Solvent-Free Multicomponent Reactions and Asymmetric Transformations in Solution and Under Mechanochemical Conditions

Solvent-free multicomponent reactions and asymmetric transformations in solution and under mechanochemical conditions

Von der Fakultä t fü r Mathematik, Informatik und Naturwissenschaften der RWTH Aachen University zur Erlangung des akademischen Grades einer Doktorin der Naturwissenschaften genehmigte Dissertation

vorgelegt von

Master of Science Plamena Krasimirova Staleva aus Sliven, Bulgarien

Berichter: Universitätprofessor Dr. rer. nat. Carsten Bolm Universitätprofessor Dr. rer. nat. Markus Albrecht

Tag der mündlichen Prüfung: 06.02.2020

Diese Dissertation ist auf den Internetseiten der Universitätsbibliothek verfügbar.

EIDESSTATTLICHE ERKLÄRUNG

Plamena Krasimirova Staleva, erklärt hiermit, dass diese Dissertation und die darin dargelegten Inhalte die eigenen sind und selbstständig, als Ergebnis der eigenen originären Forschung, generiert wurden.

Hiermit erkläre ich an Eides statt

1. Diese Arbeit wurde vollständig in der Phase als Doktorandin dieser Fakultät und Universität angefertigt; 2. Sofern irgendein Bestandteil dieser Dissertation zuvor für einen akademischen Abschluss oder eine andere Qualifikation an dieser oder einer anderen Institution verwendet wurde, wurde dies klar angezeigt; 3. Wenn immer andere eigene- oder Veröffentlichungen Dritter herangezogen wurden, wurden diese klar benannt; 4. Wenn aus anderen eigenen- oder Veröffentlichungen Dritter zitiert wurde, wurde stets die Quelle hierfür angegeben. Diese Dissertation ist vollständig meine eigene Arbeit, mit der Ausnahme solcher Zitate; 5. Alle wesentlichen Quellen von Unterstützung wurden benannt; 6. Wenn immer ein Teil dieser Dissertation auf der Zusammenarbeit mit anderen basiert, wurde von mir klar gekennzeichnet, was von anderen und was von mir selbst erarbeitet wurde; 7. Ein Teil dieser Arbeit wurde zuvor veröffentlicht und zwar in: P. Staleva, J. G. Hernández, C. Bolm, Chem. Eur. J. 2019, 25, 9202.

Aachen,

The work reported herein has been carried out at the Institute of Organic Chemistry of the RWTH Aachen University under the supervision of Prof. Dr. Carsten Bolm between March 2014 and November 2019. I would like to thank Prof. Dr. Carsten Bolm for giving me the opportunity to join his research group and work on exciting topics under excellent working conditions and for his support. Furthermore, I would like to gratefully acknowledge DBU (Die Deutsche Bundesstiftung Umwelt) for the financial support during the first year of my doctoral studies through “MOE- Austauschstipendienprogramm”.

For my family

“The impediment to action advances action. What stands in the way becomes the way.”

Marcus Aurelius

TABLE OF CONTENTS

1. INTRODUCTION ...... 1 1.1 CHIRALITY AND ASYMMETRIC SYNTHESIS ...... 1 1.2 SOLVENT-FREE REACTIONS – A SUSTAINABLE ROUTE IN CHEMICAL SYNTHESIS ...... 2 1.3 MECHANOCHEMISTRY AND ITS APPLICATION IN ASYMMETRIC CATALYSIS ...... 3 1.4 SULFOXIMINES – PROPERTIES AND APPLICATIONS ...... 7 2. RESULTS AND DISCUSSION ...... 15 2.1 SOLVENT-FREE SYNTHESIS OF CHIRAL SULFONIMIDOYLALKYL NAPHTHOLS BY BETTI CONDENSATION .. 15 2.1.1 Background of the project ...... 15 2.1.2 Research objective ...... 20 2.1.3 Optimization of the reaction conditions...... 21 2.1.3 Substrate scope of the Betti condensation ...... 23 2.1.4 Determination of the absolute configuration ...... 25 2.1.5 Postulated reaction mechanism ...... 26 2.1.6 Application as ligands in the asymmetric addition of diethylzinc to aldehydes .... 26 2.1.7 Brønsted acid mediated reaction of 62a with indole ...... 28 2.1.8 Biological tests ...... 31 2.2 STUDIES ON THE RESOLUTION OF RACEMIC MALONIC ACID INDOLE DERIVATIVES IN A REACTION TOWARDS BISINDOLYLMETANES ...... 32 2.2.1 Background and aim of the project ...... 32 2.2.2 Primary experiments on the asymmetric Friedel–Crafts alkylation of indoles catalyzed by a chiral metal-sulfoximine complex ...... 36 2.2.3 Screening of the reaction conditions for the kinetic resolution of 81a ...... 37 2.2.4 Substrate scope ...... 43 2.2.5 Studies towards the elucidation of the reaction mechanism ...... 45 2.3 COPPER-CATALYZED ASYMMETRIC MICHAEL-TYPE FRIEDEL–CRAFTS-ALKYLATIONS OF INDOLES WITH ARYLIDENE MALONATES UNDER BALL MILLING CONDITIONS ...... 48 2.3.1 Background and aim of the project ...... 48 2.3.2 Optimization of the chiral ligands ...... 49 2.3.3 Screening of Lewis acids...... 51 2.3.4 Optimization of milling conditions and milling auxiliaries ...... 53 2.3.5 Optimization of the additives ...... 55 2.3.6 Synthesis of the substrates ...... 58 2.3.7 Substrate scope of the mechanochemical asymmetric Friedel–Crafts alkylation of indoles ...... 58

2.3.8. Liquid assisted grinding experiments ...... 62 3. SUMMARY AND OUTLOOK ...... 65 4. EXPERIMENTAL PART ...... 69 4.1 GENERAL INFORMATION AND TECHNIQUES ...... 69 4.2 ANALYTICAL METHODS ...... 70 4.3 SYNTHESIS AND CHARACTERIZATION OF THE PRODUCTS ...... 71 4.3.1. General procedures for the preparation of starting materials, products and ligands ...... 71 4.3.2. Synthesis and analytical data of compounds ...... 76 5. REFERENCES ...... 109 6. ABBREVIATIONS...... 117 CURRICULUM VITAE ...... 120 ACKNOWLEDGMENTS ...... 121

INTRODUCTION

1. INTRODUCTION

1.1 CHIRALITY AND ASYMMETRIC SYNTHESIS

Chirality is one of the most prominent features of natural and bioactive compounds and plays an important role in almost all biochemical pathways and processes taking place in living organisms. The majority of the naturally occurring compounds with important biological activities are existing as a single optical isomer. Moreover, almost all amino acids, carbohydrates, proteins, enzymes, etc. are chiral. Nowadays, chiral molecules are present in various aspects of our daily life including pharmaceuticals, agrochemicals, flavors, fragrances, and modern materials. This explains the growing demand for synthetic methods to provide enantiomerically pure compounds, especially in the pharmaceutical industry. The consideration of chirality in drug design has become indispensable. This stems from the deeper understanding of stereoselective pharmacokinetics, pharmacodynamics and receptor binding of the single enantiomer of a chiral drug, resulting in different biological profiles in the chiral environment of the human body.[1]

Тhe main strategies to access chiral compounds include: a) separating the racemic mixtures using chemical, enzymatic and physical methods; b) synthesis from the chiral pool; c) asymmetric synthesis.[2] Although the first two methods are still widely used, asymmetric catalysis has emerged as a more sustainable option to access chiral compounds and some industrial processes have also been developed.[3] In this approach the chiral information is transferred to the desired product by an enantiopure catalyst, which activates the substrate forming a diastereomeric intermediate and accelerating the reaction. Since the interaction between the catalyst and the substrates is reversible, the catalyst can participate in many catalytic cycles, which makes the atom economy of the process optimal and minimizes the generation of waste (see chapter 1.2).[4]

The three main pillars of enantioselective catalysis currently include metal catalysis, biocatalysis and organocatalysis. Although a broad range of stereoselective transformations including organocatalysts[5] and enzymes[6] have been developed in recent years, (transition) metal catalysts[7] are still the most abundantly used in both academia and industry. Nowadays, a great variety of chiral ligands are available for complexation with transition metals. Amongst them, a relatively small number of compounds, called “privileged chiral catalysts”, have shown to exhibit a broad applicability for inducing enantioselectivity in mechanistically unrelated asymmetric transformations (Figure 1).[8] Accordingly, achieving sustainable asymmetric catalysis requires not only the design and employment of new broadly applicable chiral ligands, but also demands the development of strategies to improve the utility of the known enantioselective catalysts.

1 INTRODUCTION

Figure 1. Examples of privileged chiral ligands in asymmetric catalysis.

1.2 SOLVENT-FREE REACTIONS – A SUSTAINABLE ROUTE IN CHEMICAL SYNTHESIS

Since the publication of Green Chemistry: Theory and Practice by ANASTAS and WARNER 20 years ago,[9] the concept of green chemistry and its twelve principles, have guided the scientific community and shifted the strategies in chemical synthesis with focus on the development of more sustainable chemical processes.[10] This involved multidisciplinary innovations in chemical research as well as engineering, covering complex issues including waste minimization, reduction in energy usage, and the use of renewable resources.[11]

In order to measure the efficiency of a synthetic method, metrics such as the atom economy and the environmental factor (E-factor) have been applied.[12] The atom economy was termed by

TROST in 1991 and it deals with maximizing the use of atoms of all raw materials that end up in the product.[13] The E-factor, on the other hand, was introduced by SHELDON as a measurement for the efficiency of a synthetic process, which assigns value to waste minimization.[10c, 14] This parameter is defined as kg of waste per kg of product and in addition to the atom economy of a reaction, it accounts all the auxiliary components such as waste solvent as well as waste produced from chemicals used in work-up, etc.

A significant role for waste generation and pollution in chemical synthesis is played by the large- scale use of organic solvents. Their toxicity and volatility have implications for the environmental contamination. Therefore, some of the important approaches towards designing more benign chemical processes involve either substituting the classical organic solvents with “green” alternatives,[15] or performing the reactions without solvents (solvent-free synthesis).[16] In this context, mechanochemistry has emerged as a promising area of chemistry for conducting reactions in a more sustainable way.[17]

2 INTRODUCTION

1.3 MECHANOCHEMISTRY AND ITS APPLICATION IN ASYMMETRIC CATALYSIS

Mechanochemical reactions аre defined as chemical reactions “induced by direct absorption of mechanical energy”.[18] Mechanochemical activation by grinding, milling, stretching or shearing allows chemical transformations to proceed without the need of solvents. This makes mechanochemistry particularly attractive in developing economically and environmentally benign processes. The rapid development of mechanochemical processes as synthetic methods in the last decade, is also supported by their wide range of applications. These include examples in fields as broad as organic,[19] inorganic,[20] organometallic,[21] polymer,[22] supramolecular,[23] and medicinal chemistry,[24] valorization of biomass,[25] and many more.

In all these areas of synthetic chemistry, along with the possibility to perform chemical reactions under neat conditions, mechanochemistry offers numerous other advantages, such as precise stoichiometry control, improved reaction rates, shorter reaction times, higher yielding procedures, ambient conditions, and circumvention of solubility issues. But the benefits of the utilization of mechanical force go beyond environmentally concerns, since it proved to be valuable for the discovery of new reactivities and reaction pathways, and thereby accessing materials and products which were impossible to synthesize by solution-based approaches.[26] Accordingly to what is described above, in 2019, IUPAC named “mechanochemistry” to be among the “10 chemistry innovations that will change the world”.[27]

Technical characteristics and variable parameters

Historically, the first mechanochemical reactions were performed by manual grinding, using a mortar and pestle.[28] However, although this simple technique had a great role for the advancement of mechanochemistry, it comes with some limitations, such as low reproducibility, reaction time and scale-up restrictions, as well as safety issues. Therefore, automated ball mills for laboratory-scale synthesis have been developed and are now being commonly used to enhance the accuracy of the reactions performed.[19a] The two most frequently used ball mills are mixer mills and planetary mills. The reactions are performed in milling vessels, loaded with milling media (milling balls). In mixer mills the jars are placed horizontally and are oscillated side to side at the desired frequency (Figure 2, left), while in planetary mills the jars are fixed vertically on a central spinning disc and during rotation they spin opposite to their own axes (Figure 2, right). The main mechanical energy applied in the first case is the impact force, while the shear force is predominant in the second case.

3 INTRODUCTION

Figure 2. Schematic representation of the operation of a mixer mill and a planetary mill.[19g]

The implementation of electronic milling devices allows better control on various reaction parameters such as milling time, energy input (by adjusting the milling frequency or speed of rotation), ratio of the reactant weight to the volume of the reaction vessel, etc. Moreover, the reaction outcome can be affected by varying the size and number of the milling media, as well as the material used for the preparation of both milling vessels and milling balls. Depending on the required energy input to carry out the reaction as well as the reactant stability, the material density and mechanical hardness (Knoop index)[29] can be adjusted. Examples for lighter materials are agate ( = 2.7 g/cm3) and zirconium oxide ( = 5.7 g/cm3), while stainless steel ( = 7.7 g/cm3) and tungsten carbide ( = 15.6 g/cm3) are heavier.[17b]

The use of milling auxiliaries can also play an important role for the milling process and therefore, the reaction outcome. This is especially important when the starting materials are liquids. The addition of solids to the reaction mixture in those cases can increase the friction leading to an improved transfer of the mechanical energy. The grinding auxiliaries used are usually inorganic materials such as sodium chloride, magnesium sulfate, silica gel or aluminum oxide. In some examples, an additive can play a dual role in the reaction, both as grinding auxiliary and as a base[30] or an acid,[31] respectively.

Another approach for modifying the mechanochemical reaction environment is the addition of a small quantity of liquid phase. This technique is named liquid assisted grinding (LAG) and in recent years has become of interest for controlling chemical selectivity in the milling process.[32] The parameter  has been introduced to quantify the added liquid on the mechanochemical reaction, and represents the ratio of the volume of the liquid additive (in L) to the weight of the reactants (in mg).[32b] Along with the right quantity, important features that should be considered when selecting an liquid additive for a mechanochemical transformation are solvent polarity, volatility, and stability upon milling. Once the suitable liquid additive has been identified, mechanochemical reactions can be accelerated and facilitated. Moreover, LAG can lead to different

4 INTRODUCTION reactivities and unprecedented reaction outcomes compared to neat grinding and solution-based approaches.[33] This makes it a considerable variable during the development of a mechanochemical protocol.

Mechanochemical asymmetric synthesis

As discussed above, mechanochemistry has found application in diverse areas of organic synthesis. This also includes the field of asymmetric catalysis. Employing ball milling in those type of transformations has led to numerous improvements such as shorter reaction times, reduced catalyst loadings, avoidance of solvents, and therefore a higher level of sustainability.

A major part of research has been focused on asymmetric organocatalysis.[34] The first organocatalyzed mechanochemical reaction was reported in 2006 by RODRÍGUEZ and BOLM. By employing (S)-proline (4) as a catalyst, the solvent-free enantioselective aldol reaction between ketones 1 and aldehydes 2 was performed (Scheme 1).[35] The transformation proceeded efficiently to give the anti-aldol diastereomeric products 3 in high yields and enantioselectivities up to 99% ee.

Scheme 1. The first mechanochemical organocatalytic asymmetric reaction reported by RODRÍGUEZ and BOLM.

Subsequently, a plethora of mechanochemical asymmetric organocatalytic protocols have been developed, such as anhydride opening reactions[36], aldol reactions,[37] Michael addition,[38] and alkylation of Schiff bases,[39] among others.[34]

The stability of peptides[40] as catalysts under mechanochemical conditions motivated studies on the compatibility of biocatalysts with mechanochemistry. Pioneering work in this field was done by HERNÁNDEZ and BOLM in 2016, who employed Candida antarctica lipase B (CALB) in the kinetic resolution of secondary alcohols 5 through an enantioselective acylation reaction in mixer and planetary mills (Scheme 2).[41] Despite the mechanical stress, the biocatalyst proved stable and highly effective, achieving excellent enantioselectivities of up to 99% ee for the acetate 7 at high conversion rates.

5 INTRODUCTION

Scheme 2. The first mechanochemical enzyme-catalyzed asymmetric reaction reported by HERNÁNDEZ and BOLM.

