 of the parent cyclopentenone 7 yielded the corresponding alcohol which was then directly converted to cyclopentadienes of type 8 under acidic conditions. Again, and according to GC-MS analysis, a mixture of different species with equal masses were obtained Three possible isomers of 8 were resolved which we interpreted to be related by their double-bond localization. Although the current strategy did not perform nearly as well as we demanded for, with the easily produced cyclopentadiene 8 in hand we wanted to test the next step, namely the cross coupling with haloarenes.

2.2.2 Cross Coupling Reactions As outlined in the introductory part of this chapter (see page9), we are aware of only few accounts where cyclopentadiene have been coupled with haloarenes.[66, 67] The respective authors employed primarily palladium as catalysts with excess monophosphane ligands under alkaline conditions at elevated temperatures. While we were confident that such conditions could work with our system, we also wanted to expand on them and thus proposed to perform these reactions under Kumada-type conditions.[79–81] Hence, we deprotonated cyclopentadiene 8 in situ with EtMgBr and assessed the feasibility of the cross coupling with chlorobenzene. For this purpose we also selected different, classical Ni(II)-phosphane catalysts (Scheme 2.12).

1) EtMgBr, Et2O, r.t. n-C5H11 n-C5H11 2) Ni(II) cat., PhCl, r.t. Ph

Scheme 2.12: Experiments for assessing the feasibility of Kumada type couplings between substituted cyclopentadiene 8 and chlorobenzene.

2 A variety of Ni(II) phosphane complexes, namely [Ni(PPh3)2Cl2], [Ni(dppe)Cl2] and 3 [Ni(dppp)Cl2] were chosen as catalyst (2 mol %) while keeping all other parameters equal.[82] Cyclopentadiene 8 was reacted with EtMgBr for 1 h to afford the corresponding anion. The latter was then added to a suspension of the Ni(II) complexes in Et2O at room temperature. In all cases, the initial mixture turned into a colored solution, namely an intense black one in cases of [Ni(PPh3)2Cl2] and [Ni(dppe)Cl2] while an orange one was observed for the [Ni(dppp)Cl2] sample. Afterwards, chlorobenzene was added and the solutions stirred further at the same temperature. After 1 h, a white precipitate was observed in all reactors which we interpreted to be magnesium salts of the released chloride. We kept the mixtures stirring for a total of 19 h at room temperature, quenched the reactions and analyzed the organic phases qualitatively by GC-MS. In all three cases we observed the same outcome: along with unreacted chlorobenzene and substrate 8, varying amounts of ethylbenzene and a new species with a 180.1 mass to charge ratio, were detected. No formation of the desired phenyl-substituted target compounds were given in all cases. While the presence of starting materials can be explained by a prematurely arrested or absent reaction, the detection of the two mentioned byproducts is more puzzling. The formation of ethyl benzene could only be achieved by unreacted EtMgBr in the mixture which underwent the nickel-catalyzed cross coupling. This leaves

2dppe=1,2-bis(diphenylphosphanyl)ethane 3dppp=1,3-bis(diphenylphosphanyl)propane

15 Chapter 2 to explain the 180.1 m/z species which we postulate to arise from the formal addition of C2H6 to 8 (Scheme 2.13).

Et n-C H 1) EtMgBr, Et2O, r.t. 5 11 n-C5H11 + Et 2) Ni(II) cat., PhCl, r.t.

8 9

Scheme 2.13: Observed products during attempted cross coupling of cyclopentadiene 8 and chlorobenzene with Ni(II) catalysts. While different amounts of ethylbenzene were given inall samples, the amounts of putative compound 9 were always similar.

The analytical data obtained from the EI-MS fragmentation pattern corroborates the structure of 9.4 As in all three samples roughly the same amount of putative species 9 was detected, a catalytic transformation is unlikely. Due to the proven presence of unreacted EtMgBr in the mixture, an addition to a coordinated, thus activated double bond of cyclopentadienyl 8 would explain the incorporation of the ethyl fragment. If such a species is unable to react further, the observed compound would be released upon hydrolysis (Scheme 2.14).

n-C5H11

Et X Cl X=H X=Cl L Ni Et L Ni L Ni insertion EtMgBr L L L then n-C H n-C H EtMgBr 5 11 5 11

reductive + elimination H3O

n-C5H11 Et

Scheme 2.14: Putative, formal pathways explaining the addition of C2H6 to cyclopentadiene 8 (L=neutral ligand).

Alternatively the generation of a nickel hydride species can be assumed resulting from a β-H elimination from a Ni Et species. After coordination of 8, an insertion in the Ni-H bond could happen. A further transmetallation of EtMgBr could generate a species giving 9 by reductive elimination and thereby regenerating a Ni(0) species (Scheme 2.14). In the end it was clear that the cyclopentadienes were, surprisingly, not deprotonated by the Grignard reagent and seemingly coexisted with this over a rather long time. As a control experiment, we performed the same reaction with unsubstituted cyclopentadiene and [Ni(dppp)Cl2] on a larger scale. In this case deprotonation of the substrate was visually observed (evolution of gas and white precipitate) but even this procedure left the starting materials unreacted. In fact, only chlorobenzene alongside trace amounts of dicyclopentadiene and ethylbenzene were observed by GC-MS analysis.

4while the [M]+ signal reflects the required elemental composition of the postulated compound 9, several ions are detected which can describe the release of the hydrocarbon side chains during + + + fragmentation: loss of CH3 ([M-15] ), of C2H5 ([M-29] ) and of C5H11 ([M-109] )

16 Chapter 2

At this point we decided to abandon this subproject as we did not see this overall pathway to be fruitful to efficiently obtain the target structures we had in mind.

2.3 Summary and Conclusion

In our first attempt to prepare target ligand 1 we were met with little success. Already when trying to prepare the basic structure 3 many resources had to be invested. Since the oxidative coupling of 2-butanone did not proceed as reported, we could only prepare limited amounts of diketone 4 after some time. The following steps, namely the aldol condensation to cyclopentenones of type 5 and subsequent reduction to alcohols 6 luckily performed much better. A problem that we were confronted with, was the number of isomers afforded by these reactions which impeded structural assessments. We were thus limited to chromatographic and functional group-sensitive analytical techniques. Furthermore, we were not able to isolate cyclopentadiene 3 as it readily began to dimerize.

Before we would optimize the synthesis leading up to this trisubstituted cyclopentadiene, we reasoned to first explore the feasibility of the envisaged cross-coupling. Wethus decided to prepare a model substrate (8) from commercially available dihydrojasmone to mimic the substituted cyclopentadienes we wanted to use in the end. With the former compound in hand we undertook first cross coupling experiments and tried to react the magnesium salt of 8 under Kumada type conditions. To our surprise, it was clear that the employed Grignard reagent did not deprotonate the cyclopentadiene. Still being unaware of this fact, we attempted the cross coupling with chlorobenzene employing Ni(II) catalysts. As a result, we detected the presence of ethylbenzene and of a new structure which we postulate to be the outcome of the formal addition of C2H6 to cyclopentadiene 8. To explain this observation, we are tempted to invoke the formation of a nickel hydride species or the nucleophilic addition of EtMgBr to a coordinated cyclopentadiene. Eventually, we were further discouraged to follow up on these transformation since no productive cross-coupling could be observed even when we attempted an analogous reaction with unsubstituted cyclopentadiene.

Looking at these first experiments and at the significant effort required toproduce just basic materials, we decided to revise our strategy. A further drawback of this first generation approach lies in the limited modularity of the used transformations. Using the above presented oxidative coupling, introduction of three of five cyclopentadienyl substituents is accomplished in one step. Due to the nature of this reaction, all residues have to ideally be identical as any degree of diversity will complicate identification and isolation of products. Finally, we abandoned this strategy and carried on devising a new one.

17 Chapter 2

2.4 Outlook

Considering the outcome of the oxidative coupling experiments using metal-based oxidants, it might be more efficient and easy to switch to different tactics to achieve thesame goal and go beyond. The production of 1,4-diketones is inherently difficult given the dissonant relationship between the two carbonyls. This in turn prompted chemist to devise ways to obtain such substances, as for example the Stetter reaction.[83] A rather recent modification of the classical Stetter reaction, is enabled by the use ofNHC’sas catalysts, whereby acryloyl compounds are coupled with aldehydes (Scheme 2.15).[84]

O O CN- O R3 or NHC cat. R1 R2 R1 R1 R4 Base R3 O R O R2 H R4 2 R4 R3

Scheme 2.15: Access to 1,4-diketones via cyanide or NHC-promoted Stetter reaction and intramolecular aldol condensation to the corresponding cyclopentenones.

Thus a certain degree of choice could be given if various residues are desired. Otherwise, cyclopentenones can be obtained by other routes and a prominent one, the Nazarov cyclization, will be of central matter in the next chapter. Anyways, the question of the efficiency and scope of cross-couplings utilizing cyclopentadienes as substrates remains unanswered. Clearly, additional experiments are required to extend this area. Definitive observations should thus be available if unequivocally deprotonated cyclopentadienes are used, which was apparently not always the case in this work. Furthermore, the reported protocols only made use of unsubstituted cyclopentadiene or partially arylated ones. No examples are given for substrates bearing alkyl groups or other substituents.[66–69] Hence, even the expansion of these protocols to cyclopentadienes like 3 or 8 could be interesting and worth the investment.

18 Chapter 3

Second Generation Approach for the Synthesis of Polysubstituted Cyclopentadienes

In the previous chapter we attempted the preparation of the envisaged ligand class 10 via an overall known strategy. In doing so, we were confronted with a multitude of challenges which led us to abandon our previously planned synthesis. Furthermore, during this experimental work we realized that the first generation approach did not allow to produce libraries of cyclopentadienes. In fact, only two of five cyclopentadienyl residues could have been varied efficiently in this way. We were thus convinced that with a revised synthetic analysis we could extend known methods on the preparation of polysubstituted cyclopentadienes. Hence, this chapter presents our efforts towards the elaboration and execution of a new synthesis of such compounds. A part of the experimental work of this chapter was carried out by Christian Rueger¨ [85] (methyl-substituted cyclopentadienes), Salome Heilig [86] (mesityl compounds) and Raphael Lengacher [87] (triisopropylphenyl compounds).

3.1 Introduction

After having experienced several difficulties while attempting the preparation of cyclopentadienes 1, we abandoned our initial retrosynthetic analysis in favor of a new, improved one. Before we started the formulation of the latter, we devised some boundary conditions. In doing so, we intended to guide the preparatory sequence to feature the following three aspects. Firstly, the synthetic protocols have to be efficient, economical and applicable on larger scales. Secondly, the synthesis must allow for a wide and facile alteration of the substituents of the cyclopentadienyl scaffold and thus enable the preparation of ligand libraries. Thirdly, each of the envisaged intermediates has to be stable under standard conditions. With these goals in mind, we set out to reformulate the retrosynthesis of 1.

3.1.1 General Retrosynthetic Analysis As described above, we needed to revise the synthetic strategy towards 1. The first part, describing the synthesis of 1 from intermediate 1-VI, is depicted in Scheme 3.1.

19 Chapter 3

amine condensation

reduction

PGO Li PGO PGO PGO CHO CN PG N N Cy PG R* R*

1 1-I 1-V 1-VI

Scheme 3.1: Retrosynthesis of cyclopentadienyl anion 1 leading back to nitrile intermediate 1-VI (R∗=stereogenic residue, PG=protecting group).

Like in the previous synthesis (see chapter 2), we planned to generate the stereogenic center between the amino group bearing a chiral auxiliary and the cyclopentadiene by a conjugate addition of a methyl anion.[50] As a first alteration from the original plan, we intended to prepare fulvene 1-I by condensing a chiral amine with aldehyde 1-V. However, we were able to find only very few reports of analogous compounds reacting in this manner.[88–90] This intrigued and prompted us at the same time to follow up on this transformation as it would allow for a modular, late installation of different amines. The starting material, aldehyde 1-V, could be generated by the reduction of a cyano function (1-VI) using hydride reagents.[91, 92] A late formation of the reactive formyl group brings a multitude of advantages. In fact, we expected that maintaining the more inert cyano function during transformations leading to 1-VI would circumvent the use of protecting groups. This is made clear in the retrosynthetic analysis leading up to nitrile 1-VI as shown in Scheme 3.2.

- NCCH2 R addition PGO PGO O O O O CN CN CN CN CN OH

- CH3 addition R R and dehydration O Knoevenagel Nazarov 1-VI 1-VII 1-VIII 11 12

Scheme 3.2: Retrosynthesis of intermediate 1-VI via cyclopentenone I-VII which, in turn, could be obtained from diene I-VIII (PG=protecting group).

As a next step, we intended to introduce one of the three alkyl residues by adding methyl anions to a carbonyl functionality followed by dehydration to afford cyclopentenone 1-VII – as intermediate. The nucleophilic addition of CH3 -species could proceed chemoselectively by using suitable conditions which tolerate the acidic cyclopentenone.[93] However, we attributed a major risk to this transformation, as nucleophiles could as well undergo 1,4-additions with 1-VII. Hence, we envisaged more probable transformations yielding similar cyclopentadienes of type 1-VI from cyclopentenones 1-VII, as will be addressed in detail in the next section. Assuming smooth additions of nucleophiles to cyclopentenone 1-VII, we planned on preparing the latter by Nazarov cyclization of dienes 1-VIII. Interestingly, we were able to find only one report of an analogous oxo nitrile being used under the same circumstances.[94] However, we felt confident that this transformation would proceed under appropriate conditions. Furthermore, ketone 1-VIII would allow an easy installation of the aryl moiety via Knoevenagel condensation.[95–98] For this purpose,

20 Chapter 3 readily available aryl aldehydes could be introduced in a modular fashion in the ligand scaffold. This transformation leads to β-oxo nitrile 11 which we planned on synthesizing from acrylic acid 12.[99] Conversion of the latter to an ester should allow for displacement of the alkoxide by formal cyanomethyl anions, thus yielding 11. In the following section, we address the crucial step involving the conversion of cyclopentenones 1-VII to the corresponding cyclopentadienes 1-VI.

3.1.2 Conversion of Cyclopentenones to Cyclopentadienes: A Closer Look As described above, we developed a synthetic strategy where one of the cyclopentadienyl residues is introduced via nucleophilic addition to cyclopentenone 1-VII. Dehydration of the corresponding intermediate alcohol should then afford cyclopentadiene 1-VI. However, we expected this pathway to be risky because alkyl nucleophiles could be protonated due to the acidity of cyclopentenones 1-VII which is further enhanced by the cyano group. Yet, we were confident that this reactivity could be controlled by appropriate reaction conditions.[93] More concerning, though, was the possibility of cyclopentenones 1-VII undergoing 1,4-additions instead. Thus, while we would attempt the preparation of 1-VI as described above, we also planned for alternative transformations leading to corresponding variants (Scheme 3.3).

O OMe + CN 1) NaBH4 CN CH3 CN 2) H+ R R R

1-VII

Scheme 3.3: Proposed alternative transformations of cyclopentenones 1-VII towards cyclopentadienes: reduction of the carbonyl group followed by dehydration (left) and electrophilic O-alkylation and enolization (right).

Indeed, a selective reduction of the carbonyl group may be achievable with mild reagents like NaBH4. Dehydration of the formed alcohols should afford tetrasubstituted cyanocyclopentadienes in a clean manner. Following this, an identical pathway as displayed in Scheme 3.1 could be pursued towards a variant of 1. On the other hand, we considered to subject substrate 1-VII to electrophilic alkylation reagents. In doing so, we would gain access to 1-alkoxy-2-cyanocyclopentadienes which could then be transformed to ligands of type 1 as well. Eventually, we prepared several plans addressing the preparation of the target ligand 1. To test and validate the overall synthetic strategy, we proposed to do so with a model compound (13).

3.1.2.1 Model Ligand and Retrosynthetic Analysis As described above, we intended to test this second generation synthesis towards ligand 1 with a simplified model 13 (Figure 3.1).

21 Chapter 3

PGO Li Li

R* N NMe2 PG R

1 R=H, 13-H R=Me, 13-Me R=OMe, 13-OMe

Figure 3.1: Target ligand 1 and model compound 13 (PG=protecting group, R∗=stereogenic residue).

As in our previous approach, we decided to reduce the complexity of the nitrogen moiety and thus aimed for a simple tertiary amine. Likewise, a phenyl group was chosen to replace the aryloxy substituent. Following closely the above outlined strategies for 1, we adapted them for model compound 13 (Scheme 3.4).

amine condensation - conjugate conversion to formyl group NCCH2 addition addition to ester Ph Li Ph Ph O O CN CN CN NMe2 OH NMe2 R R R O Ph Nazarov Knoevenagel R=H, 13-H 13-I 13-II 14 12 R=Me, 13-Me R=H, reduction R=OMe, 13-OMe and dehydration R=Me, carbonyl alkylation and dehydration R=OMe, O-alkylation and enolization

Scheme 3.4: Retrosynthesis of 1 adapted for 13.

Racemic ligands 13 could be obtained by a conjugate addition of methyl anions to fulvenes of type 13-I. These, in turn, could be synthesized by condensing dimethyl amine with corresponding aldehydes which are obtainable from reduction of nitriles 13-II. Such species could be prepared in a threefold variety from cyclopentenone 14 via reaction of the carbonyl function. In doing so, nucleophilic C-alkylation or electrophilic O-alkylation would afford two different pentasubstituted ligands 13, containing either a third methyl residue (13-Me) or a methoxy group (13-OMe). Alternatively, tetrasubstituted variants of 13 could be prepared by chemoselective hydride-reduction of cyclopentenone 14 and subsequent dehydration (13-H). In the end, all these three derivatives converge to the same intermediate (14) that could be synthesized via Nazarov cyclization of diene 15. This would allow to introduce the phenyl group by condensing benzaldehyde with β-oxo nitrile 11. Thus, the first intermediate towards 13 could be prepared by treating esters of commercially available tiglic acid 12 with acetonitrile under alkaline conditions. With the above elaborated synthetic plans in hand, we started the experimental work towards model compound 13.

22 Chapter 3

3.2 Results and Discussion

3.2.1 Preparation of Cyclopentenones As outlined above, the synthesis of target compound 13 begins with commercially available tiglic acid (12). The first step involved the priming of this for the subsequent condensation with cyanomethyl anions. We opted to prepare esters of 12 bearing different residues in case that the released alkoxides would promote side reactions like 1,4-additions (Scheme 3.5).

O ROH O p-TsOH or H2SO4 (cat.) OH OR Benzene, 90-100 °C

12 16, R=Et 84% yield 17, R=iPr 91% yield

Scheme 3.5: Fischer esterification of tiglic acid12 ( ) to the corresponding ethyl (16) and isopropyl (17) esters.

To our delight, tiglic acid (12) was easily converted to the required esters via Fischer esterification.[100] Ethyl tiglate (16) was obtained in good yield (84 %) using catalytic amounts of p-TsOH and similarly, isopropyl tiglate (17) was received in 91 % yield, albeit only when using a stronger acid as catalyst (H2SO4). With the necessary starting materials in hand we turned our attention to the installation of the cyanomethylene fragment (Table 3.1).

Table 3.1: Determination of appropriate conditions for the preparation of β-oxo nitrile 11.

O O Base, MeCN CN OR THF

16, R=Et 11 17, R=iPr Entry Substrate (R) Base Yield/% 1 16 (Et) nBuLia 56 2 16 (Et) NaHb 68 3 17 (iPr) NaHb 73 a Acetonitrile was reacted with nBuLi at −78 ◦C before adding 16. b All reactants were mixed at r.t.and then heated to 70 ◦C.

Initially, we used nBuLi to deprotonate acetonitrile at low temperatures (entry 1, Table 3.1). This protocol has already been applied successfully with other esters and amides.[101, 102] With this procedure, product 11 was obtained as a solid in moderate 56 % yield after distillation under reduced pressure. However, this purification method is not reproducible, due to the occasional degradation of the crude product upon heating. This behavior could originate from unwanted reactions of the ambiphilic compound 11, e.g. by 1,4-additions.

23 Chapter 3

We turned our attention to other bases which would allow for cleaner reactions and thus simplify purification. Furthermore, we desired to produce 11 in larger quantities and therefore a base that is operationally simpler than nBuLi would be beneficial. Thus, we switched to the weaker, less nucleophilic base NaH which has also been applied in a reported procedure.[103] The oil-free NaH was suspended in a mixture of acetonitrile and THF which was then heated to 70 ◦C and subsequently treated with esters 16 or 17. We quickly determined that this protocol yielded qualitatively a cleaner conversion of the starting materials as compared than with nBuLi. Unfortunately, with ethyl ester 16 still a significant amount of unwanted byproducts were formed, thereby rendering the isolation tedious (entry 2, Table 3.1). A cleaner reaction was observed with isopropyl carboxylate 17 as substrate (entry 3, Table 3.1). Indeed, with the latter starting material, the target compound 11 could be isolated with little effort. This was achieved in a rather peculiar way, namely by adding a small piece of dry ice to an emulsion of the crude product in pentane. In this way, nitrile 11 precipitated from the mixture and was easily collected in good quantities. Although it is uncertain what role the dry ice played in the purification step, we were pleased with this protocol since it allowed to produce large quantities of intermediate 11 efficiently and with high enough purity to proceed with the follow-up reactions. The next transformation required the condensation of benzaldehyde with β-oxo nitrile 11 (Table 3.2).[104]

Table 3.2: Knoevenagel condensation of 11 with benzaldehyde at different concentrations.

PhCHO (1 equiv.) O Piperidine (cat.) O CN HOAc (cat.) CN Benzene, 100 °C Ph

11 15 Entry c(11)/M Yield/% 1 0.5 52 2 0.2 75

24 Chapter 3

The reaction of 11 with benzaldehyde, promoted by catalytic amounts of acetic acid and piperidine, yielded initially a mediocre 52 % yield of diene 15 (entry 1, Table 3.2). Although full consumption of carbonitrile 11 was observed, copious amounts of unreacted aldehyde remained. At this point, we assumed that the starting material would undergo unwanted side reactions such as 1,4-additions. Thus, we lowered the molarity of the latter, hoping for a smoother conversion, which was also the case when the concentration was reduced from 0.5 M to 0.2 M (entry 2, Table 3.2). Additionally, we gained further insights as we isolated byproducts as colorless solids. Spectroscopic investigations by NMR revealed a mixture of seemingly closely related species. Unfortunately, we were not able to obtain the molar mass of these species by EI-MS as the molecular ion fragmented. However, we were able to crystallize one of the byproducts by allowing an EtOAc solution to evaporate from a biphasic system with water. Single crystals were collected from the interface of the liquids and analyzed by X-ray diffraction (Figure 3.2)

O NC

Ph O CN

Figure 3.2: Left: Structure of the isolated byproduct 18 from the Knoevenagel condensation of 11 with benzaldehyde. Right: ORTEP representation of 18. Hydrogens are omitted for clarity and thermal ellipsoids are set to 50 %. Selected bond lengths ([A˚]) and angles [°]: C2-O1 1.213(6), C17-O2 1.229(7), C5-C17 1.566(7), C17-C18 1.464(7), C18-C19 1.310(7) C10-N1 1.534(7), C10-C1 1.471(7), C9-N2 1.137(8), C9-C5 1.472(7), C1-C10-N1 179.1(5), C5-C9- N2 175.4(6), C19-C18-C17 120.6(5), C5-C17-O2 114.9(4), C18-C17-O2 119.8(5), C1-C2-C3 114.6(4), C1-C2-O1 120.5(4), O1-C2-C3 124.8(5), C18-C17-C5 125.3(4), C18-C19-C17-O2 144.9(5).

It is clear, that the starting compound 11 was not consumed by reaction with itself but rather with the product of the Knoevenagel condensation 15 via a twofold 1,4-addition. Several diastereomers of 18 could be identified by 1H NMR and the analytical data for the most abundant one is reported in the experimental part on 85. Eventually, we obtained a sufficient amount of diene 15 in good purity. For the cyclization of the latter towards cyclopentenone 19 a variety of reaction conditions were subsequently evaluated (Table 3.3).[105–107]

25 Chapter 3

Table 3.3: Screening of reaction conditions for the Nazarov cyclization of diene 15.

O O O CN Acid CN CN

CH2Cl2 Ph Ph Ph

15 trans-19 cis-19 Entry Lewis acid (equiv.) T t/h Yield/%a b 1 FeCl3 (1.2) r.t. 2.5 quant. 2 MsOH (1.2) r.t. 2 quant.b 3 p-TsOH (1.2) r.t. 44 0 ◦ 4 FeCl3 (1.2) −78 C 4 0 5 MsOH (1.2) −78 ◦C 4 0 6 MsOH (1.2) r.t. 1 73c a Unless noted otherwise, isolated yields are reported. b Conversion with respect to starting material as determined by GC-MS. c The product was isolated as a 7:3 mixture of trans- and cis-diastereomers.

We treated diene 15 under the conditions given in Table 3.3 and monitored the reactions by GC-MS. Ferric chloride delivered a full conversion of starting material 15, although the removal of paramagnetic iron(III) species rendered the isolation tedious (entry 1, Table 3.3). Methanesulfonic acid (MsOH) led as well to full conversion and was easily removed from the mixture after the reaction (entry 2, Table 3.3). Switching to a less reactive acid, namely p-TsOH didn’t afford any product even after prolonged reaction times (entry 3, Table 3.3). Having identified suitable promoters, we wanted to determine an optimal reaction temperature for the cyclization. Neither FeCl3 nor methanesulfonic acid, however, yielded any product at low temperatures after 4 h (entries 4 and 5, Table 3.3). We decided to proceed with the latter due to its easy handling, commercial availability and good performance. Hence, treatment of 15 with methanesulfonic acid at room temperature yielded 73 % of the target compound 19 as a 7:3 mixture of trans- and cis-diastereomers (entry 6, Table 3.3). Having developed protocols for the gram-scale synthesis of cyclopentenone 19, we next addressed the functionalization of the carbonyl function.

3.2.2 Preparation of Cyclopentadienes As described in the retrosynthesis of model compound 13, we planned on reacting cyclopentenone 19 in three different ways (Scheme 3.3 and Scheme 3.4), the first one being the nucleophilic alkylation of the carbonyl group of 19. However, with the possibility in mind that nucleophilic alkylation agents would simply deprotonate the acidic methine proton of the cyclopentenone, we opted to use a protocol developed for malonic acid-derived substrates (Scheme 3.6).[93]

26 Chapter 3

O 1) AlMe3 O CH Cl , 0 °C CN 2 2 CN CN

2) NH4Cl Ph H2O, r.t. Ph Ph

19 20

Scheme 3.6: Attempted alkylation of cyclopentenone 19 and dehydration to yield cyclopentadiene 20.

Partial conversion of 19 was observed by treatment with AlMe3 at low temperature and subsequent acidic work-up. A single new species was observed by GC-MS with a mass to charge ratio of 227 which corroborated the addition of a methyl anion to substrate 19. It was thus possible that a 1,2-addition had occurred but not a dehydration. Yet, the fragmentation pattern was more reminiscent of a possible 1,4-addition product.1 Attempts at isolating this new species by preparatory TLC however failed as it coeluted with the starting material; a further hint that the 1,4-addition product had been obtained. In the end we did not pursue the optimization of this transformation further as we were more successful with the hydride-reduction of 19 (Scheme 3.7).[108]

O OH CN NaBH4 CN p-TsOH CN MeOH, r.t. Benzene, 90 °C Ph Ph 95% yield Ph 86% yield 19 21 22

Scheme 3.7: Reduction and cyclopentenone 19 yielding alcohol 21 and subsequent dehydration yielding cyclopentadiene 22.

We were pleased to find a high yielding and chemoselective reduction of the carbonyl function by adding NaBH4 to a solution of 19 in methanol. The intermediate alcohol 21, which was obtained as a mixture of three diastereomers (see experimental part on page 90 for further details) was smoothly dehydrated to the corresponding cyclopentadiene 22 in good yield (82 %). The constitution of the latter, as depicted in Scheme 3.7, is the thermodynamically favored one, displaying the highest degree of double-bond substitution. Additionally, we were still interested in preparing pentasubstituted cyclopentadienes and thus attempted the O-alkylation of cyclopentenone 19. For this purpose, we applied a + [109–111] mild protocol using orthoesters as formal CH3 -releasing agents (Scheme 3.8).

O HC(OMe)3 OMe p-TsOH CN CN MeOH, 60 °C Ph 90% yield Ph

19 14

Scheme 3.8: Electrophilic methylation of cyclopentenone 19 affording cyclopentadiene 14.

1Base signal with m/z 212 which indicates the fragmentation of a methyl group and thus the likely absence of a hydroxy group.

27 Chapter 3

Reaction of 19 in methanol with H(COMe)3 and p-TsOH cleanly afforded the corresponding methoxy-substituted cyclopentadiene 14 in excellent 90 % yield. With these structures in hand we proceeded to the next step, namely the generation of the formyl function.

3.2.3 Attempted Reduction of the Cyano Group After having prepared the two cyanocyclopentadienes 22 and 14, we addressed the planned reduction of these to the required aldehydes. As a proven reagent enabling this transformation, we decided to use diisobutylaluminum hydride (DIBAL) (Scheme 3.9).[91, 92]

OMe OMe 1) DIBAL CN CHO

2) H2O Ph Ph

14 23

Scheme 3.9: Attempted reduction of nitrile 14 with DIBAL to aldehyde 23.

Unfortunately, we were never able to successfully perform this reduction. Treatment of 14 with DIBAL in various solvents (THF, Et2O, toluene or dichloromethane) didn’t lead to any reaction at all and the starting material was always recollected. A possible explanation for this behavior could be a deprotonation of cyclopentadiene 14 by the aluminium reagent. It stands to reason that, if this were the case, the electrophilic nature of the cyano group would be greatly reduced and thus reluctant towards hydride reductions.

After several attempts, we decided to shift the conversion of the cyano group to a later stage of the synthesis. In fact, we realized that with methoxy-substituted cyanocyclopentadiene 14 we had obtained an interesting ligand for transition-metals and therefore steered the project towards its organometallic part. Furthermore, we expected that the reduction of the cyano group could be achieved if the cyclopentadienyl derived from 14 were bound to a Lewis acidic fragment. Before we engaged in the preparation of metallocenes containing 14, we wanted to prepare a few more variations of this basic scaffold. With the above presented methodologies, alteration of different residues of the cyclopentadienes could be possible and allowto examine the robustness of the elaborated strategy by preparing a library of related cyclopentadienes.

3.2.4 Preparation of Methoxy-Substituted Cyanocyclopentadi- enes In order to test the outlined synthetic strategy and compare the effects of different substituents of the polysubstituted cyclopentadienyls on the corresponding metallocenes, we envisaged to integrate various residues at the Knoevenagel-stage of the synthetic sequence (Scheme 3.10).

28 Chapter 3

OMe O O CN RCHO CN CN

R R

11 24, R=Me 25, R=Mes 26, R=Trip

Scheme 3.10: Proposed preparation of differently sterically demanding cyclopentadienyl ligands bearing a cyano and methoxy group (Mes=mesityl, Trip=2,4,6-triisopropylphenyl).

For this purpose, we decided to introduce residues of different steric demand, like variants of 14 where the phenyl residue is replaced with a methyl (24), mesityl (25), and 2,4,6- triisopropylphenyl (Trip) group (26), respectively. This would allow to use readily available aldehydes to alter the structure of the final ligands. We began with the preparation of the smallest derivative, bearing only methyl residues (24, Scheme 3.11).

O O MeCHO, TiCl4 O HC(OMe)3 OMe Pyridine MsOH p-TsOH CN CN CN CN

CH2Cl2 CH2Cl2, r.t. MeOH, 60 °C -78 °C - r.t. 83% yield 85% yield 64% yield d.r. 1:1 11 27 28 24

Scheme 3.11: Synthesis of cyclopentadienyl 24.

The condensation of acetaldehyde with 11 promoted by TiCl4 and pyridine afforded diene 27 in moderate 64 % yield. The subsequent Nazarov cyclization using methanesulfonic acid proceeded smoothly, yielding cyclopentenone 28 as a 1:1 mixture of cis- and trans- diastereomers in good 83 % yield. Finally, O-alkylation using methyl orthoformate cleanly afforded the corresponding cyclopentadiene 24 in good yield as well (85 %). Next, we attempted the synthesis of cyclopentadienes bearing larger residues and therefore started by condensing β-oxo nitrile 11 with mesitaldehyde (Scheme 3.12).

MesCHO O Piperidine (cat.) O O HC(OMe)3 OMe HOAc (cat.) MsOH p-TsOH CN CN CN CN

Benzene, 100 °C CH2Cl2, r.t. MeOH, 60 °C 53% yield Mes 93% yield Mes 94% yield Mes 11 29 30 25

Scheme 3.12: Synthesis of cyclopentadienyl 25.

As expected, the condensation of the bulky mesitaldehyde with 11 only afforded a mediocre 53 % yield of diene 29. However, the subsequent Nazarov cyclization proceeded well, affording cyclopentenone 30 in 93 % yield as the trans-diastereomer exclusively. The diastereoselectivity of this reaction can be explained by the large steric demand of the aryl group which is not free to rotate at room temperature as revealed by NMR analysis.2 The synthesis continued with the O-alkylation, which performed excellently giving 25 in 94 % yield .

2All three methyl substituents of the mesityl group in 30 resonate at unique NMR frequencies as reported in the experimental part.

29 Chapter 3

The successful synthesis of the latter compound prompted us to test if even larger substituents could be installed in this way. Thus, we attempted the preparation of cyclopentadiene 26 containing the extremely bulky Trip residue (Scheme 3.13).

iPr

iPr iPr

1) CHCl2(OMe), TiCl4 CH2Cl2, 0 °C-r.t. 2) H2O

iPr O

H O O O HC(OMe)3 OMe iPr iPr MsOH p-TsOH CN CN CN CN

Piperidine (cat.) CH2Cl2, r.t. MeOH, 60 °C HOAc (cat.) Trip Trip Trip Benzene, 100 °C 11 32 33 26 2% over 3 steps

Scheme 3.13: Synthesis of cyclopentadienyl 26.

Since the required aldehyde is not commercially available, we prepared it via Rieche formylation of triisopropyl benzene which afforded 31 in excellent 91 % yield.[112] As we tried to condense the latter with 11, we were met with marginal success as the reaction proceeded very slowly and nitrile 11 was predominantly consumed by side reactions. Additionally, we were not able to purify 32 to obtain an isolated yield and used the crude mixtures for the subsequent Nazarov cyclization (33) and O-alkylation. Finally, we obtained the pure target compound 26, albeit only in 2 % overall yield from 11. Contrary to our expectations, 26 has a different double bond localization as compared tothe previous cyclopentadienes 14, 24, and 25 (see Scheme 3.13).

30 Chapter 3

This structure was corroborated by NMR analysis and, moreover, by X-ray diffraction which clearly displays the location of the methine group (Figure 3.3).

Figure 3.3: ORTEP representation of compound 26. Hydrogens are omitted for clarity and thermal ellipsoids are set to 50 %. Selected bond lengths ([A˚]) and angles [°]: C7-O1 1.439(3), O1-C2 1.341(3), C2-C1 1.362(3), C2-C3 1.502(3), C3-C4 1.509(3), C3-C8 1.531(3), C4-C9 1.497(3), C1-C6 1.422(3), C6-N1 1.149(3), C1-C6-N1 175.8(2), C2-O1-C7 117.2(2), C2-C3- C8 112.6(2), C8-C3-C4 114.2(2), C4-C3-C2 102.8(2), C3-C2-O1-C7 178.1(2), C9-C4-C3-C8 58.8(3).

With this array of cyclopentadienyls in hand, we concluded the organic-synthetic part of this work, and moved on to the preparation of metallocenes.

31 Chapter 3

3.3 Summary and Conclusion

During our second attempt at obtaining our target structure 1, we were only partially successful (Scheme 3.14).

OMe CN CHO

Ph Ph 20 23

R2=Ph R2=Ph 1) AlMe3 1) DIBAL + 2) H 2) H2O

O OMe O MeCN O O 2 NaH CN R CHO CN MsOH CN HC(OMe)3 CN OR1

R2 R2 R2 12, R1=H 11 R2=Ph overall yields iPrOH 1) NaBH H+ 4 17, R1=iPr 2) H+ 14, R2=Ph 33% 2 24, R =Me 30% CN 25, R2=Mes 31% 26, R2=Trip 2% Ph 22 30% overall yield

Scheme 3.14: Overview of the most important transformations and products within this chapter.