In line with this approach, more recently the group of JUARISTI reported mechanochemical enzymatic resolution of -amino esters[42] and amines.[43] Additionally, reaction protocols using enzymes have been developed for regioselective reactions,[44] peptide synthesis,[45] oligomerisation,[46] and depolymerisation reactions.[47]

Despite the significant achievements in the field of mechanochemical asymmetric organocatalysis and in biocatalysis, till date there are only three reports on metal-catalyzed asymmetric reactions under ball milling conditions.[48] The scarcity of research on this topic could be due to the fact that in general, chiral metal-complexes require more precise reaction conditions in terms of reaction media, concentration, inert atmosphere, and especially temperature control.[49]

The first metal-catalyzed asymmetric mechanochemical reaction was reported by JINGBO and SU in 2013.[48a] In this work, cross-dehydrogenative coupling (CDC) reactions of N- aryltetrahydroisoquinolines 8 and alkynes 9 under high-speed ball milling (HSBM) conditions were performed (Scheme 3). The enantioselective alkynylation was allowed by the presence of one equivalent of DDQ, the chiral PyBOX ligand L6 and copper balls. All coupling products were obtained in good yields (60–77%) after short reaction times with enantiomeric excess (ee) up to 79%. The effect of different milling parameters on the enantioselectivity of the reaction was also studied. By performing intermittent milling (by introducing pauses between the milling cycles), the authors were able to minimize the autogenous heating of the milling jar during the reaction, which led to slight improvement in the enantioselectivity. Additionally, an improvement of the ee by reducing the milling frequency was also attempted, but those experiments resulted only in lower yields, without the desired positive impact on the selectivity.

Scheme 3. Mechanochemical copper-catalyzed asymmetric CDC reaction reported by the group of SU.

6 INTRODUCTION

In 2015, the same group reported a highly enantioselective Cu(II)-catalyzed multicomponent reaction between aldehydes 11, amines 12 and terminal alkynes 9 in a mixer mill (Scheme 4).[48b]

Under solvent-free conditions in the presence of 10 mol% of a chiral Ph-PyBOX-(CuOTf)2 complex, the desired chiral propargylamines 13 were afforded in excellent yields and enantiomeric excess. In the optimization of the mechanochemical procedure, parameters such as milling speed, and nature and amount of the milling additive showed influence on the stereoselectivity. It was also demonstrated that a single dichloromethane extraction of the crude reaction product followed by evaporation allowed for the recovery of the catalyst, which could be reused for up to four times without any loss of catalytic activity.

Scheme 4. Mechanochemical enantioselective A3-coupling reactions between aldehydes, amines and alkynes.

More recently, WANG and XU reported a copper-catalyzed mechanochemical enantioselective fluorination of -ketoesters 14 using N-fluorobenzenesulfonimide (15, NFSI) (Scheme 5).[48c] The chiral catalyst was generated in situ by milling of a chiral diphenylamine-linked bis(oxazoline) ligand L7 and Cu(OTf)2 in a planetary mill for 5 min, prior to the addition of the substrates and the NFSI. Most of the substrates reached full conversion in only four minutes of reaction time, yielding the desired fluorinated ketoesters 16 in high to excellent yields and enantioselectivities up to 99% ee.

Scheme 5. Enantioselective fluorination of -ketoesters in the ball mill.

1.4 SULFOXIMINES – PROPERTIES AND APPLICATIONS

Sulfoximines 18, the mono aza-analogues of sulfones 17, represent compounds with unique chemical properties (Figure 3). The sulfoximidoyl unit consist of a central tetracoordinated sulfur atom bound to an oxygen, a nitrogen and two carbon atoms. When the two carbon substituents

7 INTRODUCTION are not identical, the molecule bears a center of asymmetry. The S–O and S–N bonds have a high double bond character.[50] The nitrogen atom has nucleophilic and basic properties, while the imine hydrogen atom is acidic (pKa ~ 24 in DMSO, for R1 = Ph, R2 = H, R3 = H).[50b, 51] This gives the NH group an amphoteric character and thereby metal binding properties, opening possibilities for further N–H functionalizations.[52] Additionally, by varying the nature of the N-substituents, the acidity of the hydrogen atoms in α-position to the sulfur atom could be also modified (pKa ~ 32 in DMSO, for R1 = Ph, R2 = Me, R3 = H; pKa ~ 23 for R1 = Ph, R2 = Ts, R3 = H).

Figure 3. Chemical structures of sulfones 17 and sulfoximines 18 and general properties of the sulfoximidoyl functionalities.

The described specific features sulfoximines offer and their high thermal, chemical, and configurational stability as well as structural diversity, have made them an attractive moiety for numerous applications in organic synthesis.[50b, 53] These include classical auxiliary-supported asymmetric synthesis,[53a, 54] enantioselective metal catalysis,[53b, 53d, 53e, 55] and organocatalysis.[56] Moreover, sulfoximines have shown promising bioactivities, attracting attention from medicinal and agricultural chemistry.[57]

Application in asymmetric synthesis as chiral ligands

The metal-binding properties and configurational stability of chiral sulfoximines have motivated investigations towards the development of new chiral catalysts based of this unique structural motif.

The first use of sulfoximines as ligands in asymmetric catalysis was reported by the group of BOLM in 1992.[58] A nickel complex of the -hydroxysulfoximine L8 was utilized as a catalyst in the enantioselective addition of diethylzinc (20) to chalcone (19), affording product 21 in 71% yield and 70% ee (Scheme 6).

8 INTRODUCTION

Scheme 6. Enantioselective conjugate addition of diethylzinc (20) to chalcone (19) catalyzed by nickel-- hydroxysulfoximine complex.

Subsequently, -hydroxysulfoximines were successfully applied in asymmetric 1,2-additions of dialkylzinc reagents to aldehydes,[59] enantioselective borane reduction of ketones[60] and imines,[61] asymmetric cyanohydrin formations[62] as well as aryl transfer reactions to aldehydes.[63]

Later, purely coordinating N,N-bidentate sulfoximine ligands were designed and utilized in asymmetric metal-catalyzed reactions. One of the early examples is the C2-symmetric bissulfoximine L9, which was used in Pd-catalyzed allylation of 22, giving product 24 with

[64] enantioselectivities up to 93% ee (Scheme 7). Similarly, HARMATA reported C2-symmetric bisbenzothiazine L10, which proved to be an efficient ligand for this transformation, affording 24 with high enantioselectivity in shorter reaction time (Scheme 7).[65]

Scheme 7. Pd-catalyzed allylic alkylation with L9 or L10 as chiral ligands.

A series of C2- and C1-symmetric sulfoximines have been synthesized by BOLM and co-workers and have found applications in a plethora of metal-catalyzed enantioselective reactions (Figure 4).

9 INTRODUCTION

Figure 4. Examples of C2- and C1-symmetric sulfoximine ligands developed by the group of Bolm.

In this context, the aryl-bridged L11 proved to be a highly effective ligand in the Cu(II)-catalyzed hetero-Diels–Alder reaction (Scheme 8). In the presence of (S,S)-L11 and Cu(OTf)2, cyclohexadiene (25) and ethyl glyoxalate (26) underwent cycloaddition affording the desired product 27 in 81% with high enantioselectivity (Scheme 8, top).[66] Notably, the catalyst loading could be reduced to 0.5 mol% without significantly affecting the enantioselectivity. Additionally, the activated ketone 28 was tested under the established optimized reaction conditions with cyclohexadiene, giving product 29 with high enantioselectivity in 95% yield (Scheme 8, bottom).

Scheme 8. Enantioselective hetero-Diels–Alder reactions using bissulfoximine L11-Cu(OTf)2 complex.

Next, a series of C2-symmetrical sulfoximine ligands were evaluated in the enantioselective copper-catalyzed Diels–Alder reactions between cyclopentadiene (30) and acryloyl-2- oxazolidinone (31, Scheme 9).[67] The best result was achieved employing L16 in combination with Cu(ClO4)2, affording the desired product 32 in 98% yield with 93% ee (endo:exo ratio: 89:11).

10 INTRODUCTION

Scheme 9. Enantioselective Diels–Alder reactions using bissulfoximine L16-Cu(OTf)2 complex.

After the aforementioned success with bissulfoximine ligands, the studies have been extended to

C1-monosolufoximine ligands L12 (Figure 4). L12 was prepared by palladium-catalyzed N- arylation of the corresponding enantiopure sulfoximine and subsequently was applied in the copper catalyzed hetero Diels–Alder reaction, achieving high enantioselectivities.[68]

Later on, the benzene-bridged aminobenzyl-substituted sulfoximine L13 was synthesized and applied in the Mukaiyama type aldol reaction of pyruvate esters 33 with silyl enol esters 34 in the presence of Cu(OTf)2. The addition products 35 were isolated in high yields and selectivities up to 99% ee (Scheme 10).[69]

Scheme 10. Enantioselective Mukaiyama type aldol reaction using sulfoximine ligand L13.

Subsequently, a series of vinylogous Mukaiyama reactions were directed by L13 with various substrate combinations.[70] Moreover, this type of ligands were applied in copper-catalyzed carbonyle-ene reactions,[71] as well as in enantioselective halogenations.[72]

Further examples of sulfoximine containing ligands are L14 and L15 (Figure 4). Mixed bisoxazoline-sulfoximine L14 has been utilized in asymmetric Mukaiyama aldol reactions,[73] while the P,N-ligand L15 has been successfully applied in iridium-catalyzed asymmetric hydrogenation reactions.[74]

11 INTRODUCTION

Biological relevance of sulfoximines

The specific profile of sulfoximines attracted only recently greater attention from medicinal and crop protection scientists.[57] Compared to sulfones, their isoelectronic analogues, sulfoximidoyl functional groups can offer advantages related to improved solubility and metabolic stability, as well as increased synthetic diversity.[75]

In Figure 5 some examples of bioactive sulfoximines are presented. Methionine sulfoximine (MSO,

36) is the first sulfoximine described in the literature. It was discovered in 1949 by BENTLEY and

WHITEHEAD.[76] MSO was identified as the toxic factor causing canine hysteria and epileptiform fits in dogs. Subsequently, it was found that it inhibits both glutamine synthetase[77] and - glutamylcysteine synthetase,[78] resulting in enhancing the effects of cytotoxic agents.[79] Those interesting findings motivated the preparation of a series of analogues of MSO,[80] whereby the related synthetic amino acid, buthionine sulfoximine (BSO, 37) exhibited the highest activity. It has been subsequently applied in studies for cancer treatment, showing improved inhibition of the glutathione synthesis.[79]

Figure 5. Selected examples of bioactive sulfoximines.

Promising sulfoximine-containing compounds that entered clinical studies are Roniciclib (38, Bayer Pharma)[81] and AZD6738 (39, Astra Zeneca).[82] Both drug candidates exhibit anti-cancer activities, 38 by inhibiting cyclin-dependent kinases (CDK) and 39 as an ATR (ataxia telangiectasia and RAD3-related) inhibitor. In comparison with the respective sulfonamides, Roniciclib features better solubility as well as lower off-target activity.[81] Another example for a candidate with higher selectivity is N-cyanosulfoximine 40. This compound showed to be an efficient COX-2 inhibitor.[83]

12 INTRODUCTION

About the potential of sulfoximidoyl functionalities in crop science speak numerous reports of sulfoximines showing activity against insects. One of the most important example is the compound Sulfoxaflor (41, Dow Agroscience).[84] This compound is in fact the only bioactive sulfoximine introduced on the market so far.

Although the discovery of the first sulfoximines was related to their bioactive properties, the high relevance of this structural motif was neglected for a long time. This stems most probably from the low commercial availability and lack of safe synthetic strategies for introducing this type of functionalities.[57c] Nevertheless, in the last decade sulfoximines have gained increased recognition and more studies about sulfoximines in drug design and agrochemistry are reported. This tendency is directly connected to the growing development of new, safe and mild synthetic protocols[85, 86] which have granted increased accessibility to sulfoximines.

RESULTS AND DISCUSSION

2. RESULTS AND DISCUSSION

2.1 SOLVENT-FREE SYNTHESIS OF CHIRAL SULFONIMIDOYLALKYL NAPHTHOLS BY BETTI

CONDENSATION

2.1.1 BACKGROUND OF THE PROJECT

Multicomponent reactions have attracted significant attention in modern synthetic organic chemistry due to the numerous advantages they offer in terms of diversity and complexity.[87] These transformations include the one-pot reaction of three or more starting materials leading to products that incorporate major portions of all reactants in a single step. In this fashion, high levels of atom efficiency can be achieved, avoiding isolation and purification of synthetic intermediates and thus, reducing reaction time and overall energy required. These characteristics make such procedures an important tool in the way of designing sustainable syntheses.[88]

The multicomponent reaction between naphthols, aryl aldehydes and ammonia or amines is known as the Betti reaction and it was first reported in 1900 by the Italian chemist MARIO BETTI.[89] Originally, it was performed using 2-naphthol (42a), benzaldehyde (2a) and an ethanolic solution of ammonia (43) (in a ratio 1:2:1) at room temperature, resulting in the formation of compound 44 in 91 % yield (Scheme 11).

Scheme 11. Betti condensation as performed by M. BETTI in 1900.

Later, it was proven by IR-spectroscopy that in solution there is an equilibrium between the two tautomeric forms 44a and 44b.[90] Acid hydrolysis of 44 afforded the salt 45 in 91% yield. After a following basic extraction, product 46 was isolated in 75% yield. Later on, 46 was successfully

15 RESULTS AND DISCUSSION resolved into its optical isomers using tartaric acid.[91] The aminobenzylnaphthol 46 thus became known in the literature as Betti base. Interestingly, after its discovery, there were rarely any reports for applying this type of transformation in the synthesis of other derivatives.[90, 92] Only in the last two decades, the interest in the synthetic potential of this reaction has been arouse.[93] The main features of the Betti condensation attracting attention are on one hand, the formation of a C– C bond under mild conditions, and on the other, the access it offers to chiral aminonaphthols with application in asymmetric synthesis. Subsequently, by varying the three components, this transformation has been extended to the synthesis of a wide-ranging library of racemic and nonracemic more complex structures.[93] On the other hand, new Betti bases have been prepared also by modification of the original aminobenzylnaphthol 46. These new aminonaphthols have found application not only in asymmetric synthesis as chiral ligands or chiral auxiliaries, but also some of the products have exhibited interesting biological activities.[93e]

In Scheme 12 an overview of the broad scope of compounds serving as a nitrogen source applied in this reaction is presented. Various primary and secondary amines (A and B),[94] heterocyclic amines (C and D),[95] anilines (E),[96] urea (F),[97] amides (G),[98] diamines (H),[99] aminoalcohols (I),[100] and amino acid esters (J)[100a, 101] have found application in this transformation. The reaction conditions (solvent, temperature, need of catalyst etc.) strongly varied depending on the N-source reaction partner. Moreover, for many of the transformations, solvent-free thermal and microwave procedures were developed. These offer advantages such as shorter reaction times, simple work-up, and excellent yields.[102]

Scheme 12. Selected examples of different N-sources applied in the Betti condensation.

16 RESULTS AND DISCUSSION

Chiral amines as an N-source and application of the products in asymmetric transformations

Undoubtedly, one of the most important achievements in the rediscovery of the Betti reaction is the application of chiral amines as an N-source. This approach was independently developed by three research groups,[103] reporting the reaction between 2-naphthol (42a), aryl aldehydes (2) and (R)- or (S)-1-phenylethylamine (48) yielding the corresponding (R,R)- or (S,S)- aminobenzylnaphthols (49). The presence of a resolved stereogenic center in the amine induced the formation of the new stereogenic center with high stereoselectivity. The reported protocol by the group of PALMIERI[103a] involves the reaction of 2-naphthol (42a), benzaldehyde (2a) and (R)-1- phenylethyl amine (48) at 60 C under solvent-free conditions for 8 h (Scheme 13, top). After addition of small amounts of ethanol to the reaction mixture, the formed aminonaphthol (R,R)-49 crystallized spontaneously and was isolated in 93% yield with a d.r. of 99:1. Subsequently, the reaction was extended to substituted benzaldehydes and aliphatic aldehydes,[104] whereby the corresponding products were obtained in yields of 41–86% and diastereoselectivities ranging from 75:25 to 99:1. The high stereoselectivity using benzaldehyde was explained suggesting a crystallization-induced asymmetric transformation. The newly synthesized aminonaphthol 49a attracted attention not only because of the remarkable operational simplicity of the synthetic procedure, but also because of its high catalytic activity, when used as a ligand in the asymmetric addition of diethylzinc to benzaldehyde (Scheme 13, bottom).

Scheme 13. Solvent-free Betti reaction with (R)-phenylethylamine (48).

Independently, CHAN and coworkers[103c] reported the reaction of (S)-1-phenylethylamine (48), 2- naphthol (42a) and benzaldehyde (2a) in ethanol at room temperature for 6 days, affording (S,S)- 49a in 70% yield after recrystallization from methanol/acetone (3:1) (Scheme 14). Then, 49a was reacted with formaldehyde (51) followed by reduction with NaBH4 in the presence of

17 RESULTS AND DISCUSSION trifluoroacetic acid (TFA), resulting in N-methylated aminoalcohol 51 in 65% yield. The latter was subsequently applied as a ligand in the reaction of diethylzinc with various benzaldehydes 2 giving the resulting alcohols 50 in high yields and with enantioselectivities up to 99.8% ee.

Scheme 14. Synthesis of aminonaphthol 51 and its application in the asymmetric addition of diethylzinc to aldehydes.

Later on, the same group prepared compound 51 by directly applying (S)-N-- dimethylbenzylamine (52) in the reaction with 2-naphthol (42a) and benzaldehyde (2a) without the addition of any solvent at room temperature or at 95 °C giving the single diastereomer (S,S)- 51 in 70% and 78% yield, respectively (Scheme 15).[105] This was the first example of a direct synthesis of optically active tertiary aminonaphthols by Betti condensation. 51 proved to be an effective catalyst in the enantioselective alkenylation of various aldehydes 2 resulting in the formation of the chiral (E)-allyl alcohols 54 in high to excellent yields (77–95%) and high enantioselectivities (up to 99% ee) (Scheme 15).

18 RESULTS AND DISCUSSION

Scheme 15. Synthesis of aminoalcohol 51 and its application in the asymmetric alkenylation of aldehydes.

In 2005, JI et al. reported the straightforward synthesis of 55 by employing 1-naphthaldehyde (2b) in the reaction with 2-naphthol and (S)-52 (Scheme 16).[106] After 72 h at 85 C, product 55 was isolated after crystallization from methanol in 51% yield and with 98.5:1.5 d.r. Notably, the reaction was scaled up to 50 g. The obtained tertiary aminonaphthol was then applied in the asymmetric catalytic phenyl transfer to aromatic aldehydes, whereby a variety of diarylmethanols 56 was prepared in yields of 87–95% and with high ee values (up to 99% ee).

Scheme 16. Synthesis of aminonaphthol 55 and its application as a ligand in the asymmetric phenyl transfer reaction to aromatic aldehydes.

Betti bases exhibiting biological activity

As discussed before, some of the aminobenzylnaphthols synthesized by Betti reactions have been tested for their bioactivity or used as building blocks in drug design.[93e] Some selected examples are presented in Figure 6. In a patent from 2007, compounds 57 and 58 were reported to possess

19 RESULTS AND DISCUSSION an affinity towards several receptors such as adrenergic and opioid, as well as the N-methyl-D- aspartate (NMDA) receptor family.[107] Therefore, they have been evaluated as analgesic agents.

Figure 6. Examples of aminonaphthols with analgesic (57 and 58), antifungal (59) and anticancer (60) activities.

More recently, the group of CARDELLICCHIO synthesized the aminonaphthol 59, which showed antifungal activity.[100b] Noteworthy, the results of the study revealed that the stereochemistry of the aminonaphthol plays an important role for the biological activity. The compound (S,S)-59, derived from the natural (S)-prolinol, showed a strong inhibiting effect towards Candida albicans, whilst the other diastereomer (S,R)-59, prepared from the unnatural (R)-prolinol, remained inactive.

In another study, aminonaphthols 60 were prepared and subsequently evaluated for their cytotoxicity against breast cancer (MCF-7) and colon cancer (HCT116) cell lines.[108] The performed docking studies suggested that the observed inhibiting activity occurred due to binding of the compounds to the active side of phosphoinositide 3-kinase (PI3K), which is a crucial regulator of apoptosis.

2.1.2 RESEARCH OBJECTIVE

Earlier in this thesis, sulfoximines were introduced as a class of compounds with specific chemical properties and great importance for asymmetric synthesis, crop protection and medicinal chemistry. Based on our long-standing interest exploring sulfoximine chemistry and considering the great synthetic versatility of the Betti reaction, we envisioned that sulfoximines such as 61 could be suitable N-sources for this type of transformation (Scheme 17).1 Thus, this reaction could

1This project has been carried out in collaboration with Marcus Frings (IOC, RWTH Aachen University).

20 RESULTS AND DISCUSSION be utilized for the preparation of unprecedented chiral sulfonimidoylalkyl naphthols 62 which, based on the described previous reports, could be of interest for numerous applications.

Scheme 17. Envisioned condensation reaction of 2-naphthols 42, aldehydes 2 and sulfoximines 61.

2.1.3 OPTIMIZATION OF THE REACTION CONDITIONS

For the initial phase of the project we selected 2-naphthol (42a), benzaldehyde (2a) and (S)-S- methyl-S-phenylsulfoximine (61a) as substrates. The reaction was first performed under solvent- free conditions at 80 °C in a pressure tube (Table 1, entry 1). After 15 h of reaction time, the desired product 62a was isolated in 72% yield as a mixture of two diastereomers in ratio of 54:46 in favor of the (S,S)-isomer. Water was obtained as the only by-product and its condensation could be observed by eye on the upper part of the reaction vessel. Pleasingly, the single diastereomers could be separated by column chromatography. Then, the reaction time was prolonged to 24 h, resulting in an improved yield of 90% (Table 1, entry 2). Lower or higher temperatures showed no improvement of the reaction outcome (Table 1, entries 3 and 4).

In order to investigate the possible effects of solvents on the reactivity and the stereoselectivity, the reaction was next performed in solution. Heating the three components at 70 °C in polar protic solvents such as iPrOH and EtOH led to the formation of only traces of the desired product (entries 6 and 7). When toluene was employed as a solvent, after stirring the reactants at 80 °C for 24 h, the desired product 62a was obtained in 50% yield as an equal mixture of diastereomers (entry 8). Since the above few experiments showed no improvement of the reaction outcome (in particular in the diastereoselectivity), the solvent-free approach was chosen.

Next, some test reactions employing mechanical energy were conducted (Table 1, entries 9 and 10). Using a planetary ball mill, the reagents were milled for 2 h at 800 rpm. Unfortunately, only traces of product were detected by TLC and 1H NMR analysis. Assuming that the water forming in the condensation reaction could be negatively influencing the milling process, MgSO4 was used as a milling additive in order to act as a water absorbent. This attempt also proved to be unsuccessful, leading to the conclusion that probably the energy employed was insufficient for the reaction to progress.

21 RESULTS AND DISCUSSION

Table 1. Optimization of the reaction conditions.[a]

Entry Energy source Solvent T (°C) Time (h) Yield (%)[b]

1 oil bath - 80 15 72

2 oil bath - 80 24 90

[c] 3 oil bath - 70 24 77

[c] 4 oil bath - 100 24 62

[d] 5 oil bath - 80 24 61

[c] 6 oil bath iPrOH 70 18 traces

[c] 7 oil bath EtOH 70 18 traces

[c] 8 oil bath toluene 80 24 50 9 -[e] - r.t. 2 traces 10 -[e],[f] - r.t. 2 traces 11 MW - 80 1 50 12 MW - 80 4 80 13 MW - 60 3 80 14 MW - 70 1 76 15[d] MW - 70 1 50 16 MW - 70 2 86 17 MW - 70 4 87 [a] Reaction conditions: 42a (1.0 equiv), 2a (1.1 equiv), 61 (1.2 equiv); Microwave (MW) conditions: 300W, 1 min ramp time. [b] Determined after column chromatography; [c] 42a/2a/61 = 1.1:1.2:1. [d] with 10 mol% pTsOH. [e] reaction performed in the planetary mill in ZrO2 jars with 4 milling balls of the same material (15 mm of diameter) at 800 rpm. [f] MgSO4 was used as a milling additive.

Inspired by the numerous reports on Betti reactions performed under microwave irradiation,[94a, 109] we next decided to test the possibility to conduct the reaction in a microwave reactor (Table 1, entries 11–17). After a reaction time of 1 h at 80 °C, the product 62a was isolated in 50% yield. Increasing the reaction time to 4 h led to improving the yield up to 80%. Next, 60 °C and 70 °C were employed as reaction temperatures (Table 1, entries 13 and 14). A positive effect was observed at 70 °C, giving the product in 76% yield after only 1 h of reaction time (entry 14). The

22 RESULTS AND DISCUSSION yield could be further increased to 86%, when the mixture was heated for 2 h (Table 1, entry 16). Subsequent prolongation of the reaction time did not influence the yield of 62a (Table 1, entry 17).

Since the solvent-free reaction performed under conventional heating gave the highest yield of product 62a (Table 1, Entry 2) these conditions were chosen for pursuing further with the investigation of the scope of this transformation. The optimized conditions using microwave irradiation (Table 1, entry 16) were employed for comparison with two of the screened substrates.

2.1.3 SUBSTRATE SCOPE OF THE BETTI CONDENSATION

With the optimized reaction conditions established, the substrate scope of the reaction was studied (Scheme 18). Firstly, the naphthol component was varied by applying different substituted -naphthols 42. 7-methoxy- and 6-bromo-2-naphthols 42b and 42c proved to be effective substrates in the reaction giving the desired products 62b and 62c in yields of 87% and 91%, respectively, and with 55:45 d.r. Next, 3-substituted naphthols were evaluated in the reaction. The presence of an ester substituent led to the formation of the product 62d in only 28% yield, even after prolonging the reaction time to 72 h. In contrast, the naphthol 42e bearing an amide group reacted smoothly under the reaction conditions and gave product 62e in 90% yield and a d.r. of 54:46. When 9-phenanthrol was employed in the reaction, the product 62f was formed in a moderate yield and 53:47 d.r. The used phenanthrol is provided only in technical grade (60% purity) and presumably some side reactions of the impurities could account for the lower yield. Furthermore, the stability of 62f also proved to be critical as column chromatography as well as storage at room temperature over an extended period of time led to partial product degradation.

Next, the aldehyde component was varied. 2-Bromobenzaldehyde (2c) gave the product 62g in an excellent yield and as a mixture of diastereoisomers in a ratio of 58:42, which were inseparable by column chromatography. When 1-naphthaldehyde (2b) was employed in the reaction, the desired product 62h was formed in 80% yield with an increased diastereoselectivity of 62:38 d.r. In this case, the diastereomers also could not be separated. Heterocyclic aldehydes also reacted very well giving the products 62i–62l in high to excellent yields. Aliphatic aldehydes on the other hand displayed significantly lower reactivity in this transformation. Cyclopropyl carbaldehyde afforded the product 62m in 30% yield with a d.r. of 57:43. While with isobutyraldehyde the product 62n

23 RESULTS AND DISCUSSION was formed in 20% yield and 57:43 d.r. Pyrrole and imidazole carbaldehydes proved to be unsuccessful substrates under these reaction conditions.

Scheme 18. Substrate scope for various naphthols (42) and aldehydes (2). a) Reaction under MW irradiation; b) Yield after 72 h of reaction time.

Further, various sulfoximine substrates were evaluated in the reaction with 2-naphthol (42a) and benzaldehyde (2a). This study was performed by Marcus Frings (IOC, RWTH Aachen University) and selected examples are presented in Scheme 19. When dimethyl sulfoximine was employed

24 RESULTS AND DISCUSSION under the reaction conditions, product 62q was formed in 99% yield. Diphenyl sulfoximine (61b) also reacted well, giving product 62r in 80% yield. When bromine substituted methyl phenyl sulfoximine (61c) was used, product 62s was formed in 87% yield and 52:48 d.r. Isopropyl phenyl sulfoximine (61d) gave 62t in 79% yield with 46:54 d.r.

Scheme 19. Examples from the substrate scope with different sulfoximines 61.2

Using the optimized conditions under microwave irradiation (Table 1, entry 16), the reaction between 7-methoxy-2-naphthol, benzaldehyde and sulfoximine 61a was performed. The product 62b was obtained in 72% yield and 52:48 d.r. When thiophene carbaldehyde was used as a reaction partner instead of 2a, 62j was formed in 66% yield and 55:45 d.r. Both microwave experiments gave the corresponding sulfonimidoylnaphthols 62b and 62j in lower yields compared to the standard reaction conditions.

Finally, for all the above synthesized products, conditions for the separation of the single diastereomers (including also the different enantiomers, when racemic sulfoximines were applied) were developed using CSP-HPLC (chiral stationary phase high performance liquid chromatography).

2.1.4 DETERMINATION OF THE ABSOLUTE CONFIGURATION

The absolute configuration of one of the compounds – 62aa, the major diastereomer of the sulfonimidoylalkyl naphthol 62a, was determined by X-ray crystallography, which allowed the

2 Prepared by Marcus Frings (IOC, RWTH Aachen University)

25 RESULTS AND DISCUSSION unambiguous identification of all stereogenic centers. By analogy, the configuration of all other products was assigned accordingly (Figure 7). The X-ray crystal structure of compound 62aa was determined by Prof. Dr. G. Raabe.2

Figure 7. X-ray crystal structure of compound 62aa.

2.1.5 POSTULATED REACTION MECHANISM

Based on earlier reports,[95, 103b, 104] a plausible mechanism for this condensation reaction is proposed (Scheme 20). In the first step, sulfoximine 61 reacts with aldehyde 2 to afford sulfoximinium intermediate 63. A subsequent attack of naphthol 42 on 63 results in 64, which after a hydride shift leads to the desired product 62.

Scheme 20. Postulated mechanism of the three-component reaction.

2.1.6 APPLICATION AS LIGANDS IN THE ASYMMETRIC ADDITION OF DIETHYLZINC TO ALDEHYDES

As previously discussed, one of the most important areas of application of the chiral aminonaphthols synthesized by Betti condensation is their use in asymmetric synthesis as chiral ligands or chiral auxiliaries. Additionally, -hydroxysulfoximines have also been described as

26 RESULTS AND DISCUSSION successful ligands in various enantioselective transformations (see chapter 1.4, introduction). Therefore, the chiral sulfonimidoylalkyl naphthols 62aa and 62ab were next evaluated as pre- catalysts for the enantioselective addition of diethylzinc to aromatic aldehydes (Table 2). Following a reported procedure,[110] the reaction between benzaldehyde and diethylzinc was performed in the presence of 3 mol% of 62aa (Table 2, entry 1). After 10 h of reaction time, the product 50a was isolated in 87% yield and 72% ee. When 2-methoxybenzaldehyde (2l) was used as a substrate, the corresponding product 50l was obtained after only 4 h of reaction time in 99% yield with 90% ee (entry 2). Lowering the reaction temperature to −25 °C led to a very prolonged reaction time and only a slight increase in the enantioselectivity (entry 3). When the other diastereomer 62ab was also tested as a pre-catalyst under the same reaction conditions, both lower reactivity and stereoselectivity were obtained (entries 4 and 5). These few examples revealed the high catalytic activity of the synthesized chiral sulfonimidoylalkyl naphthols 62a in this asymmetric transformation.

Table 2. Asymmetric addition of diethylzinc to aldehydes 2 catalyzed by 62aa and 62ab.

Entry[a] R Time (h) Yield of 50 (%)[b] ee of 50 (%)[c]

1 H (2a) 10 87 72 (R)

2 OMe(2l) 4 99 90 (R)

[d] 3 OMe(2l) 50 88 93 (R) 4[e] H(2a) 20 77 30 (S) 5[e] OMe(2l) 8 98 76 (S)

[a] Reaction conditions: aldehyde 2 (0.9 mmol), Et2Zn (3 equiv), 62aa (3 mol%) in toluene (3 mL); [b] Yield after purification by column chromatography; [c] Determined by CSP-HPLC analysis; [d] reaction at −25 °C; [e] 62ab was used as a pre-catalyst.

27 RESULTS AND DISCUSSION

2.1.7 BRØNSTED ACID MEDIATED REACTION OF 62a WITH INDOLE

Next, aiming to further explore the potential applications of the obtained sulfonimidoylnaphthols 62, our interest was drawn towards ortho-quinone methides (o-QM). The latter represent useful synthetic intermediates and have found application in the construction of complex natural products and bioactive compounds.[111] As highly reactive chemical motif they participate easily in different transformations such as 1,4-conjugate additions, hetero Diels–Alder reactions, and 6 electrocyclizations or [4+2] cycloadditions. o-QM can be generated by a variety of methods, including thermolysis,[112] oxidation,[113] photolysis,[114] and base or acid promoted - elimination.[115] Among others, Brønsted acids (BA) have proven to be effective catalysts for the formation of o-QM. Moreover, when chiral BA are employed, the resulting products could be obtained with high stereoselectivity.[116, 117]

One particular example is the procedure developed by the group of SCHNEIDER in 2015, who used a chiral phosphoric acid catalyst C1 to generate in situ o-QM from ortho-hydroxybenzhydryl alcohols and subsequently react them with indoles 66 and phenols 42 to form diarylindolylmethanes 67 and triarylmethanes 68, respectively (Scheme 21).[116c] The described transformations proceeded smoothly at room temperature, giving the desired products in high yields and high enantioselectivities.