The first steps of the reaction sequence, starting with the esterification of12 tiglicacid( ) proceeded without any problems. The afforded isopropyl tiglate (17) reacted smoothly with formal cyanomethyl anions yielding β-oxo nitrile 11. These reactions were easily conducted on a 50 g-scale and gave the products with little effort. The subsequent Knoevenagel condensations with 11 were as well successful with all tested aldehydes. Reactive substrates like acetaldehyde, as well as bulky ones such as triisopropyl benzaldehyde could be introduced in this manner. However, the ambiphilic nature of acrylic compound 11 proved detrimental as it was partly converted to byproducts via 1,4- additions. Yet, we were able to collect enough material in each case, and the subsequent Nazarov cyclizations proceeded smoothly at room temperature. As we turned our attention to the transformation of the carbonyl group, we quickly realized that this could only be reduced by hydrides. Attempts at the addition of alkyl species to the carbonyl function with organoaluminium reagents, which are able to perform with similarly acidic substrates, proved unfruitful. However, we were pleased as we could easily O-alkylate all cyclopentenones to the corresponding enol ethers. The next intended transformation was the conversion of nitrile 14 to the corresponding aldehyde 23. Regrettably, we were unable to do so and this marked the final attempt at preparing ligand 1 using this strategy. The reason for this behavior could be a deprotonation of the rather acidic cyanocyclopentadienes. However, all reactions leading to such nitriles are clean, usually high yielding and reproducible on a multi-gram scale. Furthermore, the developed strategy presented the possibility to vary the residues displayed in the final cyclopentadienes. Thus, we prepared

32 Chapter 3 four, new pentasubstituted cyclopentadienes differing by one of their substituents, thereby demonstrating the versatility of our synthetic strategy. In this way, we should be able to prepare an array of closely related organometallic compounds and compare their properties. In conclusion, we were not able to obtain the original target ligand (1), or its model variant 13. Nevertheless, we are convinced that the second generation approach has potential which we could not yet address.

3.4 Outlook

While most of the reactions in this chapter worked well, some of them still need consideration. To reduce the amount of byproducts originating from 1,4-additions during the Knoevenagel condensations, we propose to conduct the reactions with an excess of aldehyde and low molarities of nitrile 11 (Scheme 3.15).

1) PhCHO (excess) O Piperidine (cat.) O CN HOAc (cat.) CN

2) NaHSO3 R H2O 11 1-VIII

Scheme 3.15: Proposed optimized conditions for the Knoevenagel condensation of β-oxo nitriles 11 with aldehydes.

In this way, one could increase the rate of the condensation while suppressing the formation of byproducts like 18. Afterwards, unreacted aldehyde could easily be removed by treating the crude mixture with NaHSO3. Another transformation which needs closer inspection, is the addition of alkyl nucleophiles to the carbonyl functionality of cyclopentenones 1-VII. We propose to achieve this by [113] activation of the substrates with lanthanoid chlorides like CeCl3 (Scheme 3.16).

O R2 1) CeCl3 2 CN 2) R MgBr CN

3) H+ R1 R1

1-VII

Scheme 3.16: Proposed addition of Grignard reagents to cyclopentenones.

Finally, we showed that the herein presented strategy can efficiently be employed to prepare polysubstituted cyanocyclopentadienes. While, we only varied one of five residues at the Knoevenagel-stage of the synthesis, one could also do the same during other steps (Scheme 3.17). An advantage is given with the use of oxo nitriles as intermediates since these should be readily accessible from other acrylic carboxylates (R1 and R2 in Scheme 3.17). We already demonstrated the possibility of varying the third substituent (R3) which is easily achieved by employing aldehydes of choice. After the Nazarov cyclization, O-alkylation would afford new cyclopentadienes containing a cyano and a methoxy group. Furthermore,

33 Chapter 3

O CN E O R1 CN Ph 34 O + 2 O E R R3 R1 1 OH R CN

2 R R2 R3 Nu- Nu OMe R1 CN CN

R2 R3 Ph

R3CHO 60

Scheme 3.17: Generalization of the synthetic strategy to prepare libraries of polysubstituted cyanocyclopentadienes. hydride-reduction of the carbonyl function and subsequent dehydration are feasible and hence libraries of tetrasubstituted cyanocyclopentadienes could be prepared as well. Further options would be available if other nucleophiles could undergo the same reaction. In an attempt to further demonstrate the applicability of the synthetic sequence, we started to prepare a chiral-pool derived compound 34 as shown in Scheme 3.17. Unfortunately, our work was cut short since the O-methylation didn’t proceed (see appendix on page 130 for further details). As described earlier, our methoxy-containing cyanocyclopentadienes constitute a new and rare class of ligands and we thus proceeded with the study of their coordination chemistry with transition-metals. Additionally, we hoped that the reduction of the cyano group would be possible once the ligands lack their acidic proton and are coordinated to a metal ion. These aspects and more will be the subject of the next chapter.

34 Chapter 4

Polysubstituted Ferrocenes

This final chapter describes our use of the methoxy- and/or cyano-substituted cyclopentadienes to prepare organometallic compounds. Given the unexplored chemistry of these new ligands, we devoted our initial efforts towards the preparation of corresponding homoleptic ferrocenes. As a continuation, heteroleptic ferrocenes were prepared as well, and their reactivity was investigated. A part of the experimental work of this chapter was carried out by Salome Heilig [86] (mesityl compounds) and Raphael Lengacher [87] (improved synthesis of heteroleptic ferrocenes).

4.1 Introduction

With the new functionalized ligands 351 in hand, we wanted to explore their coordination ability with transition-metals. As a fundamental reasoning, we opted to do so by preparing corresponding ferrocenes since such compounds are usually stable and readily crystallized (Scheme 4.1). Additionally, ferrocenes containing cyano groups or O-substituents are largely underrepresented as will be demonstrated in this introductory part.

R1 R1 CN R2 CN 2 R2 R Fe CN Fe R2 CN R1 R1 36 35 37 Homoleptic Heteroleptic Ferrocenes 14, R1=Ph, R2=OMe Ferrocenes 22, R1=Ph, R2=H 24, R1=Me, R2=OMe 25, R1=Mes, R2=OMe 26, R1=Trip, R2=OMe

Scheme 4.1: Overview of the planned preparations of homoleptic (36) and heteroleptic ferrocenes (37) using ligands 35.

Moreover, we also set the goal to introduce only one of the polysubstituted cyclopentadienes 35 in a ferrocene, thus generating heteroleptic complexes 37 (Scheme 4.1). While the preparation of these is very well explored and established if one considers the

1For convenience, the polysubstituted cyanocyclopentadienes will be generalized by the number 35.

35 Chapter 4

”standard” ferrocene chemistry,[114–118] the stepwise reaction of two different cyclopentadienyls with an iron(II) species is a comparably rarely applied protocol. This fact further motivated us to pursue the preparation of heteroleptic ferrocenes 37.

4.1.1 Goals and Synthetic Planning Before presenting the relevant literature, the key aspects of the planned work of this chapter will be addressed. As described above, we planned to prepare homoleptic ferrocenes 36 starting from the previously prepared cyclopentadienes (Scheme 4.2).

R1 R1 R2 CN CN 1) Base 2 CN R2 R Fe + 1 Fe R2 R CN 2) FeX2 2 R1 CN R R1 35 rac-36 meso-36

Scheme 4.2: General scheme for the preparation of homoleptic ferrocenes 36 using polysubstituted cyclopentadienes 35 (X=halide).

This should be straightforward by deprotonating the cyclopentadienes and reacting them with iron(II) salts. The only peculiarity concerning such experiments is the likely formation of isomers because of the enantiotopic nature of the two sides of ligands 35.[2] Altogether one would expect three species: a pair of enantiomers (rac-36) and an achiral meso- compound (meso-36). These experiments are meant to serve as a proof of concept, demonstrating the coordination characteristics of cyanocyclopentadienes 35. As described above, we also wanted to prepare heteroleptic variants, namely containing one ligand of type 35 and an unsubstituted cyclopentadiene (C5H5). This could be achieved with a cyclopentadienyl iron(II) transfer reagent, the chemistry of which is described later in more detail (Scheme 4.3).

R2 R1 CN 1) Base CN R2 Fe 2) [CpFeII] R1 35 rac-37

Scheme 4.3: General scheme depicting the preparation of heteroleptic ferrocenes 37 containing a polysubstituted cyclopentadienyl ligand 35 and an unsubstituted one.

Besides describing these new compounds, we planned on attempting the reduction of the cyano group of ligands 35 by addition of nucleophiles (Scheme 4.4).

36 Chapter 4

NH R1 R1 2 CN OMe 1) MeLi OMe Fe Fe 2) NaBH4

rac-37 rac-38 R1=Ph, Mes, Trip

Scheme 4.4: Possible formation of amines 38 by nucleophilic addition of alkyl nucleophiles to the cyano moiety of ferrocenes 37 and subsequent reduction.

This reaction is known to proceed with other unsubstituted cyanoferrocenes and in doing so we would come close at obtaining the general structure of target ligand 1, albeit when already bound to a metal.[119, 120] We found further motivation to prepare ferrocenes 37 while considering the functionalization of the unsubstituted ring (Scheme 4.5).

R1 R1 CN CN CN 1) Base OMe OMe OMe Fe Fe Fe Fe 2 2) ClPR 2 Ph P R2 P 2 Ph2P R2 rac-37 rac-38 Long 2004 Stepnickaˇ ˇ ˇ 2014 R1=Me, Ph, Mes, Trip

Scheme 4.5: Proposed introduction of a phosphane functionality in ferrocenes of type 37 yielding 39 which can be viewed as a combination of the systems presented by the groups of Long[121] and Stˇ ˇepniˇcka.[122]

Metallocene 37 could be deprotonated and quenched with a chloro phosphane, yielding a potential ferrocene-based ligand 39 displaying three Lewis basic sites. Further interest to prepare the latter came from the work of the Stˇ ˇepniˇcka and Long groups. The O-substituted ferrocenylphosphane ligand by Long et al. was intended as a hybrid, or hemilabile ligand, bearing two different donor groups (Scheme 4.6).[121]

OMe Fe Br B(OH)2 Ph2P + Pd2(dba)3 THF, 50 °C, 5h 89% yield 2 mol% Ligand:Pd 1:1 79% yield with dppf

Scheme 4.6: Work by Long on 1,1’-disubstituted ferrocene ligands in Suzuki reactions (dppf=1,1′-bis(diphenylphosphanyl)ferrocene).[121]

In their work, the Long group found a better performance of their system in palladium- catalyzed Suzuki-type couplings, as compared to the well known dppf ligand when using Pd(0) precursors. Temptingly, they attribute these results to the hemilabile character of the methoxy substituent on ferrocene. Disappointingly, this exact system was not further pursued in favor of other similarly hemilabile ligands.[123–125]

37 Chapter 4

The work of Stˇ ˇepniˇcka, instead, covers the chemistry of 1-phosphanyl-1’-cyanoferrocenes which form interesting oligomers with coinage metals and were applied in gold-catalyzed reactions (Scheme 4.7).[122, 126–128]

2+ Ph2 Au P N H 0.01 mol% [Au] Fe 2 NTf - Fe 2 neat, r.t., 0.5 h O HO N 92% yield P Au Ph2

[Au]

Scheme 4.7: Example of work by Stˇ ˇepniˇcka on 1-phosphanyl-1’-cyanoferrocene ligands and its application in the gold-catalyzed cyclization of alcohols to furans.[126]

The corresponding cationic gold complex showed remarkable activity at very low loadings in a variety of reactions (an example is depicted in Scheme 4.7). Like the Long group, they attribute this effect to the hemilabile nature of the ferrocene ligand which forms shelf-stable, dinuclear complexes which readily dissociate under reaction conditions. This reversible process could also be taking place in solution and thus prevent the catalyst from deactivation. Given the substitution pattern of our cyclopentadienes 35, it seemed obvious to prepare compounds 39 which would combine the two motifs described above. With our goals explained, the subsequent sections will describe the literature on the rather rare O-substituted ferrocenes and cyanoferrocenes. Nota bene: after extensive research we found only one account of a ferrocene displaying an alkoxide as well as a carbonitrile function in vicinal position. This compound is presented towards the end of this introduction to summarize the methods known nowadays to install these two functionalities.

4.1.2 O-Substituted Ferrocenes The most frequently used route to O-substituted ferrocenes requires the prefunction- alization of the metallocene scaffold. However, as mentioned, relatively few accounts are found in the literature on such compounds. This observation could temptingly be attributed to the instability of the most simple and chemically useful precursor of this substance class, namely the corresponding alcohols.

38 Chapter 4

4.1.2.1 Preparation of Ferrocenol and Derivatives Thereof

Ferrocenol, was firstly prepared in 1959 by Nesmeyanov et al.(Scheme 4.8).[129, 130]

B(OH)2 OAc OH OE - + Cu(OAc)2 OH E Fe Fe Fe Fe

O O

Scheme 4.8: Conversion of ferrocenylboronic acid to ferrocenol which is unstable towards O2 but can be rendered inert by conversion to other functional groups.

Starting from ferrocenylboronic acid, treatment with Cu(OAc)2 forms the C-O bond yielding acetoxyferrocene. Hydrolysis delivers then the free alcohol; a yellow solid which is only stable under inert atmosphere otherwise releasing the ligands as cyclopenta- dienone.[130–132] This redox behavior of ferrocenols can be defused by handling them as ferrocenyl ethers or esters. These are easily obtained by reaction of the alcohols with electrophiles other than Brønsted acids (Scheme 4.8).[129, 132–134] Although some adaptations of this protocol were developed over time,[131, 135] this overall pathway to ferrocenols remains the predominant one found in the literature until today.[136, 137] The deviations concern the use of haloferrocenes as starting materials and/or the application of Cu(I) species to form the C-O bond.[138, 139] A rather useful alteration involves the use of Cu2O and a carboxylic acid of choice. This affords in situ the corresponding copper carboxylate which is further reacted with haloferrocenes to ferrocenyl esters.[140, 141] Similarly, aryloxy- and heteroaryloxyferrocenes are readily obtained under Ullman-type conditions.2,[134, 144–146] This method has been extended to the preparation of alkoxyferrocenes as well, thus improving on the above presented literature.[147–149] Another, less frequently used method for the installation of the C-O bond,3 is the quenching of ferrocenyl anions with electrophilic oxygen sources.[152–154] Finally, a recent addition to this family of transformations involves the use of NHC’s to couple aldehydes with ferrocenylboronic acids to yield ferrocenyl esters.[155, 156] Using the above mentioned methodologies, 1,1’-dihydroxyferrocene and derivatives thereof, as well as other polysubstituted O-containing ferrocenes have been prepared.[132, 157–160] All the above presented protocols do not describe the access to O-bearing ferrocenes by introducing oxygen functions earlier on, i.e. on the free cyclopentadiene to then form corresponding ferrocenes. Few reports are provided employing such methodologies and the chemistry of these pathways remains little explored as described in the next section.

2In case of electron depleted arenes, ferrocenol can be pushed to perform nucleophilic aromatic substitutions thus affording aryloxyferrocenes as well.[142, 143] 3Two methods are not further discussed here. One stems from two reports dealing with a redox reaction between a oxotungsten species and ferrocene, yielding the tungsten bound ferrocenoate.[150, 151] The other one, performed by Nesmeyanov et al., describes the conversion of benzenediazaminoferrocenes under acidic conditions to ferrocenols.[131, 135]

39 Chapter 4

4.1.2.2 Alternative Preparations of Ferrocenols and Derivatives Thereof Few accounts exist where functionalized cyclopentadienes are used to prepare the corresponding O-substituted ferrocenes. This was first attempted by Benson et al. just before the work of Nesmeyanovs group which was presented above (Scheme 4.9).

R1 R2 OH OH OH 2 1 1) Base 1) Na, NH3 R R FeX + Fe OPG 2 O Fe Fe R2 R1 R1 R1 R2 OH OH OH R1 R2 R2 2) Deprotection 2) PhCOCl meso rac meso 3) NaOH, H2O Plenio 1997 Benson 1957

Scheme 4.9: Preparation of 1,1’-ferrocenediols from cyclopentenone-derived ligands and iron(II) halides according to Benson[161] and Plenio.[162] Depending on the substitution pattern of the ligands, up to two diastereomers are formed (R1,R2=alkyl or aryl, X=halide).

This was achieved by doubly deprotonating 3-methyl cyclopentenone with NaNH2 in liquid ammonia and treatment with iron(II) salts, yielding the desired ferrocenediols.[161] Given that 3-methyl cyclopentenone derived ligands feature enantiotopic sides, a mixture of diastereomeric ferrocenes was obtained (Scheme 4.9). The next obvious improvement on this method concerned the employment of protected, enolized, cyclopentenones (Scheme 4.9).[162–165] Many of these accounts stem from Plenio et al. who also eliminated the complication of forming diastereomers by increasing the symmetry of the employed ligands. The formation of heteroleptic ferrocenes by similar means, i.e. the stepwise introduction of two different cyclopentadienyl ligands, has been used to an even lesser [extent. 166] In fact, the most frequently encountered method is to make use of the carbonylation of butadienes with cyclopentadienyliron(II) dicarbonyl iodide (FpI) derivatives (examples are depicted in Scheme 4.10).[167–171]

R1 OEt Ph Ph NaCp 2 Fe R Li Fe Fe OC R1=OEt I R1=H Ph OC R2=H, Li OH R1=H, OEt Ph

Fuchs 1971 Allison 1983

Scheme 4.10: Examples of the synthesis of heteroleptic O-substituted ferrocenes via sequential introduction of different cyclopentadienes.[166, 167]

The small number of experiments in this field could be attributed to the lack of well established methods to prepare heteroleptic ferrocenes by the sequential introduction of two different cyclopentadienyls. This will be discussed later in this chapter. These pathways to ferrocene-based alcohols have been applied to prepare a number of compounds which were employed in different areas of chemistry.

40 Chapter 4

4.1.2.3 Applications of Ferrocenols and Derivatives Thereof Ferrocenols have given access to the majority of known oxygen-bearing ferrocene derivatives.[153, 172–174] Many efforts were further devoted to prepare macromolecules linked by ferrocenyl ethers. Corresponding crown ethers,[175–179] catenanes,[180, 181] rotax- anes,[182–184] and porphyrins[185] were thus added to the field of supramolecular chemistry. Ferrocenyl ethers have also found application as potential anti malaria agents[186–188] and aryloxyferrocenes were investigated by the Monsanto company as antioxidants, pigments and antiknock agents.[134] Of more interest for the present work, is the use of O-containing ferrocenes as ligands in coordination chemistry. Although potential, bidentate, chiral hydroxyferrocenes had been prepared in the early 1970ies,[189–191] their use as ligands arose only later. The first enantiopure compounds were obtained by derivatization with chiral auxiliaries such as sulfoxides,[152] oxazolines,[192, 193] phosphites,[194] or amines.[195–199] This area was further expanded by Erker and Ito et al. who prepared and investigated an array of Schiff bases based on ferrocenols.[197–207] The research on these kind of substances seemed to lay dormant until the first decade of the new millennium. In fact, O-bearing ferrocenes came again under investigation by the groups of Butenschon¨ and Lang (Scheme 4.11).

OH OR1 OH OMe 2 Tf LDA nBuLi PO(OR )2 PPh2 Fe Fe Fe Fe R1=Tf R=PO(OR2)2

Butenschön 2010 Lang 2014

Scheme 4.11: Examples from the groups of Butensch¨on[208] and Lang.[209] Hydroxyferrocenes are formed via Fries rearrangements which, in case of the Lang group, were further modified towards ligands for transition-metals (LDA=Lithium diisopropylamide).

Their interest started after the discovery of ferrocene triflates undergoing very efficiently anionic thio-Fries rearrangements.[208, 210] The same behavior has lately been observed with ferrocenol phosphates, undergoing a phospho-Fries rearrangement.[209, 211, 212] In the latter case, several ferrocenes have furthermore been prepared and tested as ligands in transition-metal catalysis.[213] What is more of interest for the work presented herein, and as mentioned in our goals, are the accounts on 1,1’-disubstituted ferrocenes containing an oxygen functionality and a phosphane.[123–125, 214, 215] The most relevant accounts concerning these have been presented previously (see Scheme 4.6 on page 37). Finally, further input into the field of O-containing ferrocenes is supplied by 1,1’- dihydroxyferrocenes. They also have been used in organometallic chemistry, although no chiral system has been applied to date. Such diols have instead been employed as bridging ligands in multinuclear complexes,[216] or as bidentate ligands[217] like their corresponding ethers.[218–220] To the best of our knowledge, this summarizes the known research dealing with O- substituted ferrocenes and their use. Next, the other functionality of interest, the cyano group, is presented and discussed in an analogous manner.

41 Chapter 4

4.1.3 Cyanoferrocenes Although a comparably small number of reports on O-substituted ferrocenes are known, an even smaller one can be found for such bearing a cyano group. Few single step preparations starting from ferrocene have been investigated while the majority of cases make use of multi step transformations to introduce this functionality.

4.1.3.1 Single Step Preparations of Cyanoferrocenes from Ferrocene As with many ferrocene compounds, Nesmeyanov’s group was usually among the first to tackle the preparation of new derivatives.[221] Cyanoferrocenes pose no exception to this general habit, although their first single step syntheses being of serendipitous nature. While attempting to perform nucleophilic aromatic substitutions with ferrocenium salts in 1958, they discovered that no nucleophile would undergo any reaction but cyanide. To their surprise, the expected cyanoferrocenium was not isolated but rather the reduced cyanoferrocene instead (Scheme 4.13).[222, 223]

CN HCN, THF Fe [FeCl4] Fe

+ CN- - H

H [FeIII] CN Fe + CN Fe + CN Fe

Scheme 4.12: Cyanation of ferrocenium to cyanoferrocene with HCN. The starting material oxidizes cyanide to the corresponding cation subsequently undergoing an electrophilic aromatic substitution.[222, 223]

For this transformation to take place, the twofold oxidation of cyanide by iron(III) species, like ferrocenium, has been invoked. Thus ferrocene and CN+ are formed and an electrophilic aromatic substitution is thought to take place. This reaction is also accomplished when ferrocenes are directly used as starting material,[224, 225] and the postulated mechanism has been further investigated and corroborated by other groups.[226–228] The formally identical pathway has been achieved with alternative electrophilic carbonitrile- sources like CNBr[229] or tosylcyanide.[230, 231]

4.1.3.2 Multistep Transformations Yielding Cyanoferrocenes The synthesis of organonitriles has been since long an important topic in chemistry and a multitude of functional group conversions yielding the cyano group have been developed. Naturally, these can also be applied to ferrocene-based compounds. Thus the preparation of cyanoferrocenes has been achieved from the dehydration of corresponding amides[232] or, mainly, from their oximes (Scheme 4.13).[223, 229, 233–236]

42 Chapter 4

O NOH CN H H NH2OH DCC Fe Fe Fe

Scheme 4.13: Exemplary scheme for the synthesis of cyanoferrocenes.

After conversion of formylferrocene to the corresponding oxime, the latter can be dehydrated with a variety of reagents although DCC has been predominantly used.[237–241] Some isolated methods of synthetic utility4 which have been further investigated are [132, 245, 246] the coupling of haloferrocenes with CuCN or with K3[Fe(CN)6] combined with palladium-catalysts,[247] as well as the desulfurisation of ferrocenecarbothioamides.[248] The same methods described above have been used for the synthesis of 1,1’-dicyanoferrocene and its derivatives.[249–262] The only alternative method for the preparation of similar compounds is to start with cyanocyclopentadienes.

4.1.3.3 Cyanoferrocenes from Cyanocyclopentadienes As in the case of O-substituted ferrocenes, few reports have described the reaction of cyanocyclopentadienyl ligands with Fe(II) species (Scheme 4.14).[263, 264] This observation could be explained by the surprisingly small number of records concerning the preparation of cyanocyclopentadienes (Scheme 4.14). Interestingly, the majority of the known literature yielding cyanocyclopentadiene involves flash-vacuum pyrolysis, or photolysis studies.[265–268] Of more relevance to the synthetic chemist are the two main approaches depicted in Scheme 4.14.

CN 1) ClCN CN 1) Base NaCp Fe 2) Base 2) FeCl2 CN Base ΔT

R NC PhSO2Cl R CN Pyridine

R=CO2H 1) SOCl2 2) NH3 R=CONH2

Scheme 4.14: Preparation of 1,1’-dicyanoferrocene from cyanocyclopentadienyl anions. The latter are predominantly obtained from treatment of NaCp with cyanogen chloride. Alternatively, the cyano functions can be installed on dicyclopentadienes which are then cracked under alkaline conditions.

Cyclopentadiene can be converted to the respective mono- through penta-carbonitriles by action of cyanogen chloride. This reaction was, to the best of our knowledge, performed over a century ago by Grignard et al.[269, 270] Detrimentally, handling of the mono- cyanocyclopentadiene has to be performed swiftly given its high dimerization rate.[271, 272]

4There are also observations of cyanoferrocenes being produced via flash-vacuum-pyrolysis[242] or from the photolysis of cyclopentadienyl azidoarene iron(II) complexes resulting in nitrene species which undergo ring contractions and thus the formation of the cyanocyclopentadienyl ligand.[243, 244]

43 Chapter 4

Alternatively, one may use the corresponding dicyclopentadienes as a ligand source. Thanks to the cyano group, the acidity of such dicyclopentadienes is greatly enhanced. Hence, they are easily deprotonated and thereby promoting anionic cycloreversions which liberate the desired monomers (Scheme 4.14).[273–275] Using these methodologies, and due to the polarizing character of the cyano group, cyanoferrocenes have appeared in some studies.

4.1.3.4 Applications of Cyanoferrocenes Concerning coordination chemistry, compounds with organonitriles as ligands are found in numerous accounts. In terms of binding properties, these are rivaled by their isonitrile congeners which form considerably stronger bonds to metal centers.[276–278] Organonitrile complexes thus conveniently serve as transition-metal precursors since such ligands are quite easily displaced.[279–281] Cyanoferrocenes, display the same ability to bind to metals via the nitrogen atom.[119, 282–286] Due to the geometrical arrangement of the nitrogen lone pair, polycyanoferrocenes have afforded multinuclear,[287] and polymeric assemblies.[119] These motifs have been applied to prepare models for molecular, wire-like, conductive structures which make use of the redox characteristics of ferrocene.[282–284, 288–291] As described earlier, the Stˇ ˇepniˇcka group, in particular, has promoted the study and use of cyanoferrocenes as ligands with their work on 1-phosphanyl-1’-cyanoferrocenes (see Scheme 4.7 on page 38). Due to the incapacity of such systems to act as chelating ligands, multinuclear species have been obtained,[122, 127, 128] and some were successfully applied in catalytic transformations.[126] Furthermore, the cyano group can be subjected to a vast array of transformations, thus serving as a common platform towards other functionalities. Cyanoferrocenes have been converted to corresponding imines or amines,[119, 120] oxazolines,[292] tetrazoles,[232, 293, 294] or other heterocyclic derivatives.[295–298] Although the majority of coordinatively useful Lewis bases have been additionally introduced in cyanoferrocenes, the cases where oxygen take this role are rather rare, to say the least. This overview of cyano- and O-substituted ferrocenes will conclude with the description the only ferrocene containing both of these functional groups in a vicinal pattern, known so far.

4.1.4 The Only Example of a 1-Alkoxy-2-Cyanoferrocene We have shown that the chemistry of cyano- or oxygen-substituted ferrocenes is somewhat under explored. We were thus obviously motivated to contribute to this field using our newly prepared cyclopentadienes 35 displaying both these functionalities in a vicinal relationship. During our investigation of the literature presented above, we were happy to come across one example of a ferrocene displaying the same features.[189] Disappointingly, this publication does not describe this compound more than in a single sentence.5 However, we present the preparation of the mentioned compound as a mean to summarize the most widely used synthetic methods for the introduction of the two functionalities in a ferrocene (Scheme 4.15).

5We were actually lucky that we found this entry at all: over four years, and to this date, this compound never resulted in any of our inquiries with several search engines. Thankfully, we became aware of this report as we combed through the Gmelin Handbook series.[262]

44 Chapter 4

R OH OTHP OTHP 1) Cu(OAc)2 HCl, DHP R DCC CN Fe Fe Fe Fe 2) Base

R=H R=H n 1) BBr3 1) BuLi 2) NaOH, H2O 2) DMF R=B(OH)2 R=CHO NH2OH R=NH2OH

Scheme 4.15: Preparation of the only 1-alkoxy-2-cyanoferrocene known to date (3,4-Dihydro- 2H-pyran (DHP), tetrahydropyran (THP)).[189]

Starting form ferrocene, treatment with BBr3 followed by base hydrolysis yielded ferrocenylboronic acid. Following the method of Nesmeyanov,[129, 130] the latter was reacted with Cu(OAc)2 affording ferrocenylacetate which was converted to ferrocenol under alkaline conditions. Since this species is rather unstable if not kept under inert conditions, a conversion to the corresponding tetrahydropyranyl ether was performed. Directed o-metallation and quenching with DMF afforded the corresponding aldehyde which was converted to the oxime and subsequently dehydrated to afford the cyano function. Altogether, the majority of examples of ferrocenes containing the functional groups discussed herein are prepared by multistep transformations. Syntheses of the same compounds via organometallic reactions, i.e. the sequential introduction of correspondingly decorated cyclopentadienyl ligands onto an iron(II) ion, have been largely neglected. Since we would employ this strategy with our ligands 35 to prepare heteroleptic ferrocenes 37, the next section outlines the methodologies enabling such reactions.

4.1.5 Cyclopentadienyl Iron(II) Transfer Reagents for the Prepa- ration of Heteroleptic Ferrocenes An extremely large number of heteroleptic ferrocenes have been prepared over several decades via well established transformation of the ferrocene molecule.[115, 117, 118] The only alternative pathway available and, by and large less employed and explored one, is the sequential reaction of two different cyclopentadienes with an iron(II) species (Scheme 4.16).

Rn Rn Rn R'n [FeII] FeII Fe L L R' L n

Scheme 4.16: General formulation of the sequential introduction of two different cyclopentadienyls yielding the corresponding heteroleptic ferrocenes (R=arbitrary residue,L=anionic or neutral ligand, n=1-5).

This could be viewed as a process where coordination of a first cyclopentadienyl affords a cyclopentadienyl iron(II) species which is stabilized by further ligands to accomo- date the electron household. Displacement of these additional ligands by a second cyclopentadienyl then affords the desired heteroleptic ferrocenes. This pathway has been successfully employed, for example, by B¨ackvall et al. for the synthesis of acetylferrocenes (Figure 4.1).[299]

45 Chapter 4

Bäckvall 2002 Dötz 2005 Manríquez 1985 Jonas 1995 Herberich 1998

R R - Fe Fe Fe Fe PF6 OC Me2N MeCN I O O Cl NCMe NMe MeCN R R OC 2

O R

FeCl2 hν (UV) Br

Fe Fe Fe Fe Fe R R R R R R Br yields 49% yield 86% yield 90% yield yields R=Me 57% R=H 96% R=Et 76% R=COMe 99% R=Ph 66% R=CHO 92%

Figure 4.1: Selected methods enabling the stepwise reaction of iron(II) species with cyclopentadienes and corresponding examples.

In the latter case heteroleptic ferrocenes have been obtained almost exclusively and the authors attribute this behavior to the different electronic properties and bulk of the employed ligands.[299] Hence, they postulate that the more Lewis basic, sterically demanding pentasubstituted cyclopentadienes form a monocyclopentadienyl iron(II) compound which then reacts with the smaller acetylcyclopentadienyls. This hypothesis is corroborated by taking into account that such postulated intermediates haven been isolated[300–303] or intercepted as cyclopentadienyl iron(II) carbonyl complexes.[304, 305] The latter compounds have also been used as cyclopentadienyl iron(II) transfer-reagents, yielding heteroleptic ferrocenes via treatment with a second cyclopentadienyl and subsequent extrusion of carbon monoxide,[306, 307] as exemplified by the work of the Dotz¨ group.[308] More reactive cyclopentadienyl iron(II) species have been provided by the work of Manriquez et al.[309, 310] with their acetylacetonato complex which has been used several times for the synthesis of heteroleptic ferrocenes.[311, 312] This reagent is not unfamiliar to our group since it was used in the past for the direct synthesis of pentamethylated Ugi-amines (Scheme 4.17).[50]

NMeR* NMe2 Fe Cy O O N Me2NH HOAc Fe Fe 95% yield 80% yield Li

Scheme 4.17: Previous work in our group using Manriquez’s reagent to synthesize new derivatives of Ugi’s-amine.[50]

A newer, similar reagent has been investigated and successfully applied as well,[264, 313, 314] namely the TMEDA adduct prepared by Jonas et al.[315] Likewise, the pentamethylcyclopentadienyl iron(II) acetonitrile solvate prepared by Astruc et al.,[316] has been used

46 Chapter 4 to prepare pentamethylferrocenes in excellent yields as demonstrated by Herberich.[317] While being effective reagents for the synthesis of heteroleptic ferrocenes, these last three compounds are mainly useful to transfer a pentamethylcyclopentadienyl iron(II) species. Since we required compounds which are able to transfer unsubstituted fragments, we were more interested in doing so with other reagents, as discussed next.

4.1.5.1 Heteroleptic Ferrocenes from Cyclopentadienyl Arene Iron(II) Com- pounds A special class of substances able to release cyclopentadienyl iron(II) species are their η6-arene complexes, which have been investigated and reviewed by Astruc.[318–321] The first reported synthesis of 1963 by Nesmeyanov et al. is straightforward (see Scheme 4.18).[322, 323]

AlCl , Al 3 NH4X Fe Fe Fe [AlCl ]- X- Arene, ΔT 4 R R

X=PF6, BF4, BPh4

Scheme 4.18: General scheme for the preparation of cyclopentadienyl arene iron(II) starting from ferrocene (see paragraph below for R).[322, 323]

Treatment of ferrocene with AlCl3, elemental aluminium and the corresponding arene yields first an aluminate salt of the cationic complex.[323] Normally, benzene, toluene, p-xylene, p-chloro toluene or naphthalene are used as arene ligands. The counter ion – – – is then usually replaced by PF6 , BF4 or BPh4 affording the desired compounds in moderate yields6 as yellow to brown solids which are stable towards air and moisture alike. These substances have been used as competent cyclopentadienyl iron(II) transfer-reagents (Scheme 4.19).

R yields (selection)

Fe - Fe PF6 hν R=CO2Me 98% (100 W desk lamp) R=PPh 51% MeCN R 2

Scheme 4.19: Examples by Astruc on the use of cyclopentadienyl arene iron(II) reagents for the synthesis of heteroleptic ferrocenes.[325]

6Improvements of this procedure are also given, e.g. by employing microwave irradiation.[324]

47 Chapter 4

Displacement of the arene, usually achieved by photolysis, yields initially the active solvated cyclopentadienyl iron(II) ion.[316, 326, 327] The latter can then be intercepted with a variety of cyclopentadienes, hence affording the corresponding heteroleptic ferrocenes.[328–335] These reagents were also employed to transfer cyclopentadienyl iron(II) fragments onto other metallocenes thus yielding multidecker complexes.[336, 336] Furthermore, this protocol can also be applied to intercept fulvenes, allowing the formation of functionalized ferrocenes without the need for bases.[337–340] During our research we came across a report of an interesting type of cyclopentadienyl arene iron(II) complex, namely fluorene compound 40. Without the need for irradiation, complex 40 is able to release cyclopentadienyl iron(II) species as shown by the Chung group in 1997 (Scheme 4.20).[341]

t R Fe - KO Bu Fe Fe n PF6 Fe

Results (selection)

Ph Ph CHO

Rn Ph yield ferrocene 48% 56% 64% 81% 56%

Scheme 4.20: Deprotonation of 40 yielding an neutral species which can be used to synthesize heteroleptic ferrocenes.[341]

Coordination compound 40 displays an interesting behavior since after deprotonation of the methylene group the iron retains its coordination to the six membered ring of the fluorenyl ligand.[342] Such a structure can be depicted as a zwitterion, maintaining a formal anionic charge at the former methylene carbon, or as a neutral cyclohexadienyl complex as depicted in Scheme 4.20. However, NMR and X-ray studies of this species seem to prove that these two resonance structures are only extreme descriptions.[343, 344] Since the account by Chung et al.,[341] some reports have surfaced employing this protocol.[345–348] Unfortunately, the actual mechanism in this special case has not been investigated and also no improving modifications of the established protocol have been proposed. Finally, we would attempt the synthesis of heteroleptic ferrocenes 37 containing our polysubstituted ligands 35 using cyclopentadienyl arene iron(II) compounds presented above.

48 Chapter 4

4.2 Results and Discussion

4.2.1 Synthesis of Homoleptic Ferrocenes The synthesis of homoleptic ferrocenes starting from cyclopentadienes and iron(II) species is usually straightforward and uncomplicated.[114, 115] The most general protocol involves deprotonation of the acidic cyclopentadienes and then treatment with an iron(II) salt. To prove the ability of ligands 35 to coordinate in an η5-fashion, we prepared homoleptic ferrocenes 41 and 42 from cyclopentadienes 14 and 24 (Scheme 4.21).

R R OMe 1) NaH CN CN CN THF, r.t. OMe OMe Fe + Fe OMe R CN 2) FeBr2 R r.t. - 65 °C CN OMe R

14, R=Ph rac-41, R=Ph meso-41, R=Ph 24, R=Me rac-42, R=Me meso-42, R=Me

Scheme 4.21: Synthesis of homoleptic ferrocenes 41 and 42. In both cases a 1:1 mixture of diastereomers was obtained.

Cyclopentadienes 14 and 24 were deprotonated with NaH in THF at room temperature and then treated with FeBr2. In both cases, a 1:1 diastereomeric ratio of meso- to rac-compounds was produced during the reaction as determined by 1H NMR analysis. After purification by column chromatography, we obtained ferrocene 42 in moderate 51 % yield and 41 in better 72 % yield. Although both compounds easily crystallized from organic solvents, single crystals suited for X-ray diffraction were only obtained in case of 41. The solid state analysis reveals that only one diastereomer, namely the achiral meso-species, was included in the unit cell (Figure 4.2).

Figure 4.2: ORTEP representation of compound 41. Hydrogens are omitted for clarity and thermal ellipsoids are set to 50 %.The abbreviation Cp denotes the centroids created by C1-C2-C3-C4-C5. The parameters of both cyclopentadienyls are identical. Selected bond lengths ([A˚]) and angles [°]: C1-C2 1.429(2), C2-C3 1.440(2), C3-C4 1.435(2), C4-C5 1.432(2), C1-O1 1.369(2), O1-C7 1.437(2), C2-C6 1.427(2), C6-N1 1.147(2), C3-C10 1.481(2), C4-C9 1.497(2), C5-C8 1.493(2) Cp-Fe1 1.655, C1-O1-C7 111.7(1), C2-C6-N1 178.7(2), Cp-Fe-Cp 0.00, C2-C1-O1-C7 84.6(2), C2-C3-C10-C11 136.5(2).

49 Chapter 4

Since X-ray structures are only available for ferrocenes containing either a cyano group or an alkoxide, but not both, the one of 41 is the first of its kind. Thus, we compared this solid-state structure to known examples of other cyanoferrocenes and O-substituted ferrocenes, respectively (see appendix on page 149 for data from the literature). In general, the functionalities in ferrocene 41 do not seem to affect each other to a large extent, except in certain parameters. To begin with, the methoxy group displays a rather unusual torsion (84.6(2)°) for an alkoxyferrocene, which is most likely results due to the bulk provided by the surrounding substituents. Usually, the terminal O-alkyl bond is found coplanar with the cyclopentadienyl plane and with dihedral angles between 2° and 29° as we determined by inspecting 14 structures of alkoxyferrocenes. The steric interactions are also manifested in the smaller C1-O1-C7 angle of 111.7(1)° which is usually around 115°. The nitrile function, displays bond lengths (C6-N1, 1.147(2) A˚ and C2-C6, 1.147(2) A˚) similar to those found in other substituted cyanoferrocenes, namely about 1.14 A˚ for the C-N and 1.43 A˚ for the C-CN bond respectively. Similar can be said for the C2-C6-N1 angle (178.7(2)°) which is also repeatedly encountered in cyanoferrocenes (on the order of 179°). Corresponding pairs of substituents on the two cyclopentadienyl ligands are found in an antiperiplanar orientation and no distortion of the overall ferrocene structure is observed. Pleased with these results we continued with the preparation of heteroleptic compounds 37.

4.2.2 Heteroleptic Ferrocenes As described in the introduction of this chapter, cyclopentadienyl arene iron(II) complexes have found use as cyclopentadienyl iron(II) transfer reagents. Although some of such compounds are available from commercial suppliers, we prepared them ourselves in larger quantities.

4.2.2.1 Preparation of Cyclopentadienyl Arene Iron(II) Compounds The synthesis of cyclopentadienyl arenes iron(II) is easily accomplished from cheap starting materials (Scheme 4.22).[320, 322, 323]

1) AlCl3, Al arene, ΔT Fe Fe - PF6 2) NH4PF6 H2O, r.t. R

Fe Fe - Fe - - PF6 PF6 PF6 Cl

43 44 45 8% yield 25% yield 29% yield

Scheme 4.22: Synthesis of iron(II) compounds 43, 44 and 45 from ferrocene and the respective arenes.[320, 322, 323]

A mixture of ferrocene, AlCl3 and aluminium powder was heated to reflux with the corresponding arenes as solvent. After removal of unreacted ferrocene from the mixture,

50 Chapter 4

the target compounds were precipitated by addition of NH4PF6 and collected as yellow to green solids. The products were obtained in low (8 %, 43) to moderate yields (25 %, 44 and 29 %, 45). Fluorene complex 40 was synthesized in a similar manner (Scheme 4.23).[349]

1) AlCl3, Al Fluorene, Decalin 155 - 165 °C Fe Fe - PF6 2) NH4PF6 H2O 36% yield 40

Scheme 4.23: Preparation of fluorene complex 40 from ferrocene.[349]

Since fluorene is a solid at room temperature, we applied a procedure employing decalin as solvent, which yielded compound 40 in satisfying 36 % yield.[349] With an array of cyclopentadienyl arene iron(II) species in hand, we set out to react them with our polysubstituted cyclopentadienes 35.

4.2.2.2 Synthesis of Heteroleptic Ferrocenes: Photolysis Protocol In order to establish the best conditions affording heteroleptic ferrocenes, we started by reacting ligands 24 and 14, representing different steric characteristics. Our initial experiments were conducted with the previously described cyclopentadienyl arene iron(II) compounds under photolytical conditions (Table 4.1).[325]

Table 4.1: Reaction of cyclopentadienes 24 and 14 with cyclopentadienyl iron(II) arene complexes 43, 44 and 45.

OMe R3 CN Fe PF - CN NaH, MeCN OMe 6 + 1 2 Fe R R hν R3

43, R1=R2=H 14, R3=Ph 46, R3=Ph 44, R1=Me, R2=H 24, R3=Me 47, R3=Me 45, R1=Me, R2=Cl

Entry Ligand (equiv.) Reagent Producta Output/Wb t/h 1 14 (2) 43 46 75 5.5 2 24 (2) 43 47 75 5.5 3 14 (1) 43 46 150 8 4 24 (1) 43 47 150 8 5 14 (1) 44 46 150 8 6 24 (1) 45 47 150 8 a Respective products were identified in all cases by GC-MS and 1H NMR. b A xenon arc lamp or a halogen bulb was used delivering 75 W and 150 W, respectively.

51 Chapter 4

Since we expected that due to the considerable bulk of the cyclopentadienes (14,24) a productive reaction would be slow, we commenced our experiments by employing these ligands in excess. Two equivalent of cyclopentadienes 14 and 24 were thus deprotonated with stoichiometric amounts of NaH in MeCN at room temperature, treated with benzene reagent 43 and then irradiated with a xenon bulb delivering 75 W (entries 1 and 2, Table 4.1). The reaction did not proceed to completion but the desired ferrocene products 46 and 47 were detected by GC-MS. We then attempted to isolate the target materials by column chromatography only to discover that the new ferrocenes and the unreacted ligands were inseparable. In the end we managed to collect enough quantities for analytical purposes, though this required three consecutive recrystallizations of the target compounds 46 and 47. As a measure to these observations we adapted the procedure by reacting equal molar amounts of cyclopentadienes and benzene reagent 43 while also switching to a halogen bulb supplying 150 W (entries 3 and 4, Table 4.1). These modifications were beneficial as we qualitatively assessed by GC-MS that higher amounts of the target compounds 46 and 47 had been formed after 8 h of irradiation. However, even after numerous attempts we never managed to separate ferrocenes 46 and 47 from unreacted ligands and thus never obtained an isolated yield. Experiments with toluene complex 44 did not offer any different results (entry 5, Table 4.1). A somewhat surprising side product was observed when p-chloro toluene reagent 45 was used in combination with ligand 24 (entry 6, Table 4.1). As we tried once more to isolate ferrocene 47 by column chromatography, we serendipitously collected the new organic species 48 (Scheme 4.24).

OMe OMe NaH, MeCN Fe CN PF - + CN 6 hν Cl

45 24 48

Scheme 4.24: Observed side reaction between cyclopentadiene 24 and benzene reagent 45 yielding 48.

We assume that byproduct 48 is the result of a nucleophilic aromatic substitution by cyclopentadiene 24 and the activated chlorobenzene ligand of 45. Although the nucleophilic displacement of chloride in the latter has been observed,[350] we did not expect this to happen with sterically demanding cyclopentadiene 24. With this last result we deemed the use of the photolytically activated cyclopentadienyl arene iron(II) reagents unsuitable for our case. We abandoned these protocols and turned our attention to the use of fluorene complex 40.

4.2.2.3 Synthesis of Heteroleptic Ferrocenes: Thermal Protocol Due to the insufficient results obtained while preparing heteroleptic ferrocenes byem- ploying cyclopentadienyl arene iron(II) reagents via photolysis, we switched to the use of fluorene complex 40. To our delight, this reagent performed better than other reagents (Scheme 4.25).

52 Chapter 4

KOtBu Fe - PF6 THF, 0 °C R CN 40 0 - 60 °C OMe Fe + Fe +

OMe nBuLi 46, R=Ph 67% yield CN 47, R=Me 43% yield THF, 0 °C R 14, R=Ph 24, R=Me

Scheme 4.25: Reaction of iron(II) compound 40 with ligands 14 and 24.[341]

Applying the literature protocol by Chung et al., we deprotonated ligands 24 or 14 at low temperature with nBuLi.[341] In a separate flask, reagent 40 was prepared by treatment with KOtBu, yielding the active species which was transferred to the lithiated cyclopentadienyls at 0 ◦C. The mixtures were heated to 60 ◦C and in case of ligand 24 we collected ferrocene 47 after work-up and purification in a mediocre isolated yield of 43 %. This required the separation from the copious amounts of ferrocene and fluorene liberated by the productive reaction and decomposition of the deprotonated complex 40. The formation of ferrocene had been observed as well by the authors of the published procedure.[341] In case of phenyl substituted ligand 14 the formation of product 46 was slower than the decomposition of complex 40 whereupon we added twice 0.5 equivalent of this reagent to the mixture. Eventually, we obtained heteroleptic ferrocene 46 in 67 % albeit we were again not able to separate it from unreacted ligand 14 (determined by 1H NMR). It became clear that fluorene compound 40 was the reagent of choice to synthesize heteroleptic ferrocenes of type 37 although we would need to solve the problem concerning their isolation. Attempts at purification by column chromatography failed since the afforded products always coeluted with unreacted cyclopentadienes. An efficient synthesis of heteroleptic ferrocenes of type 37 would thus require the complete consumption of the employed cyclopentadienes like 14 or 24. Hence, we performed experiments to determine improved reaction conditions employing fluorene compound 40.

4.2.2.4 Optimizations of Reaction Conditions for the Synthesis of Heterolep- tic Ferrocenes Although we found in fluorene compound 40 the reagent of choice for the preparation of heteroleptic ferrocenes 37, we needed to adapt the protocol to our needs. The problem arose from the premature decomposition of compound 40 to ferrocene, fluorenyl anions and an ill defined iron(II) species (Scheme 4.26).[341]

53 Chapter 4

Base [FeII] Fe - Fe + + 2 2 PF6

Scheme 4.26: Decomposition of deprotonated compound 40.[341]

Release of ferrocene and fluorene from 40 under alkaline conditions was observed during our previous experiments and by the authors of the original protocol.[341] This implies that an excess of 40 is necessary in order to obtain a full conversion of ligands of type 35. To our delight, we determined that we could suppress this side reaction as we reacted reagent 40 and cyclopentadiene 25 with NaH in different solvents (Table 4.2). In doing so, we also simplified the original protocol where complex 40 and the cyclopentadienes were deprotonated in separate vessels with different bases.[341]

Table 4.2: Solvent screening qualitatively comparing the distribution of byproduct ferrocene and 49. The reported distributions correspond to the situation after 5 h reaction time.

OMe Mes 1) NaH (2.5 equiv.) CN CN r.t. OMe Fe + Fe 2) Mes Fe - PF6 25 49 40 (1.5 equiv.) solvent, temperature

Entry Solvent T /◦C 49:Ferrocenea 1 THF 70 62:38 2 MTBE 60 90:10 3 1,4-dioxane 60 96:4 a Ratio of product 49 and ferrocene as determined by uncalibrated GC-MS total ion currents.

The formation of ferrocene and product 49 was easily followed by removing aliquots at regular intervals from the reaction mixtures and analyzing them by GC-MS. In doing so, we implied that the ionization-efficiency of ferrocene and product 49 are of the same order. This can be assumed since both compounds are in principle closely related. Moreover, both species generate similar fragmentation patterns once ionized and we were only interested in a qualitative assessment.7 Interestingly, ligand 25 could not always be detected in the drawn samples which deprived us of the possibility to follow its consumption. No proper explanation was found for this behavior which we also observed in all the following experiments.

7Major ions, with respect to the base signal (100%), produced by EI with 75 eV of ferrocene are + + 186.0 ([FeCp2] , 100%), 120.9 ([FeCp] , 36%) and 55.9 (16%). The major ions generated from 49 are + + + 387.1 ([M] , 43%), 372.1 ([M CH3] , 100%) and 120.9 ([FeCp] , 30%)

54 Chapter 4

However, after 5 h the concentrations of the two metallocenes remained invariant and a crude comparison of the GC-MS-determined total ion currents of both species revealed a clear picture. With THF, the solvent used so far in the literature for this reaction type,[341, 345–348] a substantial amount of ferrocene was produced compared to target compound 49 (entry 1, Table 4.2). The extent of this side reaction was far less pronounced when the reaction was conducted in MTBE or 1,4-dioxane at slightly lower temperatures (entries 2 and 3, Table 4.2). In the following experiments we applied this analytical method as well but with an internal standard (cis-decalin) added to the reaction mixtures. The samples were analyzed by GC-MS and the total ion currents of the various compounds normalized with this reference. As we were only interested in relative formation rates of the products, this method was sufficiently accurate to obtain the necessary insights on the reaction demeanor. Pleased with the previous results, we decided to use 1,4-dioxane as solvent due to its high boiling point and continued with our investigations by determining an optimal reaction temperature. Hence, we monitored the reaction of compounds 40 and cyclopentadiene 25 at 70 ◦C and 100 ◦C in 1,4-dioxane over 5 h (Figure 4.3)

OMe 1.2 Product (100 °C) CN Ferrocene (100 °C) Product (70 °C) Mes Ferrocene (70 °C) 25 0.9 1) NaH 2) (2.5 equiv.) Fe PF - r.t. 6 f e r

A 0.6 40 i (1.5 equiv.) A 1,4-dioxane 70 or 100 °C Mes 0.3 CN OMe + Fe Fe

49 50 100 150 200 250 300

t min

Figure 4.3: Monitoring the formation of 49 (blue) and ferrocene (red) at 70 ◦C (circles) and 100 ◦C (diamonds). Aliquots were analyzed by GC-MS and the displayed total ion currents were normalized towards an internal standard (cis-decalin).

The rates of formation of ferrocene were nearly equal at both temperatures while the production of target compound 49 increased nearly four times by raising the temperature from 70 ◦C to 100 ◦C. In this case, the concentrations of byproducts originating from the decomposition of 40 were affected by the productive consumption of the latter as it reacted withcy- clopentadiene 25. Before we continued with developing a protocol applicable to other cyclopentadienes of type 35, we investigated the unbiased decomposition of fluorene compound 40 to obtain an idea about its rate (Figure 4.4).

55 Chapter 4

0.8 Fluorene Ferrocene

0.7 Fe - 2 PF6 0.6

40 0.5 f e r

A 0.4 NaH i 1,4-dioxane A 100 °C 0.3

0.2

Fe + 2 0.1

0 50 100 150 200 250 300 350 400 450

t min

Figure 4.4: Monitoring the decomposition of compound 40 to ferrocene (red circles) and fluorene (green squares) at 100 ◦C. Aliquots were analyzed by GC-MS and the displayed total ion currents were normalized towards an internal standard (cis-decalin). The outlier at 120 min is considered a sampling error.

56 Chapter 4

Treatment of compound 40 with NaH at 100 ◦C resulted in a complete decomposition of the complex to ferrocene and fluorene within 3.5 h. Absence of the characteristic deep blue coloration of alkaline solutions of 40 corroborated this observation further. Since this time frame is on the order of magnitude required to perform productive reactions yielding heteroleptic ferrocenes 37, we established a final protocol where complex 40 is added in portions. Such a procedure would minimize the required amount of this reagent and limit the contamination of the final mixture by its decomposition products. Thus, we treated ligand 25 under the above elucidated optimal conditions while adding 40 in intervals (Figure 4.5).

OMe 2.4 Product CN Ferrocene 2.1 Mes 25 1.8 1) NaH 2) (3 equiv.) Fe PF - 1.5 r.t. 6 f

e + 1 equiv. + 1.5 equiv. + 0.5 equiv. r

A 1.2 40 i (3 equiv.) A 1,4-dioxane 0.9 100 °C Mes 0.6 CN OMe + 0.3 Fe Fe

49 0 2 4 6 8 10 12 14 16 18 20 22 24 26

t h

Figure 4.5: Monitoring the formation of target compound 49 (blue circles) accompanied by decomposition product ferrocene (red diamonds) under optimized conditions. Reagent 40 was added in three portions (vertical dashed lines). Aliquots were analyzed by GC-MS and the displayed total ion currents were normalized towards an internal standard (cis-decalin).

After the usual deprotonation of ligand 25, we added 1.0 equivalent of 40 which was consumed within 5 h. Further reagent 40 (1.5 equivalent) was added to ensure a complete consumption of ligand 25. Although the concentrations stabilized within the following hour, we monitored the reaction for a total of 20 h. After this time we were not able to detect any increment in product formation although the precision of the measurements became greatly reduced. To ensure that all of cyclopentadiene 25 had been coordinated, we added a further small amount of 40 (0.5 equivalent). However, at this point the analytical precision was degraded to a degree which rendered interpretation difficult. We assume that these fluctuations of the measurements originate from the increasing ionic strength in the mixture, especially considering the iron(II) species which are released from the decomposition of reagent 40. To protect the GC-MS from wearing, aliquots were absorbed on compressed cotton and eluted with a 4:1 EtOAc/MeOH solution. Normally a black solid remained on the cotton which, most likely, could have contained amounts of lewis-basic cyanoferrocene 49. Nevertheless, after work-up of the mixture we were pleased to find that all of cyclopentadiene 25 had been consumed and we isolated the target compound in good 74 %

57 Chapter 4 yield. Yet, a somewhat embarrassing mistake concerning our execution of the above described reaction has to be brought to the attention of the reader. After we conducted the reaction, we bitterly realized that the employed amount of base (3 equivalent) would in theory not suffice to deprotonate both the cyclopentadiene and reagent 40. In short, we missed adding one equivalent of NaH. Still, we observed for the first time a complete conversion of one of our polysubstituted cyclopentadienes and thus reasoned that maybe this last equivalent was not really required. Closer inspection of the steadily increasing concentration of ferrocene originating from the decomposition of complex 40, brought us to believe that the mixture remained quite alkaline throughout the reaction. This assumption is further supported by the fact that the metathesis between complex 40 and cyclopentadienyls 35 liberates a fluorenyl anion (Figure 4.6).

Fe - PF6

40 NaH

NaPF6 + H2

R2 Na CN NaPF6 +

R 35 1

R2 CN 1 Na R Fe - Fe PF6

37 40

Figure 4.6: Proposed general mechanism for the recycling of released fluorenyl anions deprotonating reagent 40.

The majority of reagent 40 is deprotonated, and thus activated, by NaH and the subsequent reaction with cyclopentadienyls 35 releases a fluorenyl anion. This in turn could deprotonate a further reagent compound 40 and thereby regenerate an active species which could reenter the productive cycle yielding heteroleptic ferrocenes 37.

58 Chapter 4

In any case, as a last measure towards establishing a general protocol for the synthesis of heteroleptic ferrocenes 37, we adapted the reaction time and amounts of fluorene 40 to be added while maintaining the amount of base used. With the insight of the previous experiment, we concluded that the second portion of reagent 40 could be added earlier on and a third one should not be required. We continued by applying this procedure also to the remaining cyclopentadienes of type 35 (Table 4.3).

Table 4.3: Reaction of prepared cyclopentadienes of type 35 with 40 under optimized conditions.

OMe R 1) NaH (3 equiv.) CN CN 1,4-dioxane, r.t. OMe Fe 2) R Fe - PF6

40 (2.5 equiv.) 1,4-dioxane, 100 °C

Entry Ligand (R) T /◦C Product Yield/%a 1 25 (Mes) 100 49 88 2 14 (Ph) 100 46 80 3 26 (Trip) 100 50 13 4 24 (Me) 100 47 decomposition 5c 24 (Me) 50 47 86b a Unless noted otherwise, isolated yields are reported. b Conversion with respect to cyclopentadiene determined by uncalibrated GC-MS c A third portion of 40 (0.5 equivalent) was added after 4 h and stirring continued for further 18 h

Fortunately, we obtained better results by adding reagent 40 in two portions, namely 1.0 equivalent at the beginning and 1.5 equivalent after 1 h. In this way, product 49 was obtained in superior 88 % yield (entry 1, Table 4.3). Phenyl substituted cyclopentadiene 14 behaved very similar to mesityl compound 25 (entry 2, Table 4.3). This was not the case for the very bulky substrate 26 which we collected in low 13 % yield (entry 3, Table 4.3). While we might explain this last result with steric demand, we cannot do so when considering the reaction of ligand 24 which decomposed under the same conditions (entry 4, Table 4.3). Lowering of the reaction temperature to 50 ◦C was beneficial but residual free ligand 24 prevented us from determining an isolated yield (entry 5, Table 4.3). This required feeding the reaction mixture with reagent 40 over 22 h which still didn’t result in a complete conversion of ligand 24. Not sure how to interpret this observation, we gained an idea as we monitored the reaction of tetrasubstituted cyanocyclopentadiene 22 with reagent 40 (Figure 4.7).

59 Chapter 4

CN Product 3 Ferrocene Ph Fluorene 22 2.5 1) NaH 2)

(3 equiv.) Fe - PF6 r.t. 2 f e 40 r A (3 equiv.) i 1.5 + 0.5 equiv. A 1,4-dioxane 100 °C 1 Ph CN + 1.5 equiv. + 1 equiv. + + 0.5 Fe Fe

0 51 0 60 120 180 240

t min

Figure 4.7: Monitoring the reaction yielding 51 (blue circles) with reagent 40 which decomposes to ferrocene (red diamonds) and fluorene (green squares). Reagent 40 was added in three portions (vertical dashed lines). Aliquots were analyzed by GC-MS and the displayed total ion currents were normalized towards an internal standard (cis-decalin.)

After addition of the first equivalent of reagent 40 to deprotonated 22, an accelerated formation of product 51 was observed compared to the one previously manifested with pentasubstituted ligand 25. In fact, the concentration of the latter became stable after 30 min which speaks for a faster reaction compared to when pentasubstituted cyclopentadienes were used. A second portion of compound 40 (1.5 equivalent) was added affecting the concentration of 51 which first increased and then steadily decreased. Similar can be said forthe concentration of fluorene which, while alimented by the decomposition of 40, was also decreasing. Addition of a third portion of reagent 40 (0.5 equivalent) did not change these trends. Clearly, a separate reaction pathway removed target compound 51 and the released fluorene from the mixture. We postulate this to be occurring by an addition of fluorenyl anions to cyanoferrocene 51, thus affording imine 52 (Scheme 4.27).

NH Ph Ph CN

Fe Fe

51 52

Scheme 4.27: Postulated formation of imine 52 by reaction of fluorenyl anions with nitrile 51

We invoke this side reaction also to explain the fate of methyl-substituted compound 47 (entries 4 and 5 Table 4.3), though we were never able to isolate compounds such as 52. This assumption is supported by the results we obtained as we successfully synthesized ferrocene 51 by reducing the amount of reagent 40 and adding it in a single portion to keep the reaction time short.

60 Chapter 4

Ph 1) NaH (3 equiv) CN CN 1,4-dioxane, r.t. Fe 2) Ph Fe - PF6 22 51 40 55% yield (1.5 equiv) 1,4-dioxane, 100 °C

Scheme 4.28: Synthesis of tetrasubstituted cyanoferrocene 51.

Purification of the crude product offered moderate 55 % yield of cyanoferrocene 51 which was then recrystallized affording large and beautiful, brick red needles. In the end, we were able to prepare substantial amounts of heteroleptic ferrocenes 37. Since these structures are new among metallocenes, we subjected them to an extensive solid and liquid state structural investigation.

4.2.2.5 Structural Considerations of Heteroleptic Cyanoferrocenes All prepared heteroleptic ferrocenes afforded crystals suited for X-ray diffraction. Since these compounds offered the first solid-state structures of ferrocenes containing botha carbonitrile and an alkoxide, we compared them with examples of cyanoferrocenes and of O-substituted ferrocenes, as was the case for the homoleptic ferrocene 41 (see page 49, see appendix on page 149 for data from the literature). In all cases, parameters of the cyano and methoxy group don’t vary significantly from those found in cyano- or alkoxyferrocenes. Concerning the latter, these are about 1.36 A˚ for the C(Cp)-O and 1.44 A˚ for the O-C(R) bond, respectively. For the cyano moiety the values are usually about 1.43 A˚ for the C(Cp)-CN and 1.14 A˚ for the C-N bond and the angle C(Cp)-C-N of the order of 179°. Furthermore, and except for the case concerning tetrasubstituted ferrocene 51, all pentasubstituted cyclopentadienes are located slightly closer to the iron core than the unsubstituted ones. In the following discussion the atom-labels have been adapted to permit an easier comparison between the structures. Beginning from the sterically least demanding compound 47, minor deviations from other alkoxy or cyano substituted ferrocenes are observed (Table 4.4).

61 Chapter 4

Table 4.4: ORTEP representation of compound 47. Hydrogens are omitted for clarity and thermal ellipsoids are set to 50 %. Cp and Cp’ denote the centroids generated by the carbon atoms of the unsubstituted and substituted ring, respectively.

Parameter Value (d/A,˚ ̸ /°) C1-C2 1.444(3) C2-C6 1.425(3) C6-N1 1.146(3) C1-O1 1.365(3) O1-C7 1.424(3) Cp’-Fe 1.644 Fe-Cp 1.663 C2-C6-N1 176.9(3) C1-O1-C7 117.3(2) Cp’-Fe-Cp 3.98 C2-C1-O1-C7 -41.0(3)

Concerning the methoxy group, the measured angle C1-O1-C7 of 117.3(2)° is somewhat larger than observed for most methoxy-substituted compounds (between 114.4° and 115.5°)[121, 124, 209, 212, 213] and resembles more the one of alkoxyferrocenes bearing residues larger than methyl (between 117.4 and 117.6°).[147, 148] While usually a coplanar arrangement of the O-CH3 bond and the cyclopentadienyl is observed, with torsions ranging between 2 and 29°, we measure a dihedral angle C2-C1-O1-C7 of 41.0(3)°. What is more evident is the distortion of ferrocene 47 which is most likely caused by the different steric demand of the ligands. This is manifested in a 3.98° angle between the two planes of the cyclopentadienyls. Average C-Fe distances amount to about 2.049 A˚ for the substituted and 2.057 A˚ for the unsubstituted ligand, respectively.

62 Chapter 4

Exchanging one methyl for a phenyl substituent affects primarily the tilting of the two rings around the iron core (Table 4.5, left). This distortion is lessened, if the methoxy substituent is absent (Table 4.5, right)

Table 4.5: ORTEP representation of compound 46 (left) and compound 51 (right). Hydrogens are omitted for clarity and thermal ellipsoids are set to 50 %. Cp and Cp’ denote the centroids generated by the carbon atoms of the unsubstituted and substituted ring, respectively.

Parameter (46) Value (d/A,˚ ̸ /°) Parameter (51) Value (d/A,˚ ̸ /°) C1-O1 1.370(5) C2-C6 1.434(2) O1-C7 1.436(6) C6-N1 1.141(2) C2-C6 1.422(7) Cp-Fe 1.638 C6-N1 1.145(7) Cp’-Fe 1.647 Cp-Fe 1.667 Cp’-Fe-Cp 0.82 Cp’-Fe 1.650 C2-C6-N1 177.9(2) Cp’-Fe-Cp 4.80 N1-C6-C2 176.9(5) C7-O1-C1 116.4(4) C2-C1-O1-C7 47.6(6)

In case of ferrocene 46, the two ligands are somewhat more twisted with 4.80° compared to the previous case (47). Furthermore, the substituted ligand displays average C-Fe distances of 2.052 A˚ while these are about 2.057 A˚ concerning the unsubstituted one. As mentioned, the distortion of tetrasubstituted metallocene 51 is more alleviated as it lacks the methoxy group. Indeed, the angle between the two cyclopentadienyls is reduced to 0.82° and the two ligands are located closer to the iron core (1.638 A˚ for the substituted and 1.647 A˚ for the unsubstituted ligand). In this case the mean C-Fe bond lengths amount to 2.041 A˚ and 2.040 A˚ considering the substituted and unsubstituted cyclopentadienyl, respectively.

63 Chapter 4

Ferrocenes 49 and 50 display a pronounced distortion of the structure due to the large substituents they contain (Table 4.6).

Table 4.6: ORTEP representation of 49 (left) and 50 (right). Hydrogens are omitted for clarity and thermal ellipsoids are set to 50 %. Cp and Cp’ denote the centroids generated by the carbon atoms of the unsubstituted and substituted ring, respectively.

Parameter (49) Value (d/A,˚ ̸ /°) Parameter (50) Value (d/A,˚ ̸ /°) C1-O1 1.362(2) C1-O1 1.360(3) O1-C7 1.422(3) O1-C7 1.408(4) C2-C6 1.424(2) C2-C6 1.398(4) C6-N1 1.145(2) C6-N1 1.135(4) Fe1-C1 2.045(1) Fe1-C1 2.034(3) Fe1-C2 2.036(1) Fe1-C2 2.054(3) Fe1-C3 2.074(2) Fe1-C3 2.090(3) Fe1-C4 2.060(1) Fe1-C4 2.056(3) Fe1-C5 2.053(1) Fe1-C5 2.036(3) Cp’-Fe1 1.652 Cp’-Fe1 1.656 Cp-Fe1 1.664 Cp-Fe1 1.668 Fe1-C16 3.723(2) Fe-C16 3.631(2) C1-O1-C7 117.4(1) C1-O1-C7 117.3(2) N1-C6-C2 178.7(2) N1-C6-C2 177.7(3) Cp’-Fe-Cp 8.39 C2-C1-O1-C7 -23.7(4) C2-C1-O1-C7 20.3(3) C2-C3-C10-C15 90.0(3) C2-C3-C10-C15 -113.6(2)

The mesityl and tri(isopropyl)phenyl substituents increase the angle between the two ligands around the iron core to 8.39° and 9.86°, respectively. An η5-hapticity of these cyclopentadienyls is still ensured since the C3-atoms are not exceedingly removed from the plane spanned by C1-C2-C4-C5 (0.017 A˚ in 49 and 0.020 A˚ for 50). While in the case of 53 the aryl is rotated out of the ligand-plane by 73.1(2)°, in compound 50 it is nearly perpendicular with a 90.0(3)° dihedral angle. Furthermore, the ipso-carbons of the aryl substituents are dislocated above the cyclopentadienyl plane by 0.468 A˚ in 49 and 0.424 A˚ in 50 respectively. In the liquid-state, further insights were gained by NMR analysis about the freedom of rotation of the aryl substituents. While for phenyl-containing 46 this motion is unrestricted at room temperature, this is not the case for the other two aryl substituted

64 Chapter 4 ferrocenes. This became evident during the NMR analysis of compound 49 (Figure 4.8).

1 OMe CN Fe 2 3

3 2

ppm0.5 7.07.5 6.57.0 6.06.5 5.56.0 5.05.5 4.55.0 4.04.5 3.54.0 3.03.5 2.53.0 2.02.5 1.52.0 1.01.5 0.51.0

1 Figure 4.8: 500 MHz H NMR spectrum of 49 in CDCl3 recorded at 298 K. The methyl groups of the aryl substituent were identified thanks to NOE interactions (green arrow).

In fact, all nuclei of the substituted ligand of ferrocene 49 resonate at unique frequencies which is likely caused by a hindered rotation of the mesityl residue. The identical picture is provided by compound 50 where even the rotations of the individual isopropyl groups are slow on the NMR time-scale (Figure 4.9).

1' 1 Ha O 2 and 2' Hb CN Fe 3 and 3' 1 and 1'

2 2' 3 Hc 3' 1.4 1.31.4 1.21.3 1.11.2 1.01.1 50

b Ha Hc H

5.62.9 2.91.75 1.801.0 1.751.80

ppm0.5 7.58.05.6 7.07.5 6.57.0 6.06.5 5.56.0 5.05.5 4.55.0 4.04.5 3.54.0 3.03.5 2.53.0 2.02.5 1.52.0 1.01.5 0.51.0

1 Figure 4.9: 500 MHz H NMR spectrum of 50 in CDCl3 recorded at 298 K. The methyl and methine groups of the aryl substituent were identified thanks to NOE interactions (green arrows).

With a complete characterization of these compounds, we were confident that we could track their fate during subsequent transformations.

65 Chapter 4

4.2.3 Investigations on the Reactivity of Heteroleptic Ferrocenes As described in the introduction, we saw the opportunity to extend the work on the 1,1’-disubstituted ferrocenes investigated by the Stˇ ˇepniˇcka and Long groups.[121, 126] More specifically we planned to deprotonate the unsubstituted cyclopentadienyl of heteroleptic ferrocenes 37 and subsequently react them with chloro phosphanes (Scheme 4.29).

R1 R1 R1 CN CN CN 2 OMe Base OMe ClPR 2 OMe Fe Fe Fe

R2 P rac-37 R2 rac-38

Scheme 4.29: Proposed introduction of a phosphane in the newly prepared heteroleptic ferrocenes 37.

To gain extensive insight into the reactivity of the previously described ferrocenes, we firstly investigated their behavior towards deprotonation only. This was attempted by treating the heteroleptic ferrocenes with organolithium bases and then quenching with sources of deuterons at low temperature (Table 4.7).

Table 4.7: Results of the reaction of ferrocenes 49 and 46 with organolithium bases.

1) R2Li NH(D) R1 R1 R1 CN additive R2 CN OMe THF, -78 °C OMe OMe Fe Fe Fe

2) CD3OD -78 °C - r.t. D 46, R1=Ph 54-59 not observed 49, R1=Mes

Entry Substrate Base (equiv.) Additive (equiv.) Imine product (R2) yield/%a 1 49 nBuLi (1.3) TMEDA (1.4) 54 (nBu) 21 2 46 nBuLi (1.3) TMEDA (1.4) 55 (nBu) 67 3 49 sBuLi (1.3) TMEDA (1.4) 56 (sBu) -b 4 46 sBuLi (1.3) TMEDA (1.4) 57 (sBu) 52 5 46 iPrLi (1.3) TMEDA (1.4) 58 (iPr) -b 6 49 tBuLi (2) none 59 (tBu) 66 a Conversion to imines with respect to cyanoferrocenes determined by uncalibrated GC-MS. b Imine and substrate species coeluted on GC-MS.