Scheme 21. Chiral phosphoric acid catalyzed synthesis of diarylindolylmethanes (67) and triarylmethanes (68).

28 RESULTS AND DISCUSSION

In 2015, the group of KLIMOCHKIN reported the synthesis of 14H-Dibenzo[a,j]xanthenes, starting from Betti bases 69.[118] After refluxing a solution of 69 in acetic acid for 6 h the authors were able to obtain the products 70a–e in yields of 36–50% (Scheme 22). According to the proposed mechanism, in the acidic medium a part of the aminonaphthol molecules undergo a retro-Betti reaction to form 2-naphthol (42a). Another part of the molecules 69 generates quinone methides, which undergo Michael addition with 2-naphthol (42a), followed by subsequent cyclodehydration to form dibenzoxanthene 70. The same group reported other types of transformations including the use of aminonaphthols 69 as a starting material for the generation of o-QM.[119]

Scheme 22. Synthesis of dibenzoxanthene 70 under acidic conditions.

In 2016, DEB and BARUAH reported a p-toluenesulphonic acid-catalyzed reaction of 69 with indoles (66) resulting in the formation of products 67 (Scheme 23).[120] In the next step, intramolecular dehydrogenative C2-alkoxylation was performed, giving the corresponding chromeno[2,3- b]indoles 71. In this case, quinone methides also were pointed as the key intermediates for the reaction.

Scheme 23. Brønsted-acid-mediated divergent reactions of Betti bases with indoles (66).

Considering the reports described above, we decided to test the newly synthesized sulfonimidoyl naphthols 62 as substrates for generating o-QM in presence of a Brønsted acid. A mixture of the two diastereomers was used to determine if there is a difference in their reactivity. Initially, the reaction of 62a with indole (66a) was performed in the presence of 5 mol% of chiral phosphoric acid C2 as a catalyst in dichloromethane at room temperature (Table 3, entry 1). After 24 h, only

29 RESULTS AND DISCUSSION traces of the desired product 67a were detected. Increasing the amount of the catalyst to 20 mol% resulted in the formation of 67a in 12% yield after the same reaction time (Table 3, entry 2).

Table 3. Optimization of the Brønsted acid-catalyzed reaction between sulfonimidoylnaphtol (62a) and indole (66a).[a]

Yield of ee of 66a Cat. T Time d.r. of 62a Entry Solvent 67a 67a (equiv) (mol %) (°C) (h) recovered[d] (%)[b] (%)[c] 1 DCM 1.0 C2 (5) rt 25 traces - - 2 DCM 2.0 C2 (20) rt 25 12 - - 3 DCM 2.0 C2 (20) 55 25 64 0 59:41

4 CH3Cl 2.0 C2 (20) 75 6 84 0 71:29

5 CH3Cl 1.0 C2 (20) 75 25 83 0 67:33 6 toluene 1.0 C2 (20) 75 25 71 0 64:36

7 CH3Cl 1.0 C3 (20) 75 24 80 6 83:17 [a] Reaction conditions: 62a (0.15 mmol, d.r. 54:46), 66a, catalyst (5–20 mol%) in 1.5 mL solvent. [b] Yield after purification by column chromatography. [c] Determined by CSP-HPLC analysis. [d] Determined by 1H NMR spectroscopy.

Next, in an attempt to improve the reactivity, the reaction mixture was heated, and after 24 h of reaction time 67a could be obtained in 64% yield (Table 3, entry 3). When chloroform was used as a solvent, the yield could be further improved to 84% (Table 3, entry 4). Moreover, the amount of indole could be reduced to one equivalent without having an influence on the reaction outcome (Table 3, entry 5). Additionally, toluene was tested as a solvent in this transformation, but it gave the product 67a in lower yield (Table 3, entry 6). In a final attempt to induce the enantioselective formation of 67a, the more hindered chiral phosphoric acid C3 was employed as a catalyst in the

30 RESULTS AND DISCUSSION reaction (Table 3, entry 9). Disappointingly, the desired diarylindolylmethan 67a was formed in 80% yield, but with only 6% ee. In this case, the d.r. of the recovered starting material 62a was 83:16, showing that in the presence of a more sterically hindered catalyst, there is a more distinct difference in the reactivity of both diastereomers.

2.1.8 BIOLOGICAL TESTS

Considering the numerous examples of Betti bases as well as sulfoximines exhibiting various biological activities (see sections 2.1.1 and 1.4), it was of high interest to evaluate the properties of the newly synthesized sulfonimidoylnaphthols 62.

The biological tests were performed by the Australian open-access screening initiative Co-ADD (The Community for Open Antimicrobial Drug Discovery). Both diastereomers of compounds 62a–f, 62i–l, and the diastereomeric mixtures of 62g, 62h, 62n, were studied in terms of their biological activity by whole cell growth inhibition assays at a test concentration of 32 g/mL. The inhibition of growth was measured against five different microbial strains: Escherichia coli, Klebsiella pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa and Staphylococcus aureus, and two fungi: Candida albicans and Cryptococcus neoformans. The study identified one compound (62ja, Figure 8) with an inhibitory activity considered to be a confirmed hit against Candida albicans (activity ≤ 16 g/mL). Interestingly, the other diastereomer 62jb, as well as the structurally very similar 62k and 62l, showed low activity at the tested concentrations. Furthermore, additional tests for cytotoxicity against a human embryonic kidney cell line,

HEK293, were performed with 62ja by determining its CC50 value. The screening revealed that the sulfonimidoylnaphthol 62ja exhibits no cytotoxicity against HEK293 cells at the tested concentrations. These positive results certainly encourage further investigation of the biological relevance of this type of compounds.

Figure 8. Structure of the sulfonimidoylnaphthols 62ja, 62jb, 62k and 62l and their inhibitory activity against Candida albicans.

31 RESULTS AND DISCUSSION

2.2 STUDIES ON THE RESOLUTION OF RACEMIC MALONIC ACID INDOLE DERIVATIVES IN A

REACTION TOWARDS BISINDOLYLMETANES

2.2.1 BACKGROUND AND AIM OF THE PROJECT

The indole scaffold is one of the most widely represented nitrogen-containing heterocycle found in nature. A plethora of indole-based natural products and pharmaceuticals cover a vast range of biological activity (Figure 9).[121] These compounds exhibit a high affinity and an excellent binding ability for a diverse array of receptors. Hence, the indole ring system has been regarded as a “privileged structure” and represents an essential structural motif in drug design.[122]

Figure 9. Selected examples of natural and synthetic indole derivatives with biological activity.[121d, 123]

The importance of substituted indoles for medicinal chemistry stimulated extensive efforts for the development of efficient synthetic methods for the construction and direct functionalization of the indole skeleton.[124] Since biologically active indole derivatives often carry stereocenters in - or -position of their side chains, special attention has been drawn to the asymmetric catalytic methods towards enantioenriched functionalized indoles. Among them, the Friedel–Crafts alkylation of indoles promoted by chiral Lewis or Brønsted acids, represents one of the most efficient strategies (Scheme 24).[124g, 125] Various electrophiles have been successfully applied in this reaction, such as aldehydes or ketones, imines or enamines, ,-unsaturated carbonyl compounds, arylidene malonates, and nitroalkenes, among others.[124g, 125h]

32 RESULTS AND DISCUSSION

Scheme 24. Catalytic Friedel–Crafts alkylation of indoles 66; EWG: COX, NO2.[124g]

Friedel–Crafts alkylation of indoles with arylidene malonates

Arylidene malonates (80) represent highly reactive Michael acceptors for Michael-type Friedel– Crafts alkylation of indoles and have been successfully utilized for the generation of synthetically valuable carboxylic acid derivatives with indole systems.

In a pioneering work in 2001,[126] ZHUANG and JØRGENSEN reported the asymmetric alkylation reaction of indoles 66 with benzylidene malonates 80, employing a chiral copper(II)-BOX complex with the bis(oxazoline) ligand L5, which resulted in good yields and moderate enantioselectivities (up to 60% ee) of the desired products 81.

Figure 10. Examples of chiral ligands applied in the asymmetric alkylation of indole 66 with benzylidene malonates 80.

33 RESULTS AND DISCUSSION

Subsequently, the group of TANG reported protocols with L17 and L18 as ligands in the reaction, performing detailed studies on the influence of solvent, temperature, ligand/metal ratio, and additives on the selectivity.[127] When iBuOH was used as a solvent with L18, the alkylation product was formed with an enantioselectivity up to 93%. Furthermore, when the reactions were carried out in 1,1,2,2-tetrachloroethane (TTCE), the products were obtained as the opposite enantiomer (up to −78% ee). Thus, by changing only the solvent, either one of both enantiomers of the alkylation product could be efficiently prepared using the same catalytic system.

Afterwards, REISER and co-workers developed a method for the alkylations of indoles 66 with benzylidene malonates 80 using aza-bis(oxazoline) L19-Cu(II) complexes.[128] In this study it was reported that the ratio of ligand to copper salt plays an important role for achieving excellent enantioselectivities.

Additionally, heteroarylidene malonate-derived bis(oxazoline) L20-Cu(II) reported by SUN et al.[129] and N,N’-dioxide L21-scandium(III) complexes developed by the group of FENG[130] proved to be also efficient catalysts for this transformation. More recently, WAN and co-workers demonstrated a Cu-catalyzed Friedel‒Crafts alkylation using bis-sulfonamide diamine ligands L22a (Figure 10).[131] The desired products were obtained in excellent yields and enantioselectivities up to 96% ee.

Friedel–Crafts alkylation of indoles with carbonyl compounds and imines. Bisindolylmethane derivatives

When carbonyl compounds or imines are used as electrophiles in the asymmetric alkylation of indole, it was found that attention should be paid to the strength of the promoting agent used (Scheme 25).[132] Since the stability of 82 is often critical, an elimination reaction assisted by the presence of a Lewis acid could occur leading to the intermediate 83. Then a subsequent second Friedel–Crafts reaction with another indole molecule affords the compound 84.

Scheme 25. Formation of bisindoyl compounds 84 in the LA-catalyzed addition of carbonyl/imine compounds 78 to indole 66.[125a]

34 RESULTS AND DISCUSSION

Thus, the acid catalyzed double addition of indoles to carbonyl compounds is one of the main synthetic strategies used for the preparation of symmetrical bis(3-indolyl)alkanes 84. This type of compounds have also shown important biological activities (Figure 9) and therefore their preparation has been broadly studied.[133]

Another strategy for accessing both symmetrical as well as unsymmetrical bisindoles 86 is the use of preformed indole derivatives 85, containing a suitable leaving group (Scheme 26). Some examples are 3-indolylmethanols,[134] -(3-indolyl)benzylamines,[135] indolylmethyl barbituric[136] and Meldrum’s acid derivatives.[137] By substituting these leaving groups for an indolyl moiety a wide range of bisindoles 86 is accessible. There are also few examples employing chiral Brønsted acids as catalysts in the reaction, affording the desired products 86 in an enantiomerically enriched form.[138]

Scheme 26. Use of leaving groups in the preparation of bisindolemethanes 86.

As discussed in the introduction of this thesis (section 1.3), sulfoximine based ligands, promoted successfully relevant metal-catalyzed asymmetric transformations such as Diels–Alder and hetero-Diels–Alder reactions. In this context, aiming to examine the stereoselective ability of C2- symmetric bissulfoximine ligands in other transformation, the catalytic Friedel‒Crafts alkylation of indoles 66 with benzylidene malonates 80 was envisioned as possible further application of this type of ligands.

35 RESULTS AND DISCUSSION

2.2.2 PRIMARY EXPERIMENTS ON THE ASYMMETRIC FRIEDEL–CRAFTS ALKYLATION OF INDOLES

CATALYZED BY A CHIRAL METAL-SULFOXIMINE COMPLEX

In our initial experiments, we used complexes derived from the chiral bissulfoximine ligand L11 and various metal salts as catalysts in the Friedel–Crafts reaction of indole (66a) with diethyl benzylidene malonate (80a) (Table 4). The complexes were prepared by stirring the ligand and the Lewis acid in TBME for 30 min under argon atmosphere. Pleasingly, employing

Cu(ClO4)2·6H2O provided the product 81a in 79% yield with 70:30 e.r. after 3 h reaction time (Table 4, entry 1). Along with the desired product the bisindole 84a was isolated in 8% yield. When tin and scandium triflates were employed as Lewis acids (Table 4, entries 2 and 3), 81a was formed in high yield, but with very low enantiomeric excess, while product 84a was either not formed or found only in traces.

Table 4. Primary screening of the reaction conditions of the asymmetric Friedel–Crafts alkylation of indole (66a) with diethyl benzylidene malonate (80a).[a]

81a, Yield 84a, Yield Entry Lewis acid Time (h) T (C) 81a, e.r. (%)[c] (%)[b] (%)[b,d]

1 Cu(ClO4)2·6H2O 3 r.t. 79 70:30 8

2 Sn(OTf)2 48 r.t. 70 43:57 0

3 Sc(OTf)3 2 r.t. 90 48:52 traces

4 Cu(OTf)2 8 r.t. 55 91:9 20

[e] 5 Cu(OTf)2 8 r.t. 52 88:12 16

[e] 6 Cu(OTf)2 1 r.t. 54 75:25 14

[e] 7 Cu(OTf)2 3 10 65 72:28 6

[e] 8 Cu(OTf)2 3.5 −10 82 60:40 4.5 [a] Reaction conditions: 66a (0.2 mmol), 80a (0.2 mmol), Lewis acid/L11 (0.02 mmol) in TBME (2 mL). [b] Determined after column chromatography. [c] Determined by CSP-HPLC analysis. [d] Calculated to 0.2 mmol. [e] 4 Å MS was added.

36 RESULTS AND DISCUSSION

Next, Cu(OTf)2 was employed as a catalyst giving the desired product 81a in moderate yield, but pleasingly with an increased enantioselectivity of 91:9 e.r. (Table 4, entry 4). Under those conditions the yield of 84a also increased to 20%. Nevertheless, the reproducibility of these results proved to be challenging. The amount of byproduct formed as well as the enantiomeric excess of 81a, varied strongly depending on the quality of the solvent, copper triflate and ligand used. In order to suppress the formation of product 84a and hopefully increase the enantioselectivity, the reaction was performed at lower temperatures (Table 4, entries 7 and 8). This modification led to a decrease in the yield of product 84a and an increased yield of 81a, but at the cost of an unexpected dramatic drop in the enantioselectivity. Those surprising results motivated us to perform a control experiment, employing rac-81a in the presence of indole (2.0 equiv.) with 20 mol% of catalyst (Scheme 27). After 18 h reaction time 84a was isolated in 60% yield, while 40% of 81a were recovered with an enantiomeric ratio of 86:14. The obtained results clearly pointed out that compound 81a undergoes kinetic resolution in the reaction with indole to 84a, which could partly explain the unreproducible results obtained in the model reaction when different amounts of 84a were formed. Since we could not find any literature reports about the obtained kinetic resolution of 81a under similar reaction conditions, we decided to focus our studies on this process.

Scheme 27. Kinetic resolution of rac-81a in the reaction with indole (66a).

2.2.3 SCREENING OF THE REACTION CONDITIONS FOR THE KINETIC RESOLUTION OF 81A

In order to get a better understanding about the temperature dependence of the obtained kinetic resolution, the reaction of rac-81a and indole 66a was performed at different temperatures (Table 5, entries 1–3). At low temperature product 84a was formed in only 11% yield after 18 h reaction time and the recovered starting material 81a was racemic (Table 5, entry 2). Next, the reaction was performed at 40 °C for 3 h whereby product 84a was isolated in 80% yield, while 81a was recovered in 19% yield and 97:3 e.r. (Table 5, entry 4). Lowering the reaction temperature to 35 °C resulted in a very reduced reaction rate (Table 5, entry 7). Here should be

37 RESULTS AND DISCUSSION noted that the addition of molecular sieves to the reaction mixture and the precise control of the reaction temperature proved to be essential for achieving reproducibility.

Table 5. Primary screening of the reaction conditions for the kinetic resolution of rac-81a.[a]

84a,Yield 81a, Yield 81a, e.r. Entry 66a (equiv) Time (h) T (C) (%)[b] (%)[b] (%)[c] 1 2 18 r.t. 60 39 86:14

2 2 18 0 11 82 50:50

3 2 2 40 65 33 99:1

4[d] 2 3 40 80 19 97:3

5[d,e] 2 3 40 63 35 98:2

6[d,e] 1 22 40 60 40 88:11

7[d,e] 2 3 35 31 68 60:40

[a] Reaction conditions: rac-81a (0.1 mmol), 66a (0.2 mmol), Cu(OTf)2/L11 (0.02 mmol) in TBME (2 mL). [b] Determined after column chromatography. [c] Determined by CSP-HPLC analysis. [d] 4 Å MS was added. [e] Scaled up to 0.2 mmol of rac-81a.

Screening of ligands

Subsequently, we focused on evaluating the effect of different chiral ligands on the transformation (Table 6). First, amino sulfoximine ligand L13 was tested in the reaction (Table 6, entry 2). After 3 h unreacted 81a was isolated in 24% yield and 88:11 e.r. Afterwards, a series of C2-symmetrical bissulfoximine ligands were tested (Table 6, entries 3–6). All of them showed selectivity towards the resolution of the two enantiomers of 81a. When L24 was employed, an enhancement of the reactivity was achieved, whereby the results obtained with L11, could be reproduced in much shorter reaction time (30% yield of 81a, 97:3 e.r, entry 5). Subsequently a mixed sulfoximine- oxazoline ligand L26 and classical BOX and PyBOX ligands (L5, L27, L28, L29 and L30) were employed in the reaction, but further improvement could not be achieved (Table 6, entries 7–12).

38 RESULTS AND DISCUSSION

Table 6. Screening of the chiral ligands.[a]

Entry L Time (h) 84a, Yield (%)[b] 81a, Yield (%)[b] 81a, e.r. (%)[c]

1 L11 3 63 35 98:2

2 L13 3 78 24 88:11

3 L23 1 44 53 30:70 4 L16 1 55 45 28:72 5 L24 1 69 30 97:3 6[d] L25 18 33 53 78:22

7[e] L26 24 40 54 51:49

8[e] L5 24 traces - -

9[e] L27 24 38 58 57:43

10[e] L28 24 44 50 40:60

11[d,e] L29 17 52 37 63:37

12[d,e] L30 1 n.r. - -

[a] Reaction conditions: 66a (0.4 mmol), rac-81a (0.2 mmol), Cu(OTf)2/L (0.02 mmol) in TBME (2 mL). [b] Determined after column chromatography, n.r. = no reaction. [c] Determined by CSP-HPLC analysis. [d] Reaction with 0.2 mmol of 66a. [e] Cu(OTf)2/L (0.01 mmol).

39 RESULTS AND DISCUSSION

Having identified L24 as the best ligand (Table 6, entry 5), we next screened the effect of the different amounts of indole (66a) and catalyst on the reaction outcome in order to achieve 50 % conversion of the starting material 81a (Table 7). The best result was achieved when 0.6 equivalents of 66a were employed, giving the unreacted 81a in 48% yield and with an enantiomeric ratio of 74:26 (Table 7, entry 3). Gratifyingly, the catalyst loading could be reduced to 10 mol% without affecting the results (Table 7, entry 5). Further reduction of the catalyst loading was not beneficial for the reaction outcome (Table 7, entry 6).

Table 7. Optimization of the amount of indole (66a) and amount of catalyst.[a]

Catalyst 84a, Yield 81a, Yield 81a, e.r. Entry Time (h) 66a (equiv) (mol%) (%)[b] (%)[b] (%)[c] 1 1 2 20 69 30 97:3 2 1 1 20 49 50 75:25 3 5 0.6 20 34 48 74:26

4 3 0.5 20 22 68 63:37

5 3 0.6 10 45 49 73:27

6 20 0.6 5 17 77 59:41

[a] Reaction conditions: 66a, rac-81a (0.2 mmol), Cu(OTf)2/L24 in TBME (2 mL). [b] Determined after column chromatography. [c] Determined by CSP-HPLC analysis.

Screening of solvents

Once we had identified the best ligand and substrates ratio (Table 7, entry 3), we focused on evaluating the effects of the nature of the solvent and the Lewis acid. Firstly, a plethora of different solvents with diverse polarities was tested in the presence of 10 mol% of catalyst at 40 °C (Table 8). From the various ethers employed, diethyl ether showed the best result in terms of selectivity, giving the recovered product in 53% yield with 78:22 e.r. (Table 8, entry 4). When methanol was used, no product formation was detected even after an extended reaction time of 20 h. Polar aprotic solvents such as acetonitrile and acetone had the same negative effect on the reactivity

40 RESULTS AND DISCUSSION

(Table 8, entries 9 and 10). Furthermore, additional nonpolar solvents were screened, out of which them the best result was achieved using toluene, whereby the recovered 81a was obtained in 49% yield with 82:18 e.r. (Table 8, entry 14).

Table 8. Screening of different solvents.[a]

Entry Solvent Time (h) 84a, Yield (%)[b] 81a, Yield (%)[b] 81a, e.r. (%)[c]

1 TBME 3 45 49 73:27

2 THF 3 22 69 60:40

3 dioxane 5 55 41 56:44

4 Et2O 3 27 53 78:22

5 iPr2O 20 15 79 57:43

6 nBu2O 24 11 87 53:47

7 Ph2O 2 52 42 79:21

8 MeOH 20 n.r. - -

9 CH3CN 20 n.r. - -

10 acetone 3 30 70 51:49

11 DCM 2 44 44 57:43

12 CH3Cl 1 57 36 58:42

13 benzene 1 55 43 61:39

14 toluene 1 47 49 82:18

15 PhCF3 1 37 51 68:32

18 PhCH2CH3 1.5 48 52 81:19 19 anisole 1 45 30 53:47 20 o-xylene 1.5 45 52 76:24

[a] Reaction conditions: 66a (0.18 mmol), rac-81a (0.3 mmol), Cu(OTf)2/L24 (0.03 mmol) in solvent (2 mL). [b] Determined after column chromatography, n.r. = no reaction. [c] Determined by CSP-HPLC analysis.

41 RESULTS AND DISCUSSION

Next, several Lewis acids were employed in the reaction in combination with L24 (Table 9).

Zn(OTf)2 and Ni(ClO4)2·6H2O showed to be unsuitable catalysts for this transformation (Table 9, entries 2 and 3). The same outcome was observed for copper salts with ClO4 and SbF6 counter anions (Table 9, entries 4 and 5) as well as for the benzene complex of Cu(I) triflate (Table 9, entry 6). Pleasingly, Cu(ClO4)2·6H2O gave similar results to those obtained with Cu(OTf)2 (Table 9, entry 7). The selectivity could be further improved by prolonging the complexation time from 30 to 60 min. Using Cu(ClO4)2·6H2O/L24 as a catalyst, product 84a was formed in 53% yield, and 81a was recovered in 47% yield with 86:14 e.r. (Table 9, entry 8). As no further improvements of the reaction outcome could be achieved, these reaction conditions were regarded as the optimal conditions for this transformation.

Table 9. Screening of the Lewis acid.[a]

84a, Yield 81a, Yield 81a, e.r. Entry Lewis acid Time (h) (%)[b] (%)[b] (%)[c]

1 Cu(OTf)2 1 47 49 82:18

[d] 2 Zn(OTf)2 48 traces - -

3 Ni(ClO4)2·6H2O 24 n.r. - -

[e] 4 Cu(ClO4)2 24 4 89 52:48

[e] 5 Cu(SbF6)2 24 2 94 50:50

6 (Cu(OTf))2·benzene 72 8 82 52:48

7 Cu(ClO4)2·6H2O 1 43 53 80:20

8 Cu(ClO4)2·6H2O 1.5 53 47 86:14

[a] Reaction conditions: 66a (0.18 mmol), rac-81a (0.3 mmol), Lewis acid/L24 (0.03 mmol) in toluene (2 mL). [b] Determined after column chromatography, n.r. = no reaction. [c] Determined by CSP-HPLC analysis. [d] With

L11 and in MTBE. [e] Prepared from CuCl2 and the corresponding silver salt.

42 RESULTS AND DISCUSSION

2.2.4 SUBSTRATE SCOPE

With the optimized conditions in hand (Table 9, entry 8), we continued our studies with examining the applicability of the disclosed protocol by varying the substituents in the starting racemic compound 81 (Table 10). Introducing a halogen substituent on the phenyl ring of 81 led to significant drop in the stereoselectivity (Table 10, entries 2–4). The effect of electron-donating substituents was even more profound resulting in racemic 81 being recovered (Table 10, entries 6 and 7). Similarly, no stereoselectivity was obtained with substrates 81h and 81i.

Table 10. Substrate scope with differently modified substrates 81.[a]

84, Yield 81, e.r. Entry R1 R2 Time (h) 81, Yield (%)[b] (%)[b] (%)[c]

1 C6H5 (81a) Et 1.5 53 47 86:14

2 2-ClC6H4 (81b) Et 1.5 41 58 68:32

3 4-ClC6H4 (81c) Et 0.75 48 50 67:33

4 3-BrC6H4 (81d) Et 1.5 45 55 69:31

5 4-NO2C6H4 (81e) Et 16 traces 92 50:50

6 4-MeC6H4 (81f) Et 1.5 45 41 50:50

7 1-naphthyl (81g) Et 1 57 42 50:50

8 2-thienyl (81h) Et 0.5 58 39 50:50

9 C6H5 (81i) Me 1 50 40 55:45

10 C6H5 (81j) iPr 1 47 47 72:28

11 C6H5 (81k) tBu 24 3 95 50:50

[a] Reaction conditions: 81 (0.3 mmol), 66a (0.18 mmol), Cu(ClO4)2·6H2O/L24 (0.03 mmol) in toluene (2 mL). [b] Determined after column chromatography. [c] Determined by CSP-HPLC analysis.

Finally, the nature of the ester group of the substrates 81 was modified. Both methyl and isopropyl esters reacted smoothly under the reaction conditions, whereby 81i was recovered in 40% yield and 55:45 e.r. after the reaction, while 81j in 47% and with 72:28 e.r. tBu-ester 81k

43 RESULTS AND DISCUSSION showed almost no reactivity even after 24 h reaction time. The obtained results with the differently modified substrates 81 showed the significant effect of the substituents R1 and R2 for the stereoselection between the catalyst and the substrate. The observed higher enantioselectivities with 81a could be due to a possible π−π stacking interactions between the catalyst and the model substrate. Presumably, by introducing different R1 substituents those interactions could have been hampered, which resulted in decreased stereoselectivity.

Subsequently, we continued our studies with examining the applicability of the disclosed protocol for the preparation of dissymmetrical bisindoylmethanes 86 by using substituted indoles (66) in the transformation (Table 11).

Table 11. Substrate scope with substituted indoles (66).[a]

86, e.r. 81a, Yield 81a e.r. Entry R1 Time (h) 86/87/84a[b] (%)[c] (%)[d] (%)[c]

1 5-Br (66b) 1 1.0:0.2:0.4 50:50 49 80:20

2 6-Cl (66c) 0.75 1.0:0.1:0.1 50:50 46 82:18 3 7-Br (66d) 1 n.d. 50:50 46 78:24 4 4-Me (66g) 24 n.r. - - - 5[e] 5-Br (66b) 8 1.0:0.2:0.1 50:50 59 74:26

[a] Reaction conditions: rac-81a (0.3 mmol), 66 (0.18 mmol), Cu(ClO4)2·6H2O/L24 (0.03 mmol) in toluene (2 mL). [b] Determined by 1H NMR analysis, n.d. = not determined. [c] Determined by CSP-HPLC analysis. [d] Determined after column chromatography, n.r. = no reaction. [e] The reaction was performed at room temperature.

44 RESULTS AND DISCUSSION

When different indoles with substituents on the phenyl ring were employed under the reaction conditions, the unreacted 81a was recovered with moderate to good enantioselectivities (78:24– 82:18 e.r., Table 11, entries 1–3). However, dissymmetrical bisindoylmethanes 86 were formed in racemic form and moreover, along with the desired product, the crossover products 87 and 84a were always detected and in most of the cases the mixture of the three compounds was inseparable, or only partly separable. An attempt to suppress the formation of 87 and 84a was made by performing the reaction at room temperature (Table 11, entry 7). This experiment resulted in dramatically increased reaction time and reduced amount of product 84a, while it did not influence the formation of 87b or the enantioselectivity towards 86b.

2.2.5 STUDIES TOWARDS THE ELUCIDATION OF THE REACTION MECHANISM

Based on earlier reports,[137] and the results obtained, two possible reaction pathways were postulated (Scheme 28). The first proposed mechanism involves initial coordination of the chiral metal complex to the carbonyl oxygens of 81a resulting in formation of the diastereomeric intermediates 88 (Scheme 28, a). Thus, the malonic ester moiety is converted to a better leaving group, which in the next step is cleaved in a E1-like process, forming the iminium ion 89a. A difference in the rates of this step could be the reason for the obtained resolution of 81. A subsequent nonstereoselective attack of 66 on 89a affords the racemic bisindole product 86. Presumably, this last step is reversible in the presence of the Lewis acid, whereby both types of vinylogous iminium intermediates (89a and 89) are formed, together with the corresponding indoles (Scheme 28, c). Following recombination reactions could explain the formation of crossover products 84a and 87.

The second proposed mechanism (mechanism B) also involves a coordination of the chiral complex to 81a as a first step, resulting in formation of the diastereomeric intermediates 88 (Scheme 28, bottom). In this case the elimination of the malonic ester group is assisted by the nucleophilic attack of indole 66 on 88, which is more favored towards one of the diastereomers. As a result, unreacted 81a is recovered in enantioenriched form and 86 is formed. Analogously to mechanism A, the product 86 undergoes fragmentation forming iminium ions 89a and 89 and the corresponding indoles 66 and 66a, which recombine to form products 87 and 84a (Scheme 28, c).

45 RESULTS AND DISCUSSION

Scheme 28. Possible mechanisms for the kinetic resolution of rac-81a.

In order to elucidate the most probable reaction pathway, two control experiments were conducted. In the first one the rac-81a was subjected to the reaction conditions in the absence of the nucleophile (Scheme 29). This experiment aimed to examine the effects induced by the chiral Lewis acid complex on this substrate. After 24 h 81a was recovered in 79% yield in a racemic form. This result pointed out the important role of the indole in the elimination step, as well as on

46 RESULTS AND DISCUSSION the stereoselection, supporting the proposed reaction mechanism B. Besides, no indole (66a) or benzylidene malonate (80a) were detected, which could exclude a retro-Friedel–Crafts reaction pathway.

Scheme 29. Control experiment in the absence of a nucleophile.

In the second control experiment, the optimized conditions were employed in the reaction of 84a and 5-Br-indole (Scheme 30). After 16 h of reaction time the reaction mixture was filtered through a pad of silica gel and analyzed by NMR spectroscopy. The analysis showed that the crude reaction mixture contains products 84a, 86b and 87b in a ratio 1:0.8:0.1. Indole (66a) and Br- indole (66b) were also detected. The CSP-HPLC analysis of the mixture revealed that it 86 is obtained as a racemic mixture. The obtained results from this experiment support the assumption of a fragmentation of the bisindole products under the reaction conditions.

Scheme 30. Reaction of bisindolylmethane 84a with Br-indole (66b) towards crossover products 86b and 87b.

47 RESULTS AND DISCUSSION

2.3 COPPER-CATALYZED ASYMMETRIC MICHAEL-TYPE FRIEDEL–CRAFTS-ALKYLATIONS OF

INDOLES WITH ARYLIDENE MALONATES UNDER BALL MILLING CONDITIONS

2.3.1 BACKGROUND AND AIM OF THE PROJECT

In the previous chapter the importance and the broad utility of Friedel–Crafts reactions for accessing various chiral indole derivatives was highlighted. Despite their effectiveness in terms of yield and enantioselectivity, the reported solution-based procedures feature some drawbacks, such as strong dependence of the catalytic activity on the nature of the solvent used, inert atmosphere, additional cooling needed and long reaction times. These are still limiting the overall sustainability of these types of transformations.

In the beginning of the thesis (see section 1.3), mechanochemistry was introduced as an efficacious alternative for the implementation of a wide range of chemical transformations, offering benefits such as solvent-free conditions, short reaction times, and low catalyst loadings, among others. The utilization of ball milling for the development of solvent-free asymmetric transformations was also discussed in the introduction section. Although mechanochemistry has already been applied successfully for the construction[139] and the derivatization[140] of the indole skeleton, till date, there is only one reported attempt of performing an asymmetric alkylation reaction of indoles in the ball mill.[141] In 2011, HESTERICOVÁ and ŠEBESTA described the Michael addition of indole (66a) to -nitrostyrene (90a), employing and evaluating a plethora of thiourea- and squaramide-based organocatalysts (Scheme 31).

Scheme 31. Thiourea-catalyzed asymmetric Michael addition of nitrostyrene to indole (66a) in the ball mill.

48 RESULTS AND DISCUSSION

The reactants and catalysts were milled at 20 Hz for 6 h in a HSBM. Depending on the employed catalyst, the resulting alkylation product 91 was isolated either in high yield, but in racemic form, or in an enantioenriched form, but in unsatisfactory yields.