Initially, ferrocenes 49 and 46 were reacted with organolithium bases in combination with TMEDA (N,N,N′,N′-tetramethylethane-1,2-diamine). In each case, the addition products with the bases were observed i.e. the corresponding imines; a reaction also observed with other cyanoferrocenes (entries 1 through 5, Table 4.7).[119] Even when bulky 49 was treated with tBuLi we observed a clean addition of the organolithium reagent (entry 6, Table 4.7).

66 Chapter 4

However, the reactivity drastically changed as we turned to the use of Schlosser’s base (Scheme 4.30).

Mes 1) tBuLi, KOtBu (cat.) Mes CN CN THF, -78 °C OMe OMe Fe Fe D 2) CD3OD -78 °C - r.t.

49 67% yield 49-d

Scheme 4.30: Reaction of 49 with a mixture of tBuLi and KOtBu at low temperature and subsequent quenching with CD3OD.

Treatment of a solution of 49 at low temperature with 2 equivalent of tBuLi and catalytic amounts of KOtBu (0.125 equiv.) afforded a deep black solution. To assess if deprotonation of 49 was successful, CD3OD was added at low temperature regenerating the original red coloration of the mixture. While we determined by mass spectrometry that a deuteron had been incorporated, we were surprised to find this at the methyl group vicinal to the methoxy substituent (Figure 4.10).

1H NMR 13C{1H} NMR

1H NMR Starting material

13C{1H} NMR Starting material

Mes 49 H CN OMe H Fe H/D

49 and 49-d

13C{1H} NMR Product mixture 1H NMR Prooduct mixture

49 + 49-d

ppm1.95 2.40 2.352.40 2.302.35 ppm2.259.42.30 12.4 12.22.2012.42.25 12.012.2 2.1511.82.2012.0 11.611.8 2.102.1511.411.6 11.211.42.052.10 11.011.2 10.82.0011.02.05 10.610.8 1.9510.42.0010.6 10.210.4 10.010.2 9.810.0 9.69.8 9.49.6

Figure 4.10: 500 MHz 1H and 126 MHz 13C{1H} NMR resonances of the highlighted methyl group in 49 and 49-d.

The NMR spectra clearly revealed that a mixture of unreacted 49 and its deuterated congener 49-d had been obtained. The latter was produced in 67 % yield according to 1H NMR integration. Localization of the deuteron was assessed by comparison with chemical shifts of the original compound 49 which we elucidated using two dimensional NMR methods (see experimental on page 106 for a complete comparison). Also, the coupling constants 2 1 [351] JH,D of 1.85 Hz and J13C,D of 19.74 Hz are in the expected range for such moieties. To explain this behavior, we assume a directing effect of the methoxy group guiding the alkyl base towards the adjacent methyl which is then deprotonated. This one could perform similarly as in an o-lithiation which has also been observed with other alkoxyferrocenes.[191]

67 Chapter 4

4.3 Summary and Conclusion

We were able to show that polysubstituted cyclopentadienyls of type 35 react with iron(II) species affording corresponding ferrocenes (Scheme 4.31).

Fe - R R PF6 R1 CN CN R2 CN OMe FeBr 2 OMe 2 CN R Fe + Fe 40 Fe OMe R CN R2=OMe Base CN OMe R1 R Homoleptic Ferrocenes 35 Heteroleptic Ferrocenes Yields Yields 72% 41, R1=Ph 80% 46, R1=Ph, R2=OMe 51% 42, R1=Me 43% 47, R1=Me, R2=OMe 1:1 mixtures of 88% 49, R1=Mes, R2=OMe meso and rac 13% 50, R1=Trip, R2=OMe 55% 51, R1=Ph, R2=H

Scheme 4.31: Overview of prepared and characterized ferrocenes.

Ligands of type 35 were treated with iron(II) salts, yielding homoleptic metallocenes as a 1:1 mixture of meso- and rac-diastereomers. Heteroleptic variants were also successfully prepared as racemic mixtures using cyclopentadienyl iron(II) transfer reagents. We determined that fluorene complex 40 performed best in our case although we had to invest significant resources to find efficient reaction conditions. Depending onthe used base, solvent and reaction temperature, reagent 40 eventually yielded the desired heteroleptic ferrocenes in good to acceptable yields. Pentasubstituted cyclopentadienes bearing aryl substituents underwent cleaner reactions, except for the case where a tri(isopropyl)phenyl substituted substrate was used. While the isolated yield in this latter case was comparatively low, we were pleased with this result nonetheless given the extreme steric demand of this ligand. However, when less bulky ligands were treated with reagent 40, sluggish reactions were observed. In case of the smallest pentasubstituted cyclopentadiene 24 we obtained best results following the originally published protocol rather than under our optimized conditions. Likewise, tetrasubstituted cyanoferrocene 51 clearly degraded during its preparation. To explain these observations, we propose that the cyano group of these ferrocenes reacted with fluorenyl anions which were released during the reactions. Our endeavors were worthwhile since the major part of the prepared ferrocenes are among the first displaying an alkoxy and a cyano function in vicinal position. Hence, theywere characterized in the liquid- and solid-state, and their reactivity towards organolithium bases further investigated (Scheme 4.32).

NH Mes Mes Mes t CN CN Bu 1) tBuLi, KOtBu (cat.) OMe tBuLi OMe OMe Fe Fe Fe D 2) D+

59 49 49-d 67% yield

Scheme 4.32: Observed deprotonation of ferrocene 49 versus addition to the cyano group.

68 Chapter 4

Contrary to expectations that we could deprotonate the unsubstituted cyclopentadiene in ferrocene 49 with Schlosser’s base, we discovered after treatment with deuterons that the methyl group adjacent to the alkoxide had reacted. In all other cases, we observed clean additions of organolithium reagents to the cyano moiety, hence yielding the corresponding imines like 59.

4.4 Outlook

During our work we were required to adapt a published procedure to synthesize heteroleptic ferrocenes.[341] After having invested significant resources to accomplish this goal, we eventually established a protocol which performed very well when relatively bulky cyclopentadienyls were reacted. It would thus be interesting to widen the scope of this developed method by testing it with other ligands than those of this work. Concerning the prepared ferrocenes, a multitude of options are evident in view of further functionalizations. Especially the cyano group could serve as a versatile platform towards other functionalities. Hence, a variety of potential 1,2-disubstituted ferrocene-based ligands could be prepared in this manner and if additional stereocenters are introduced, even enantiopure forms should be accessible.

NH R 2

OMe Fe

NH R R R CN CN OMe OMe OMe Fe Fe Fe R2P

N R O OMe Fe

Scheme 4.33: Outlook on possible transformations of newly prepared heteroleptic ferrocenes.

Moreover, we discovered that the polysubstituted metallocenes can be deprotonated at the methyl adjacent to the methoxy group. This reaction clearly deserves to be further scrutinized, for example with respect to the structure of the afforded ferrocenyl anions. If these species can be obtained in a quantitative way, the option is presented to intercept these with electrophiles like chloro phosphanes and thus obtain potential bidentate ligands.

Chapter 5

General Conclusion and Outlook

5.1 Summary

The specific goal of this thesis was the synthesis of a pentasubstituted ligand 1 that we approached by devising synthetic plans which, however, were only tested with model substrates (Figure 5.1).

first generation second generation target compound model compound model compounds

PGO MeO

N NMe NMe Cy 2 2 PG R

1 2 13-H, R=H, 13-Me, R=Me 13-OMe, R=OMe

Figure 5.1: Target compound 1 and corresponding models designed to test the first2 ( ) and second generation (13) synthetic approaches.

The two strategies will be presented in the following in their adapted forms for the synthesis of the first generation (2) and second generation (13) models, respectively.

71 Chapter 5

5.1.1 First Generation Synthesis The key aspects of our first approach towards ligand 1 were the introduction of the aryl fragment in a trisubstituted cyclopentadiene via cross-coupling and the installation of the ethylamino moiety by condensation of a formamide. Subsequent treatment of the obtained fulvene with sources of methyl anions was supposed to afford model structure 2 (Scheme 5.1).

O O O PbO2 NaOH, H2O 1) LiAlH4 15% yield 2) HCl O 4 5 3 cross- coupling

MeO DMF MeO MeO MeLi Me2SO4 NMe2 NMe2

Scheme 5.1: Synthesis of cyclopentadiene 3 and envisaged further transformations towards ligand 2.

As we started by examining the synthetic sequence towards compound 2, we were immediately met with misfortune. Preparation of the basic cyclopentadiene scaffold 3 relied on a published procedure which we could only reproduce in part.[70] The oxidative coupling of 2-butanone proceeded very slowly and we managed to obtain an unsatisfying 15 % yield of the required diketone 4 after multiple attempts. Hence, we were only able to prepare a sufficient quantity of this starting material with significant effort. Nonetheless, we continued with the intramolecular aldol condensation of diketone 4 which afforded a mixture of cyclopentenones 5. Subsequent reduction and dehydration afforded trimethylcyclopentadiene 3 which readily underwent Diels-Alder dimerization. This latter unproductive reaction finally prevented us from isolating the pure monomer 3. In the end, we found these transformations not performing in our hands which led us to abandon this strategy before attempting to optimize the individual synthetic steps. Still, we were keen on investigating the cross coupling of cyclopentadienyl anions under Kumada conditions and for this reason, we prepared substituted cyclopentadiene 8 from commercially available dihydrojasmone. As a last set of experiments we reacted cyclopentadiene 8 with ethylmagnesium bromide and subsequently with nickel(II) phosphanes and chlorobenzene (Scheme 5.2).

1) EtMgBr, Et O, r.t. n-C5H11 2 n-C H n-C5H11 5 11 Et 2) Ni(II) cat., PhCl, r.t. Ph

8 9 not observed proposed based on mass spectrum

Scheme 5.2: Attempted cross coupling of dihydrojasmone derived cyclopentadiene 8 with chlorobenzene.

72 Chapter 5

However, after work-up we only detected unreacted starting materials, ethylbenzene and a new species which we postulate to be the result of a formal addition of C2H6 to substrate 8. We have no further data on substance 9 than what we had obtained from the EI-MS analysis. Further discouragement found us as we tried the same reaction of chlorobenzene with unsubstituted cyclopentadiene which left the starting materials unreacted. With these last results we discontinued the first generation approach in favor of an alternative one.

5.1.2 Second Generation Synthesis In a second instance we developed a more modular strategy for the preparation of the envisaged ligand class 1. This led us to formulate a synthesis towards variants of type 13 like 13-OMe (Scheme 5.3).

PhCHO O O O NaH O Piperidine MeCN CN HOAc CN MsOH CN OiPr CH2Cl2 Ph Ph 17 11 15 19

HC(OMe)3 1) NaBH4 1) AlMe3 H+ 2) H+ 2) H+

OMe OMe 1) HNMe 2 DIBAL CN CN 2) MeLi CHO CN NMe2 Ph Ph OMe Ph Ph 13-OMe 14 22 20

Scheme 5.3: Second generation approach towards target compound 1 applied on model compounds of type 13.

Our second approach relied on the early introduction of the aryl and nitrogen moieties. The synthesis started form isopropyl tiglate 17 which was readily converted on a 50 g-scale to β-oxo nitrile 11. The latter was subsequently reacted with benzaldehyde to afford diene 15 which underwent a clean Nazarov cyclization to the corresponding cyclopentenone 19. From this point on, three possibilities were available to obtain the base cyclopentadiene scaffold. The first one was the addition of nucleophiles to the carbonyl functionality followed by dehydration which however didn’t work in our hands. We were more fortunate with the reduction-dehydration sequence which allowed the isolation of tetrasubstituted cyclopentadiene 22. Furthermore, we were pleased to discover that cyclopentenone 19 could be O-alkylated under very mild conditions to pentasubstituted cyclopentadiene 14. Subsequently, the reduction of the cyano group was attempted but after several experiments with DIBAL, this transformation was not achieved. At this point we were on one hand discouraged, while on the other pleased that we had prepared a new class of functionalized cyclopentadienes like 14. Our interest, therefore, turned towards coordination compounds of these ligands but before doing so, we wanted to prove the versatility of this second generation approach. Therefore, we successfully created a small library of cyclopentadienes (Scheme 5.4).

73 Chapter 5

OMe OMe OMe OMe CN CN i CN CHO Pr

i Ph Pr iPr 24 14 25 26 30% 33% 31% 2%

Scheme 5.4: Library of cyclopentadienes obtained with the second generation approach and corresponding overall yields over 5 steps.

By varying the aldehyde used during the Knoevenagel stage of the synthesis, we were able to introduce bulky substituents like mesityl and tri(isopropyl)phenyl into the final scaffolds. Finally, we wanted to test the synthetic strategy against the synthesis ofa more complicated, chiral framework (Scheme 5.5, see appendix on page 129 for further details).

O O O OMe 1) NaO2Cl + HC(OMe)3, H H DMSO OMe CN CN or 2) H2SO4 Me SO , H+ MeOH Ph 2 4 Ph

Myrtenal 34 60

Scheme 5.5: Attempted synthesis of pinene-derived cyclopentadiene 60.

Starting from commercially available myrtenal, we prepared the corresponding ester via Pinnick oxidation and subsequent Fischer esterification. From there on we applied the second generation protocols which successfully led to the corresponding cyclopentenone 34. Disappointingly, we did not manage to perform the O-alkylation in this case, even when subjecting the starting material to vigorous conditions. Nonetheless, we eventually prepared a variety of unprecedented polysubstituted cyclopentadienes and continued with their conversion to corresponding ferrocenes.

5.1.3 Synthesis of Ferrocenes As a proof of concept, we initially prepared homoleptic metallocenes with ligands 24 and 14 (Scheme 5.6).

R R OMe 1) NaH CN CN CN THF, r.t. OMe OMe Fe + Fe OMe R CN 2) FeBr2 R CN OMe R

14, R=Ph rac-41, R=Ph meso-41, R=Ph 24, R=Me rac-42, R=Me meso-42, R=Me

Scheme 5.6: Synthesis of homoleptic ferrocenes using ligands 24 and 14.

Since the two faces of the ligands are enantiotopic, compounds 42 and 41 were obtained as mixtures of two diastereomers in a 1:1 ratio. These substances are to date the second example of ferrocenes containing a cyano and an oxygen substituent on the same

74 Chapter 5 cyclopentadiene; a fact which prompted us to investigate these compounds further. We continued with the synthesis of corresponding heteroleptic variants (Scheme 5.7).

Fe - Yields PF6 R1 R2 CN 80% 46, R1=Ph, R2=OMe R2 1 2 CN 40 43% 47, R =Me, R =OMe Fe 88% 49, R1=Mes, R2=OMe Base 13% 50, R1=Trip, R2=OMe 1 R 55% 51, R1=Ph, R2=H 35

Scheme 5.7: Synthesis of heteroleptic ferrocenes using ligands of type 35.

After having evaluated different cyclopentadienyl iron(II) transfer reagents, we determined that fluorene complex 40 was best suited for our work. However, optimization of the reaction conditions were required in order to obtain the desired target compounds efficiently. Thus we examined the behavior of the reaction towards different solvents, temperature, base, method of addition, and, in doing so, found good conditions for the synthesis of the target compounds. However, only sterically encumbered ligands performed best under these conditions while less bulky ones were degraded under the same circumstances. Our investigations led us to believe that in such cases the cyano group reacted with fluorenyl anions which are released during the synthesis. Nonetheless, we managed to obtain good quantities of ferrocenes 51 and 47 by adapting the elaborated conditions. With these heteroleptic ferrocenes in hand, we investigated their behavior towards organolithium reagents (Scheme 5.8).

NH R1 n s i R1 Mes BuLi, BuLi, PrLi CN CN R TMEDA 1) tBuLi, KOtBu OMe OMe OMe Fe Fe Fe D or 2) D+ t BuLi R1=Mes R1=Mes, Ph 49-d

Scheme 5.8: Reactions of heteroleptic ferrocenes with organolithium bases.

Treatment of aryl substituted metallocenes 46 and 49 with a number of lithiated bases in combination with TMEDA led to the alkylation of the cyano group. However, we discovered via deuteron-quenching, that Schlosser’s base deprotonated selectively the methyl group adjacent to the methoxy substituent. These were the last experiments conducted in this work.

75 Chapter 5

5.2 Outlook and Concluding Remarks

The original goal of this thesis was the synthesis of a new class of polysubstituted cyclopentadienes which was not achieved. Especially considering the first generation approach we were discouraged as we were not able to reproduce the published procedures despite significant efforts towards this end. Though not being successful, our initial experiments proved useful in terms of the lessons learned during these mishaps. This doesn’t mean that an eventual revision of the first generation approach would be in vain. We are of the opinion that the synthetic sequence leading up to the basic trimethylcyclopentadiene could be improved by modifying the published protocols. This would allow to devote resources to accomplish and investigate the subsequent envisaged cross-coupling reactions of this substrate.

However, we were more keen on developing an alternative pathway towards the original target structures and to say that the formulation of the second generation approach was biased by our previous experiences, is an understatement. The design of the latter was shaped by our wish and need for efficient and reproducible reactions which would afford stable intermediates. Furthermore, we wanted to be able to alter inamodular fashion any of the five cyclopentadienyl substituents which would have allowed the facile preparation of ligand libraries.

These goals were eventually only partially met, as we were again not able to access our initially intended target ligands since the decisive reduction of the cyano function did not take place. We are however confident that under the appropriate conditions, this transformation is possible and it should thus only be a matter of few crucial experiments before a further step towards the main goal is completed.

Nevertheless, at this point we actually managed to synthesize a new class of functionalized, pentasubstituted cyclopentadienes. Our endeavors at installing these in corresponding ferrocenes proved fruitful and given the (basically) unprecedented nature of such metallocenes is more than enough motivation for further investigations. Several physical characteristics, like redox properties, still ought to be determined. More importantly, a number of new potential ferrocene-based ligands could be prepared by further transformations of the compounds presented herein.

Finally, the following quote by Ulrich Siemeling from a 1999 review on functionalized cyclopentadienes,[352] accurately reflects, in the author’s opinion, our motivations and endeavors which led us from rocky beginnings to the brink of new and exciting prospects: ”For the task of “teaching an old dog new tricks” a different and more flexible concept is needed which is based on the interplay of several constituent ligand components. Ligand functionalization is the key here. The introduction of functional groups can give rise to fascinating emergent properties.”

76 Chapter 6

Experimental

6.1 General remarks

6.1.1 Techniques Small scale (up to 0.25 L total liquid volume) moisture and/or air-sensitive reactions were carried out in an Ar atmosphere using standard Schlenk techniques. In case of air and moisture sensitive, larger scale reactions (more than 0.25 L total liquid volume), the reactor was equipped with a three-way gas inlet leading to a bubbler filled with paraffin oil as exhaust and constantly purged with 50 mbar of N2. In the case of only moisture sensitive large scale reactions, the reactor was equipped with a bent drying-tube filled ◦ with CaCl2 pellets. Glassware was either heated in an oven at 140 C for at least 12 h, with a heat gun for several minutes under dynamic high vacuum or with a butane flame under dynamic high vacuum.

Solvents for air and moisture sensitive reactions were distilled under Ar using an appropriate drying agent (toluene from Na, hexane from Na/benzophenone/tetraglyme, pentane from Na/benzophenone/diglyme, MeOH, CH2Cl2 and MeCN from CaH2, EtOH from [353] Na/diethyl phthalate, Et2O and THF from Na/benzophenone) or were purchased from Acros as bottled solvent over molecular sieves (3 A˚ for MeOH and MeCN, else 4 A˚).[354] For large scale reactions, reagent grade solvents were used which were then stored over molecular sieves once opened. Thin layer chromatography and column chromatography were performed with technical grade solvents.

Deuterated solvents were purchased from Armar Chemicals (CDCl3, CO(CD3)2) or Cambridge Isotope Laboratories (CD2Cl2, CD3CN, C6D6, CD3OD). The solvents were used as received or distilled (from CaH2 for CD2Cl2 or CaSO4 else), degassed by several freeze-pump-thaw cycles and stored in a Young Schlenk over the appropriate molecular sieves under an Ar atmosphere.

6.1.2 Chemicals Chemicals were purchased from abcr, Acros, Apollo Scientific, Fluka, Fluorochem, Lancaster, Sigma-Aldrich, Strem, TCI and VWR and used without further purification unless noted otherwise. TMEDA and piperidine were distilled from KOH under Ar.[353]

77 Experimental

6.1.3 Analytics Thin layer chromatography (TLC) was performed on Merck TLC Silica Gel F254 glass plates visualized by fluorescence quenching under UV light at 254 nm and/or 366 nm, KMnO4 or vanillin/H2SO4 staining.

Column chromatography was performed on Fluka Silica gel 60 (230-400 mesh ASTM) with solvents reproted as volume ratios. The eluent flow was forced by 0.1-0.3 bar overpressure.[355]

Gas chromatography-mass spectrometry (GC-MS) used for monitoring reactions was performed on an Agilent GC 7890A with an HP-5MS column (30 m x 250 µm x 0.25 µm), with a column flow of 1.7 mL min−1 using He as carrier gas, and an Agilent mass spectrometer 5975C VL MSD operating in EI positive mode. Sample injection was done by an Agilent autosampler ALS 7693, 1 µL at ≤ 1 mg mL−1 split mode (split ratio 100:1). The standard method used consisted of the following temperature program: 2 min at 50 ◦C, ramp of 20 ◦C min−1 to 300 ◦C and holding at the same temperature for 2 min. For less volatile substances the following temperature program was used: 2 min at 50 ◦C, ramp of 20 ◦C min−1 to 300 ◦C and holding at the same temperature for 8 min.

High resolution mass spectrometry (HRMS) was performed by the Mass Spectrom- etry Service Lab in the Laboratory of Organic Chemistry at ETH Zurich. The signals are given as mass-to-charge ratio (m/z). Ions from EI sources were measured with a Waters Micromass AutoSpec Ultima EI-Sector-MS, form ESI sources with a Bruker maXis Qq-TOF-MS or a solariX FTICR-MS, or from MALDI sources with a Bruker UltraFlex II MALDI-TOF-MS or a solariX FTICR-MS.

Melting points (M.P.) were measured on a Buchi¨ B-450 in an open capillary and are uncorrected.

For structure elucidation by X-ray diffraction, intensity data for single crystals mounted on MiTeGen MicroLoops were collected. The crystals were cooled to 100 K for mea- surement and the diffraction pattern was collected by a Bruker SMART APEX, APEXII platform with CCD detector or Venture D8. Graphite monochromated Mo-Kα-radiation (λ=0.71073 A)˚ was applied. The program SMART was used for data collection, integration was performed with SAINT.[356] The structures were solved by direct or heavy atom (Patterson) method, respectively, or by charge flipping, using the program SHELXS- 97.[357] The refinement and all further calculations were carried out using SHELXL-97.[358] All non-hydrogen atoms were refined anisotropically using weighted full-matrix least- squares on F2. The hydrogen atoms were included in calculated positions and treated as riding atoms using the SHELXL default parameters. An absorption correction was applied (SADABS)[359] and the weighting scheme was optimized in the final refinement cycles. The absolute configuration of chiral compounds was determined on the basisof the Flack parameter.[360][361] The standard uncertainties (s.u.) are rounded according to the “Notes for Authors” of Acta Crystallographica.[362] Detailed information about the crystal structures and their solutions is given in appendix E. All measurements and solutions were performed by Mona Wagner or Lukas Sigrist. The reader is supplied with the Cartesian coordinates of the herein presented structures. To obtain a basic digital model, the coordinates can be copied into a basic text file with the extension .xyz. This file can than be opened with any program suited for displaying crystal structures.

78 Experimental

Nuclear magnetic resonance (NMR) spectra were recorded on a Bruker DPX-250, Avance Nanobay III-300, Avance III-400 and Avance III-500. All spectra were recorded at room temperature in the given solvent at the given frequency in non-spinning mode. Chemical shifts (δ) are given in ppm relative to the residual solvent signal in 1H and 13C 19 31 spectra. F spectra were externally referenced towards CFCl3 and P spectra to 85% H3PO4. Multiplicities are abbreviated as follows: s for singlet, d for doublet, t for triplet, q for quartet, quint for quintet, sext for sextet, sept for septet, and m for multiplet. The description br describes an obvious broadening of the signal. Coupling constants (J) are given in Hertz (Hz). Unresolved frequencies are cited as multiplets. Signal assignments were determined by standard 2D-spectroscopy (COSY, HSQC, HMBC, NOESY). No assignment was made if the resolution of the signals was insufficient.

6.2 Syntheses

6.2.1 First Approach 3,4-Dimethylhexane-2,5-dione (4). [70] Method A: PbO2 (23.9 g, 0.1 mol, 1 equiv.) was suspended in 2-butanone (62 mL, 0.7 mol, 7 equiv.) and the ◦ resulting mixture heated for 7 h at 90 C. After cooling to O room temperature, the solids were removed via filtration of the mixture over celite and the filtrate concentrated in vacuo. A tiny amount of a yellow oil remained which was discarded O due to the unsatisfying performance of the reaction (below 5 % yield).

Method B:[74] In an oven dried round bottom flask equipped with a soxhlet extractor with a cellulose cartridge filled with a homogeneous mixture of PbO2 (152.2 g, 0.64 mol, 1 equiv.) and sand (40 g), 2-butanone (400 mL, 4.47 mol, 7 equiv.) was heated under a positive Ar-pressure for 20 h at 120 ◦C. After cooling to r.t., unreacted 2-butanone was removed under reduced pressure at 15 mbar and 30 ◦C bath temperature. The pressure was further lowered to 1.4 mbar and the bath temperature increased to 35 ◦C which allowed the target compound to distill with a vapor temperature of 32 to 35 ◦C. This protocol yielded 13.5 g (95.2 mmol, 15 %) of the title product (yellow liquid) as a a mixture of meso- and rac-diastereomers in satisfying purity.

Method C:[77] In a flame dried Schlenk tube, 2-butanone (4.5 mL, 50 mmol, 1.0 equiv.) was added dropwise at r.t. to a suspension of a NaH dispersion in mineral oil (60 %, 2.4 g, 60 mmol, 1.2 equiv.) in THF (50 mL) and the resulting mixture stirred for 1 h at the same temperature. In a separate Schlenk tube, FeCl3 (8.9 g, 55 mmol, 1.1 equiv.) was dissolved at r.t. in DMF (50 mL)(exothermic!). The mixture containing the enolate was cooled ◦ to −78 C and to this was added the FeCl3 solution dropwise. After completion of the addition, the solution was allowed to warm to r.t. and stirred at the same temperature for 14 h. The mixture was treated with an aqueous HCl solution (1 M, 150 mL) and the aqueous mixture extracted with pentane (3 x 100 mL). The organic layer was washed with an aqueous HCl solution (1 M, 50 mL), H2O(50 mL) and brine (50 mL), dried over

79 Experimental

MgSO4 and concentrated in vacuo. GC-MS analysis displayed many impurities and the product was thus discarded. 1 H NMR (300 MHz, CDCl3): δ (ppm) = 2.88–2.77 (m, 4 H, both diastereomers), 2.16 (s, 6 H, rac), 2.17 (s, 6 H, meso), 1.08–1.06 (m, 12 H, both diastereomers); 13C NMR (75 MHz, CDCl3): δ (ppm) = 212.3 (1 C), 211.3 (1 C), 49.0 (1 C), 48.6 (1 C), 29.5 (1 C), 28.9 (1 C), 15.1 (1 C), 13.9 (1 C). GC-MS (EI, m/z ) = exact mass calculated for + C8H14O2 ([M] ) 142.1, found 142.1.

Trimethylcyclopentenones (5).[70] To a solution of NaOH (0.95 g, 23.8 mmol, 0.25 equiv.) in H2O(120 mL) boiling at 100 ◦C was added diketone 4 (13.54 g, O O O 95.22 mmol, 1.00 equiv.) in one portion. The formed emulsion was stirred vigorously at the same temperature for 15 min and then cooled to r.t. with the help of an ice- water bath. The mixture was extracted with Et2O (3 x 100 mL) and the combined organic layers washed with H2O(150 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by distillation at 14 mbar and 80 ◦C bath temperature (vapor temperature of product was between 63 and 67 ◦C). In this manner, 9.47 g (76.22 mmol, 80 %) of the title compounds were collected as a colorless liquid as a mixture of isomers. GC-MS resolved four compounds (retention times 6.46 min, 6.89 min, 6.95 min, 7.28 min all bearing the expected m/z of 124.1 for C8H12O) which we attribute to be related by the position of the double bond. The compounds were not further analyzed and used directly for the next step.

Trimethylcyclopentenols (6).[70] To a suspension of LiAlH4 (3.18 g, 83.8 mmol, 1.1 equiv.) in Et2O(80 mL) cooled to 0 ◦C was added a solution of OH OH OH 5 (9.47 g, 76.22 mmol, 1.0 equiv.) in Et2O (20 mL) dropwise over 10 min. The suspension was allowed to warm to r.t.and then stirred for 16 h at the same temperature. The reaction was quenched by the slow addition of Et2O, which was previously shaken with H2O, until a white suspension manifested (about 50 mL). The suspension was filtered, the solid washed with Et2O (3 x 15 mL) and the collected organic phases washed with H2O(100 mL), dried over MgSO4 and concentrated in vacuo. The title compounds were collected as a colorless liquid containing several isomers. GC-MS resolved six compounds (retention times 5.67 min, 5.81 min, 6.01 min, 6.04 min, 6.13 min and 6.35 min all bearing the expected m/z of 126.1 for C8H14O). These compounds were not further analyzed and used directly for the successive transformation.

80 Experimental

1,2,3-Trimethylcyclopenta-1,3-diene (3).[70] A solution containing alcohols 6 in Et2O(50 mL) was added over 1.5 h at r.t. to a mixture of Et2O (50 mL) and an aqueous HCl solution (conc., 0.5 mL). The mixture was then stirred for 6 h at r.t., washed with brine (100 mL) and the organic phase concentrated in vacuo without heating (tempering with water bath at 20 ◦C). GC-MS displayed a full conversion of the starting material to a species bearing the expected mass (m/z 108.1) but also the corresponding dimer of 3 (m/z 216.2, retention times 4.67 min and 9.98 min respectively).

6.2.1.1 Kumada Coupling Experiments 1-Methyl-2-pentylcyclopentadienes (8). Commercially available dihydrojasmone (11.64 g, 70 mmol, 1.0 equiv.) was added to a suspension of LiAlH4 (2.92 g, ◦ 77 mmol, 1.1 equiv.) in Et2O (100 mL) at 0 C over 10 n-C5H11 min. The afforded mixture was allowed to warm to r.t. and then stirred for 17 h. Unreacted LiAlH4 was quenched by the slow addition of Et2O, which was previously shaken with H2O, until a white precipitate was given. The suspension was filtered, the solid washed with Et2O, the filtrate washed with H2O (100 mL), dried over MgSO4 and concentrated in vacuo. The afforded alcohols were used directly for the next step and thus dissolved in Et2O at r.t. An aqueous solution of HCl (conc., 1 mL) was added at the same temperature. The mixture was stirred for 30 min before brine (100 mL) was added. The phases were separated, the organic layer dried over MgSO4 and concentrated in vacuo. This procedure afforded a multitude of isomers of the title compound as determined by GC-MS (retention times 7.12 min, 7.27 min, 7.64 min all bearing the expected m/z of 150.1) IR (neat, ν/˜ cm−1) = 2956, 2925, 2872, 2855, 1454, 1378, 1022, 959, 914, 901, 841, 745, 685.

General procedure for Kumada couplings

With jasmone-derived cyclopentadiene (8): A solution of substrate 8 (1 equiv.) in Et2O (0.5 M) was treated with an EtMgBr solution in Et2O (3 M, 1.05 equiv.) at r.t. and then stirred for 1 h. In separate flasks, the nickel catalysts ([Ni(dppp)Cl2], [Ni(dppe)Cl2] or [Ni(PPh3)2Cl2], 0.02 equiv.) were suspended at r.t. in Et2O to afford a 10 mM mixture. An aliquot containing 2.15 mmol of 8 was transferred to the suspended nickel catalysts at r.t. and the mixtures subsequently treated with chlorobenzene (2.58 mmol). The mixtures were stirred for 19 h at r.t. and then quenched by the addition of an aqueous NH4Cl solution (sat., 5 mL). The aqueous layer was extracted with MTBE and the organic layers dried over MgSO4 and concentrated in vacuo. The crude mixtures were subsequently analyzed by GC-MS. In all cases only starting materials, ethylbenzene and a new species with a m/z of 180.1 was detected (see page 16 for a detailed interpretation).

With unsubstituted cyclopentadiene: Cyclopentadiene (2.95 mL, 35 mmol, 1.0 equiv.) was dissolved in Et2O (25 mL) at r.t. To this mixture, a solution of EtMgBr in Et2O (3 M, 12.25 mL, 36.75 mmol, 1.05 equiv.) was added dropwise and the resulting

81 Experimental

◦ suspension then heated to 50 C for 4 h. The mixture was cooled to r.t. and [Ni(dppp)Cl2] (190 mg, 0.35 mmol, 0.01 equiv.) was added in one portion followed by chlorobenzene (3.92 mL, 38.5 mmol, 1.1 equiv.). After stirring for 24 h at r.t., an aqueous solution of NH4Cl (3.5 M, 30 mL) was added, the phases separated and the organic phase extracted with MTBE (50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. GC-MS analysis of the crude product displayed copious amounts of unreacted chlorobenzene and traces of dicyclopentadiene and ethylbenzene.

6.2.2 Second Approach 6.2.2.1 Syntheses of Starting Materials Ethyl tiglate or Ethyl (E)-2-methylbut-2-enoate (16). In an oven-dried round bottom flask equipped with a Dean- Stark trap and a CaCl2 tube, tiglic acid (47.3 g, 0.47 mol, 1.00 equiv.) was dissolved at r.t. in EtOH (47 mL, 0.82 mol, O 1.75 mol) and benzene (100 mL). At the same temperature 5 2 7 pTsOH · H2O(2.6 g, 14.1 mol, 0.03 equiv.) was added and 1 O 6 the resulting mixture heated to 90-100 ◦C for 18 h until the 3 entrainment of H2O had ceased. The solvent was removed 4 in vacuo and the crude product purified by eluting it over a SiO2 plug with pentane to afford 50.6 g (0.39 mol, 84 %) of the title compound as a colorless to yellow liquid with an apple-like scent containing small amounts of benzene. 1 Rf (SiO2, Hexane/EtOAc 4:1) = 0.73; H NMR (500 MHz, CDCl3): δ (ppm) = 6.85 (qq, J = 7.1, 1.5 Hz, 1 H, H-C(3)), 4.18 (q, J = 7.1 Hz, 2 H, H-C(6)), 1.83 (quint, J = 1.2 Hz, 3 H, H-C(4)), 1.78 (dq, J = 7.1, 1.1 Hz, 3 H, H-C(5)), 1.29 (t, J = 7.1 Hz, 13 1 3 H, H-C(7)); C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 168.3 (1 C, C(1)), 137.0 (1 C, C(3)), 128.9 (1 C, C(2)), 60.5 (1 C, C(6)), 14.4 (2 C, C(4), C(7)), 12.2 (1 C, C(5)); IR (neat, ν/˜ cm−1) = 2982, 2933, 1707, 1652, 1445, 1381, 1367, 1342, 1254, 1134, 1076, + + 1040, 733; HRMS (EI, m/z ) = exact mass calculated for C7H12O2 ([M] ) 128.0837, found 128.0828.

Isopropyl tiglate or Isopropyl (E)-2-methylbut-2-enoate (17). In an oven dried two-neck round bottom flask equipped with a Dean-Stark trap and a CaCl2 tube, tiglic acid (100 g, 1 mol, 1.0 equiv.) was dissolved at r.t. in isopropanol (230 mL, O 7 3 mol, 3 equiv.) and benzene (200 mL). At the same temper- 5 2 7 ature H2SO4 (10.6 mL, 0.2 mol, 0.2 equiv.) was added and 1 O 6 the resulting mixture was heated to 100 ◦C for 44 h until 3 the entrainment of H2O had ceased. The mixture was then 4 allowed to cool to r.t. and diluted with MTBE (300 mL), washed with H2O(500 mL), an aqueous NaHCO3 solution (0.6 M, 300 mL), again with H2O(300 mL) and then dried with brine (100 mL). The thus afforded solution was further dried over4 MgSO and the solvent removed in vacuo (down to 100 mbar at 40 ◦C). The crude product was purified by distillation at reduced pressure over a 30 cm Vigreux column. The bath temperature was set to 70 ◦C and the effective performance of the pump adjusted (using a tube clamp) such that the product maintained a vapor temperature of 39 to 42 ◦C. The first 5 mL were discarded and then the

82 Experimental following fraction collected. This procedure afforded 129.2 g (0.91 mol, 91 %) of the title compound as a colorless liquid with a peppermint-like scent containing negligible benzene contaminations. 1 Rf (SiO2, Hexane/EtOAc 4:1) = 0.75; H NMR (400 MHz): δ (ppm) = 6.82 (qq, J = 7.1, 1.4 Hz, 1J(H,C) = 157.0 Hz, 1 H, H-C(3)), 5.05 (sept, J = 6.3 Hz, 1J(H,C) = 141.5 Hz, 1 H, H-C(6)), 1.81 (quint, J = 1.3 Hz, 1J(H,C) = 127.7 Hz, 3 H, H-C(5)), 1.77 (dq, J = 7.1, 1.2 Hz, 1J(H,C) = 126.8 Hz, 3 H, H-C(4)), 1.25 (d, J = 6.3 Hz, 1 13 1 J(H,C) = 126.5 Hz, 6 H, H-C(7)); C{ H} NMR (101 MHz, CDCl3): δ (ppm) = 167.8 (1 C, C(1)), 136.6 (1 C, C(3)), 129.3 (1 C, C(2)), 67.6 (1 C, C(6)), 22.0 (2 C, C(7)), 14.4 (1 C, C(4)), 12.1 (1 C, C(5)); IR (neat, ν/˜ cm−1) = 2980, 2936, 2877, 1706, 1652, 1468, 1454, 1374, 1352, 1258, 1180, 1160, 1143, 1107, 1074, 734; HRMS (ESI, m/z ) + = exact mass calculated for C8H18NO2 ([M+NH4] + ) 160.1338, found 160.1331.

(E)-4-Methyl-3-oxohex-4-enenitrile (11). Method A:To a solution of MeCN (3.1 mL, 60 mmol, 1.2 equiv.) in THF (200 mmol) at −78 ◦C was added dropwise a solution of nBuLi in hexane (1.6 M, 37.5 mL, 60 mmol, O . . N 1 2 equiv ) over 15 min. The afforded red suspension was 7 2 ◦ 4 stirred at −78 C for 20 min. At the same temperature, a 3 1 solution of ethyl tiglate 16 (6.9 mL, 50 mmol, 1.0 equiv. ) in 5 THF (35 mL) was added dropwise over 25 min. The mixture 6 was then kept stirring at −78 ◦C. After 1 h, the mixture was allowed to warm to r.t. and stirred at the same temperature for 3 h. The reaction was quenched by the slow addition of an aqueous NH4Cl solution (3.5 M, 200 mL). The phases were separated and the aqueous layer extracted with MTBE (2 x 100 mL). The combined organic phases were washed with brine (100 mL) and dried −2 over MgSO4. The crude product was distilled under reduced pressure (p=10 mbar) at a bath temperature of 100 ◦C affording 3.45 g (28 mmol, 56 %) of the title compound as a colorless solid. This purification procedure could subsequently not always be reproduced

Method B: In a 1 L three-neck round bottom flask equipped with an addition funnel, a Dimroth condenser and a CaCl2 tube, a NaH dispersion in mineral oil (60 %, 28.9 g, 703 mmol, 2 equiv.) was washed at r.t. with hexane (3 x 40 mL). The washed NaH was then suspended at the same temperature in THF (370 mL) and MeCN (37 mL, 703 mmol, 2 equiv.). Afterwards, a solution of isopropyl tiglate (17)(50 g, 352 mmol, 1 equiv.) in THF (30 mL) was added over 10 min at r.t. via the addition funnel which was subsequently rinsed with further THF (20 mL). The afforded suspension was then heated to 70 ◦C for 2.5 h. After cooling to r.t. with the help of a water-bath, the mixture was treated with an aqueous NH4Cl solution (3.5 M, 600 mL) while still immersed in the water-bath (the mixture tends to solidify upon addition at first, but after further careful addition of the NH4Cl solution it turns quickly liquid again). The phases were separated, the aqueous phase extracted with MTBE (2 x 150 mL), the combined organic layers dried with brine (100 mL), further dried over MgSO4 and concentrated in vacuo. The thus afforded residue was emulsified by addition of hexane200 ( mL) at r.t. and concentrated again until no leftover solvent could be distilled at 40 ◦C and 100 mbar. The afforded orange oil was overlayered with pentane (200 mL) at r.t., then cooled to 0 ◦C and emulsified by rapid stirring. At the same temperature a small piece ofdryice was added to the mixture, which led the product to precipitate. The afforded solid was filtered and washed with pentane (3x 50 mL) affording 31.5 g (257 mmol, 73 %) of the

83 Experimental target compound as a yellow solid. The stated protocol affords the desired compound in a high enough purity to be used for further transformations. 1 Rf (SiO2, Hexane/EtOAc 4:1) = 0.26; H NMR (300 MHz, CDCl3): δ (ppm) = 6.72 (qq, J = 6.9, 1.3 Hz, 1 H, H-C(5)), 3.76 (s, 2 H, H-C(2)), 1.93 (dq, J = 6.9, 1.1 Hz, 3 13 1 H, H-C(7)), 1.82 (quint, J = 1.2 Hz, 3 H, H-C(5)); C{ H} NMR (101 MHz, CDCl3): δ (ppm) = 188.2 ,1 C ,C(3)), 141.4 ,1 C ,C(5)), 137.2 ,1 C ,C(4)), 114.5 ,1 C ,C(1)), 28.3 ,1 C ,C(2)), 15.3 ,1 C ,C(7)), 11.2 ,1 C ,C(6)); IR (neat, ν/˜ cm−1) = 2962, 2931, 2873, 2253, 1676, 1638, 1432, 1394, 1378, 1355, 1316, 1239, 1069, 1002, 960, 895, 815, 736, + + 650; HRMS (EI, m/z ) = exact mass calculated for C7H9NO ([M] ) 123.0684, found 123.0677.

2,4,6-Triisopropylbenzaldehyde (31).[112] 1,3,5-triisopropylbenzene (25.0 mL, 102.8 mmol, 1.0 equiv.) was placed in a dried 500 mL round-bottom flask equipped with a dropping funnel, a Dimroth condenser, a N2 bypass 9 8 and was dissolved in CH2Cl2 (300 mL). The mixture was O ◦ cooled over 10 min to 0 C. Then, TiCl4 (37.2 mL, 339.2 3 1 4 mmol, 3.3 equiv.) was added dropwise over 15 min at the 2 H same temperature, affording a dark red solution which was 7 5 6 stirred further for 15 min. Dichloromethoxymethane (18.6 mL, 205.6 mmol, 2.0 equiv.) was added dropwise over 30 min at 0 ◦C via the dropping funnel. The addition funnel was rinsed with CH2Cl2 (50 mL), the mixture allowed to warm to r.t. and kept stirring for 22 h. The mixture was poured into vigorously stirred ice-water (500 mL) and then stirred for further 10 min. The layers were separated and the aqueous phase extracted with CH2Cl2 (3 x 100 mL). Some crystals of hydroquinone were added to the combined organic layers (to retard oxidation of the aldehyde) which were then dried over MgSO4 and concentrated in vacuo. The crude product was purified by vacuum distillation at 2-4 mbar (bath temperature 115-120 ◦C, vapor temperature 85-90 ◦C) affording 21.8 g (93.8 mmol, 91 %) of the title compound as a yellow liquid which was kept under inert atmosphere and stored at −20 ◦C. 1 H NMR (500 MHz, CDCl3): δ (ppm) = 10.70 (s, 1 H, H-C(1)), 7.16 (s, 2 H, H-C(4)), 3.65 (sept, J = 6.8 Hz, 2 H, H-C(8)), 2.96 (sept, J = 6.9 Hz, 1 H, H-C(6)), 1.30 (d, J = 6.9 Hz, 12 H, H-C(9)), 1.29 (d, J = 6.9 Hz, 6 H, H-C(7)); 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) = 195.1 (1 C, C(1)), 153.7 (1 C, C(5)), 150.5 (2 C, C(3)), 130.3 (1 C, C(2)), 121.7 (2 C, C(4)), 34.8 (1 C, C(6)), 28.9 (2 C, C(8)), 24.3 (4 C, C(9)), 23.8 (2 C, C(7)). IR (neat,ν/ ˜ cm−1) = 2961, 2929, 2869, 1688, 1603, 1459, 879.

84 Experimental

6.2.2.2 Knoevenagel Condensations (E)-2-((E)-benzylidene)-4-methyl-3-oxohex-4-enenitrile (15). In an oven-dried round bottom flask equipped with a Dean- Stark trap, a Dimroth condenser and a CaCl2 tube, nitrile 11 (4.52 g, 36.7 mmol, 1.0 equiv.) was dissolved at O r.t. in benzene (150 mL). At the same temperature, ben- N 7 4 2 zaldehyde (3.73 mL, 36.7 mmol, 1.0 equiv.), HOAc (1.1 mL, 3 1 18.35 mmol, 0.5 equiv.) and piperidine (0.36 mL, 3.7 mmol, 10 5 8 9 0.1 equiv.) were sequentially added while stirring. The 6 11 mixture was heated to 100 ◦C and then stirred at this tem- 12 perature for 3.5 h until the entrainment of H2O had ceased. After cooling to r.t., the mixture was diluted with H2O (100 mL), the phases separated and the aqueous layer extracted with MTBE (2 x 150 mL). The organic layer was washed with an aqueous HCl solution (1 M, 2 x 100 mL), an aqueous NaHCO3 solution (sat., 2 x 100 mL) and with brine (100 mL). The solution was further dried over MgSO4 and then concentrated in vacuo. The crude product was purified by column chromatography (SiO2, hexane/MTBE 4:1) to afford. 5 85 g (27.68 mmol, 75 %) of the title compound as a yellow oil. 1 Rf (SiO2, Hexane/MTBE 4:1) = 0.50; H NMR (500 MHz, CDCl3): δ (ppm) = 7.98–7.95 (m, 2 H, H-C(10)), 7.87 (s, 1 H, H-C(8)), 7.56–7.48 (m, 3 H, H-C(11), H-C(12)), 6.82– 6.76 (m, 1 H, H-C(5)), 1.95–1.93 (m, 6 H, H-C(6), H-C(7)); 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) = 190.0 (1 C, C(3)), 153.7 (1 C, C(8)), 141.1 (1 C, C(5)), 136.3 (1 C, C(4)), 132.9 (1 C, C(12)), 132.2 (1 C, C(9)), 130.8 (2 C, C(10)), 129.3 (2 C, C(11)), 117.3 (1 C, C(2)), 110.5 (1 C, C(1)), 15.0 (1 C, C(6)), 12.5 (1 C, C(7)); IR (neat, ν/˜ cm−1) = 3055, 3030, 2854, 2212, 1639, 1594, 1576, 1495, 1448, 1379, 1346, 1319, 1294, 1262, 1210, 1190, 1142, 1128, 1022, 752, 734, 686, 663; HRMS (ESI, m/z ) = + + exact mass calculated for C14H13NO ([M] ) 211.0997, found 211.0986.

5,6-Dimethyl-1-((E)-2-methylbut-2-enoyl)-4-oxo- 2-phenylcyclohexane-1,3-dicarbonitrile (18). This product was obtained from the reaction affording 15. After O 7 isolation of the the latter from the SiO2 column, a very polar 8 CN 1 compound was eluted with pure EtOAc. Crystals suitable 2 6 for X-ray diffraction were grown by overlayering2 aCH Cl2 3 5 12 4 11 solution with hexane and allowing it to evaporate at r.t., or 9 13 15 10 alternatively from evaporation of an EtOAc solution placed O CN 14 over H2O. 16 18

85 Experimental

1H NMR (400 MHz): δ (ppm) = 7.40–7.35 (m, 3 H, H-C(14), H-C(13)), 7.31–7.27 (p, 2 H, H-C(12)), 6.11–6.05 (m, 1 H, H-C(17)), 4.42 (dd, J = 13.7, 4 Hz, 1 H, H-C(6)), 3.75 (d, J = 13.7 Hz, 1 H, H-C(5)), 2.72 (dq, J = 12.6, 6.3 Hz, 1 H, H-C(2)), 2.50 (dq, J = 12.6, 6.3 Hz, 1 H, H-C(3)), 1.58 (dq, J = 6.9, 1.0 Hz, 3 H, H-C(19)), 1.51 (quint, J = 1.1 Hz, 3 H, H-C(18)), 1.22 (d, J = 6.4 Hz, 3 H, H-C(8)), 1.08 (d, J = 6.5 Hz, 3 H, 13 1 H-C(9)); C{ H} NMR (101 MHz, CDCl3): δ (ppm) = 197.7 (1 C, C(1)), 195.5 (1 C, C(15)), 140.2 (1 C, C(17)), 137.0 (1 C, C(16)), 133.9 (1 C, C(11)), 129.7 (1 C, C(14)), 129.5 (2 C, C(13)), 128.5 (2 C, C(12)),1 118.4 (1 C, C(10)), 113.9 (1 C, C(7)), 60.9 (1 C, C(4)), 53.1 (1 C, C(5)), 47.1 (1 C, C(3)), 46.7 (1 C, C(2)), 46.3 (1 C, C(6)), 16.1 (1 C, C(9)), 14.7 (1 C, C(19)), 12.6 (1 C, C(18)), 11.4 (1 C, C(8)); IR (neat, ν/˜ cm−1) = 3059, 3035, 2988, 2966, 2939, 2878, 2256, 2228, 1732, 1666, 1637, 1584, 1494, 1456, 1391, 1383, 1336, 1246, 1064, 912, 729, 703; HRMS (ESI, m/z ) = exact mass calculated for + + C21H22N2O2 ([M] ) 334.1681, found 334.1680.

(2E,4E)-2-ethylidene-4-methyl-3-oxohex-4-enenitrile (27). Nitrile 11 (1 g, 8 mmol, 1.0 equiv.) was dissolved at r.t. in CH2Cl2 (30 mL) and the resulting solution then cooled to ◦ −78 C. Separately, acetaldehyde was collected by conden- O sation at 0 ◦C in a graduated vessel and subsequently diluted N 7 4 2 with CH2Cl2 to afford a 6 M solution. From this solution 3 1 1.5 mL (containing 8.8 mmol, 1.1 equiv. of acetaldehyde) was ◦ 5 8 transferred to the solution of nitrile 11 at −78 C. At the 6 9 same temperature, TiCl4 (2.3 mL, 20.2 mmol, 2.5 equiv.) was added dropwise over 5 min yielding a dark red solution which was stirred further for 20 min. Still at −78 ◦C, pyridine (2.3 mL, 28.8 mmol, 3.6 equiv.) was added dropwise over 10 min (the mixture tends to solidify at a certain point during this addition, in which case further CH2Cl2 can be added (maximum 10 mL) to ensure efficient stirring and agglomerates can be broken up with a glassrod). After stirring for 2.5 h at −78 ◦C, the mixture was warmed up to r.t. (ca. 20 min) and then stirred further for 40 min. The mixture was then treated with an aqueous HCl solution (2 M, 100 mL) and the layers were separated. The aqueous phase was extracted with CH2Cl2 (50 mL) and the combined organic layers dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography 2(SiO , hexane/EtOAc 4:1) affording 0.77 g (5.1 mmol, 64 %) of the title compound as a yellow oil. 1 Rf (SiO2, hexane/EtOAc 4:1) = 0.35; H NMR (500 MHz, CDCl3): δ (ppm) = 7.32 (q, J = 7.1 Hz, 1 H, H-C(8)), 6.71 (qq, J = 6.9 Hz, 1 H, H-C(5)), 2.21 (d, J = 7.1 Hz, 3 H, H-C(9)), 1.91 (dq, J = 6.9, 1.1 Hz, 3 H, H-C(6)), 1.86 (quint, J = 1.2 Hz, 3 H, H-C(7)); 13 1 C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 188.9 (1 C, C(3)), 156.7 (1 C, C(8)), 141.3 (1 C, C(5)), 136.4 (1 C, C(4)), 117.8 (1 C, C(1)), 115.3 (1 C, C(2)), 18.0 (1 C, C(9)), 15.0 (1 C, C(6)), 12.2 (1 C, C(7)); IR (neat, ν/˜ cm−1) = 3054, 2979, 2923, 2855, 2227, 1648, 1639, 1617, 1438, 1377, 1348, 1272, 1179, 1101, 1085, 1015, 976, 962, 855, 734, + + 656; HRMS (EI, m/z ) = exact mass calculated for C8H8NO ([M CH3] ) 134.0606, found 134.0601.

1These resonances are manifested as a broad signal centered around the reported shift.

86 Experimental

(E)-4-methyl-3-oxo-2-((E)-2,4,6-trimethylbenzylidene)hex-4-enenitrile (29). In an oven-dried round-bottom flask equipped with a Dean-Stark trap, Dimroth-condenser and a CaCl2 tube, nitrile 11 (7.92 g, 64.3 mmol, 1.0 equiv.) was O dissolved at r.t. in benzene (65 mL). At the same N 7 4 2 temperature, mesitaldehyde (10 mL, 67.5 mmol, 3 1 10 1.0 equiv.), HOAc (0.7 mL, 12.86 mmol, 0.2 equiv.) 11 5 8 9 and piperidine (0.6 mL, 6.4 mmol, 0.1 equiv.) were 6 12 sequentially added while stirring. The mixture was 13 heated to 100 ◦C and stirred at this temperature for 14 1 h until the entrainment of H2O had ceased. After cooling to r.t., the mixture was diluted with H2O (200 mL) and MTBE (200 mL) and the phases subsequently separated. The organic layer was washed with an aqueous NaHSO3 solution (40 %, 3 x 50 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, hexane/EtOAc 9:1) to remove polar byproducts. To the con- centrate of the fractions containing the title compound, pentane (150 mL) was added which precipitated the product. The afforded yellow solid was filtered off and washed with pentane (3 x 50 mL). The mother liquor was then reduced to a volume of 100 mL and allowed to crystallize at -20 ◦C overnight. This second crop of crystals was filtered off as well and the retained solids washed with pentane (3x 15 mL). Combination of both crops amounted to 8.9 g (33.9 mmol, 53 %) of the title compound. 1 Rf (SiO2, Hexane/EtOAc 9:1) = 0.48; H NMR (500 MHz, CDCl3): δ (ppm) = 8.07 (s, 1 H, H-C(8)), 6.93 (s, 2 H, H-C(12)), 6.86–6.81 (m, 1 H, H-C(5)), 2.30 (s, 3 H, H-C(14)), 2.29 (s, 6 H, H-C(10)), 1.97–1.94 (m, 6 H, H-C(6), H-C(7)); 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) = 189.1 (1 C, C(3)), 156.2 (1 C, C(8)), 141.6 (1 C, C(5)), 139.8 (1 C, C(13)), 136.6 (1 C, C(4)), 136.0 (2 C, C(11)), 129.5 (1 C, C(9)), 129.0 (2 C, C(12)), 118.0 (1 C, C(1)), 116.1 (1 C, C(2)), 21.3 (1 C, C(14)), 20.5 (2 C, C(10)), 15.1 (1 C, C(6)), 12.3 (1 C, C(7)); IR (neat, ν/˜ cm−1) = 3051, 3024, 2968, 2915, 2854, 2211, 1655, 1636, 1607, 1445, 1373, 1343, 1266, 1138, 1029, 864, 855, 762; HRMS (EI, m/z ) = + + exact mass calculated for C17H19NO ([M] ) 253.1467, found 253.1468.

6.2.2.3 Nazarov Cyclizations General procedure for Nazarov cyclizations The corresponding dienes (1.0 equiv.) were dissolved at r.t. in CH2Cl2 to afford a 0.5 M solution. At the same temperature, MsOH (1.2 equiv.) was added dropwise and then the afforded orange solutions stirred further until reaction monitoring by TLC orGC-MS displayed a complete conversion of the starting material (on the order of 0.5-1.0 h). The mixture was then poured into ice-water, neutralized by the slow addition of an aqueous NaHCO3 solution (sat.) and vigorously stirred for 10 min. The phases were separated and the organic layer washed with brine, dried over MgSO4 and concentrated in vacuo.

87 Experimental

3,4-Dimethyl-2-oxo-5-phenylcy- clopent-3-ene-1-carbonitrile (19). O O The title compound was obtained from 7 diene 15 (16.17 g, 76.54 mmol) following 2 1 5 CN CN 6 the general procedure. The crude product 4 was purified by column chromatography 3 8 9 (SiO2, hexane/EtOAc 4:1) affording 11.86 g (56.17 mmol, 73 %) of the title 10 compound as a yellow oil. The d.r. was 11 12 determined by 1H NMR analysis and was constantly on the order 7:3 in favor of the trans cis trans diastereomer. −1 Rf (SiO2, hexane/EtOAC 4:1) = 0.26; IR (neat, ν/˜ cm ) = 3062, 3029, 2921, 2245, 1710, 1642, 1494, 1454, 1384, 1324, 760, 700, 640; HRMS (EI, m/z ) = exact mass + + 1 calculated for C14H13NO ([M] ) 211.0997, found 211.0986; cis-isomer: H NMR (400 MHz, CDCl3): δ (ppm) = 7.40–7.31 (m, 3 H, H-C(10/11/12), cis or trans), 7.13– 7.07 (m, 2 H, H-C(10/11/12), cis or trans), 4.17 (d, J = 7.4 Hz, 1 H, H-C(4)), 3.84 (d, J = 7.4 Hz, 1 H, H-C(5)), 1.91 (s, 3 H, H-C(7/8)), 1.88–1.85 (m, 3 H, H-C(7/8)); 13 C NMR (101 MHz, CDCl3): δ (ppm) = 197.5 (1 C, C(1)), 170.5 (1 C, C(3)), 136.3 (1 C, C(9)), 135.8 (1 C, C(2)), 129.6 (1–3 C, C(10/11/12), cis or trans), 129.3 (1–3 C, C(10/11/12), cis or trans), 128.7 (1–3 C, C(10/11/12), cis or trans), 128.5 (1–3 C, C(10/11/12), cis or trans), 128.3 (br, 1–3 C, C(10/11/12), cis or trans), 127.4 (1–3 C, C(10/11/12), cis or trans), 115.1 (1 C, C(6)), 51.7 (1 C, C(4)), 43.6 (1 C, C(5)), 16.1 (1 C, C(8)), 8.6 (1 C, C(7)); 1 trans-isomer: H NMR (400 MHz, CDCl3): δ (ppm) = 7.40–7.31 (m, 3 H, H-C(10/11/12), cis or trans), 7.13–7.07 (m, 2 H, H-C(10/11/12), cis or trans), 4.11–4.09 (m, 1 H, H- C(4)), 3.28 (d, J = 3.7 Hz, 1 H, H-C(5)), 1.88–1.85 (m, 6 H, H-C(7), H-C(8)); 13C NMR (101 MHz, CDCl3): δ (ppm) = 196.8 (1 C, C(1)), 170.8 (1 C, C(3)), 138.3 (1 C, C(9)), 136.2 (1 C, C(2)), 129.6 (1–3 C, C(10/11/12), cis or trans), 129.3 (1–3 C, C(10/11/12), cis or trans), 128.7 (1–3 C, C(10/11/12), cis or trans), 128.5 (1–3 C, C(10/11/12), cis or trans), 128.3 (br, 1–3 C, C(10/11/12), cis or trans), 127.4 (1–3 C, C(10/11/12), cis or trans), 116.5 (1 C, C(6)), 54.3 (1 C, C(4)), 45.1 (1 C, C(5)), 15.7 (1 C, C(3)), 8.8 (1 C, C(2)). 2,3,4-Trimethyl-5-oxocyclopent-3- ene-1-carbonitrile (28). The title compound was obtained from diene O O 27 (3.6 g, 24.2 mmol) following the 7 2 1 5 CN CN general procedure. The crude product 6 was purified by column chromatography 4 3 (SiO2, hexane/EtOAc 4:1) affording 3.0 g (19.81 mmol, 83 %) of the title compound 8 9 as a yellow oil. The d.r. was found to be constantly on the order 1:1 by 1H NMR trans cis analysis. −1 Rf (SiO2, Hexane/EtOAc 4:1) = 0.18; IR (neat, ν/˜ cm ) = 3054, 2979, 2923, 2855, 2227, 1648, 1639, 1617, 1438, 1377, 1348, 1272, 1179, 1101, 1085, 1015, 976, 962, 874, + + 855, 734, 656; HRMS (EI, m/z ) = exact mass calculated for C8H8NO ([M CH3] ) 1 134.0606, found 134.0599; cis-diastereomer: H NMR (700 MHz, CDCl3): δ (ppm) =

88 Experimental

3.57 (d, J = 7.0 Hz, 1 H, H-C(5)), 3.02 (quint, J = 7.2 Hz, 1 H, H-C(4)), 2.06 (s, 3 H, H-C(8)), 1.75–1.74 (m, 3 H, H-C(7)), 1.37 (d, J = 7.3 Hz, 3 H, H-C(9)); 13C NMR (176 MHz, CDCl3): δ (ppm) = 197.3, (1 C, C(1)), 173.4, (1 C, C(3)), 134.4, (1 C, C(2)), 116.8, (1 C, C(6)), 42.1, (1 C, C(5)), 39.2, (1 C, C(4)), 18.1, (1 C, C(9)), 15.5 (1 C, C(8)), 8.6 or 8.4, (1 C, C(7)); 1 trans-diastereomer: H NMR (700 MHz, CDCl3): δ (ppm) = 3.08–3.06 (m, 1 H, H-C(4)), 2.94 (d, J = 3.7 Hz, 1 H, H-C(5)), 2.05 (s, 3 H, H-C(8)), 1.75–1.74 (m, 3 H, H-C(7)), 13 1.34 (d, J = 7.1 Hz, 3 H, H-C(9)); C NMR (176 MHz, CDCl3): δ (ppm) = 196.5, (1 C, C(1)), 172.6, (1 C, C(3)), 135.0, (1 C, C(2)), 115.7, (1 C, C(6)), 43.3, (1 C, C(4)), 43.2, (1 C, C(5)), 17.1, (1 C, C(9)), 15.0, (1 C, C(8)), 8.6, or 8.4, (1 C, C(7)).

(E)-2-mesityl-3,4-dimethyl-5-oxocyclopent-3-ene-1-carbonitrile (30). The title compound was obtained from O diene 29 (5.1 g, 20 mmol) following the 7 general procedure. The crude product 2 1 5 CN 6 was purified by column chromatography 4 11 (SiO2, hexane/EtOAc 3:1) affording 4.7 g 3 9 10 (18.6 mmol, 93 %) of the title compound 8 17 12 16 as a clear, viscous liquid. Under certain 13 circumstances the target compound turned 15 14 faintly green without decomposing. 1 Rf (SiO2, Hexane/EtOAc 3:1) = 0.48; H NMR (500 MHz, CDCl3): δ (ppm) = 6.95–6.94 (m, 1 H, H-C(12)), 6.80–6.80 (m, 1 H, H-C(15)), 4.66–4.64 (m, 1 H, H-C(4)), 3.45 (d, J = 4.6 Hz), 1 H, H-C(5)), 2.49 (s, 3 H, H-C(11)), 2.27 (s, 3 H, H-C(14)), 1.95 (s, 3 H, H-C(17)), 1.89–1.89 (m, 3 H, H-C(8)), 1.84–1.83 (m, 3 H, H-C(7)); 13C NMR (126 MHz, CDCl3): δ (ppm) = 196.4 (1 C, C(1)), 173.1 (1 C, C(2)), 138.1 (1 C, C(10)), 137.9 (1 C, C(13)), 136.1 (1 C, C(16)), 135.4 (1 C, C(3)), 131.5 (1 C, C(15)), 130.2 (1 C, C(12)), 129.9 (1 C, C(9)), 117.2 (1 C, C(6)), 49.1 (1 C, C(4)), 42.0 (1 C, C(5)), 21.6 (1 C, C(11)), 20.9 (1 C, C(14)), 19.3 (1 C, C(17)), 15.5 (1 C, C(8)), 8.7 (1 C, C(7)); IR (neat, ν/˜ cm−1) = 2969, 2920, 2867, 2244, 1711, 1642, 1611, 1558, 1482, 1451, 1384, 1324, 1013, 853, + + 735; HRMS (EI, m/z ) = exact mass calculated for C17H19NO ([M] ) 253.1467, found 253.1467.

6.2.2.4 Syntheses of Cyclopentadienes 2-Methoxy-3,4-dimethyl-5-phenylcyclopenta-1,3-diene-1-carbonitrile (14). In a round-bottom flask equipped with a Dimroth condenser and a CaCl2 tube, cyclopentenone 13 19 (1.3 g, 6.3 mmol, 1.0 equiv.) was dissolved at r.t. in OMe MeOH (30 mL). At the same temperature HC(OMe)3 1 7 2 5 CN (0.9 mL, 8.2 mmol, 1.3 equiv.) and pTsOH · H2O(0.6 g, 6 3.1 mmol, 0.5 equiv.) were added sequentially and the 4 3 ◦ . afforded mixture subsequently heated to 70 C. After 2 5 h, 8 9 the solution was cooled to r.t., diluted with MTBE (100 mL) 10 and alkalized by addition of a NaHCO3 solution in H2O (0.6 M, 100 mL). The phases were separated and the aqueous 11 12 layer extracted with MTBE (2 x 100 mL). The combined organic phases were washed with H2O(150 mL), dried

89 Experimental

over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, hexane/EtOAc 9:1) affording 1.28 g (5.7 mmol, 90 %) of the title compound as a yellow solid. 1 Rf (SiO2, Hexane/EtOAc 4:1) = 0.55; H NMR (400 MHz, CDCl3): δ (ppm) = 7.35–7.31 (m, 2 H, H-C(11)), 7.28–7.25 (m, 1 H, H-C(12)), 7.07–7.04 (m, 2 H, H-C(10)), 4.25 (s, 3 H, H-C(13)), 4.09–4.08 (m, 1 H, H-C(4)), 1.81 (m, 3 H, H-C(7)), 1.75 (m, 3 H, 13 1 H-C(8)); C{ H} NMR (101 MHz, CDCl3): δ (ppm) = 171.1 (1 C, C(1)), 148.9 (1 C, C(3)), 136.4 (1 C, C(9)), 131.4 (1 C, C(2)), 129.0 (2 C, C(11)), 128.0 (2 C, C(10)), 127.6 (1 C, C(12)), 118.5 (1 C, C(6)), 83.7 (1 C, C(5)), 59.5 (1 C, C(4)), 58.9 (1 C, C(13)), 13.1 (1 C, C(7)), 9.2 (1 C, C(8)); IR (neat, ν/˜ cm−1) = 3061, 3026, 2942, 2921, 2855, 2193, 1709, 1655, 1578, 1490, 1451, 1384, 1359, 1301, 1127, 703, 697; HRMS + + (EI, m/z ) = exact mass calculated for C15H15NO ([M] ) 225.1154, found 225.1150. 2-Hydroxy-3,4-dimethyl-5-phenylcy- clopent-3-ene-1-carbonitriles (21). To a solution of 19 (11.66 g, 55.17 mmol, OH OH 1.0 equiv.) in MeOH (120 mL) at 0 ◦C 7 . . 2 1 5 CN CN was added NaBH4 (3 13 g, 82 75 mmol, 6 1.5 equiv.) in portions over 10 min. The 4 mixture was allowed to warm to r.t. 3 9 Ph after completion of the addition and 8 then stirred at the same temperature for 10 1.5 h. The solvent was removed under 11 12 reduced pressure (bath temperature 40 ◦C, 200 mbar) and the residue dissolved in anti, anti syn, syn MTBE (200 mL). While stirring at r.t., an aqueous NH4Cl solution (0.3 M, 200 mL) OH OH was added slowly. The phases were CN CN separated, the organic layer washed with brine (100 mL) and dried over MgSO4. The crude product was purified by column Ph Ph chromatography (SiO2, hexane/MTBE 1:1) affording .11 23 g (52.65 mmol, 95 %) anti, syn syn, anti of the title compounds as mixture of three of four possible diastereomers in a 82:10:8 ratio. The 13C{1H} NMR frequencies are only reported for the major diastereomer since these were not resolved for the other two. The NMR resonances could not unambiguously be assigned to the respective diastereomers. −1 Rf (SiO2, hexane/MTBE 1:1) = 0.46, 0.28; IR (neat, ν/˜ cm ) = 3421, 3063, 3028, 2976, 2938, 2858, 2240, 1601, 1492, 1454, 1439, 1336, 1278, 1180, 1129, 1035, 750, + 701, HRMS (EI, m/z ) = exact mass calculated for C14H15NO ([M] ) 213.1154, found 213.1149; 1 First diastereomer: H NMR (500 MHz, CDCl3): δ (ppm) = 7.37–7.32 (m, 2 H, H-C(11)), 7.30–7.27 (m, 1 H, H-C(12)), 7.20–7.17 (m, 2 H, H-C(10)), 4.91–4.89 (m, 1 H, H-C(1)), 3.80–3.78 (m, 1 H, H-C(4)), 2.72 (dd, J = 7.1, 5.6 Hz, 1 H, H-C(5)), 2.49 (d, J = 6.3 Hz, 1 H, H-O), 1.78 (dquint, J = 2.1, 1.1 Hz, 3 H, H-C(7)), 1.47 (dq, J = 1.9, 1.0 Hz, 3 H, 13 1 H-C(8)); C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 140.7 (1 C), 135.5 (1 C), 134.4 (1 C), 129.1 (2 C), 128.0 (2 C), 127.8 (1 C), 121.4 (1 C), 82.5 (1 C), 58.0 (1 C), 45.9 (1 C), 12.8 (1 C), 11.4 (1 C);

90 Experimental

1 Second diastereomer, aromatic range excluded: H NMR (500 MHz, CDCl3): δ (ppm) = 4.78 (t, J = 6.7 Hz, 1 H, H-C(1)), 4.14–4.12 (m, 1 H, H-C(4)), 3.04 (t, J = 6.7 Hz, 1 H, H-C(5)), 2.17 (d, J = 7.2 Hz, 1 H, H-O), 1.83–1.82 (m, 3 H, H-C(7)), 1.50 (sext, J = 1.1 Hz, 3 H, H-C(8)); 1 Third diastereomer, aromatic range excluded: H NMR (500 MHz, CDCl3): δ (ppm) = 4.70 (t, J = 6.5 Hz, 1 H, H-C(1)), 3.85 (d, J = 8.8 Hz, 1 H, H-C(4)), 3.60 (dd, J = 8.7, 6.6 Hz, 1 H, H-C(5)), 2.25 (d, J = 6.6 Hz, 1 H, H-O), 1.85–1.84 (m, 3 H, H-C(7)), 1.55 (dq, J = 2.0, 1.0 Hz, 3 H, H-C(8)).