Despite the scarcity of research in the field of mechanochemical metal-catalyzed asymmetric reactions, the findings described in section 1.3 indicate a degree of stability of chiral metal complexes under ball milling conditions. This made us envisage the potential application of this approach for the development of more sustainable and efficient procedures for the preparation of chiral 3-substituted indoles. Accordingly, in order to examine the possibility to perform an asymmetric copper-catalyzed alkylation of indoles in the ball mill, arylidene malonates 80 and - nitrostyrenes 90 were selected as initial reaction partners (Scheme 32).

Scheme 32. Envisioned copper-catalyzed Michael-type Friedel–Crafts asymmetric alkylations of indole in the ball mill.

2.3.2 OPTIMIZATION OF THE CHIRAL LIGANDS

Optimization experiments with benzylidene malonate (80a)

For the initial studies, indole (66a) and benzylidene malonate (80a) were selected as substrates and Cu(OTf)2 as a Lewis acid (Scheme 33). Firstly, the Lewis acid and the chiral ligands were ground together for 10 min at 25 Hz in a mixer mill to form the chiral metal complexes. Next, the substrates were directly added to the milling vessel and the mixture was further milled for another 60 min at 25 Hz. To begin with, ligands L7 and L31 were employed in the catalytic reaction. In the presence of L7, after 60 min of milling, the desired product 81a was obtained in 80% yield and with 56:44 e.r. in favor of the (S)-enantiomer.[127d] L31 gave 81a in 70% yield, and with increased enantioselectivity of 63:37 e.r. When PyBOX ligands L32 and L33 were applied, the desired product was formed in high yield, but as an equal mixture of enantiomers. Next, ligands L34, L35, L22, L36, L24, and L37 were employed in the same reaction, all providing the product 81a in high yield, but with low enantioselectivity. From the classic BOX ligands screened, tBu-BOX ligand L5 gave the desired product 81a in excellent yield of 95% with an e.r. of 65:35, while the Ph-, Bn- and iPr-analogs, L27, L28, and L29, exhibited nearly no enantioselectivities.

49 RESULTS AND DISCUSSION

The use of the indane-BOX ligand L38 provided results similar to the ones obtained with ligand L5. Pleasingly, when L39 was employed, the enantioselectivity could be improved to 78:22 e.r. However, with the more substituted L41 the reaction outcome was the same as with L39.

Scheme 33. Chiral ligands screened for the alkylation of indole (66a) with benzylidene malonate (80a); yields after purification by column chromatography. a) After 30 min reaction time.

Optimization experiments with -nitrostyrene

Parallel to the screenings with benzylidene malonate 80a, reactions with -nitrostyrene (90a) as a substrate were performed under the same milling conditions (Scheme 34). Several chiral complexes were evaluated in the reaction with indole. In all cases, the desired product 91a was obtained in moderate yields (60–67%), but with almost no enantioselectivity. The highest e.r. of 54:46 for 91a was obtained with ligand L5. Since substrate 90a showed both lower reactivity and almost no enantioselectivity in the alkylation of indole in the ball mill in comparison with benzylidene malonate 80a, we further focused our studies only on optimizing the reaction with the latter.

50 RESULTS AND DISCUSSION

Scheme 34. Chiral ligands screened for the alkylation of indole (66a) with -nitrostyrene (90a); yields after purification by column chromatography.

2.3.3 SCREENING OF LEWIS ACIDS

After identifying L39 as the most suitable ligand for the transformation, next, the effect of different Lewis acids on the reaction was investigated (Table 12). Following the above described reaction procedure, the chiral complexes were generated in situ, before the substrates were added, followed by 60 min of milling at 25 Hz. Taking into consideration that the appropriate choice of metal plays a crucial role on the catalysis, we first focused on varying the metal center in the catalytic complex (Table 12, entries 1–5). When Ni(OTf)2 was used as a Lewis acid in the presence of L39, the product 81a was formed in only 30% yield, and 53:47 e.r. (Table 12, entry 3). Zinc, iron and scandium triflates on the other hand showed to be efficient catalysts for the transformation, giving 81a in excellent yield (Table 12, entries 3–5). Nevertheless, no stereoselectivity was induced in their presence. Having identified copper as the best choice of metal for this reaction, next, we focused on examining additional copper salts. When

Cu(ClO4)2∙6H2O was used as an alternative copper source, the desired product 81a was afforded in 97% yield and an e.r. of 73:17 (Table 12, entry 6). Next, both benzene and toluene complexes of copper(I) triflate were employed, resulting in the formation of 81a in excellent yields and just slightly lower enantioselectivities (Table 12, entries 7 and 8). These results indicated that copper(I) could catalyze the reaction as effectively as copper(II), demanding the evaluation of both copper(I) and copper(II) salts.

51 RESULTS AND DISCUSSION

Table 12. Screening of Lewis acids for the alkylation of indole (66a) with benzylidene malonate (80a).[a]

Entry Lewis Acid Yield (%)[b] e.r. (%)[c]

1 Cu(OTf)2 97 78:22

2 Ni(OTf)2 30 53:47

3 Zn(OTf)2 89 51:49

4 Fe(OTf)2 99 50:50

5 Sc(OTf)3 98 50:50

6 Cu(ClO4)2·6H2O 97 73:27

7 (Cu(OTf))2·Toluene 99 76:24

8 (Cu(OTf))2·Benzene 99 76:24

9 CuCl2/AgSbF6 94 79:21

10 CuCl2 /AgBF4 99 78:22

11 CuCl2/AgPF6 99 80:20

12 CuCl2/AgClO4 98 72:28

13 CuCl2/AgNTf2 97 81:19

14 CuCl/AgNTf2 97 85:15

15 CuCl/AgBF4 97 83:17

16 CuCl/AgPF6 98 85:15

17 CuCl/AgSbF6 51 83:17

d 18 AgNTf2 n.r. - 19 CuCl traces -

[e] 20 CuCl/AgNTf2 99 85:15 [a] Reaction conditions: 66a (0.30 mmol), 80a (0.30 mmol), Lewis acid/L39 (10 mol%), silica gel used as milling auxiliary (60 mg per 0.30 mmol of 66a), for entries 9–18: AgX (10 mol%). [b] Determined by 1H NMR spectroscopy with dimethylsulfone as an internal standard. [c] Determined by CSP-HPLC analysis. [d] n.r. = no reaction. [e] The chiral Cu-complex was prepared in solution by stirring of CuCl, AgNTf2 and ligand L39 (0.06 mmol each) in DCM (2 mL) for 1 h under argon atmosphere. After addition of silica gel the mixture was concentrated in vacuo resulting in a white powder, which was directly used in the ball mill.

52 RESULTS AND DISCUSSION

Since many studies showed that the counterpart of the cationic chiral complexes could have a pronounced effect on the reaction rate and the stereoselectivity of the catalyst,[142] further, the catalytic activity of complexes formed by milling of CuCl2, the appropriate silver salts and L39 were investigated (Table 12, entries 9–17). Among the tested salts, AgNTf2 proved to be the best choice, affording the product 81a in 97% yield and 81:19 e.r. (Table 12, entry 13). Gratifyingly, the enantioselectivity could be further improved when CuCl2 was replaced with CuCl (Table 12, entry 14). Accordingly, the reaction was also performed with some of the previously tested silver salts and CuCl. These reactions showed better stereoselectivities in all cases (Table 12, enries 15–

17). The high yields could be maintained, with exception of the reaction with CuCl/AgSbF6, which gave 81a in a moderate yield of 51% (Table 12, entry 17). Additionally, control experiments were performed using CuCl or AgNTf2 singly, resulting in no product formation (Table 12, entries 18 and 19).

Finally, to ensure that the formation of the catalyst under mechanochemical conditions is complete, the complex generated from CuCl and AgNTf2 with ligand L39 was prepared in solution. The mixture was stirred under argon for 2 h in dichloromethane, followed by addition of silica gel and removal of the solvent under reduced pressure. The obtained white powder was then used in the mechanochemical procedure, giving the product in a comparable yield and identical ee (Table 12, entries 14 and 20). Based on this result, it could be concluded that the complex preparation under ball milling conditions is as effective as in solution.

2.3.4 OPTIMIZATION OF MILLING CONDITIONS AND MILLING AUXILIARIES

Experiments in the planetary mill

After identifying the best catalyst for the reaction (Table 12, entry 14), the effects of milling conditions and milling auxiliaries were studied (Table 13). First, the type of the ball mill used for performing the reaction was varied. Several experiments were conducted in the planetary mill, since it is known to provide milder milling and an option to set the milling cycles with pauses in between. Analogously to the previous experiments, the chiral complex was prepared first by milling CuCl/AgNTf2, L39 and silica gel at 500 rpm for 10 min. Subsequently, the substrates were added, and the mixture was ground for another 60 min, affording product 81a in 91% yield and 87:13 e.r. (Table 13, entry 1). Next, in order to allow the reaction mixture to cool down, the milling was performed in 10 min intervals with 5 min pauses between the intervals. After a total milling time of 60 min, the reaction outcome did not differ greatly from the one obtained in the previous experiment (Table 13, entry 2). This indicated that there was either no overheating during the milling without a pause, or if there is, it has no influence on the enantioselectivity. Furthermore,

53 RESULTS AND DISCUSSION

the material of the reaction vessels was varied, substituting the stainless-steel milling jars with

ZrO2 jars and compatible balls of the same material (Table 13, entry 3). This modification resulted in a decrease in the reaction rate giving 81a in 79% yield after 60 min of reaction time. However, the enantioselectivity of 87:13 e.r. was retained using the softer material. The above described experiments suggested that the planetary mill does not provide benefits in comparison with the mixer mill in terms of yield. The observed slight improvement in the enantioselectivity (87:13 e.r.) is possibly due to the milder reaction regime used, which was envisioned could also be achieved in the mixer mill by optimizing of the milling frequency. Therefore, the further optimization of the mechanochemical reaction was continued in the mixer mill.

Table 13. Optimization of the milling conditions and milling auxiliaries.[a]

Catalyst Entry Ball Mill[b] Freq. [Hz] Milling auxiliary Yield (%)[c] e.r. (%)[d] (mol%) 1 10 PM - Silica gel 91 87:13

[e] 2 10 PM - Silica gel 97 86:14 3[f] 10 PM - Silica gel 79 87:13 4 10 MM 25 Silica gel 97 85:15 5 5 MM 25 Silica gel 97 85:15 6 5 MM 20 Silica gel 92 87:13 7 5 MM 15 Silica gel 41 87:13

8 5 MM 20 Al2O3 (neutral) n.r. -

9 5 MM 20 Al2O3 (basic) n.r. - 10 5 MM 20 NaCl n.r -

11 5 MM 20 MgSO4 95 86:14 12 5 MM 20 Silica gel[g] 69 87:13 13 10 PM - - 97 86:14

[a] Use of 66a (0.30 mmol), 80a (0.30 mmol), CuCl/AgNTf2/L39 (x mol%) and milling auxiliary (60 mg per 0.30 mmol of 66a). [b] Milling conditions for 1) planetary mill (PM): 500 rpm, stainless steel jars and balls of the same material (15 balls, 5 mm of diameter); 2) Mixer mill (MM): stainless steel jars and one stainless steel ball (10 mm of diameter). [c] Determined by 1H NMR spectroscopy with dimethylsulfone as an internal standard. [d]

54 RESULTS AND DISCUSSION

Determined by CSP-HPLC analysis. [e] The reaction was carried out in 10 min intervals with 5 min pause between the intervals for a total milling time of 60 min. [f] ZrO2 milling jars and balls of the same material (15 balls, 5 mm of diameter) were used. [g] 0.24 g of silica gel were used.

Firstly, an attempt to reduce the catalyst loading was made. Pleasingly, performing the reaction with 5.0 mol% of catalyst showed no adverse effect on the yield and enantioselectivity (Table 13, entry 6). Afterwards, the effect of the milling frequency was examined (entries 7 and 8). When the reaction was carried out at 20 Hz for 60 min the product 81a was formed in 92% yield and 87:13 e.r. (entry 7). As discussed above for the planetary mill experiments, the overall lowering of the reaction temperature as a result of the reduced energy input could be an explanation for the observed improvement in the enantioselectivity. However, reducing the milling frequency to 15 Hz led to a highly decreased reaction rate, without further improvement of the enantioselectivity (entry 8).

Complementary, the effect of different milling auxiliaries on the reaction was studied, since it is known that they can have a profound influence on the milling process (Table 13, entries 8– 13).[48b] The screening revealed silica gel to be the preferred choice. When aluminium oxide (neutral or basic) or sodium chloride were used, a slurry mixture was obtained after grinding for 60 min and no product was formed (entries 8–10). Magnesium sulphate, on the other hand, gave similar results as the reaction in the presence of silica gel (entry 11). Next, the amount of added silica gel was varied. Using more additive (240 mg instead of 60 mg), or in other words diluting the reaction mixture, only led to reduced reaction rate and 81a was obtained in 69% yield, while the e.r. remained the same (entry 12). On the other hand, performing the reaction without any milling auxiliary proved to have no effect on the yield or the enantioselectivity (entry 13).

2.3.5 OPTIMIZATION OF THE ADDITIVES

In our attempts to further improve the stereoselectivity of the reaction, next, the effects induced by various additives were studied (Scheme 35). Since alcohols, used as a solvent or added in stoichiometric amounts, have already shown beneficial effects on the outcome of the solution- based protocols,[127d, 131] we first focused on screening different alcohols in our mechanochemical procedure. For all reactions the additive was added in the first step when the Lewis acid and the ligand were ground to form the metal complex, whereby a change of color of the formed complexes was observed. Methanol, isopropanol and trifluoroethanol (TFE), added in equimolar amount to the reaction, had a positive influence on the reaction rate. However, the enantioselectivity was the same or slightly lower than the one obtained without an additive.

55 RESULTS AND DISCUSSION

Scheme 35. Screening of additives for the mechanochemical alkylation of indole with benzylidene malonate. a) 10 mol% additive used. b) n.r. = no reaction.

Pleasingly, employing the more acidic hexafluoroisopropanol (HFIP) resulted in the formation of product 81a in an excellent yield and, moreover, with a slight improvement in the e.r. to 88:12. Encouraged by this result, the screening was extended to various phenols in the ball mill reaction. Phenol (92) afforded the product in 97% yield and 89:11 e.r, while catechol (93), 2,6- dimethoxyphenol (94), and 1-naphthol (95) suppressed the product formation. When bulkier, di or tri tBu-substituted phenols 96 and 97 were employed, the product 81a was formed in excellent yields with an e.r. of 87:13. Next, halogenated phenols 98–101 were tested in the reaction, providing a similar reaction outcome to the one with unsubstituted phenol (92). The best result was achieved by employing pentafluorophenol (103, PFP), forming product 81a in 95% yield and 91:9 e.r. Based on the results obtained with the different additives it could be concluded that the acidity of the additive takes precedence over steric or other factors. Therefore, next, acid additives were tested. Unfortunately, using only 10 mol% of the acid lowered the yield of product 81a in the

56 RESULTS AND DISCUSSION case of benzoic acid (104) to 25%, while with pivalic acid (105) the product formation was fully suppressed. Thus, it was concluded that acids are unsuitable additives for this transformation.

Having identified PFP (103) as the optimal additive for the reaction, some final optimization experiments were performed by varying the amount of the additive and the catalyst loading (Table 14). The screening revealed that using 0.5 equivalents of 103 gave the product in slightly lower e.r., while adding more than one equivalent did not result in any improvement (Table 14, entries 1–3).

Table 14. Screening of different amounts of PFP in the catalytic reaction.[a]

Entry Catalyst (mol%) PFP (equiv) Yield (%)[c] e.r. (%)[d] 1 5.0 1.0 95 91:9 2 5.0 0.5 95 89:11 3 5.0 2.0 92 89.5:10.5 4 2.5 1.0 95 90:10 5 1.0 1.0 37 85:15 6[d] 1.0 1.0 87 77:23

[a] Reaction conditions: 66a (0.30 mmol), 80a (0.30 mmol), CuCl/AgNTf2/L39 (x mol%), silica gel used as milling auxiliary (60 mg per 0.30 mmol of 66a). [b] Determined by 1H NMR spectroscopy with dimethylsulfone as an internal standard. [c] Determined by CSP-HPLC analysis. [d] 180 min reaction time.

Next, further lowering the amount of the catalyst was attempted. For the screening of lower catalyst loadings, the chiral copper complex was prepared prior to the reaction on a bigger scale by milling CuCl, AgNTf2, L39 and silica gel (60 mg for 0.03 mmol of CuCl) for 5 min at 25 Hz. The formed pale grey powder was stored in a vial covered with aluminium foil in a desiccator. After every use the vial was flushed with argon. Treated in this way, the catalyst could be stored for at least several weeks without losing its catalytic properties.