3,4-Dimethyl-2-phenylcyclopenta-1,3-diene-1-carbonitrile (22). To a solution of alcohol 21 (11.23 g, 7 52.65 mmol, 1.0 equiv.) in benzene (100 mL) at r.t. was 2 1 5 CN 6 added pTsOH · H2O(8.0 g, 42.12 mmol, 0.8 equiv.) at ◦ 4 the same temperature. The mixture was heated to 90 C 3 ◦ whereby it turned green-brown. Upon reaching 90 C, the 8 9 mixture was kept at this temperature for 1 min, cooled 10 to r.t., and the solvent removed under reduced pressure 11 12 (bath temperature 40 ◦C, 200 mbar). The afforded residue was then suspended in MTBE (100 mL) and an aqueous NaHCO3 solution (0.6 M, 200 mL) was added carefully while stirring. The phases were separated, the organic phase washed with H2O(100 mL), brine (100 mL), dried over MgSO4 and concentrated in vacuo. The crude material was adsorbed on SiO2 and purified by column chromatography (SiO2, hexane/MTBE, 5:1) affording 8.87 g (45.42 mmol, 86 %) of the target compound as a dark-orange oil which turned darker over time.2 1 Rf (SiO2, hexane/MTBE 5:1) = 0.36; H NMR (500 MHz, CDCl3): δ (ppm) = 7.48–7.44 (m, 2 H, H-Ph), 7.43–7.39 (m, 3 H, H-Ph), 3.30 (q, J = 1.6 Hz, 1 H, H-C(1)), 2.07 (q, J = 1.0 Hz, 3 H, H-C(7)), 1.87–1.86 (m, 3 H, H-C(8)); 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) = 163.5 (1 C, C(4)), 144.9 (1 C, C(2)), 135.8 (1 C, C(3)), 133.8 (1 C, C(9)), 129.1 (1 C, C(12)), 128.7 (2 C, C(10)), 128.3 (2 C, C(11)), 118.1 (1 C, C(5)), 105.7 (1 C, C(6)), 46.8 (1 C, C(1)), 14.4 (1 C, C(7)), 12.0 (1 C, C(8));

2-Methoxy-3,4,5-trimethylcyclopenta-1,3-diene-1- carbonitrile (24). In a round-bottom flask equipped with a Dimroth condenser and a CaCl2 tube, cyclopentenone 10 28 (1.82 g, 12.17 mmol, 1.0 equiv.) was dissolved at r.t. in OMe 1 MeOH (25 mL). At the same temperature HC(OMe)3 7 2 5 CN (3.34 mL, 30.43 mmol, 2.5 equiv.) and pTsOH · H2O 6 . . . . 4 (1 16 g, 6 10 mmol, 0 5 equiv ) were added sequentially and 3 the resulting mixture then heated to 70 ◦C for 2 h. The 8 9 solution was cooled to r.t., diluted with MTBE (50 mL) and alkalized by addition of an aqueous NaHCO3 solution (sat., 50 mL). The phases were separated and the aqueous layer extracted with MTBE (2 x 30 mL). The combined organic phases were washed with H2O(50 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by adsorbing it on 2SiO (4 g) and passing through a SiO2 plug (20 g) eluting with

2The product was stored at r.t. under normal atmosphere. Although given the discoloration, no decomposition could be determined by GC-MS or NMR analysis after several months.

91 Experimental hexane/EtOAc (9:1, 250 mL) affording 1.69 g (10.35 mmol, 85 %) of the title compound as a yellow liquid with a caramel-like scent. 1 Rf (SiO2, Hexane/EtOAc 4:1) = 0.65; H NMR (400 MHz, CDCl3): δ (ppm) = 4.18 (s, 3 H, H-C(10)), 3.00 (qq, J = 7.5, 1.4 Hz, 1 H, H-C(4)), 1.87 (q, J = 1.0 Hz, 3 H, H-C(8)), 1.71 (dt, J = 2.4, 1.1 Hz, 3 H, H-C(7)), 1.21 (d, J = 7.5 Hz, 3 H, H-C(9)); 13C{1H} NMR (101 MHz, CDCl3): δ (ppm) = 170.0 (1 C, C(1)), 149.8 (1 C, C(3)), 130.0 (1 C, C(2)), 118.9 (1 C, C(6)), 83.1 (1 C, C(5)), 58.7 (1 C, C(10)), 48.1 (1 C, C(4)), 14.8 (1 C, C(9)), 12.6 (1 C, C(8)), 9.0 (1 C, C(7)); IR (neat, ν/˜ cm−1) = 2969, 2942, 2931, 2873, 2857, 2191, 1656, 1646, 1579, 1444, 1385, 1358, 1317, 1220; HRMS (EI, m/z ) + + = exact mass calculated for C10H13NO ([M] ) 163.0997, found 163.0998.

5-Mesityl-2-methoxy-3,4-dimethylcyclopenta-1,3-diene-1-carbonitrile (25). In a round-bottom flask equipped with a Dimroth condenser and a CaCl2 tube, cyclopentenone 18 30 (2 g, 7.9 mmol, 1.0 equiv.) was dissolved at r.t. in OMe MeOH (40 mL). At the same temperature HC(OMe)3 1 7 2 5 CN (4.6 mL, 41.2 mmol, 5.2 equiv.) and pTsOH · H2O(0.75 g, 6 3.95 mmol, 0.5 equiv.) were added sequentially and the 4 11 ◦ 3 9 10 resulting mixture then heated to 70 C for 8 h. The solution 8 17 12 was cooled to r.t., diluted with MTBE (100 mL) and 16 13 alkalized by addition of an aqueous NaHCO3 solution in (0.6 15 M, 50 mL). The phases were separated and the aqueous 14 layer extracted with MTBE (2 x 30 mL). The combined organic phases were washed with brine (35 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography (SiO2, hexane/EtOAc 9:1 to 7:3) affording 1.28 g (5.7 mmol, 90 %) of the title compound as a yellow solid. 1 Rf (SiO2, Hexane/EtOAc 5:1) = 0.62; H NMR (500 MHz, CDCl3): δ (ppm) = 6.90– 6.89 (m, 1 H, H-C(12)), 6.72–6.72 (m, 1 H, H-C(15)), 4.61–4.60 (m, 1 H, H-C(4)), 4.24 (s, 3 H, H-C(18)), 2.45 (s, 3 H, H-C(11)), 2.24 (s, 3 H, H-C(14)), 1.80 (dq, 3 H, J = 1.9, 1.0 Hz, H-C(7)), 1.77 (s, 3 H, H-C(17)), 1.72 (q, 3 H, J = 1.0 Hz, H-C(8)); 13 1 C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 170.3 (1 C, C(18)), 148.9 (1 C, C(3)), 137.9 (1 C, C(10)), 137.8 (1 C, C(16)), 136.8 (1 C, C(13)), 131.0 (1 C, C(2)), 130.6 (1 C, C(15)), 129.5 (1 C, C(12)), 128.8 (1 C, C(9)), 118.3 (1 C, C(6)), 81.0 (1 C, C(5)), 58.9 (1 C, C(18)), 55.1 (1 C, C(4)), 21.9 (1 C, C(11)), 21.0 (1 C, C(14)), 17.8 (1 C, C(17)), 13.1 (1 C, C(8)), 9.2 (1 C, C(7)); IR (neat, ν/˜ cm−1) = 3003, 2974, 2942, 2919, 2858, 2194, 1649, 1612, 1572, 1482, 1450, 1384, 1361, 1299; HRMS (ESI, m/z ) = exact + + mass calculated for C18H21NO ([M] ) 267.1623, found 267.1624.

92 Experimental

2-Methoxy-3,4-dimethyl-5-(2,4,6-triisopropylphenyl)- cyclopenta-1,4-diene-1-carbonitrile (26). In a 250 mL O two-neck flask equipped with a Dean-Stark trap, benzene N (120 mL) was degassed by bubbling with Ar for 30 min. Afterwards, the required amount of benzene was transferred 11 to fill the Dean-Stark trap (20 mL). Nitrile 11 (4.92 g, 40 mmol, 1.0 equiv.) and aldehyde 31 (14.9 mL, 60 mmol, 1.5 equiv.) were added to the degassed benzene in the reactor at r.t.HOAc (1.14 mL, 20 mmol, 0.5 equiv.) and piperidine O N (0.40 mL, 4 mmol, 0.1 equiv.) were added sequentially at the same temperature and the mixture was then heated to 100 ◦C. After 18 h the temperature was increased to 120 ◦C Trip 32 as progression of the reaction was slow. After 22 h, copious amounts of the aldehyde 31 but no more nitrile 11 were detected. Further nitrile 11 (3.69 g, 30 mmol, 0.75 equiv.) was added to the mixture which was stirred for further 1 h O ◦ at 120 C. After cooling to r.t., the solvent was removed in CN vacuo and the residue diluted with MTBE (100 mL), washed with water (100 mL), an aqueous NaHCO3 solution (0.6 M, Trip 80 mL), and brine (100 mL). The organic phase was dried 33 over MgSO4 and concentrated in vacuo. Crude 32 was purified by column chromatography (SiO2, hexane/MTBE 7:1, Rf =0.54) which did not allow to separate the title 7 compound form unreacted aldehyde 31. This mixture was OMe 1 33 8 2 5 CN used further for the next step to cyclopentenone . 6 23 4 21 3 22 32 9 10 20 The mixture containing was dissolved in CH2Cl2 (120 12 11 19 mL) at r.t. in a flask equipped with a Dimroth condenser 13 14 15 and a CaCl2 tube. At the same temperature, MsOH (4.7 16 17 18 mL) was added dropwise over 5 min yielding a dark red 18 solution which was stirred further for 4 h. The temperature was increased to 40 ◦C and stirring maintained for 4 h more. As reaction progress was slow, further MsOH (1.5 mL) was added and the mixture left stirring at 40 ◦C for further 13 h. The solution was allowed to cool to r.t. and poured into ice-water (100 mL) while stirring. The mixture was diluted with MTBE (100 mL) and neutralized with an aqueous NaHCO3 solution (sat, 100 mL). The phases were separated and the aqueous phase extracted with CH2Cl2 (80mL). The combined organic phases were washed with brine (80 mL), dried over MgSO4, and concentrated in vacuo. The crude product was purified by column chromatography 2(SiO , hexane/EtOAc 4:1, Rf =0.53) which did not allow to separate the product from unreacted aldehyde 31 from the previous reaction. This mixture was then directly used for the next step to cyclopentadiene 26.

The mixture containing cyclopentenone 33 was dissolved in MeOH (65 mL) in a flask equipped with a Dimroth condenser and a CaCl2 tube. To this solution HC(OMe)3 (16.41 mL) and pTsOH · H2O (5.70 g) were added at r.t. and the mixture subsequently heated to 70 ◦C for 3 h. The solution was cooled to r.t., poured into water (200 mL) and diluted with MTBE (150 mL). The phases were separated and the organic layer washed with an aqueous NaHCO3 solution (sat., 200 mL), brine (100 mL), dried over MgSO4 and

93 Experimental

concentrated in vacuo. The crude product was purified by column chromatography 2(SiO , hexane/EtOAc 6:1) which again did not allow for removal of the formerly employed aldehyde 31. The fractions containing the title product were combined, concentrated in vacuo and the resulting orange oil left standing to the open atmosphere. After 1.5 weeks, yellow crystals had formed. The mother liquor was decanted and the crystals washed with pentane. This afforded 415.7 mg (1.18 mmol, 2 % relative to 11) of the title product. (The NMR sample contained leftover pentane. Integrals of the C(18) and C(8) moieties have been corrected to support the crystal structure.) 1 H NMR (400 MHz, CDCl3): δ (ppm) = 6.99 (s, 2 H, H-C(15), H-C(19)), 4.21 (s, 3 H, H-C(7)), 3.04 (q, J = 7.6 Hz, 1 H, H-C(2)), 2.92–2.80 (m, 3 H, H-C(12), H-C(17), H-C(21)), 1.57 (d, J = 0.7 Hz, 3 H, H-C(9)), 1.27 (d, J = 6.9 Hz, 6 H, H-C(18)), 1.26 (d, J = 7.6 Hz, 3 H, H-C(8)), 1.21 (d, J = 6.9 Hz, 3 H, H-C(13) and H-C(14) or H-C(22) and H-C(23)), 1.20 (d, J = 6.9 Hz, 3 H, H-C(13) and H-C(14) or H-C(22) and H-C(23)), 1.12 (d, J = 6.9 Hz, 3 H, H-C(13) and H-C(14) or H-C(22) and H-C(23)), 1.10 (d, J = 6.9 Hz, 3 H, H-C(13) and H-C(14) or H-C(22) and H-C(23)); 13C{1H} NMR (101 MHz, CDCl3): δ (ppm) = 178.4 (1 C, C(1)), 148.6 (1 C, C(16)), 147.57 (1 C, C(11) or C(20)), 147.55 (1 C, C(11) or C(20)), 132.9 (1 C, C(4)), 131.6 (1 C, C(3)), 127.4 (1 C, C(10)), 120.7 (2 C, C(15), C(19)), 116.7 (1 C, C(5) or C(6)), 87.4 (1 C, C(5) or C(6)), 59.4 (1 C, C(7)), 49.0 (1 C, C(2)), 34.3 (1 C, C(17)), 30.93 (1 C, C(12) or i i C(21)), 30.79 (1 C, C(12) or C(21)), 24.60 (1 C, Pr-CH3), 24.45 (1 C, Pr-CH3), 24.38 i i i (1 C, Pr-CH3), 24.35 (1 C, Pr-CH3), 24.16 (1 C, Pr-CH3), 14.0 (1 C, C(8)), 12.4 ( C, C(9)).

Attempted synthesis of 2,3,4-trimethyl-5-phenylcyclopenta-1,3-diene-1-carbonitrile (20). To a solution of cyclopentenone 19 (78.2 mg, 0.37 mmol, 1 equiv.) in ◦ CH2Cl2 (4 mL) at 0 C was added a solution of AlMe3 in CN toluene (2 M, 0.4 mL, 0.74 mmol, 2 equiv.). The solution was stirred for 1 h at the same temperature and then treated with an aqueous NH4Cl solution (3.5 M, 10 mL). Ph The phases were separated and the aqueous layer extracted with EtOAc (10 mL). The combined organic layers were dried over MgSO4 and then concentrated in vacuo. It was attempted to purify the crude product by preparatory TLC (SiO2, hexane/EtOAc 4:1) without success as the two species coeluted.

Attempted syntheses of 2-Methoxy-3,4-dimethyl-5- phenylcyclopenta-1,3-diene-1-carbaldehyde (23). Cy- clopentadiene 19 (1 equiv.) was dissolved in the respective OMe solvent (CH2Cl2, toluene, THF, Et2O) to afford a 0.3 M solution which was cooled to −78 ◦C. At the same temperature CHO a solution of DIBAL in hexane (1 M, 2.2 equiv.) was added dropwise and the resulting mixture stirred for 0.5 h. Still at ◦ Ph −78 C, EtOAc (about 5 equiv.) was added to the solution, the mixture stirred further for 5 min and then allowed to warm to r.t. An aqueous solution of Rochelles salt was added to the mixture which was then vigorously stirred for 1 h. The organic phase was decanted, filtered through MgSO4 and analyzed by GC-MS. In all cases the starting material was collected and no new species had been formed.

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6.2.2.5 Pinene-Derived Cyclopentadiene (1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-ene-2-carboxylic acid (61). To a solution of Myrtenal (4.00 g, 26.63 mmol, 1.0 equiv.) in DMSO, MeCN and MeOH (total H Ha 6 b 1 70 mL, 3:3:1) tempered by a H2O bath to r.t., was added CO H . 2 2 a solution of NaH2PO4 in H2O (0.8 M, 10 mL, 8 00 mmol, 7 3 3 0.3 equiv.). At the same temperature, a solution of NaO2Cl 9 5 8 4 in H2O (about 1 M, 40 mL, 37.28 mmol, 1.4 equiv.) was ◦ added dropwise so that the mixture was kept below 50 C. 10 The mixture was then stirred at r.t. and further NaO2Cl was added when conversion of the aldehyde to the carboxylic acid would slow down or stop. For example, in this case after 20 h at r.t., TLC displayed no progression of the reaction and thus further solid NaO2Cl (1 g) was added and the mixture stirred further at the same temperature. After 6 h reaction progression stopped again and more NaO2Cl (1 g) was added and stirred for further 16 h at r.t. Once full conversion was achieved, the mixture was alkalized by addition of an aqueous NaHCO3 solution (60 mM, about 120 mL) until pH=10-14 was achieved. The solution was washed with hexane (3 x 70 mL) and then acidified to pH=0-2 by addition ofan aqueous HCl solution (conc., about 10 mL) and extracted with EtOAc (3 x 100 mL). The organic phase was dried over MgSO4 and concentrated in vacuo. The crude product was adsorbed on SiO2 and purified by passing it over a SiO2 plug (hexane/MTBE, 1:1) affording 4.21 g (25.32 mmol, 95 %) of the title product as a slightly yellow oil which solidified after some days at r.t. 1 Rf (SiO2, hexane/EtOAc 4:1) = 0.22; H NMR (500 MHz, CDCl3): δ (ppm) = 11.65 (s, br, 1 H, OH),4 6.99 (tt, J = 3.2, 1.6 Hz, 1 H, H-C(3)), 2.78 (td, J = 5.7, 1.5 Hz, 1 H, H-C(7)), 2.51–2.39 (m, 3 H, H-C(4), Ha-C(6)CH2), 2.13 (ttd, J = 5.7, 2.8, 1.4 Hz,), 1 H, H-C(5)), 1.33 (s, 3 H, H-C(9)), 1.12 (d, J = 9.1 Hz, 1 H, Hb-C(6)), 0.79 (s, 3 H, 13 1 H-C(10)); C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 171.7 (1 C, C(1)), 139.80 (1 C, C(2)), 139.63 (1 C, C(3)), 41.0 (1 C, C(7)), 40.3 (1 C, C(5)), 37.8 (1 C, C(8)), 32.5 (1 C, C(4)), 31.4 (1 C, C(6)), 26.0 (1 C, C(9)), 21.1 (1 C, C(10)); IR (neat, ν/˜ cm−1) = 3051,5 2974, 2950, 2934, 2918, 2885, 2871, 2821, 2782, 2670, 2607, 2532, 2607, 2532, 1674, 1621, 1421, 1265, 1074, 753; MS (ESI, m/z ) = exact mass calculated for + + C10H14NaO2 ([M] ) 189.0886, found 189.0891.

(1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-ene-2-carboxylic acid (62). To a solution of carboxylic acid 61 (2.9 g, 17.4 mmol, 1.0 equiv. ) in MeOH (15 mL) at r.t., was H Ha 6 b 1 11 added H2SO4 (0.2 mL, 3.5 mmol, 0.2 equiv. ). The mixture ◦ 2 CO2Me was heated to 65 C and the reaction progress monitored 7 3 by TLC or GC-MS. The solution was cooled to r.t. after 9 5 8 4 H 24 h, diluted with MTBE (50 mL) and treated with an b Ha aqueous NaHCO3 solution (0.6 M, 100 mL). The phases 10 were separated and the aqueous layer extracted with MTBE (2 x 100 mL). The combined organic phases were washed

380 % grade. Indicated mass of the reagent include this factor. 4This signal is manifested as a very broad signal centered around the reported chemical shift. 5The COO-H vibration is manifested as a broad absorption with onset around 3700 cm−1, featuring a shoulder at the reported wavenumber and is further hidden by C-H vibrations.

95 Experimental

with H2O(150 mL), dried over MgSO4 and concentrated in vacuo. The crude product was purified by eluting through a short SiO2 plug with hexane/MTBE 18:1 affording 2.77 g (15.4 mmol, 88 %) of the title compound as a colorless liquid with a flowery scent. 1 Rf (SiO2, hexane/EtOAc) = 0.83; H NMR (500 MHz, CDCl3): δ (ppm) = 6.81 (tt, J = 3.3, 1.6 Hz, 1 H, H-C(3)), 3.72 (s, 3 H, H-C(11)), 2.79 (td, J = 5.7, 1.5 Hz, 1 H, H-C(7)), 2.47–2.35 (m, 3 H, Ha-C(4), Hb-C(4), Ha-C(6)), 2.12 (ttd, J = 5.8, 2.9, 1.4 Hz, 1 H, H-C(5)), 1.32 (s, 3 H, H-C(9)), 1.10 (d, J = 9.1 Hz, 1 H, Hb-C(6)), 0.78 (s, 3 H, 13 1 H-C(10)); C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 166.9 (1 C, C(1)), 140.2 (1 C, C(2)), 136.6 (1 C, C(3)), 51.6 (1 C, C(11)), 41.4 (1 C, C(7)), 40.4 (1 C, C(5)), 37.8 (1 C, C(8)), 32.3 (1 C, C(4)), 31.5 (1 C, C(6)), 26.0 (1 C, C(9)), 21.1 (1 C, C(10)); MS + + (ESI, m/z ) = exact mass calculated for C11H17O2 ([M] ) 181.1223, found 181.1226.

3-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2-en-2- yl)-3-oxopropanenitrile (63). A dispersion of NaH in mineral oil (60 %, 1.23 g, 30.7 mmol, 2.0 equiv.) was O washed at r.t. with hexane (3 x 5 mL) and then suspended CN in THF (40 mL). MeCN (1.7 mL, 32.3 mmol, 2.1 equiv.) was added at r.t. to the suspension which was then heated to 70 ◦C. As soon as this temperature was reached, ester 62 (2.77 g, 15.4 mmol, 1.0 equiv.) was added dropwise over 5 min. The mixture was stirred at 70 ◦C until full conversion was achieved (usually 4-5 h). The afforded dark brown mixture was cooled to r.t. and an aqueous NH4Cl solution was added (0.6 M, 50 mL) while stirring. The phases were separated and the aqueous layer extracted with MTBE (2 x 50 mL). The combined organic phases were dried over MgSO4 and concentrated in vacuo. The crude product was purified by adsorbing it on SiO2 and then eluting from a short SiO2 plug first with hexane (about 100 mL) to remove apolar impurities, and then with a hexane/EtOAc 4:1 mixture. This procedure afforded 2.57 g (13.6 mmol, 88 %) of the title compound as a dark yellow oil. 1 Rf (SiO2, hexane/EtOAc 4:1) = 0.25; H NMR (400 MHz, CDCl3): δ (ppm) = 6.80 (tt, J = 3.3, 1.6 Hz, 1 H), 3.78 (d, J = 18.5 Hz, 1 H), 3.74 (d, J = 18.6 Hz, 1 H), 2.94 (td, J = 5.7, 1.7 Hz, 1 H), 2.61–2.45 (m, 3 H), 2.16 (ttd, J = 5.7, 2.8, 1.1 Hz, 1 H), 1.33 13 1 (s, 3 H), 1.03 (d, J = 9.3 Hz, 1 H), 0.73 (s, 3 H), C{ H} NMR (101 MHz, CDCl3): δ (ppm) = 185.5, 147.9, 140.9, 114.5, 40.1, 39.8, 37.6, 33.0, 31.0, 27.9, 25.8, 20.9, IR (neat, ν/˜ cm−1) = 2952, 2972, 2921, 2887, 2872, 2258, 1672, 1614, 1368; MS (ESI, + + m/z ) = exact mass calculated for C12H15NO ([M] ) 189.1154, found 189.1151.

(E)-2-((1R,5S)-6,6-Dimethylbicyclo[3.1.1]hept-2- ene-2-carbonyl)-3-phenylacrylonitrile (64). To a solution of nitrile 63 (2.57 g, 13.56 mmol, 1.0 equiv.) in O benzene (50 mL) at r.t. was added sequentially benzalde- CN hyde (1.52 mL, 14.92 mmol, 1.1 equiv.), HOAc (0.4 mL, 6.78 mmol, 0.5 equiv.) and piperidine (0.13 mL, 1.36 mmol, 0.1 equiv.). The mixture was stirred at 100 ◦C for 2 h, Ph then cooled to r.t. and diluted with MTBE (150 mL). The solution was washed with an aqueous NaHCO3 solution (0.3 M, 100 mL), H2O (100 mL), an aqueous NaHSO3 solution (40 %, 3 x 50 mL) and H2O (100 mL) again. The organic layer was dried over MgSO4 and concentrated in vacuo. The crude product was purified by eluting from a short SiO2 plug with hexane/EtOAc

96 Experimental

7:1 as eluent, affording 3.58 g (12.92 mmol, 95 %) of the title product as a yellow oil. 1 Rf (SiO2, hexane/EtOAc 4:1) = 0.50; H NMR (500 MHz, CDCl3): δ (ppm) = 7.98–7.96 (m, 2 H), 7.95 (s, 1 H), 7.55–7.47 (m, m H), 6.92 (tt, J = 3.3, 1.6 Hz, 1 H), 2.88 (td, J = 5.6, 1.6 Hz, 1 H), 2.64–2.49 (m, 3 H), 2.19 (ttd, J = 5.7, 2.8, 1.2 Hz, 1 H), 1.36 13 1 (s, 3 H), 1.21 (d, J = 9.3 Hz, 1 H), 0.85 (s, 3 H); C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 186.5, 153.9, 147.2, 140.3, 132.9, 132.1, 130.9, 129.3, 117.4, 109.8, 41.8, 40.2, 37.9, 32.8, 31.2, 25.9, 21.0.

(4R,6R)-5,5-Dimethyl-3-oxo-1-phenyl-2,3,4,5,6,7- hexahydro-1H-4,6-methanoindene-2-carbonitrile (34). To a solution of 64 (3.58 g, 12.92 mmol, 1.0 equiv.) O in CH2Cl2 at r.t. was added dropwise MsOH (1 mL, 12.92 mmoL, 1.0 equiv.) and the resulting red solution was CN left stirring at the same temperature. After 24 h, the mixture was diluted with MTBE (50 mL) and an aqueous Ph NaHCO3 solution (0.6 M, 50 mL) was added carefully. The phases were separated and the aqueous layer extracted with and EtOAc/MTBE mixture (9:1, 3 x 50 mL). The combined organic layers were dried over MgSO4 and concentrated in vacuo. A mixture of two species was afforded which were purified by column chromatography (SiO2, hexane/EtOAc 2:1). The combined fractions containing both species were redissolved in a MTBE/MeOH mixture (6:1, 35 mL) and pentane was slowly added while stirring at r.t. until a red oil had deposited at the bottom of the flask. The supernatant solution was decanted, concentrated, and the resulting solid dissolved in the minimum amount of MTBE (about 20 mL). Slow addition of pentane at r.t. while stirring led the product to precipitate as a pale yellow solid which was filtered off and washed with pentane. This afforded 734.5 mg (2.65 mmol, 21%) of the title product as a mixture oftwo diastereomers (corroborated also by GC-MS: tr=12.85 min, 13.73 min, m/z 277.1) Due to the complexity of the NMR spectra, no assignments were made and thus only shifts and multiplicities are reported here. 1 Rf (SiO2, hexane/EtOAc 2:1) = 0.5, 0.26; H NMR (500 MHz, CDCl3): δ (ppm) = 7.42– 7.32 (m), 4.72 (s), 4.48 (d, J = 1.5 Hz), 3.70 (d, J = 12.6 Hz), 3.60 (d, J = 12.2 Hz), 3.30–3.24 (m), 3.11 (s), 3.01 (s), 2.88–2.83 (m), 2.34–2.29 (m), 2.24–2.12 (m), 1.99– 1.86 (m), 1.63–1.58 (m), 1.51–1.47 (m), 1.21 (s), 1.19 (s), 1.13 (s), 1.06 (s), 0.97 13 1 (s); C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 137.1, 136.4, 129.50, 129.42, 128.59, 128.48, 127.31, 127.14, 115.8, 115.5, 88.0, 86.4, 66.7, 63.8, 52.3, 51.9, 51.7, 51.0, 50.6, 49.7, 47.6, 44.6, 40.9, 40.1, 39.3, 38.9, 38.2, 37.5, 33.2, 32.2, 29.0, 27.1, 24.8, 24.3, 20.5; IR (neat, ν/˜ cm−1) = 3061, 3032, 2972, 2877, 2248, 1749, 1351, 1333, 1174, 946, 699.

(4R,6R)-3-Methoxy-5,5-dimethyl-1-phenyl-4,5,6,7- tetrahydro-1H-4,6-methanoindene-2-carbonitrile (60). Method A: A solution of compound 34 (1.73 g, 6.31 OMe mmol, 1.0 equiv.), pTsOH · H2O (0.6 g, 3.16 mmol, 0.5 equiv.) and HC(OMe)3 (1.73 mL, 15.78 mmol, 2.5 equiv.) CN in MeOH (15 mL) was stirred at 60 ◦C. Reaction monitoring by TLC and GC-MS did not reveal any conversion of the Ph starting materials during 5 h.

97 Experimental

Method B: A solution of compound 34 (70 mg, 0.25 mmol), ◦ HC(OMe)3 (1 mL) and H2SO4 (0.1 mL) was stirred at 100 C. After 3 days GC-MS analysis revealed small quantities of two species with fitting m/z of 291 at 12.75 min and 12.89 min.

6.2.3 Ferrocenes and Related Compounds 6.2.3.1 Cyclopentadienyl Arene Iron(II) Salts General procedure for the synthesis cyclopentadienyl arene iron(II) compounds: Ferrocene (6 g, 32 mmol, 1.0 equiv.) was dissolved at r.t. in the corresponding arene (100 mL) to afford a 0.3 M solution.3 AlCl (7.7 g, 57.6 mmol, 1.8 equiv.) and a fine aluminium powder (0.7 g, 25.6 mmol, 0.8 equiv.) were added to the solution at the same temperature. The afforded suspension was then refluxed for 18 h, cooled to r.t.and then quenched by the slow addition of H2O (150 mL). The afforded mixture was filtered over cotton to remove unreacted aluminium powder. The phases were separated and the organic layer extracted with H2O (2 x 50 mL). The combined aqueous (!) phases were washed with hexane (3 x 100 mL) to remove unreacted ferrocene and arene. The aqueous phase was then filtered over celite affording clear or turbid green mixture. The corresponding products were precipitated while vigorously stirring by the slow addition of an aqueous NH4PF6 solution (1.5 M, 6.26 g, 38.4 mmol, 1.2 equiv.). The precipitate was filtered off, washed with2 H O (3 x 15 mL) and dissolved in acetone (10-50 mL). The crude product was purified at r.t. by trituration of the acetone solution2 withEt O (40-100 mL), the afforded powder filtered off and washed2 withEt O and pentane, and then dried in air.

(η6- Benzene)cyclopentadienyliron(II)-hexafluorophosphate (43). The title compound was obtained from benzene according to the general method which afforded 0.91 g (2.65 mmol, 8 %) of the target molecule as a beige to yellow powder. Fe - The product was stored under standard conditions PF6 and no discoloration or decomposition was observed over the time of 1 year. 1 6 13 1 H NMR (500 MHz, CD3CN): δ (ppm) = 6.25 (s, br, 6 H), 5.04 (s, br, 5 H); C{ H} 19 NMR (126 MHz, CD3CN): δ (ppm) = 89.2 (6 C), 77.5 (5 C); F NMR (471 MHz, CD3CN): 31 δ (ppm) = −72.77 (d, J = 707.2 Hz, 6 F); P NMR (202 MHz, CD3CN): δ (ppm) = −144.56 (sept, J = 706.9 Hz, 1 P).

(η6- Toluene)cyclopentadienyliron(II)-hexafluorophosphate (44). The title compound was obtained from toluene according to the general method which afforded 2.9 g (8.1 mmol, 25 %) of the target molecule as a brown powder. The Fe - product was stored under standard conditions and PF6 no discoloration or decomposition was observed over the time of 1 year.

6The signals were exceedingly broadened.

98 Experimental

1 H NMR (500 MHz, CD3CN): δ (ppm) = 6.51 (s, br, 2 H), 6.26 (s, br, 2 H); 5.08 (s, br, 13 1 5 H); 2.40 (s, br, 3 H); (s, br, 5 H); (s, br, 5 H); C{ H} NMR (126 MHz, CD3CN): δ (ppm) = 106.9 (1 C), 104.2 (1 C); 89.2 (2 C), 88.9 (2 C), 80.1 (5 C), 20.3 (1 C), 19F 31 NMR (471 MHz, CD3CN): δ (ppm) = −72.7 (d, J = 706.8 Hz, 6 F); P NMR (202 MHz, CD3CN): δ (ppm) = −144.55 (sept, J = 706.8 Hz, 1 P).

(η6- p-Chlorotoluene)cyclopentadienyliron- (II)-hexafluorophosphate (45). The title compound was obtained from p-chlorotoluene according to the general method which afforded 3.69 g (9.4 mmol, 29 %) of the target molecule Fe - as a bright green powder. The product was stored PF6 under standard conditions and no discoloration or Cl decomposition was observed over the time of 1 year. 1 7 H NMR (500 MHz, CD3CN): δ (ppm) = 6.17 (s, br, 5 H), 4.98 (s, br, 5 H), 2.45 13 1 (s. br, 3 H); C{ H} NMR (126 MHz, CD3CN): δ (ppm) = 104.8 (1 C), 89.6 (2 C), 19 88.5 (2 C), 87.3 (1 C), 77.7 (5 C), 21.0 (1 C), F NMR (471 MHz, CD3CN): δ (ppm) 31 = −72.73 (d, J = 706.9 Hz, 6 F); P NMR (202 MHz, CD3CN): δ (ppm) = −144.56 (sept, J = 706.7 Hz, 1 P).

(η6-Fluorene)cyclopentadienyliron(II)-hexafluorophosphate (40). In an oven-dried 1 L 3-neck flask equipped with a Dimroth condenser, a N2 bypass and with 14 a large magnet bar, ferrocene (27.9 g, 150 mmol, 1.0 equiv.) and fluorene24 ( .9 g, 150 mmol, 1.0 equiv.) were suspended Fe 1 - while stirring in a cis/trans mixture of decalin (100 mL) 12 13 2 3 PF6 at r.t. At the same temperature and while stirring, AlCl3 11 4 8 7 (24.0 g, 180 mmol, 1.2 equiv.) and aluminium-grit (4.1 g, 10 9 6 5 150 mmol, 1.0 equiv.) were added sequentially. The solids were rinsed from the flask walls with the addition of further cis/trans mixture of decalin (200 mL) and the suspension was then heated to 160 ◦C for 24 h. The mixture was cooled to about 30 ◦C and, while still warm, diluted with hexane (150 mL), and slowly hydrolyzed with a MeOH/H2O mixture (250 mL, 1:4). The mixture was further cooled to r.t. while stirring. The leftover aluminium-grit was removed by filtration over a paper filter, and the residue washed with a MeOH/H2O mixture (100 mL, 1:4). The phases were separated, the aqueous layer washed with hexane (3 x 250 mL) and the organic phases discarded. The dark green aqueous phase was filtered over celite and the filter cake rinsed witha MeOH/H2O mixture (100 mL, 1:4). While stirring the aqueous solution at r.t., a solution of NH4PF6 (12.2 g, 75 mmol, 0.5 equiv.) in H2O(40 mL) was slowly added to precipitate the product. The afforded bright green suspension was stirred for about 10 min at r.t. and then filtered. The retained material was washed2 withH O (3 x 50 mL) and Et2O (3 x 50 mL) and dried in air. The crude product was dissolved in CH2Cl2 (230 mL) and triturated by slow addition of Et2O(350 mL) at r.t. to precipitate the product (this has to be performed swiftly since the product degrades when dissolved in CH2Cl2). The compound was isolated by filtration and washed with2 Et O (2 x 50 mL) and pentane (2 x

7This signal is exceedingly broadened which affected its integration (expected integral is 4 protons).

99 Experimental

50 mL), dried in air and then under reduced pressure to afford the target compound 24.7 g (57.2 mmol, 38 %) as a brown to green powder. 1 H NMR (500 MHz, CD3CN): δ (ppm) = 8.02 (d, J = 7.2 Hz, 1 H, H-C(6)), 7.69 (d, J = 7.3 Hz, 1 H, H-C(3)), 7.59–7.53 (m, 2 H, H-C(4), H-C(5)), 6.95 (d, J = 6.1 Hz, 1 H, H-C(9)), 6.77 (d, J = 6.1 Hz, 1 H, H-C(12)), 6.25 (t, J = 6.1 Hz, 1 H, H-C(11)), 6.20 (t, J = 6.0 Hz, 1 H, H-C(10)), 4.65 (s, 5 H, H-C(14)), 4.28 (d, J = 22.2 Hz, 1 H, 13 1 Hexo-C(1)), 4.10 (d, J = 22.3 Hz, 1 H, Hendo-C(1)); C{ H} NMR (126 MHz, CD3CN): δ (ppm) = 145.1 (1 C, C(7)), 138.3 (1 C, C(2)), 131.2 (1 C, C(5)), 128.9 (1 C, C(4)), 126.9 (1 C, C(3)), 123.2 (1 C, C(6)), 107.7 (1 C, C(8)), 105.8 (1 C, C(13)), 86.7 (1 C, C(11)), 86.4 (1 C, C(12)), 86.1 (1 C, C(10)), 81.1 (1 C, C(9)), 78.6 (1 C, C(15)), 38.2 19 (1 C, C(1)); F NMR (471 MHz, CD3CN): δ (ppm) = −72.75 (d, J = 706.3 Hz, 6 F); 31 P NMR (202 MHz, CD3CN): δ (ppm) = −144.59 (sept, J = 706.7 Hz, 1 P).

6.2.3.2 Homoleptic Ferrocenes General procedure for the synthesis of homoleptic ferrocenes: The corresponding cyclopentadiene (1.0 equiv.) was dissolved at r.t. in THF to afford a 1 M solution. A dispersion of NaH in mineral oil (60 %, 1.2 equiv.) was added to the solution which was then stirred for 3 h at the same temperature. FeBr2 (0.48 equiv.) was added to the mixture which was then heated to 65 ◦C for 3 h and then stirred for 19 h at r.t. The solvent was removed in vacuo and replaced with CH2Cl2. Water was added, the phases separated and the aqueous layer extracted three times with CH2Cl2. The combined organic layers were dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography.

Bis((1-cyano-2-methoxy-3,4- dimethyl-5-phenyl)cyclopentadienyl)iron(II) (41) 13 . 12 The title compound was obtained from cyclopentadiene 14 (138.6 mg, 0.615 mmol) 11 following the general procedure. The crude 10 7 Ph 8 4 3 2 CN product was purified by column chromatog- CN 6 raphy (SiO2, CH2Cl2) affording 108.4 mg 9 5 1 OMe OMe Fe Fe (0.215 mmol, 72 %) as a bright red solid. OMe Ph CN During the reaction a 1:1 ratio of both CN OMe diastereomers was produced which was al- Ph tered during the column to a 7:3 ratio. It was not further possible to assign the two rac meso diastereomers by NMR spectroscopy. −1 Rf (SiO2, CH2Cl2) = 0.56, 0.63; IR (neat, ν/˜ cm ) = 3057, 2984, 2922, 2861, 2215, 1735, 1626, 1600, 1578, 1485, 1450, 1395, 1384, 1362, 1266, 1214, 1139, 1105, 1079, 1032, 999, 986, 917, 844, 825, 758, 735, 699, 672, 651, 631; HRMS (MALDI, m/z ) = + + exact mass calculated for C30H28FeN2O2 ([M] ) 504.1500, found 504.1494. 1 Major diastereomer: H NMR (400 MHz, Acetone d6): δ (ppm) = 7.25–7.22 (m, 4 H, H-C(11)), 7.20–7.16 (m, 2 H, H-C(13)), 7.10–7.05 (m, 4 H, H-C(12)), 3.87 (s, 6 H, H-C(6)), 1.97 (s, 6 H, H-C(8)), 1.89 (s, 6 H, H-C(9)); 13C{1H} NMR (101 MHz, Acetone d6): δ (ppm) = 132.2 (2 C, C(10)), 130.8 (4 C, C(11), 128.6 (4 C, C(12)), 128.0 (2 C, C(13)), 124.8 (2 C, C(1)), 118.7 (2 C, C(2) or C(7)), 85.9 (2 C, C(3)), 81.8 (2 C, C(4)), 79.0 (2 C, C(5)), 61.6 (2 C, C(6)), 46.4 (2 C, C(2) or C(7)), 9.3 (2 C, C(8)),

100 Experimental

7.5 (2 C, C(9)). 1 Minor diastereomer: H NMR (400 MHz, Acetone d6): δ (ppm) = 7.66–7.63 (m, 4 H, H-C(11)), 7.45–7.36 (m, 6 H, H-C(12), H-C(13)), 3.80 (s, 6 H, H-C(6)), 1.96 (s, 6 13 1 H, H-C(8)), 1.80 (s, 6 H, H-C(9)); C{ H} NMR (101 MHz, Acetone d6): δ (ppm) = 133.1 (2 C, C(10)), 130.8 (4 C, C(11)), 129.0 (6 C, C(12), C(13)), 125.1 (2 C, C(1)), 118.6 (2 C, C(2) or C(7)), 85.6 (2 C, C(3)), 81.5 (2 C, C(4)), 78.3 (2 C, C(1)), 61.5 (2 C, C(6)), 46.0 (2 C, C(2) or C(7)), 10.1 (2 C, C(8)), 7.6 (2 C, C(9)). Bis((1-cyano-2-methoxy-3,4,5- trimethyl)cyclopentadienyl)iron(II) (42). The title compound was obtained 10 7 3 from cyclopentadiene 24 (408.0 mg, 2.45 8 4 2 CN CN mmol) following the general procedure. 9 5 1 OMe 6 OMe The crude product was purified by column Fe Fe OMe CN chromatography (SiO2, CH2Cl2) affording 232.5 mg (0.611 mmol, 51 %) as a CN OMe bright red solid. A 1:1 ratio of the two diastereomers had been obtained. It was not further possible to tell to which rac meso diastereomer the NMR resonances belong to and the resolution insufficient to connect and assign the individual spin systems. 1 Rf (SiO2, CH2Cl2) = 0.43; H NMR (400 MHz, acetone d 6): δ (ppm) = 3.79 (s, 6 H, H-C(6)), 3.77 (s, 6 H, H-C(6)), 1.89 (s, 6 H, H-C(10)), 1.87 (s, 6 H, H-C(10)), 1.85 (s, 6 H, H-C(9)), 1.84 (s, 6 H, H-C(9)), 1.81 (s, 6 H, H-C(8)), 1.79 (s, 6 H, H-C(8)); 13C{1H} NMR (101 MHz, acetone d 6): δ (ppm) = 124.1 (2 C, C(1)), 124.0 (2 C, C(1)), 118.5 (2 C, C(7)), 118.3 (2 C, C(7)), 81.5 (2 C, C(4)), 81.5 (2 C, C(4)), 80.7 (2 C, C(3)), 80.1 (2 C, C(3)), 77.3 (2 C, C(5)), 76.7 (2 C, C(5)), 61.2 (2 C, C(6)), 61.1 (2 C, C(6)), 46.5 (2 C, C(2)), 46.5 (2 C, C(2)), 9.5 (2 C, C(10)), 9.4 (2 C, C(10)), 8.7 (2 C, C(8)), 8.6 (2 C, C(8)), 7.6 (2 C, C(9)), 7.5 (2 C, C(9)); IR (neat, ν/˜ cm−1) = 3055, 2954, 2919, 2855, 2212, 1717, 1642, 1577, 1491, 1453, 1381, 1359, 1265, 1208, 1162, 1091, 1054, 1028, 1001, 968, 872, 805, 736, 703, 644, 627; HRMS (MALDI, m/z ) = exact mass + + calculated for C20H24FeN2O2 ([M] ) 380.1187, found 380.1181.

6.2.3.3 Heteroleptic Ferrocenes General procedures for the synthesis of heteroleptic ferrocenes Method A: The corresponding cyclopentadiene (1.0 equiv.) was dissolved ar r.t. in THF to afford a 0.1 M solution. At the same temperature a solution of nBuLi in hexane (1.6 M, 1.5 equiv.) was added dropwise and the resulting solution stirred for 1 h. In a separate flask, reagent 40 (1.1 equiv.) was suspended at r.t. in THF to afford a 0.1 M solution which was then cooled to 0 ◦C. To the latter was added dropwise a KOtBu solution in THF (1 M, 2.2 equiv.) at the same temperature, affording an intense blue solution which was stirred for 20 min. The solution containing the lithiated cyclopentadiene was transferred at 0 ◦C to the one of deprotonated reagent 40. The resulting mixture was then ◦ heated to 60 C for 4 h, cooled to r.t. and quenched by the addition of an aqueous NH4Cl solution (sat.). The phases were separated and the aqueous layer extracted with MTBE. The combined organic layers were dried over MgSO4 and concentrated in vacuo to afford

101 Experimental the crude product which was purified by column chromatography.

Method B: A dispersion of NaH in mineral oil (60 %, 3.0 equiv.) was placed in a flask equipped with a Dimroth condenser and then washed three times with hexane. The oil-free NaH was suspended in 1,4-dioxane to afford a 0.1 M solution with respect to the cyclopentadiene (1.0 equiv.) which was added subsequently at r.t. The mixture was then heated to 100 ◦C for 20 min. At the same temperature the first portion of reagent 40 (1 equiv.) was added yielding an intense blue mixture. After 1 h the second portion of 40 (1.5 equiv.) was added and the mixture kept stirring at 100 ◦C for further 1.5 h. The mixture was then allowed to cool to r.t. and treated with an aqueous NH4Cl solution (sat.). The layers were separated and the aqueous phase extracted with MTBE. The combined organic layers were washed with brine, dried over MgSO4 and concentrated in vacuo. The crude product was purified by column chromatography.

Method C: According to Table 4.1 on page 51, a dispersion of NaH in mineral oil (60 %, 1.1 equiv.) was added to a 0.1 M solution of the corresponding cyclopentadiene (1 equiv.) in MeCN at r.t. and the resulting mixture stirred for 0.5 h. Afterwards one of reagents (43, 44, 45) was added to the mixture which was irradiated with a xenon arc lamp (75 W) or a halogen bulb (150 W). The reactions were quenched by addition of an aqueous NH4Cl solution (sat.) and the phases separated. The aqueous layer was extracted with CH2Cl2, the combined organic phases dried over MgSO4 and concentrated in vacuo.

1-Cyano-2-methoxy-3,4-dimehtyl-5-phenylferrocene (46). The title compound was obtained 14 8 from cyclopentadiene (2 g, 8.9 mmol) according 7 9 3 to general method B. The crude product was 4 2 OMe 10 purified by column chromatography 2(SiO , hex- 5 1 CN ane/MTBE 9:1) which afforded 2.51 g (7.3 mmol, 13 Fe 6 11 82 %) of the title product as a red crystalline solid. 12 Single crystals suited for X-ray diffraction were 14 obtained from a pentane solution at −20 ◦C. ◦ 1 Rf (SiO2, Hexane/MTBE 9:1) = 0.23; m.p. = 107-109 C; H NMR (500 MHz, CDCl3): δ (ppm) = 7.6 (d, J = 7.2 Hz, 2 H, H-C(11)), 7.39 (t, J = 7.5 Hz, 2 H, H-C(12)), 7.33 (t, J = 7.4 Hz, 1 H, H-C(13)), 4.18 (s, 5 H, H-C(14)), 3.97 (s, 3 H, H-C(7)), 2.06 (s, 3 H, H-C(8) or H-C(9)), 2.06 (s, 3 H, H-C(8) or H-C(9)); 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) = 134.4 (1 C, C(10)), 130.4 (2 C, C(11)), 128.3 (2 C, C(12)), 127.6 (1 C, C(13)), 125.2 (1 C, C(2)), 120.4 (1 C, C(1) or C(6)), 83.4 (1 C, C(5)), 79.5 (1 C, C(3) or C(4)), 77.0 (1 C, C(3) or C(4)),8 73.8 (5 C, C(14)), 61.2 (1 C, C(7)), 12.5 (1 C, C(8) or C(9)), 10.3 (1 C, C(8) or C(9)); IR (neat, ν/˜ cm−1) = 3088, 3058, 2977, 2953, 2918, 2868, 2215, 1600, 1486, 1392, 1362, 1106, 1001, 823, 701; HRMS (MALDI, m/z + + ) = exact mass calculated for C20H19FeNO ([M] ) 345.0811, found 345.0810.

8This resonance is obscured by the solvent signal and was thus identified via HMBC technique.

102 Experimental

1-Cyano-2-methoxy-3,4,5-trimehtylferrocene (47). 8 The title compound was obtained form cyclopentadiene 7 9 3 24 (81.6 mg, 0.5 mmol) according to general method A. 4 2 OMe The crude product was purified by column chromatography 10 5 1 CN (SiO2) first eluting with hexane to remove ferrocene and Fe 6 fluorene and then with hexane/EtOAc 1:1. In this way61 mg (0.22 mmol, 43 %) of the title compound were collected 11 as a red solid. Single crystals suited for X-ray diffraction were obtained from a pentane solution at −20 ◦C. 1 Rf (SiO2, hexane/EtOAc 4:1) = 0.55 H NMR (400 MHz, CDCl3): δ (ppm) = 4.09 (s, 5 H, H-C(11)), 3.90 (s, 3 H, H-C(7)), 2.05 (s, 3 H, H-C(10)), 1.94 (s, 3 H, H-C(8)), 1.92 13 1 (s, 3 H, H-C(9)); C{ H} NMR (101 MHz, CDCl3): δ (ppm) = 124.4 (1 C, C(2)), 120.5 (1 C, C(6)), 79.9 (1 C, C(4)), 78.7 (1 C, C(1)), 76.0 (1 C, C(3)), 72.9 (5 C, C(11)), 61.1 (1 C, C(7)), 40.4 (1 C, C(1)), 11.8 (1 C, C(10)), 11.3 (1 C, C(9)), 10.2 (1 C, C(8)); IR (neat, ν/˜ cm−1) = 3097, 2973, 2915, 2210, 1728, 1647, 1577, 1488, 1390, 1058, 821; + + HRMS (MALDI, m/z ) = exact mass calculated for C15H17FeNO ([M] ) 283.0660, found 283.0654.

2-Methoxy-3,4,5-trimethyl-5-(p- tolyl)cyclopenta-1,3-diene-1-carbonitrile (48). The title compound was OMe the major product from the reaction of cyclopentadiene 24 with reagent 45 CN according to general method C. The molecule was isolated by column chromatography (SiO2, hexane/EtOAc 4:1) as a yellow oil. 1 Rf (SiO2, hexane/EtOAc 4:1) = 0.55 H NMR (400 MHz, CDCl3): δ (ppm) = 7.09 (d, J = 8.2 Hz, 2 H), 7.00 (d, J = 8.2 Hz, 2 H), 4.19 (s, 3 H), 2.30 (s, 3 H), 1.79–1.78 (m, br, J = 0.9 Hz, 3 H), 1.65–1.64 (m, br J = 0.9 Hz, 3 H), 1.57 (s, 3 H).

1-Cyano-2-methoxy-3,4-dimehtyl-5-mesityl- ferrocene (49). The title compound was obtained from cyclopentadiene 25 (2.37 g, 8.9 mmol) 18 8 7 9 3 according to general method B. The crude product 17 4 2 16 OMe was purified by column chromatography (SiO2, 10 5 15 1 CN hexane/MTBE 9:1) which afforded 2.04 g (7.85 Fe 6 % 14 mmol, 88 ) of the title product as a red crystalline 13 12 solid. Single crystals suited for X-ray diffraction 11 19 were obtained from a 50:1 CH2Cl2/hexane solution at −20 ◦C. ◦ 1 Rf (SiO2, hexane/MTBE 9:1) = 0.31; m.p. = 162-166 C; H NMR (500 MHz, CDCl3): δ (ppm) = 6.96 (s, 1 H, H-C(13)), 6.81 (s, 1 H, H-C(16)), 4.24 (s, 5 H, H-C(19)), 3.94 (s, 3 H, H-C(7)), 2.98 (s, 3 H, H-C(11)), 2.27 (s, 3 H, H-C(14)), 2.13 (s, 3 H, H-C(8)), 1.71 13 1 (s, 3 H, H-C(18)), 1.68 (s, 3 H, H-C(9)); C{ H} NMR (126 MHz, CDCl3): δ (ppm) = 139.7, (1 C, C(17)), 137.2, (1 C, C(15)), 136.8, (1 C, C(12)), 129.3, (1 C, C(13)), 128.8, (1 C, C(16)), 126.9, (1 C, C(10)), 124.2, (1 C, C(2)), 120.2, (1 C, C(1) or C(6)), 84.3, (1 C, C(5)), 80.5, (1 C, C(4)), 75.3, (1 C, C(3)), 74.2, (5 C, C(19)), 60.6, (1 C, C(7)), 40.5, (1 C, C(1) or C(6)), 22.5, (1 C, C(11)), 21.1, (1 C, C(18)), 21.0, (1 C, C(14)), 11.9, (1

103 Experimental

C, C(8)), 10.6, (1 C, C(9)); IR (neat, ν/˜ cm−1) = 3010, 2961, 2952, 2918, 2857, 2733, 2215, 1735, 1609, 1568, 1482, 1441, 1389, 1351, 1263, 1208, 1108, 1032, 1007, 998; + + HRMS (MALDI, m/z ) = exact mass calculated for C23H25FeNO ([M] ) 387.1297, found 387.1280.

1-Cyano-2-methoxy-3,4-dimehtyl-5-- (2,4,6-triisopropylphenyl)ferrocene (50). The title compound was obtained 24 23 26 from cyclopentadiene (175.8 mg, 0.5 8 22 7 mmol) according to general method B. 9 3 21 4 2 OMe The crude product was purified by column 20 10 5 1 chromatography (SiO2, hexane/MTBE CN 6 16 Fe 4:1) affording 30.6 mg (0.065 mmol, 19 17 11 15 12 13 %) of the title compound as a red solid. 18 25 Single crystals suited for X-ray diffraction 14 13 were obtained from a 1:1 CH2Cl2/pentane solution at −20 ◦C. 1 Rf (SiO2, hexane/MTBE 4:1) = 0.39; H NMR (500 MHz, CDCl3): δ (ppm) = 7.06 (d, J = 1.7 Hz, 1 H, H-C(15)), 6.87 (d, J = 1.7 Hz, 1 H, H-C(20)), 5.57 (sept, J = 6.9 Hz, 1 H, H-C(12)), 4.27 (s, 5 H, H-C(25)), 3.93 (s, 3 H, H-C(7)), 2.87 (sept, J = 6.9 Hz, 1 H, H-C(17)), 2.14 (s, 3 H, H-C(8)), 1.74 (sept, J = 6.8 Hz, 1 H, H-C(22)), 1.64 (s, 3 H, H-C(9)), 1.44 (d, J = 6.9 Hz, 3 H, H-C(13) or H-C(14)), 1.40 (d, J = 6.9 Hz, 3 H, H-C(13) or H-C(14)), 1.26 (d, J = 6.9 Hz, 6 H, H-C(18), H-C(19)), 0.93 (d, J = 6.9 Hz, 3 H, H-C(23) or H-C(24)), 0.91 (d, J = 6.9 Hz, 3 H, H-C(23) or H-C(24)); 13C{1H} NMR (126 MHz, CDCl3): δ (ppm) = 150.3 (1 C, C(21)), 148.5 (1 C, C(16)), 146.6 (1 C, C(11)), 124.2 (1 C, C(10)), 123.8 (1 C, C(2)), 121.3 (1 C, C(20)), 121.0 (1 C, C(15)), 120.0 (1 C, C(5)), 84.2 (1 C, C(1) or C(6)), 81.5 (1 C, C(4)), 75.0 (1 C, C(3)), 74.0 (1 C, C(25)), 60.8 (1 C, C(7)), 41.8 (1 C, C(1) or C(6)), 34.1 (1 C, C(17)), 30.2 (1 C, C(22)), 29.1 (1 C, C(12)), 25.9 (1 C, C(13) or C(14)), 25.1 (1 C, C(13) or C(14)), 24.9 (1 C, C(23) or C(24)), 24.1 (1 C, C(23) or C(24)), 24.05 (1 C, C(18) or C(19)), 24.04 (1 C, C(18) or C(19)), 12.2 (1 C, C(9)), 10.6 (1 C, C(8)); IR (neat, ν/˜ cm−1) = 2958, 2926, 2867, 2219, 1724, 1673, 1608, 1568, 1477, 1461, 1395, 1382, 1361, 1313, 1209, 1194, 1167, 1141, 1109, 1002, 878, 823.

1-Cyano-3,4-dimethyl-2-phenylferrocene (51). The title compound was obtained from cyclopentadiene 22 (1.56 g, 8 mmol) according to general method B, except that 22 7 8 3 4 was deprotonated at r.t. over 50 min and that the 1.5 equiv. 2 9 of 40 were added in one portion and the reaction quenched 5 1 CN after 1 h at 100 ◦C. The crude product was purified by col- 12 Fe 6 10 umn chromatography (SiO2, hexane/MTBE 9:1). Fractions 11 containing the product were combined and concentrated in 13 vacuo. The afforded red solid was recrystallized by dissolving in hot hexane (45 mL), allowing to cool to r.t. and then to crystallize at 5 ◦C over night. The afforded brick red needles were filtered off and washed with pentane. In this manner 1.4 g (4.43 mmol, 55 %) of the title product was collected as large needles. ◦ 1 Rf (SiO2, hexane/MTBE 9:1) = 0.31; m.p. = 135-136 C; H NMR (400 MHz, CDCl3): δ (ppm) = 7.64–7.61 (m, 2 H, H-C(10)), 7.43–7.39 (m, 2 H, H-C(11)), 7.36–7.32 (m,

104 Experimental

1 H, H-C(12)), 4.65 (s, 1 H, H-C(2)), 4.16 (s, 5 H, H-C(13)), 2.10 (s, 3 H, H-C(8)), 13 1 2.06 (s, 3 H, H-C(7)); C{ H} NMR (101 MHz, CDCl3): δ (ppm) = 134.8 (1 C, C(9)), 130.1 (2 C, C(10)), 128.3 (2 C, C(11)), 127.6 (1 C, C(12)), 120.8 (1 C, C(6)), 90.7 (1 C, C(5)), 86.1 (1 C, C(3)), 84.7 (1 C, C(4)), 73.2 (5 C, C(13)), 71.2 (1 C, C(2)), 49.9 (1 C, C(1)), 13.4 (1 C, C(8)), 12.5 (1 C, C(7)); IR (neat, ν/˜ cm−1) = 3088, 3058, 2975, 2954, 2916, 2868, 2218, 1786, 1729, 1664, 1601, 1575, 1505, 1449, 1411, 1389, 1107, + + 1002; HRMS (MALDI, m/z ) = exact mass calculated for C19H17FeN ([M] ) 315.0705, found 315.0705.

6.2.4 Deprotonation Experiments General procedure for the attempted deprotonation of heteroleptic ferrocenes The corresponding heteroleptic ferrocene (1.0 equiv.) was dissolved at r.t. in THF to afford a 0.1 M solution which was then cooled to −78 ◦C. To this mixture was added the corresponding organolithium base. Organolithium/TMEDA combinations were prepared separately at 0 ◦C and then transferred to the ferrocene solution kept at −78 ◦C. The organolithium bases were used as solutions: nBuLi in hexane (1.6 M), sBuLi in cyclohexane (1.4 M), tBuLi in pentane (1.9 M) and iPrLi in pentane (0.7 M). After addition, stirring ◦ was continued for 2 h at −78 C and the reactions then quenched with CD3OD (0.7 mL) at the same temperature. The mixtures were allowed to warm to r.t. and then directly analyzed by GC-MS

Table 6.1: Results and conditions of the reactions of ferrocenes 49 and 46 with organolithium bases. Samples were analyzed by GC-MS and corresponding retention times and mass to charge ratios of the formed imines are reported.

NH NH NH NH NH NH Ph Ph Ph Mes Mes Mes nBu sBu iPr nBu sBu tBu OMe OMe OMe OMe OMe OMe Fe Fe Fe Fe Fe Fe

55 57 58 54 56 59 calculated 403.16 389.14 445.21 masses [g/mol]

a + Substrate Base (equiv.) Additive (equiv.) Product yield/% m/z ([M] ) tr/min 49 nBuLi (1.3) TMEDA (1.4) 54 21 445.3 14.3-15.6 46 nBuLi (1.3) TMEDA (1.4) 55 67 403.2 14.22 49 sBuLi (1.3) TMEDA (1.4) 56 -b 445.3 14.0-15.0 46 sBuLi (1.3) TMEDA (1.4) 57 52 403.2 14.04 46 iPrLi (1.3) TMEDA (1.4) 58 -b 389.2 13.73 49 tBuLi (2) none 59 66 403.3 14.26 a Conversion with respect to substrates determined by uncalibrated GC-MS. b Imine and substrate species coeluted on GC-MS.

105 Experimental

Deprotonation experiments with Schlosser’s base

18 H/D 8 7 9 3 17 4 2 16 OMe 10 5 15 1 CN 6 14 Fe 13 12 11 19

To a solution of heteroleptic ferrocene 49 (193.6 mg, 0.5 mmol, 1.0 equiv.) in THF (5 mL) was added at r.t. a solution of KOtBu in THF (1 M, 0.13 mL, 0.063 mmol, 0.125 equiv.). The afforded red solution was cooled to −78 ◦C and a solution of tBuLi in pentane (1.9 M, 0.53 mL, 1.0 mmol, 2.0 equiv.) was added dropwise over 1 min yielding immediately an intense dark red solution. After 2 h, CDOD3 (0.7 mL) was added to the mixture which was then allowed to warm to r.t. and finally treated with H2O (5 mL). The phases were separated and the aqueous layer extracted with MTBE (20 mL). The combined organic layers were washed with H2O (3 x 10 mL), dried over MgSO4 and concentrated in vacuo. The title compound was purified by column chromatography (SiO2, hexane/MTBE 4:1) in order to obtain a clean sample for NMR analysis. A 33:67 mixture of 49 and deuterated 49-d was detected by 1H integration. The following table compares the 1H (500 MHz) and 13C{1H} (126 MHz) NMR signals of the obtained sample with the one of pure 49

1H(δ/ppm) 49 49 and 49-d Assignment 6.96 6.97 H-C(13) 6.81 6.82 H-C(16) 4.24 4.25 H-C(19) 3.94 3.95 H-C(7) 2.98 2.99 H-C(11) 2.27 2.28 H-C(14) 2.13 2.14 H-C(8) - 2.12 t, J=1.9 Hz, C(8)H2D 49-d 1.71 1.72 H-C(18) 1.68 1.69 H-C(9)

106 Experimental

13C{1H} (δ/ppm) 49 49 and 49-d Assignment 139.7 139.7 C(17) 137.2 137.1 C(15) 136.8 136.7 C(12) 129.3 129.2 C(13) 128.8 128.8 C(16) 126.9 126.8 C(10) 124.2 124.17 C(2) - 124.16 C(2) 49-d 120.2 120.1 C(1) or C(6) 84.3 84.2 C(5) 80.5 80.4 C(4) 75.3 75.23 C(3) - 75.18 C(3) 49-d 74.2 74.18 C(19) - 74.10 possible impurity (small intensity) 60.6 60.6 C(7) 40.5 40.4 C(1) or C(6) 22.5 22.5 C(11) 21.1 21.04 C(18) 21.0 20.94 C(14) 11.9 11.9 C(8) 10.6 10.6 C(9) - 10.3 t, J=19.7 Hz, C(8)H2D 49-d

107

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[358] Sheldrick, G. M.; SHELXL-97 Program for Crystal Structure Refinement; 1999.

[359] Blessing, R. H. Acta Crystallogr. Sect. A. 1995, 51, 33–38.

[360] Flack, H. D. Acta Crystallogr. Sect. A 1983, 39, 876–881.

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[362] Acta Crystallographica Section C 2010, 66, e1–e8.

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125

Appendix A: Monitoring the Oxidative Coupling of 2-Butanone

O O O O PbO2 + + 100-120 °C O O O 4 4a 4b 6 4a or 4b (4.47 min) 4a or 4b (4.52 min) 4 (4.99 min)

5 4 (5.22 min) 4 f e r A 3 i A 2 1 0

0 20 40 60 80 t h

Figure A.1: Monitoring the reaction between 2-butanone and PbO2 yielding diketone 4 as a mixture of two diastereomers (red and dark red dots) alongside byproducts 4a and 4b. The vertical dashed line denotes the point in time where the bath temperature was incremented to 120°. Aliquots were analyzed by GC-MS and the total ion currents referenced to adamantane as internal standard. Retention times and molecular ions: 4.47 min, m/z =142.1, 124.1, 109.1, 99.1, 55.1, 43.1; 4.52 min, m/z =142.1, 99.1, 55.1, 43.1; 4.99 min, m/z =142.1, 100.1, 85.1, 43.1; 5.22 min, m/z =142.1, 100.1, 85.1, 43.1.

127 Appendix B: Attempted Synthesis of Technetium Complexes

The group of Prof. Roger Alberto from the University of Zurich¨ (UZH) has devoted significant resources towards the successful synthesis, application and investigation of cyclopentadienyl complexes for radiopharmaceutical use.[363–365] During a conversation with Prof. Alberto in 2015, he became interested in our ligands since complexes thereof could be soluble in aqueous media. With pleasure, we supplied him with samples of ligands 14 and 24 and his doctoral student Angelo Frei attempted the synthesis of the corresponding technetium compounds (Scheme B.1).

OMe R [99mTc(CO) (H O) ]+ CN 3 2 3 undefined CN + 99m - OMe 99m [ TcO4] 99mTc Base Tc species OC CO R Microwave OC

14, R=Ph not formed 24, R=Me

Scheme B.1: Attempted synthesis of technetium complexes of ligands 14 and 24 by Angelo Frei in the Group of Prof. Roger Alberto at UZH.

The ligands were reacted in a microwave under alkaline conditions with a technetium precursor and the resulting mixture analyzed by HPLC coupled with γ-detection. In all attempts, and based on the retention times, the chromatograms showed the formation of – [TcO4] and an additional broad signal (usually eluting for 10 min). Their interpretation of these results is that the target compound had not been formed since, in their experience such species elute at other retention times. As a possible explanation, they assume that the solubility of the supplied ligands might have been insufficient to enable a successful reaction.

We are grateful to Prof. Roger Alberto and his group for their interest and efforts in this matter.

128 Appendix C: Towards an Enantiopure Polysubstituted Cy- clopentadiene

To further demonstrate the versatility of our synthetic sequence we attempted the synthesis of a more complex polysubstituted cyclopentadiene. For this reason the synthesis of pinene-derived cyclopentadiene 60 was proposed (Scheme C.1).

OMe O CN H

Ph 60 Myrtenal

Scheme C.1: Envisaged natural pool-derived cyclopentadiene 60 to be obtained form myrtenal.

At first, the conversion of commercially available myrtenal to the corresponding carboxylic acid was required. A three step transformation had been published which would have yielded the required acid 61 via the corresponding nitrile.[366–369] For obvious reasons we preferred to do the same in a single transformation via Pinnick oxidation (Scheme C.2).[370]

O NaO2Cl, NaH2PO4 O O DMSO H2SO4 H OH OMe MeCN, MeOH, H2O MeOH, 65 °C r.t. 95% yield Myrtenal 61 88% yield 62

Scheme C.2: Oxidation of Myrtenal to the corresponding carboxylic acid 61 and subsequent esterification yielding compound 62.

Myrtenal was converted in excellent 95 % yield to carboxylic acid 61 by using sodium chlorite in conjunction with DMSO as scavenger for formed hypochlorous acid. Esterifica- tion of acid 61 in methanol afforded ester 62 in good 88 % yield which was then reacted with acetonitrile under alkaline conditions yielding oxo nitrile 63 as well in good quantity (88 %)(Scheme C.3)

1) PhCHO HOAc (cat.) NaH O piperidine (cat.) O O MeCN benzene, 100 °C MsOH 62 CN CN CN

THF, 70 °C 2) NaHSO3, H2O CH2Cl2, r.t. r.t. Ph Ph 88% yield 63 95% yield 64 21% yield 34

Scheme C.3: Application of the second generation synthetic sequence to ester 62 affording 34.

The Knoevenagel condensation between substrate 63 and benzaldehyde proceeded smoothly and we received diene 64 in high 95 % yield. Our streak of luck, however,

129 Appendix C was soon over as the subsequent Nazarov cyclization only offered cyclopentenone 34 in unsatisfying 21 % yield as a mixture of diastereomers. These species produced together the most complicated NMR spectra within this work (see experimental part for a partial assignment of the NMR resonances). Nonetheless, this did not stop us from continuing with the last required reaction towards cyclopentadiene 60 (Scheme C.4).

O HC(OMe)3, p-TsOH OMe MeOH, 60 °C CN CN or Ph HC(OMe)3, H2SO4 Ph (in situ Me2SO4) 34 100 °C 60

Scheme C.4: Attempted O-methylation of cyclopentenone 34.

Annoyingly, this last step did not work neither under the standard conditions with p-TsOH , nor when heating cyclopentenone 34 in neat H(COMe)3 and H2SO4. The only hint that this transformation is still feasible, was offered to us by GC-MS analysis which revealed the presence of two new species of correct mass. Given the fused stereogenic pinene fragment, the formation of two diastereomers is expected to take place when 60 is formed. We are certain that this last reaction could be achieved under appropriate circumstances, e.g. with methyl triflate.