Using 2.5 mol% of this preformed catalyst gave the product in 95% yield and with only a slight change in the e.r. to 90:10 (Table 14, entry 4). When the amount of catalyst was further lowered to 1.0 mol%, the reaction could not reach completion even after 180 min of milling, while the enantioselectivity dropped notably (Table 14, entries 5 and 6).

57 RESULTS AND DISCUSSION

2.3.6 SYNTHESIS OF THE SUBSTRATES

Various arylidene malonates 80 were synthezised, in order to be later employed as substrates in the developed mechanochemical protocol. A Knoevenagel condensation between the corresponding commercially available aldehydes 2 and malonic esters 23 was performed, following a modified procedure (Scheme 36).[143] Thereby, the desired products 80 were obtained in good to excellent yields.

Scheme 36. Synthesis of arylidene malonates 80 by Knoevenagel condensation.

2.3.7 SUBSTRATE SCOPE OF THE MECHANOCHEMICAL ASYMMETRIC FRIEDEL–CRAFTS

ALKYLATION OF INDOLES

With the optimized conditions and the synthesized substrates in hand, we focused on the general applicability and the limitations of the developed mechanochemical protocol. Since for the model substrates the results with 5.0 and 2.5 mol% catalyst were comparable (Table 14, entries 1 and 4), both catalyst loadings were evaluated for the scope of the reaction. Various structurally different arylidene malonates 80 and indoles 66 were applied (Scheme 37 and Scheme 38) and pleasingly, for the majority of the examples the lower catalyst loading was sufficient to provide the desired products without a significant effect on the yields or the enantioselectivities. In some cases, the reaction time was prolonged to 90 or 180 min in order to assure a full conversion of the substrates.

58 RESULTS AND DISCUSSION

Scheme 37. Substrate scope of the mechanochemical Cu-catalyzed alkylation of indole (66a) with arylidene malonates 80. a) After 90 min reaction time. b) After 180 min reaction time. c) Determined by 1H NMR spectroscopy with dimethylsulfone as an internal standard.

First, a range of -unsaturated esters bearing different aryl substituents were tested (Scheme 37). Benzylidene malonates, both with electron-donating and electron withdrawing substituents, reacted smoothly with indole to afford the alkylation products 81 in excellent yields and good enantioselectivities (Scheme 37). The only exception was p-thiomethyl substituted substrate 80l, which differed in its reactivity and gave the product 81l in a moderate yield, even after 180 min of milling. 1-Naphthyl substituted arylidene malonate 80g showed to be also slightly less reactive, but after prolonging the reaction time, the product 81g could be obtained in an excellent yield and

59 RESULTS AND DISCUSSION high enantioselectivity. As an example for a heterocyclic arylidene malonate, 80h was applied in the reaction proving to be a competent substrate in this transformation and giving the product 81h in a yield of 90% with 83:17 e.r.

When ethylidene malonate 80n was employed, the product 81n was formed in a high yield, but a significant drop in the enantioselectivity to 71:29 e.r. was observed in comparison with the ones with aryl-containing substrates. However, this result corresponds to the reported reactions in solution with this substrate.[131]

Next, the substituents on the indole and the ester group of the malonates were varied (Scheme 38). The reaction between N-methyl indole and 80a proceeded smoothly in the ball mill to give product 81o in a good yield and enantioselectivity. On the other hand, applying indoles bearing a substituent on the 2-position was not well tolerated under the reaction conditions. 2-methyl indole gave the corresponding product 81p in excellent yield, but the e.r. reached only 74:26. Whereas the more sterically hindered 2-phenyl indole showed to be even less reactive in the transformation, yielding product 81q in only 52% yield after 180 min of milling with an enantiomeric ratio of 57:43.

Introducing an electron donating group on the 4- and 5-position of the indole ring also proved to be challenging. No product was detected using 4-methyl indole, while 5-methyl indole gave the desired product after 180 min of milling in only 48% yield with 71:29 e.r. Pleasingly, performing the reaction with 5- or 6-halogen substituted indoles resulted in the respective products 81s and 81r in excellent yields and good enantioselectivities. At last, the nature of the ester group in the benzylidene malonates 80 was altered. Methyl and isopropyl esters gave the corresponding products 81i and 81j in excellent yields and slightly reduced enantioselectivities compared to the model substrate, whereas dibenzyl benzylidene malonate showed identical results (Scheme 38, 81v).

60 RESULTS AND DISCUSSION

Scheme 38. Substrate scope of the mechanochemical Cu-catalyzed alkylation of indoles 66 with arylidene malonates 80. a) After 90 min reaction time. b) After 180 min reaction time. c) With 1.5 equiv of indole 66b; n.d. = not determined.

Finally, to demonstrate the practical applicability of the developed mechanochemical methodology, a four-fold scale-up synthesis of 81a was conducted (Scheme 39). To our delight, using 2.5 mol % of catalyst, the desired product could be obtained in 90 % yield with 91:9 e.r after 90 min of milling at 20 Hz. Moreover, the enantiopurity of the product could be additionally enhanced to 99.9% ee by single recrystallization from a mixture of heptane/chloroform.

61 RESULTS AND DISCUSSION

Scheme 39. Scale up experiment of the mechanochemical Cu-catalyzed alkylation of indole.

2.3.8. LIQUID ASSISTED GRINDING EXPERIMENTS

As discussed in the introduction of this thesis (see section 1.3), in some cases using a small amount of a liquid additive could have a tremendous effect on the reaction outcome (liquid- assisted grinding, LAG). Moreover, many asymmetric transformations are strongly dependent on the solvent used. Therefore, additional experiments were conducted in order to investigate the effect of LAG on the enantioselectivity in the mechanochemical asymmetric alkylation of indole (66a) with benzylidene malonate 80a. The reactions catalyzed by the chiral complexes of ligands

L22 and L29 with Cu(OTf)2 in which the product 81a was obtained with low enantioselectivity in the ball mill (Table 15, entry 1 and 2) were of particular interest. While in solution the Cu- complexes of L22 and L17 (structurally very similar to L29) proved to be much more effective catalysts for this transformation (entry 1 and 2, values in brackets).[127a, 131]. Since in both solution-based protocols iBuOH was used as a solvent, we decided to first test this alcohol as a liquid additive in the mechanochemical procedure. Following the previously described procedure, first the chiral complex was formed and then iBuOH, indole (66a) and benzylidene malonate 80a were added and further 60 min of milling at 25 Hz was performed. In the case of L22, using 50 L of iBuOH led to acceleration of the reaction rate and increased the yield of 81a to 97%, while the e.r. dropped to 54:46 (entry 4). Astonishing, when the same additive was applied in the reaction with L29, a significant change in the stereoselectivity was observed, reaching an e.r. of 86:14 (entry 5). This result encouraged us to perform additional experiments with L29 varying the amount and the nature of the solvent added (enties 5–11). HFIP, EtOH and CH2Cl2 led to lower stereoselectivities. The best result (96% yield and 90:10 e.r., entry 8) was obtained with 100 L of iBuOH. When the same conditions were applied in the reaction with L39, a similar increase of the e.r. from 78:22 to 86:14 (entries 3 and 12) was achieved, albeit not as prominent as in the case of L29 (entries 2 and 12).

62 RESULTS AND DISCUSSION

Table 15. Effect of LAG on the asymmetric induction under mechanochemical conditions.[a]

Entry Ligand Additive(L) Yield (%)[b] e.r. (%)[c] 1 L22 - 77 (98)[131] 61:39 (95:5)[131] 2[d] L29 - 99 (99)[127a] 56:44 (91:9)[127a] 3 L39 - 97 78:22 4 L22 iBuOH (50) 97 54:46 5 L29 iBuOH (50) 99 86:14 6 L29 HFIP (50) 98 56:44 7 L29 iBuOH (25) 99 80:20 8 L29 iBuOH (100) 96 90:10 9 L29 iBuOH (150) 96 89:11 10 L29 EtOH (100) 93 87:13

11 L29 CH2Cl2 (100) 83 62:38 12 L39 iBuOH (100) 94 86:14

[a] Reaction conditions: 66a (0.30 mmol), 80a (0.30 mmol), Cu(OTf)2/ligand (5.0 mol%), silica gel was used as milling auxiliary (60 mg per 0.30 mmol of 66a). [b] Determined by 1H NMR spectroscopy with dimethylsulfone as an internal standard. [c] Determined by CSP-HPLC analysis. [d] Results in the brackets are reported with ligand L17.

The results described above show that in some cases the addition of a small amount of solvent to the reaction mixture could have a great influence on the stereoselectivity induced by a chiral catalyst in the ball mill. This could be especially important for very strongly solvent dependent catalytic systems. Therefore, by developing a mechanochemical alternative to a reported asymmetric transformation, the use of LAG should be also considered for achieving high enantioselectivities.

SUMMARY AND OUTLOOK

3. SUMMARY AND OUTLOOK

In the first part of this thesis the development of a straightforward synthetic protocol towards the unprecedented chiral sulfonimidoylalkyl naphthols 62 was described. These products were obtained by the multicomponent reaction between 2-naphthols 42, aldehydes 2 and chiral sulfoximines 61 under solvent- and catalyst-free conditions. The developed method features operational simplicity, reactants in almost ideal stoichiometry, and water as the only by-product and gives rise to a broad range of products 62 in uniformly high yields. The compounds bear a stereogenic sulfur and carbon atom and in almost all cases the diastereomers were fully separated by column chromatography. Additionally, efficient analytical separation methods were developed using CSP-HPLC. The absolute configuration of one of the sulfonimidoylalkyl naphthols 42 was determined by X-ray crystallography, which allowed unambiguous identification of all stereogenic centers.

Scheme 40. Synthesis of novel sulfonimidoylalkyl naphthols by multicomponent reaction between 2-naphtols, aldehydes and sulfoximines.

Furthermore, two of the newly synthesized chiral compounds were evaluated as ligands in the enantioselective addition of diethyl zinc to aldehydes and as substrates for the formation of o- quinone methides. Additionally, the sulfonimidoylalkyl naphthols 62 were also included in a biological study for cell growth inhibition of bacteria strains and fungi. Out of which, one of the products (62ja) showed promising inhibitory activity against Candida albicans. Further evaluation of the properties of the prepared sulfonimidoylalkyl naphthols 62 as chiral ligands in additional enantioselective metal-catalyzed transformations would be of interest for future research projects. Moreover, the biological activity of the new sulfoximine-containing derivatives should be further explored.

The second project in this thesis focused on exploring the reaction of racemic malonic acid indole derivatives 81 with indoles 66, promoted by a copper-sulfoximine complex. It was found that in the presence of the chiral catalyst, the two enantiomers of 81 exhibit different reactivity towards the formation of bisindoles 84 (86, respectively). As a result, 81 was recovered in an

65 SUMMARY AND OUTLOOK enantioenriched form after the reaction. After optimization of the reaction conditions with the model substrates, the effect of various substituents on 81 and 66 was studied. The investigation of the scope of the reaction revealed strong dependence of the reactivity and the enantioselectivity on the substituent R1 as well as on the nature of the ester group of 81. When substituted indoles 66 were employed in the reaction, along with the desired product 84 (86, respectively), crossover bisindole products were also formed.

Scheme 41. Kinetic resolution of malonic acid indole derivatives in the reaction towards bisindolylmethanes.

Finally, additional experiments aiming towards the elucidation of the reaction mechanism were performed, showing the important role of indole for the resolution reaction. Further studies could be performed in order to get deeper understanding of the process. Moreover, the evaluation of other nucleophiles in this transformation could be of interest.

In the last project, a mechanochemical procedure for the copper-catalyzed asymmetric Michael- type Friedel–Crafts alkylation of indoles 66 with benzylidene malonates 80 was developed. The transformation proceeded smoothly in a mixer mill under ambient atmosphere and solvent-free conditions. Notably, the chiral catalyst could be formed after only 5 min of milling, while in solution stirring of up to few hours is required for preparing the same type of catalyst. In the optimization process, apart from the catalyst screening, the effects of different milling parameters and additives on the reaction outcome were studied in detail. Thus, the corresponding products 81 were formed in high to excellent yields, with good enantioselectivities, and in shorter reaction times, compared to analogous coupling reactions taking place in solution. Additionally, a scale-up experiment was conducted providing the product in an excellent yield, without any loss of enantioselectivity.

66 SUMMARY AND OUTLOOK

Scheme 42. Mechanochemical asymmetric copper-catalyzed alkylation of indoles with benzylidene malonates.

Finally, the effect of liquid-assisted grinding (LAG) on the enantioselectivity was briefly studied, showing that some catalytic systems could be strongly influenced by the addition of small amounts of solvent to the reaction mixture. The obtained results demonstrate that ball milling is a technique which can be effectively applied in asymmetric metal catalysis after fine-tuning of the reaction conditions. In the future, the improvement of the milling devices and implementation of better tools for temperature control during the milling process could open further possibilities for developing more efficient mechanochemical asymmetric reaction protocols. Thus, the potential of mechanochemistry as a sustainable tool for synthesis of chiral compounds will further unfold.

EXPERIMENTAL PART

4. EXPERIMENTAL PART

4.1 GENERAL INFORMATION AND TECHNIQUES

Unless otherwise noted, all commercially available compounds and solvents were used without further purification. All air- or moisture sensitive reactions were carried out under argon atmosphere in dried glassware using standard Schlenk and vacuum line techniques.[144] In addition, air- and moisture sensitive chemicals were stored in an M.Braun LABmaster© 130 Glovebox or a desiccator.

Solvents: Solvents for column chromatography were distilled before use. Solvents for anhydrous reactions were either purchased or dried according to standard procedures.

Diethyl ether distilled over Solvona®

Dichloromethane distilled over calcium hydride

TBME distilled over calcium hydride

THF distilled over Solvona®

Toluene distilled over Solvona®

From 2017 on dry solvents were obtained from a solvent purification system (MBraun SPS5).

Chromatography and TLC: Flash column chromatography (FCC) was performed with silica gel 60 (63–200 μm) purchased from Merck with application of a light pressure of nitrogen (0.1–0.5 bar). Analytical thin layer chromatography (TLC) was performed with aluminium sheets silica gel 60 F254 (Merck), and the products were visualized with UV irradiation (254 nm) or by treatment with potassium permanganate or Seebach’s stain.

Ball milling: Mechanochemical reactions were carried out in a RETSCH MM400 mixer mill or in a FRITSCH planetary micro mill model “PULVERISETTE 7 classic line” using milling jars made of either stainless steel (SS) or zirconium oxide (ZrO2) with milling balls made up of the material corresponding to the milling jars used.

Microwave: Reactions under microwave irradiation were performed in a discover® microwave LabMate from CEM featuring an IntelliVentTM Pressure Control System and SynergyTM software. The reaction mixtures were prepared in appropriate glass vessels with a stirring bar.

69 EXPERIMENTAL PART

4.2 ANALYTICAL METHODS

NMR spectroscopy: Nuclear magnetic resonance (NMR) spectra were recorded on an Agilent VNMR 400 (1H NMR: 400 MHz, 13C NMR: 101 MHz) or an Agilent VNMR 600 (1H NMR: 600 MHz, 13C NMR: 151 MHz) spectrometer. The chemical shifts δ are given in parts per million (ppm)

1 relative to the residual solvent peak of the nondeuterated solvent (CHCl3: H NMR: δ = 7.26 ppm,

13 [145] C NMR: CDCl3: δ = 77.00 ppm). The multiplicity was reported with the following abbreviations: s = singlet, d = doublet, t = triplet, m = multiplet, br = broad signal, and coupling constants were given in Hertz (Hz).

IR spectroscopy: Infrared spectra (IR) were recorded on a PerkinElmer Spectrum 100 spectrometer using the attenuated total reflectance (ATR) technique. The wavenumbers  of the absorption peaks are listed in cm–1.

MS spectroscopy: Mass spectra were recorded on a Finnigan SSQ 7000 spectrometer and the resulting signals are given according to their m/z values and their relative intensity is reported in parentheses. For high resolution mass spectra (HRMS) a Thermo Fisher Scientific LTQ Orbitrap XL spectrometer (electrospray ionization (ESI) in positive ion mode) was used.

Melting points: To determine the melting points with open capillaries, a machine Melting Point B-540 from Büchi was used.

Optical rotation: Optical rotation was measured with a PerkinElmer model 241 polarimeter (20 °C, λ = 589 nm).