130 Appendix D: Abbreviations and Acronyms

Ac Acetyl Ar Aryl acac Acetylacetonato Bu Butyl Bz Benzoyl Cat. Catalyst Cp Cyclopentadienyl (C5H5 ) CCDC The Cambridge Crystallographic Data Centre CSD Cambridge Structural Database DCC N,N′-dicyclohexylcarbodiimide DIBAL Diisobutylaluminum hydride DHP 3,4-Dihydro-2H-pyranyl DMF N,N-dimethylformamide dppe 1,2-Bis(diphenylphosphanyl)ethane dppf 1,1’-bis(diphenylphosphanyl)ferrocene dppp 1,3-Bis(diphenylphosphanyl)propane d.r. Diastereomeric ratio ee Enantiomeric excess EI Electron Ionization ESI Electrospray ionization Et Ethyl FT Fourier transfrom HMBC Heteronuclear multiple bond correlation HSQC Heteronuclear single quantum correlation ICR Ion cyclotron resonance IR Infrared LDA Lithium diisopropylamide

131 Appendix D

MALDI Matrix-assisted laser desorption/ionization Me Methyl Mes Mesityl m.p. Melting Point MTBE Methyl tert-butyl ether Ms Methanesulfonyl NHC N-heterocyclic carbene NMR Nuclear magnetic resonance NOE Nuclear Overhauser effect NOESY Nuclear Overhauser effect spectroscopy Ph Phenyl Pr Propyl quant. Quantitative r.t. Room temperature TBS tert-Butyldimethylsilyl TBDPS tert-Butyldiphenylsilyl Tf Triflyl THP Tetrahydropyranyl TIPS Triisopropylsilyl TMEDA N,N,N′,N′-Tetramethylethane-1,2-diamine TMS Trimethylsilyl TLC Thin layer chromatography Ts Tosyl Trip (2,4,6-Triisopropyl)phenyl sat. Saturated

132 Appendix E: Crystallographic Data

Identification code AL-M56L-180(4) θmin, θmax/° 7.506, 106.4 Empirical formula C21H22N2O2 Completness (to θ/°) 0.995 (53.200) Moiety Formula C21H22N2O2 Limiting Miller indices -16≤h≤16 Formula weight 334.40 -6≤k≤6 Crystal size/mm 0.09 × 0.05 × 0.03 -17≤l≤17 Habitus plate Collected, unique ref. 24231, 2089 Colour white Rint 0.0472 T /K 100 µ/mm−1 0.636 Crystal system Monoclinic F(000) 712.0 Space group P21/n Absorbtion correction Multi-Scan a/A˚ 16.3085(10) Max, min transmission 0.587, 0.751 b/A˚ 6.5974(4) Data 2089 c/A˚ 16.6909(10) Restraints 0 α/° 90 Parameters 230 β/° 91.119(3) Goodness-of-fit on F2 1.093 γ/° 90 Final R1 [I ≥ 2σ(I)] 0.0833 3 V /A˚ 1795.49(19) Final R1 [all data] 0.0908 −3 Z 4 ∆ρmax, ∆ρmin /e A˚ 0.57, -0.27 −3 ρcalc/g cm 1.237

133 Appendix E

47 a l m 5 6 l 1 8 0 4 O 11.806691 6.733306 12.140481 O 10.433974 6.081483 6.940421 N 14.928517 6.392221 10.952149 N 10.679156 2.121064 9.500317 C 13.413912 4.370118 8.257082 C 10.896571 4.600367 8.722670 C 11.527678 5.892138 11.312603 C 12.633122 5.208647 10.491568 H 12.716333 4.269178 10.823653 C 13.833893 3.086264 8.630887 H 13.500297 2.693059 9.428560 C 10.133721 5.378200 11.040593 H 10.115198 4.418939 11.320947 C 13.966103 4.937494 7.122318 H 13.718211 5.820226 6.872002 C 13.916539 5.880263 10.745221 C 12.335995 5.140694 9.004692 H 12.362247 6.080164 8.662594 C 10.784569 3.185225 9.113162 C 9.835159 5.412507 9.543705 H 9.886625 6.365831 9.246664 C 10.457220 3.879931 6.167780 C 11.212108 2.809173 6.177793 H 11.710408 2.631043 6.967122 C 10.588419 4.893292 7.215769 C 15.233594 2.972129 6.688437 H 15.833218 2.489859 6.131067 C 14.738222 2.385620 7.836552 H 15.012273 1.510145 8.083530 C 14.865018 4.242788 6.354683 H 15.237299 4.651167 5.580373 C 9.136370 6.123707 11.921705 H 9.395231 6.026725 12.862892 H 8.240347 5.750294 11.789872 H 9.132942 7.073732 11.679733 C 8.421926 4.917702 9.256677 H 8.289195 4.853707 8.287120 H 7.772004 5.545774 9.633819 H 8.294953 4.034310 9.662188 C 11.353455 1.840675 5.036353 H 11.404164 2.335480 4.193623 H 10.575898 1.243610 5.017996 H 12.169795 1.311563 5.156505 C 9.555084 4.276435 5.012990 H 9.974336 5.002808 4.505684 H 8.690444 4.578596 5.361763 H 9.418183 3.504539 4.423914

134 Appendix E

CCDC number 1835908 θmin, θmax/° 5.748, 54.962 Empirical formula C24H33NO Completness (to θ/°) 0.999 (27.481) Moiety Formula C24H33NO Limiting Miller indices -12≤h≤12 Formula weight 351.51 -22≤k≤22 Crystal size/mm 0.16 x 0.12 x 0.06 -15≤l≤15 Habitus Plate Collected, unique ref. 25231, 4840 Colour Orange Rint 0.0644 T /K 100.0 µ/mm−1 0.066 Crystal system Monoclinic F(000) 768.0 Space group P21/n Absorbtion correction Multi-Scan a/A˚ 9.9920(3) Max, min transmission 1.000, 0.988 b/A˚ 17.3394(5) Data 4840 c/A˚ 12.2097(4) Restraints 0 α/° 90 Parameters 248 β/° 91.256(3) Goodness-of-fit on2 F 1.132 γ/° 90 Final R1 [I ≥ 2σ(I)] 0.0748 3 V /A˚ 2114.89(11) Final R1 [all data] 0.1019 −3 Z 4 ∆ρmax, ∆ρmin /e A˚ 0.34, -0.23 −3 ρcalc/g cm 1.104

135 Appendix E

59 r l 0 3 5 O 10.122801 14.989218 10.030544 N 6.766871 13.603973 11.972763 C 4.022140 10.382486 8.916066 C 8.110838 13.565826 9.783235 C 5.123888 12.525289 8.522764 C 3.966840 11.748657 8.612728 H 3.139682 12.147984 8.467834 C 6.375223 11.915982 8.735284 C 7.633080 12.720010 8.650325 C 6.444766 10.550505 9.072557 C 5.258123 9.817742 9.145187 H 5.304449 8.912452 9.356486 C 9.284093 14.147043 9.409830 C 2.752462 9.555917 9.038866 H 3.020180 8.641957 9.269818 C 7.389559 13.625994 11.007208 C 5.044571 14.013356 8.175482 H 5.750957 14.469729 8.679011 C 9.753151 15.431026 11.349729 H 8.884540 15.839542 11.318114 H 10.396696 16.070156 11.666007 H 9.730123 14.677802 11.944321 C 7.763000 9.866465 9.423990 H 8.483136 10.519814 9.300335 C 8.514600 12.802373 7.637408 C 9.649385 13.721881 8.015939 C 3.714240 14.665838 8.558164 H 3.011775 14.303271 8.012522 H 3.771274 15.614130 8.417786 H 3.526114 14.488803 9.482216 C 1.964575 9.484478 7.740799 H 1.645877 10.360292 7.510823 H 1.218746 8.891644 7.851392 H 2.532506 9.156937 7.039642 C 9.838014 14.909456 7.068938 H 9.031249 15.428598 7.042084 H 10.039191 14.587637 6.187610 H 10.561551 15.456341 7.382652 C 8.463694 12.105849 6.313340 H 7.688065 11.541105 6.279161 H 9.253499 11.572316 6.202258 H 8.415161 12.758331 5.610230 C 7.772020 9.434714 10.881112 H 7.570940 10.188631 11.438961 H 8.638344 9.091047 11.108157 H 7.110603 8.751195 11.015386 C 5.318879 14.244837 6.693092 H 6.164347 13.854181 6.458600 H 5.343746 15.187580 6.515972 H 4.622876 13.838575 6.171741 C 1.862420 10.068816 10.167016 H 2.365072 10.094999 10.984869 H 1.109693 9.481184 10.273215 H 1.551356 10.951565 9.953397 C 8.049947 8.674555 8.504454 H 7.379591 8.000399 8.636287 H 8.914701 8.310774 8.711969 H 8.037019 8.964470 7.590167 H 10.585282 13.247302 8.032052

136 Appendix E

CCDC number 1835106 θmin, θmax/° 4.552, 60.064 Empirical formula C30H28FeN2O2 Completness (to θ/°) 1.000 (30.032) Moiety Formula C30H28FeN2O2 Limiting Miller indices -24≤h≤24 Formula weight 504.39 -10≤k≤10 Crystal size/mm 0.289 × 0.195 × 0.092 -26≤l≤26 Habitus Prism Collected, unique ref. 26078, 3544 Colour Orange Rint 0.0689 T /K 100 µ/mm−1 0.657 Crystal system Monoclinic F(000) 1056.0 Space group C2/c Absorbtion correction None a/A˚ 17.6417(5) Max, min transmission 0.941, 0.857 b/A˚ 7.6315(2) Data 3544 c/A˚ 18.6616(5) Restraints 0 α/° 90 Parameters 163 β/° 106.502(2) Goodness-of-fit on F2 0.978 γ/° 90 Final R1 [I ≥ 2σ(I)] 0.0336 3 V /A˚ 2408.97(12) Final R1 [all data] 0.0444 −3 Z 4 ∆ρmax, ∆ρmin /e A˚ 0.41, -0.41 −3 ρcalc/g cm 1.391

137 Appendix E

63 al−mcp−005 Fe 6.170447 3.815750 8.946463 O 7.835419 4.579663 6.471155 N 10.277443 3.904352 9.309689 C 5.994049 5.541843 7.841753 C 7.272715 4.959025 7.660140 C 7.921746 4.868744 8.930359 C 5.841472 5.830542 9.236328 C 7.033503 5.418823 9.921806 C 8.603662 6.323690 11.609288 H 9.194556 6.514248 10.916474 C 7.400449 5.671044 11.333737 C 9.222367 4.324771 9.150442 C 6.555660 5.347392 12.395861 H 5.761754 4.891028 12.231604 C 8.923996 6.690536 12.911177 H 9.720509 7.140031 13.083307 C 4.654366 6.518217 9.835383 H 3.873671 5.972412 9.714069 H 4.523383 7.365161 9.402732 H 4.805368 6.657721 10.773330 C 8.065297 6.391381 13.952366 H 8.274319 6.650089 14.820710 C 5.008153 5.806808 6.752253 H 5.001575 5.068079 6.139063 H 5.255019 6.608116 6.283995 H 4.132261 5.915176 7.132120 C 6.889015 5.701494 13.694887 H 6.321756 5.474838 14.396648 C 8.644816 5.625179 5.908423 H 9.026666 5.323734 5.081591 H 9.347959 5.851071 6.521971 H 8.101404 6.399013 5.745418 O 4.505476 3.051837 11.421770 N 2.063452 3.727148 8.583236 C 6.346846 2.089657 10.051172 C 5.068180 2.672475 10.232785 C 4.419148 2.762756 8.962566 C 6.499423 1.800958 8.656597 C 5.307391 2.212677 7.971119 C 3.737233 1.307810 6.283638 H 3.146338 1.117252 6.976452 C 4.940446 1.960456 6.559189 C 3.118528 3.306729 8.742483 C 5.785235 2.284108 5.497065 H 6.579141 2.740472 5.661322 C 3.416899 0.940964 4.981748 H 2.620385 0.491469 4.809618 C 7.686528 1.113283 8.057542 H 8.467223 1.659088 8.178856 H 7.817512 0.266339 8.490193 H 7.535527 0.973779 7.119595 C 4.275597 1.240119 3.940559 H 4.066575 0.981411 3.072215 C 7.332741 1.824692 11.140672 H 7.339320 2.563421 11.753863 H 7.085876 1.023384 11.608930 H 8.208634 1.716324 10.760805 C 5.451879 1.930006 4.198038 H 6.019138 2.156662 3.496278 C 3.696078 2.006321 11.984502 H 3.314228 2.307766 12.811335 H 2.992935 1.780429 11.370954 H 4.239491 1.232487 12.147507

138 Appendix E

CCDC number 1835103 θmin, θmax/° 5.296, 56.704 Empirical formula C15H17FeNO Completness (to θ/°) 0.999 (28.275) Moiety Formula C15H17FeNO Limiting Miller indices -11≤h≤11 Formula weight 283.14 -30≤k≤30 Crystal size/mm 0.217 × 0.195 × 0.127 -9≤l≤9 Habitus Prism Collected, unique ref. 25629, 3207 Colour Red Rint 0.0680 T /K 103.1 µ/mm−1 1.154 Crystal system Monoclinic F(000) 592.0 Space group P21/c Absorbtion correction Multi-Scan a/A˚ 8.3086(5) Max, min transmission 0.579, 0.505 b/A˚ 22.6999(12) Data 3207 c/A˚ 7.3970(4) Restraints 0 α/° 90 Parameters 167 β/° 112.2040(10) Goodness-of-fit on2 F 1.064 γ/° 90 Final R1 [I ≥ 2σ(I)] 0.0364 3 V /A˚ 1291.65(13) Final R1 [all data] 0.0638 −3 Z 4 ∆ρmax, ∆ρmin /e A˚ 0.42, -0.60 −3 ρcalc/g cm 1.456

139 Appendix E

35 al−mcp−010 Fe 0.290319 8.797346 4.643262 N 2.554209 8.847059 8.184606 O 1.051585 6.003216 5.802023 C −1.592703 6.227945 4.390554 H −0.904357 5.609145 4.065936 H −2.032948 6.655611 3.626949 H −2.256595 5.731725 4.913777 C −1.504297 8.548555 5.623278 C −0.560201 9.247258 6.440986 C 0.578257 8.366502 6.613567 C 1.690638 8.646619 7.458668 C 0.324335 7.156143 5.867769 C 2.468193 6.128292 5.730799 H 2.705767 6.748680 5.010340 H 2.865475 5.250487 5.549315 H 2.809784 6.471741 6.583434 C −0.958129 7.273729 5.252091 C −0.703454 10.605393 7.046390 H −1.221022 11.179701 6.443725 H 0.184760 10.995832 7.186784 H −1.167549 10.532754 7.906558 C −2.863742 9.049996 5.224697 H −3.083305 8.721302 4.327548 H −2.862903 10.028816 5.222643 H −3.531671 8.725842 5.863660 C 0.827013 10.596086 3.809804 H 0.762007 11.445290 4.229615 C −0.184809 9.964575 3.031817 H −1.043741 10.321645 2.838006 C 0.310365 8.712222 2.596255 H −0.161777 8.081164 2.065498 C 1.637329 8.558316 3.088660 H 2.208688 7.813306 2.940733 C 1.952697 9.725091 3.844731 H 2.773000 9.892616 4.293990

140 Appendix E

CCDC number 1835104 θmin, θmax/° 5.054, 51.362 Empirical formula C20H19FeNO Completness (to θ/°) 1.000 (25.681) Moiety Formula C20H19FeNO Limiting Miller indices -10≤h≤8 Formula weight 345.21 -19≤k≤19 Crystal size/mm 0.119 × 0.092 × 0.065 -28≤l≤28 Habitus Prism Collected, unique ref. 37160, 6123 Colour Red Rint 0.1296 T /K 105.3 µ/mm−1 0.941 Crystal system Orthorhombic F(000) 1440.0 Space group P212121 Absorbtion correction Multi-Scan a/A˚ 8.4899(3) Max, min transmission 0.876, 0.785 b/A˚ 16.1211(8) Data 6123 c/A˚ 23.5097(12) Restraints 678 α/° 90 Parameters 420 β/° 90 Goodness-of-fit on2 F 1.022 γ/° 90 Final R1 [I ≥ 2σ(I)] 0.0444 3 V /A˚ 3217.7(3) Final R1 [all data] 0.0773 −3 Z 8 ∆ρmax, ∆ρmin /e A˚ 0.32, -0.36 −3 ρcalc/g cm 1.425 Flack parameter -0.009(12)

141 Appendix E

94 almcp011 Fe 2.683997 8.820337 13.952302 O −0.179986 9.406662 15.037509 N 1.262448 12.785644 13.388304 C 1.973902 10.631865 14.587769 C 3.337380 10.407782 15.048559 C 4.204198 7.788103 13.040831 H 5.110071 7.763922 13.327649 C 1.178398 9.566261 15.114386 C 1.973902 7.275452 12.783399 H 1.128308 6.851468 12.869210 C 1.558746 11.807094 13.903637 C 4.471630 11.317012 14.771145 C 3.171827 6.901443 13.449899 H 3.266065 6.180830 14.063503 C 5.781622 12.661512 13.254769 H 5.935289 12.985546 12.375506 C 6.622122 13.041970 14.286845 H 7.353951 13.623942 14.119926 C 3.637073 8.715067 12.128654 H 4.096377 9.427619 11.698427 C 1.988335 8.715067 15.897259 C 5.320620 11.705531 15.803220 H 5.171198 11.379884 16.684834 C 2.271048 8.392645 11.968788 H 1.654682 8.850484 11.411608 C 4.720384 11.810318 13.496919 H 4.151561 11.558829 12.779873 C 3.322098 9.226106 15.873749 C 4.497100 8.595771 16.567286 H 4.384184 7.622056 16.581391 H 4.551435 8.931089 17.486515 H 5.320620 8.821466 16.087688 C −0.772581 9.596891 13.743771 H −0.477981 8.881114 13.141922 H −0.496659 10.464206 13.381721 H −1.748919 9.572709 13.826055 C 6.385254 12.568010 15.558719 H 6.953228 12.830783 16.273414 C 1.505259 7.507596 16.654271 H 0.600236 7.275452 16.355698 H 1.492524 7.705886 17.613467 H 2.108042 6.753129 16.482651 Fe 3.000076 4.654000 8.714340 O 3.130226 3.694956 5.740128 N −0.634196 3.511176 7.409787 C 1.709866 6.101836 8.119310 C 0.339596 4.102820 7.353834 C 1.531578 4.889530 7.344195 C 2.792328 4.638040 6.659358 C 0.640987 6.819225 8.867859 C −0.594293 8.869829 9.229908 H −0.739470 9.785508 9.025374 C 3.052119 6.554839 7.921829 C −1.143590 6.911116 10.473571 H −1.676755 6.477458 11.129492 C 3.687164 7.752637 8.559882 H 3.201541 7.981557 9.380370 H 3.654053 8.510329 7.939226 H 4.620204 7.549511 8.778522 C 0.397327 8.166949 8.569286 H 0.920305 8.603831 7.908663 C −0.152818 6.193727 9.824704 H −0.014433 5.276436 10.031589 C 3.714331 5.643997 7.043506 C −1.375364 8.249167 10.186753 H −2.058801 8.727964 10.638139 C 5.135541 5.729439 6.568610 H 5.672102 6.217908 7.226882 H 5.165255 6.200175 5.708155 H 5.498059 4.825045 6.458115 C 2.369531 3.258074 10.120926 H 1.496769 2.896962 10.222018 C 2.866190 4.430078 10.753337 H 2.383964 4.989480 11.348132 C 4.210990 4.615471 10.334864 H 4.785757 5.323187 10.602875 C 4.545492 3.559539 9.446197 H 5.383446 3.435406 9.015970 C 3.406997 2.719630 9.314543 H 3.350115 1.936144 8.780873 C 2.281236 2.566479 5.604712 H 2.703184 1.908738 5.014619 H 1.422907 2.846986 5.223855 H 2.130965 2.163452 6.486326 C 2.691298 4.273704 10.727476 H 1.984939 4.612247 11.265848 C 3.973273 4.858900 10.572312 H 4.279759 5.655282 10.990785 C 4.724629 4.041560 9.685996 H 5.618616 4.196322 9.403880 C 3.905354 2.951773 9.291033 H 4.150712 2.250506 8.700940 C 2.646302 3.095251 9.937550 H 1.905134 2.506831 9.852915

142 Appendix E

CCDC number 1835107 θmin, θmax/° 5.722, 56.564 Empirical formula C19H17FeN Completness (to θ/°) 0.999 (28.282) Moiety Formula C19H17FeN Limiting Miller indices -11≤h≤10 Formula weight 315.18 -20≤k≤22 Crystal size/mm 0.15 × 0.15 × 0.05 -27≤l≤19 Habitus Needle Collected, unique ref. 11439, 3641 Colour Red Rint 0.0368 T /K 100 µ/mm−1 1.017 Crystal system Orthorhombic F(000) 1312.0 Space group Pbca Absorbtion correction Multi-Scan a/A˚ 8.5129(3) Max, min transmission 0.859, 0.950 b/A˚ 16.6410(5) Data 3641 c/A˚ 20.7675(12) Restraints 0 α/° 90 Parameters 192 β/° 90 Goodness-of-fit on2 F 1.094 γ/° 90 Final R1 [I ≥ 2σ(I)] 0.0431 3 V /A˚ 2942.0(2) Final R1 [all data] 0.0573 −3 Z 8 ∆ρmax, ∆ρmin /e A˚ 0.32, -0.33 −3 ρcalc/g cm 1.423

143 Appendix E

38 al−mcp−062 Fe 3.346676 10.938961 12.597150 C 2.817770 10.138696 10.767533 C 2.943761 9.107120 11.746929 C 4.272625 9.141567 12.288545 C 4.954508 10.234381 11.623777 N 7.365361 11.061273 11.983678 C 4.881297 8.243119 13.290992 C 5.850065 8.705240 14.188356 H 6.084170 9.626818 14.190433 C 1.939239 11.231011 14.038622 H 1.236073 10.633599 14.263119 C 4.547591 6.882551 13.327543 H 3.892949 6.543241 12.728401 C 4.050438 10.840613 10.696924 H 4.240275 11.582136 10.132463 C 6.299546 10.679861 11.842044 C 3.230646 11.242826 14.614297 H 3.545623 10.655232 15.291110 C 6.472358 7.841572 15.070975 H 7.139769 8.170731 15.662848 C 5.162223 6.024708 14.229891 H 4.917051 5.107123 14.248582 C 1.872838 12.259758 13.072726 H 1.122000 12.474094 12.531109 C 3.967863 12.279227 14.009963 H 4.867676 12.510704 14.207047 C 6.126734 6.493817 15.097349 H 6.550677 5.902563 15.708537 C 3.137004 12.914914 13.059642 H 3.379621 13.650612 12.508265 C 1.609789 10.429747 9.924788 H 0.803618 10.378992 10.479281 H 1.550199 9.771595 9.202079 H 1.686405 11.329193 9.542666 C 1.821761 8.173726 12.111191 H 1.937536 7.869529 13.035760 H 1.831976 7.400253 11.509349 H 0.966214 8.643335 12.026459

144 Appendix E

CCDC number 1835105 θmin, θmax/° 5.92, 56.55 Empirical formula C23H25FeNO Completness (to θ/°) 0.999 (28.275) Moiety Formula C23H25FeNO Limiting Miller indices -10≤h≤10 Formula weight 387.29 -11≤k≤11 Crystal size/mm 0.5x0.16x0.12 -19≤l≤19 Habitus Prism Collected, unique ref. 18507, 4661 Colour Red Rint 0.0359 T /K 100.01(10) µ/mm−1 0.812 Crystal system Triclinic F(000) 408.0 Space group P -1 Absorbtion correction Multi-Scan a/A˚ 8.2259(5) Max, min transmission 1.000, 0.846 b/A˚ 8.4117(5) Data 4661 c/A˚ 14.3435(8) Restraints 0 α/° 78.978(5) Parameters 241 β/° 76.477(5) Goodness-of-fit on2 F 1.056 γ/° 81.120(5) Final R1 [I ≥ 2σ(I)] 0.0332 3 V /A˚ 940.89(10) Final R1 [all data] 0.0368 −3 Z 2 ∆ρmax, ∆ρmin /e A˚ 0.39, -0.40 −3 ρcalc/g cm 1.367

145 Appendix E

51 r l 0 0 6 Fe 6.832341 3.415504 10.395525 O 6.810108 2.918457 7.345531 N 10.557973 2.463638 8.885048 C 9.334747 5.708380 10.723633 C 8.389322 3.814180 9.145304 C 8.235382 4.911096 10.088475 C 11.177264 7.592268 11.742087 C 7.151788 3.713380 8.397566 C 9.985136 6.618587 9.861525 C 6.907586 5.417698 9.915063 C 6.248027 4.682275 8.888902 C 10.887585 7.539630 10.383965 H 11.308701 8.137004 9.808813 C 6.162519 3.090218 12.310769 H 6.231348 3.686787 13.021072 C 9.583516 3.053056 8.999418 C 5.374108 1.977172 10.470395 H 4.836577 1.714565 9.759267 C 5.089049 3.009695 11.391821 H 4.327393 3.543659 11.394298 C 7.113477 2.104119 11.957614 H 7.917601 1.938790 12.394861 C 9.657173 5.714122 12.088223 C 6.317580 6.571700 10.660048 H 5.444442 6.333167 10.980035 H 6.248041 7.328594 10.074437 H 6.880834 6.793350 11.405309 C 9.699133 6.631755 8.380363 H 9.926961 5.778846 8.003122 H 10.222036 7.318295 7.959081 H 8.766212 6.806722 8.235715 C 6.628198 1.411811 10.824652 H 7.055166 0.710451 10.388231 C 4.849006 4.901122 8.393713 H 4.481328 4.066706 8.093957 H 4.861556 5.525660 7.664555 H 4.307938 5.251106 9.105529 C 12.108426 8.651287 12.292052 H 12.933080 8.638383 11.801680 H 12.285175 8.472199 13.219258 H 11.697857 9.514663 12.204933 C 10.575874 6.658916 12.564832 H 10.788658 6.657358 13.469743 C 9.039757 4.760932 13.074197 H 8.135167 5.027983 13.253665 H 9.544750 4.773198 13.890887 H 9.044885 3.873975 12.707278 C 7.581153 1.742434 7.135509 H 7.127869 1.169304 6.512601 H 7.695293 1.281414 7.970091 H 8.440665 1.982189 6.782353

146 Appendix E

CCDC number 1835108 θmin, θmax/° 2.61, 56.562 Empirical formula C29H37FeNO Completness (to θ/°) 1.000 (28.281) Moiety Formula C29H37FeNO Limiting Miller indices -11≤h≤11 Formula weight 471.44 -13≤k≤13 Crystal size/mm 0.32x0.23x0.11 -21≤l≤21 Habitus Block Collected, unique ref. 49771, 6161 Colour Red Rint 0.0868 T /K 100(2) µ/mm−1 0.630 Crystal system Triclinic F(000) 504.0 Space group P -1 Absorbtion correction Multi-Scan a/A˚ 8.7481(3) Max, min transmission 0.933, 0.840 b/A˚ 9.8874(3) Data 6161 c/A˚ 16.1690(5) Restraints 0 α/° 77.530(2) Parameters 298 β/° 77.216(2) Goodness-of-fit on F2 1.078 γ/° 66.552(2) Final R1 [I ≥ 2σ(I)] 0.0568 3 V /A˚ 1238.41(7) Final R1 [all data] 0.0833 −3 Z 2 ∆ρmax, ∆ρmin /e A˚ 0.86, -0.46 −3 ρcalc/g cm 1.264

147 Appendix E

69 r l 0 4 2 Fe 10.223881 4.068096 13.004252 O 9.903092 1.017169 12.894852 C 8.688913 4.205919 11.593131 C 7.593057 5.100081 11.089048 C 5.491467 6.648668 10.022515 C 5.902142 5.477776 9.408095 H 5.456593 5.195832 8.617793 C 9.953272 4.031909 10.966071 C 6.944217 4.699254 9.902658 C 6.141832 7.025482 11.180813 H 5.878166 7.828938 11.612639 C 8.496771 3.084954 12.486435 C 7.313880 3.411273 9.168382 H 8.197197 3.105085 9.522957 C 7.169342 6.270376 11.737021 C 9.651897 2.232783 12.339112 C 10.545311 2.818873 11.429109 N 6.335083 2.678679 13.743366 C 7.461276 3.599979 7.661127 H 6.585653 3.801023 7.269409 H 7.816991 2.778511 7.261606 H 8.077015 4.341685 7.483215 C 4.385531 7.517774 9.439151 H 3.878307 6.968375 8.775416 C 10.201829 5.162462 14.749503 H 9.427112 5.500873 15.183358 C 10.968808 5.835994 13.766619 H 10.801934 6.707514 13.426090 C 7.776788 6.750792 13.034840 H 8.561007 6.163432 13.232572 C 6.300936 2.316360 9.456943 H 6.224844 2.188571 10.425001 H 6.596577 1.479781 9.040723 H 5.429077 2.572782 9.090663 C 7.315138 2.867157 13.201828 C 12.029009 4.977527 13.380988 H 12.697939 5.172653 12.734731 C 4.959407 8.723337 8.710806 H 5.441157 9.290698 9.348167 H 4.230992 9.235846 8.302545 H 5.576321 8.419269 8.012269 C 3.400364 7.992221 10.513488 H 3.113630 7.227807 11.055495 H 2.618948 8.399051 10.083223 H 3.838260 8.653953 11.088268 C 11.888741 2.274333 11.012577 H 12.527594 3.012671 10.924402 H 11.802261 1.812598 10.151891 H 12.210288 1.643866 11.690671 C 11.918154 3.786309 14.120726 H 12.499564 3.037084 14.058145 C 10.794759 3.892835 14.971425 H 10.491379 3.232788 15.582879 C 10.518944 4.940028 9.917952 H 10.225349 5.859189 10.089466 H 10.203724 4.655514 9.034480 H 11.498140 4.900296 9.944327 C 8.287521 8.171775 12.931371 H 8.883389 8.249569 12.157299 H 8.780620 8.402127 13.747580 H 7.530328 8.784838 12.823687 C 6.785547 6.595509 14.189394 H 5.969129 7.097969 13.987916 H 7.188648 6.942167 15.013250 H 6.566460 5.648152 14.306285 C 9.226502 0.699257 14.087797 H 8.305916 0.433437 13.880233 H 9.215554 1.482685 14.676154 H 9.686537 −0.040424 14.537258

148 Appendix F: Literature Crystal Structures

In the following, X-ray crystal structures of alkoxy- and cyanoferrocenes from the literature are presented. A wireframe representation of each species is depicted alongside with the relevant pararmeters discussed in this work. For clarity, hydrogens as well as solvent molecules (noted by superscript a) and counterions (noted by superscript b) are omitted. The examples can be accessed in digital format on the Cambrdige Structural Database (CSD) using the reported database identifiers, deposition numbers or journal references.

149 Appendix F a,b [ 121 ] [ 148 ] IYISUE/236262 OTOWAW/781731 C30-C29-O29-C34C30’-C29’-O29’-C34’ 69(1) -4(3) [ 121 ] [ 148 ] IYISOY/236261 OTOVUP/781730 [ 147 ] [ 121 ] IYISIS/236260 PAYTIS/1229097 C6-O1-C21C16-O2-C23C7-C6-O1-C21 116.70C17-C16-O2-C23 117.65 8.29 -3.25 C6-O6-C11 C29-O29-C34 C10-C6-O6-C11 C29’-O29’-C34’ 112(1) 165.1(7) 115.9(6) 109(2) [ 213 ] [ 148 ] BOJFIR/978226 ParameterC2-O1O1-C11 ValueC2-O1-C11C1-C2-O1-C11 Parameter 1.366(2) 159.9(2) 115.0(1) 1.430(2) C5-O C1-C5-O-C11 C11-O-C5 O-C11 Value 171.8(4) C11-O1-C1-C2 115.5(3) Parameter 156.5(2) C1-O1-C11 C11-O1-C1-C5 1.357(5) 1.422(5) 15.2(2) C1-O1 O1-C11 Value 117.6(2) C1-O1-C11 Parameter 1.442(3) 1.365(3) 117.5(1) O1-C11 Value C1-O1 1.454(2) 1.372(2) OTOWEA/781732 ParameterC1-O1O1-C11 ValueC1-O1-C11C11-O1-C1-C2 1.360(2) 166.0(2) 117.7(1) 1.447(2) Parameter C6-O1 O2-C23 C16-O2 O1-C21 Value 1.4412 1.3205 1.3679 Parameter 1.4115 C9-C19-O-C11 C10-O-C11 C10-O Value O-C11 28(1) 115.0(7) Parameter O29-C34/O29’-C34’ C29-O29/C29’-O29’ 1.36(1) 1.37(2)/1.38(3) 1.44(1) 1.42(2)/1.43(3) C6-O6 O6-C11 Value 1.41(1) 1.370(8)

150 Appendix F a [ 212 ] [ 209 ] MANNOH/1508133 [ 212 ] NUBSUA/1021420 [ 209 ] MANNEX/1508131 NUBLON/1028721 [ 124 ] [ 212 ] YENKOS/292849 MANNAT/1508130 a [ 212 ] C12’-C11’-O2’-C21’ 15(7) [ 212 ] MANPUP/1508139 ParameterC12-O2O2-C21C12-O2-C21 ValueC13-C12-O2-C21 16.5(9) Parameter 1.355(8) 115.6(5) C6-O6 1.427(6) C10-C6-O6-C12 C6-O3-C12 O6-C12 17.4(5) Value C3-C2-O1-C11 115.5(3) 17.3(4) Parameter C2-O1-C11 1.358(4) C3-C2-O1-C12 1.424(5) C2-O1 16.6(2) O1-C11 114.5(2) Value C2-O1-C12 Parameter 1.368(2) 114.5(1) 1.439(4) C2-O1 O1-C12 Value 1.436(2) 1.363(2) MANLOF/1474107 ParameterC22-O3O3-C31C22-O3-C31 ValueC21-C22-O3-C31 164.2(4) Parameter 1.355(5) 115.1(3) C11-C12-O2-C21 C12-O2/C11’-O2’ 1.431(4) C12-O2-C21/C11’-O2’-C21’ O2-C21/C21’-O2’ 111(1)/119(3) C12-O2-C21 1.357(5)/1.28(6) 168(2) C12-O2 1.41(2)/1.48(5) 115.4(4) Value C2-O3-C11 O2-C21 114.9(4) C13-C12-O2-C21 1.354(6) 14.6(6) C2-O3 1.422(6) Parameter C3-C2-O3-C11 O3-C11 2.3(7) 1.356(6) Value 1.423(6) Parameter Value

151 Appendix F [ 209 ] MANMIA/1474112 [ 209 ] NUBTOV/1024124 [ 246 ] a JEPSOP/1038141 [ 209 ] ParameterC9-C11 Value C11-N1C9-C11-N1 1.429(5) 179.5(4) 1.129(6) NUBTEL/1024122 C11-O1-C5-C4C42-O5-C33-C34 14.0(7) -15.3(7) C44-C43-O6-C52’ C13-C12-O2-C21 3(2) -1(2) [ 209 ] NUBTUB/1024125 ParameterC12-O4O4-C21C12-O4-C21 ValueC21-O4-C12-C11 166.7(3) Parameter 1.354(4) 114.4(2) C33-O5-C42 C5-O1/C33-O5 1.430(4) C5-O1-C11 O1-C11/O5-C42 1.357(6)/1.357(6) 1.430(7)/1.434(8) Value 114.6(4) C12-O2/C43-O6 O2-C21/O6-C52’ 114.9(4) 1.35(1)/1.44(2) 1.44(2)/1.39(2) C2-O1 O1-C11 C43-O6-C52’ Parameter C12-O2-C21 1.432(2) 1.357(3) 117(1) 114(1) Value C11-O1-C2-C1 165.0(2) C11-O1-C2 Parameter 114.4(2) Value

152 Appendix F [ 288 ] [ 239 ] ZOSTIM/981408 NUTWEF/755179 C21-N2C11-C10-N1 178.6(2) C22-C21-N2 1.144(2) 176.4(2) C45-N46C14-C15-N36 175.7(2) C44-C45-N46 1.147(3) 174.1(2) [ 122 ] [ 225 ] MUZQAB/966379 UDUZOJ/657582 [ 122 ] [ 228 ] MUZPUU/966378 TEGQEB01/643481 [ 241 ] [ 264 ] TEGQEB/127075 KOGFIW/662374 ParameterC11-C1 ValueC1-N1C11-C1-N1 1.431(6) 178.7(5) Parameter 1.133(6) C2-C12 Value C2-C12-N13 C12-N13 179.4(3) 1.432(3) 1.139(3) Parameter C8-C13-N1 178.1(2) C8-C13 Value C13-N1 1.428(3) 1.145(3) C15-N36 Parameter C14-C15 1.145(3) C44-C45 Value 1.430(2) 1.433(3) ParameterC1(B)-C6(B)C6(B)-N1(B)C1(B)-C6(B)-N1(B) 179.5(2) Value 1.429(2) C1-C11-N C1-C11 1.150(2) 177.3(2) Parameter C11-N Value 1.430(2) 1.144(2) C1-C11-N 177.5(2) C1-C11 Parameter C11-N Value 1.430(2) 1.143(2) C10-N1 C11-C10 1.141(3) Parameter C22-C21 1.434(3) Value 1.426(2)

153 Appendix F [ 290 ] b [ 127 ] FOZWAU/1032801 QEHKIA/1470469 [ 290 ] [ 127 ] FOZVOH/1032799 [ 289 ] QEHKAS/1470467 b [ 126 ] COXBUO/1015252 SAFGOY/1412078 [ 288 ] C211-N2C101-C111-N1 177.4(4)C201-C211-N2 C101-C111-N1 178.5(4) 1.136(5) 177.9(3) C201-C211-N2 C211-N2 179.7(3) C101-C111-N1 177.4(4) 1.148(3) C201-C211-N2 178.5(4) C211-N2 1.136(5) [ 126 ] ZOSVEK/981412 ParameterC2-C1 ValueC27-C28C1-N1 1.430(8)C28-N2 1.425(8)C2-C1-N1 1.128(8)C27-C28-N2 1.139(8) 178.0(7) 179.9(7) Parameter Value C2-C1 C1-N1 Parameter C2-C1-N1 1.430(4) 1.141(3) 179.5(3) Value C13-C14 C14-N1 C13-C14-N1 178.6(3) 1.433(4) 1.138(4) Parameter C6-C12-N1 Value C6-C12 178.1(4) C12-N1 1.430(6) 1.144(6) SAFFUD/1412074 Parameter ValueC1-C11C11-N 1.433(4) ParameterC1-C11-N 178.8(3) C101-C111 1.144(4) C11-N1 Value C201-C211 1.434(5) C101-C111 Parameter 1.429(5) C201-C211 1.147(4) 1.426(3) C111-N1 Value 1.430(3) C101-C111 1.140(3) C201-C211 Parameter 1.434(5) C111-N1 1.429(5) Value 1.147(4)

154 Appendix G: List of Contributions

Oral Presentations

”Polysubstituted Cyclopentadienyls Exploiting Classical Reactions” Public PhD presenta- tion, Laboratory for Inorganic Chemistry, ETH Zurich,¨ December 5, 2017.

”Synthesis of Pentasubstituted Cyclopentadienyl Ligands and Their Corresponding Fer- rocenes” 15th Ferrocene Colloquium, Mainz, Germany, February 19-21, 2017.

Articles

”Asymmetric synthesis of N-stereogenic molecules: diastereoselective double aza-Michael reaction” Lauber A.; Zelenay, B.; Cvengroˇs, J. Chem. Commun. 2014, 50, 1195-1197.

“Cobalt-Catalyzed Coupling of Alkyl Iodides with Alkenes: Deprotonation of Hydridocobalt Enables Turnover” Weiss, M. E.; Kreis, L. M.; Lauber A.; Carreira E. M. Angew. Chem. Int. Ed., 2011, 50, 11125-11128.

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