HPLC: The enantiomeric excess of the optically active products was determined by high performance liquid chromatography (HPLC) using systems of an Agilent 1100 or 1200 series with chiral stationary phases (Chiralcel OD-H, Chiralpak AD-H, Chiralpak AS-H, Chiralpak IB and Chiralpak IA) from Chiral Technologies Inc. To identify the enantiomers, the HPLC retention times () of the racemates were used.

70 EXPERIMENTAL PART

4.3 SYNTHESIS AND CHARACTERIZATION OF THE PRODUCTS

4.3.1. GENERAL PROCEDURES FOR THE PREPARATION OF STARTING MATERIALS, PRODUCTS AND

LIGANDS

4.3.1.1 Synthesis of sulfonimidoylalkyl naphthols 62 (GP1)

In a pressure tube equipped with a stirring bar, 2-naphthol 42 (1.0 equiv), aldehyde 2 (1.1 equiv) and sulfoximine 61 (1.2 equiv.) were added and the mixture was heated to 80 °C. The so formed melt was stirred at that temperature for 24 h. Afterward, the mixture was dissolved in DCM and purified by flash column chromatography (pentane/EtOAc), giving the product 62 as a mixture of two diastereomers. The single diastereomers were isolated after a second FCC using a mixture of pentane/EtOAc/Et3N as an eluent. In all the cases the diastereomer eluting first was the major one, indicated with “a”, while the second eluting one, the minor diastereomer, was indicated with “b“.

4.3.1.2 Enantioselective addition of diethylzinc to aldehydes in the presence of 62aa or 62ab (GP2)

In a Schlenk flask under argon the ligand 62aa or 62ab (3 mol%) was dissolved in 3 mL of dry toluene. The so formed solution was cooled to 0 °C and diethylzinc (20, 2.68 ml, 1M solution in heptane, 3.0 equiv) was added. The mixture was stirred at that temperature for 30 min and then cooled down to −25 °C followed by the addition of the aldehyde (2, 0.9 mmol, 1.0 equiv). Then, the reaction mixture was allowed to warm up to ambient temperature and further stirred until the aldehyde was fully consumed (monitored by TLC). Then, the mixture was quenched with an solution of NH4Cl and extracted with Et2O (3x10 mL). The organic phase was dried over Na2SO4,

71 EXPERIMENTAL PART filtered and the solvent was removed under reduced pressure. The product was purified by FCC

(pentane/Et2O) to give the desired alcohol 50.

4.3.1.3 Brønsted acid mediated reaction of sulfonimidoylalkyl naphthols 62a with indole (GP3)

Sulfonimidoylnaphthol rac-62a (d.r. = 54:46), indole (66a) and catalyst C2 or C3 were placed in a pressure tube and 1.5 ml of solvent was added. The mixture was heated at 75 °C and stirred at this temperature for 6–24 h. The solvent was removed under reduced pressure and the product was isolated after FCC (pentane/DCM = 1:1).

4.3.1.4 General procedure for the synthesis of arylidene malonates 80 (GP4)

A round-bottom flask was charged with the appropriate aldehyde (1.0 equiv), followed by benzene, dimethyl malonate (1.0 equiv), piperidine (20 mol%), and acetic acid (20 mol%). The flask was equipped with a Dean-Stark trap and condenser and the solution heated to reflux. Upon completion (monitored by TLC), evaporation of the solvent gave the crude product, which was purified by silica gel column chromatography. Analytical data are in accordance with those previously reported.[143]

72 EXPERIMENTAL PART

4.3.1.5 General procedure for the preparation of the racemic malonic acid indole derivatives 81 (GP5)

A round-bottom flask equipped with a stirring bar was charged with indole (66a, 1.0 equiv), benzylidene malonate 80 (1.2 equiv) and Cu(OTf)2 (5.0–20 mol%, depending on the reactivity of the substrates, monitored by TLC), diethyl or diisopropyl ether was added and the formed suspension was cooled down to 0 °C. The reaction mixture was stirred at this temperature upon completion (monitored by TLC). Evaporation of the solvent gave the crude product, which was purified by FCC on silica gel (pentane/DCM = 1:1 or DCM).

4.3.1.6 General procedure for the kinetic resolution reaction (GP6)

In a dry Schlenk tube Cu(ClO4)2·6H2O (10 mol%), ligand L24 (10 mol%) and 4 Å molecular sieves (60 mg) were added under argon atmosphere. Toluene was added and the mixture was stirred for 1 h at room temperature forming a green-blue suspension. Then, rac-81 (0.30 mmol) and indole 66 (0.18 mmol, 0.60 equiv.) were added and the reaction mixture was heated to 40 °C and stirred at this temperature until the indole was consumed (or no further change on TLC was observed). Then, the so formed red suspension was filtered over a pad of silica and washed with DCM. After the solvent was removed under reduced pressure, the mixture was separated by FCC on silica gel (pentane/DCM = 2:1, followed by DCM) to provide the desired products 84 (86, respectively) and 81.

73 EXPERIMENTAL PART

4.3.1.7 Mechanochemical procedures

General procedure for the optimization of the reaction conditions (GP7)

In an oven dried ball milling vessel (stainless steel, 10 mL), charged with 1 stainless steel grinding ball (10 mm in diameter), the Lewis acid and the chiral ligand were grinded for 10 min to form the metal complexes. Then indole (66a, 0.30 mmol) and diethyl benzylidene malonate (80a; 0.30 mmol) were added. After 60 min of reaction at 25 Hz, the milling was stopped, and the content was purified by FCC or analyzed by 1H NMR spectroscopy using dimethylsulfone as an internal standard. The enantiomeric excess of the product was determined by CSP-HPLC analysis.

Synthesis of the chiral copper complex

A mixture of CuCl (6.1 mg, 0.06 mmol), AgNTf2 (23.3 mg), L39 (20.2 mg) and 0.24 g silica gel was charged in an oven dried 10 mL stainless steel milling jar with one 10 mm ball of the same material and milled in a mixer mill at 25 Hz for 5 min. The resulting pale grey powder was transferred in a vial covered with aluminium foil, flashed with argon and stored in a desiccator.

General procedure for the mechanochemical asymmetric alkylation of indoles (GP8):

A mixture of indole 66 (0.3 mmol), arylidene malonate 80 (0.3 mmol), pentafluorophenol (103, 0.3 mmol) and chiral complex (5.0 mol%, prepared by the procedure described above) was charged in an oven dried 10 mL stainless steel milling jar with one 10 mm ball of the same material and milled in a mixer mill for 60–180 min at 20 Hz . At the end of the milling process, the mixture was extracted from the milling vessel with organic solvent (EtOAc or DCM) and washed with aqueous NaOH (0.1 N). The combined organic layers were dried over anhydrous Na2SO4 and concentrated in vacuo. The product 81 was isolated after purification by FCC with DCM used as an eluent.

Procedure for the scale up experiment

A mixture of indole (66a, 1.2 mmol), arylidene malonate (80a, 1.2 mmol), pentafluorophenol (1.2 mmol) and chiral complex (CuCl/AgNTf2/L39, 2.5 mol%) were charged in an oven dried 10 mL stainless steel milling jar with six 5 mm balls of the same material and milled for 90 min. At the end of the milling process, the mixture was extracted from the milling vessel with EtOAc and

74 EXPERIMENTAL PART washed with aqueous 0.1 N NaOH. The combined organic layers were dried over anhydrous

Na2SO4 and concentrated in vacuo. After purification by FCC (DCM used as an eluent), product 81a was isolated as a white solid (0.41 g, 92% yield, 91:9 e.r.). An enantiopurity of >99.9% ee was achieved after recrystallization of 81a from a mixture of heptane/CHCl3=10:1.

4.3.1.6 Preparation of chiral ligands using reported procedures

(1S,1'S)-(1,2-phenylenebis(azaneylylidene))bis(methyl(phenyl)-6-sulfanone) (L11)[66]

(1R,1'R)-(1,2-phenylenebis(azaneylylidene))bis((2-methoxyphenyl)(methyl)-6-sulfanone) (L16)[67]

N,N'-((2R,2'R)-(((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-phenylpropane-1,2- diyl))bis(4-methylbenzenesulfonamide) (L22)[131]

(1R,1'R)-((4,5-dimethyl-1,2-phenylene)bis(azaneylylidene))bis((2-methoxyphenyl)(methyl)-6- sulfanone) (L23)[67]

(1S,1'S)-((4,5-dimethyl-1,2-phenylene)bis(azaneylylidene))bis(methyl(phenyl)-6-sulfanone) (L24)[67] bis(2-((S)-4-benzyl-4,5-dihydrooxazol-2-yl)phenyl)amine (L31)[146]

(4S,4'S)-2,2'-(2-(thiophen-2-yl)ethene-1,1-diyl)bis(4-phenyl-4,5-dihydrooxazole) (L34)[129a]

(4S,4'S)-2,2'-(2-(thiophen-2-yl)ethene-1,1-diyl)bis(4-(tert-butyl)-4,5-dihydrooxazole) (L35)[129a]

N,N'-((2R,2'R)-(((1R,2R)-1,2-diphenylethane-1,2-diyl)bis(azanediyl))bis(3-methylbutane-1,2- diyl))bis(4-methylbenzenesulfonamide) (L36)[131] bis((S)-4-(tert-butyl)-4,5-dihydrooxazol-2-yl)methane (L37)[142c]

(3aS,3a'S,8aR,8a'R)-2,2'-(propane-2,2-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (L38)[142c]

(3aS,3a'S,8aR,8a'R)-2,2'-(cyclopropane-1,1-diyl)bis(3a,8a-dihydro-8H-indeno[1,2-d]oxazole) (L34)[142c] bis((3aS,8aR)-5-isopropyl-3a,8a-dihydro-8H-indeno[1,2-d]oxazol-2-yl)methane (L41)[147]

75 EXPERIMENTAL PART

4.3.2. SYNTHESIS AND ANALYTICAL DATA OF COMPOUNDS

(S)-(((2-Hydroxynaphthalen-1-yl)(phenyl)methyl)imino)(methyl)(phenyl)-6-sulfanone (62a)

The title compound was prepared according to GP1 and isolated after FCC on silica gel (pentane/EtOAc 4:1) as a mixture of two diastereomers. The single diastereomers were isolated after second FCC (pentane/EtOAc 6:1

with 10% Et3N). Yield: 90% (combined yield of isolated diastereomers).

d.r. = 54:46. Molecular formula: C24H21NO2S. Molecular mass: 387.13 g mol-1.

1 (SC,SS)-62aa (pale yellow solid): m.p. 120–121 °C. H NMR (600 MHz, CDCl3):  = 11.00 (s, 1H), 7.80 – 7.70 (m, 2H), 7.69 – 7.64 (m, 2H), 7.42 – 7.35 (m, 4H), 7.28 – 7.22 (m, 4H), 7.21 – 7.09 (m,

13 1 4H), 6.10 (s, 1H), 3.22 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 155.5, 143.5, 138.1, 133.5, 131.7, 129.5 (3C), 128.6, 128.6 (3 C), 128.5 (2 C), 127.6 (2 C), 127.2, 126.4, 122.6, 121.7, 120.2, 118.1, 57.3, 45.1 ppm. IR (ATR):  = 3092, 3060, 3023, 2932, 2777, 2566, 2115, 1985, 1620, 1599, 1517,1466, 1444, 1404, 1376, 1316, 1229, 1136, 1085, 1029, 978, 954, 897, 836,812 740, 689 cm- 1. MS (EI+, 70 eV): m/z (%): 388.2 (2, [M+H]+), 387.2 (7, [M+]), 232.1 (41), 231.2 (100), 202.1 (12),

+ + + 156.0 (53), 115.0 (11), 77.0 (12). HR-MS (ESI ): m/z: calcd. for [M+Na] = [C24H21NNaO2S] : 410.1185; found: 410.1179. HPLC: Chiralpack IB, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4,

20 minor = 10.2 min. OR: [] D = +356.0 (c 0.50, CHCl3, 99% ee).

1 (RC,SS)-62ab (pale yellow solid): m.p. 132–134 °C. H NMR (600 MHz, CDCl3):  = 11.22 (s, 1H), 7.83 – 7.78 (m, 2H), 7.74 – 7.70 (m, 3H), 7.61 – 7.57 (m, 1H), 7.49 – 7.45 (m, 2H), 7.33 – 7.29 (m, 1H), 7.26 – 7.24 (m, 2H), 7.24 – 7.20 (m, 2H), 7.11 – 7.07 (m, 2H), 7.07 – 7.04 (m, 1H), 6.33 (s, 1H),

13 1 3.13 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 155.4, 143.1, 139.0, 133.4, 131.7, 129.5, 129.5 (2C), 128.9, 128.9, 128.4 (2C), 128.3 (2C), 127.6 (2C), 127.1, 126.6, 122.7, 121.8, 120.4, 118.7, 57.2, 45.1 ppm. IR (ATR):  = 2918, 2322, 2095, 1914, 1720, 1600, 1447, 1313, 1216, 1110, 978, 734, 695 cm-1. MS (EI+, 70 eV): m/z (%): 388.1 (3, [M+H]+), 387.0 (10, [M+]), 246.0 (11), 232.1 (41), 231.1 (100), 202.0 (21), 155.9 (62), 140.9 (10), 139.9 (18), 124.9 (19), 115.0 (28), 91.9 (30), 76.9 (47), 65.0 (11), 51.2 (19). HR-MS (ESI+): m/z: calcd. for [M+Na]+ =

+ [C24H21NNaO2S] : 410.1185; found: 410.1182 HPLC: Chiralpack IB, n-heptane/iPrOH 80:20, 0.8

20 mL/min,  = 254.4, minor = 12.5 min. OR: [] D = –88.4 (c 0.50, CHCl3, 99% ee).

76 EXPERIMENTAL PART

(S)-(((2-Hydroxy-7-methoxynaphthalen-1-yl)(phenyl)methyl)imino)(methyl)(phenyl)-6- sulfanone (62b)

with 10% Et3N). Yield: 91% (combined yield of isolated diastereomers).

d.r. = 55:45. Molecular formula: C25H23NO3S. Molecular mass: 417.15 g mol-1.

1 (SC,SS)-62ba (white solid): m.p. 104–105 °C. H NMR (600 MHz, CDCl3):  = 10.98 (s, 1H), 7.86 – 7.67 (m, 2H), 7.60 (d, J = 8.8 Hz, 1H), 7.56 (d, J = 8.8 Hz, 1H), 7.48 – 7.42 (m, 1H), 7.42 – 7.36 (m, 2H), 7.34 – 7.27 (m, 2H), 7.26 – 7.22 (m, 2H), 7.20 – 7.15 (m, 1H), 7.03 (d, J = 8.8 Hz, 1H), 6.83 (dd, J = 8.8, 2.4 Hz, 1H), 6.63 (d, J = 2.4 Hz, 1H), 5.97 (s, 1H), 3.58 (s, 3H), 3.23 (s, 3H) ppm. 13C{1H}

NMR (151 MHz, CDCl3):  = 158.1, 156.1, 143.5, 138.1, 133.6, 132.9, 130.1, 129.5 (2C), 129.2, 128.7 (2C), 128.6 (2C), 127.5 (2C), 127.2, 123.9, 117.6, 117.5, 114.5, 101.2, 57.6, 55.1, 45.2 ppm. IR (ATR):  = 3849, 2930, 2291, 2066, 1905, 1740, 1618, 1455, 1218, 1120, 981, 822, 736 cm-1. MS (EI+, 70 eV): m/z (%): 417.0 (2, [M+]), 262.1 (20), 261.0 (48), 218.1 (19), 189.0 (12). HR-MS

+ + + (ESI ): m/z: calcd. for [M+H] = [C25H24NO3S] : 418.1471; found: 418.1467. HPLC: Chiralpack IB,

20 n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4 nm,  = 11.5 min. OR: [] D = +390.8 (c 0.50,

CHCl3, 99% ee).

1 (RC,SS)-62bb (offwhite solid) m.p. 126–127 °C. H NMR (600 MHz, CDCl3):  = 11.39 (s, 1H), 7.85 – 7.71 (m, 2H), 7.62 (dd, J = 8.8, 5.6 Hz, 2H), 7.60 – 7.53 (m, 1H), 7.49 – 7.42 (m, 2H), 7.26 – 7.21 (m, 2H), 7.17 – 6.98 (m, 4H), 6.96 (d, J = 2.3 Hz, 1H), 6.89 (dd, J = 8.8, 2.3 Hz, 1H), 6.21 (s, 1H), 3.72

13 1 (s, 3H), 3.14 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 158.2, 156.1, 143.0, 139.1, 133.3, 132.9, 130.3, 129.4 (2C), 129.2, 128.5 (2C), 128.2 (2C), 127.7 (2C), 127.1, 124.2, 117.8, 117.6, 114.4, 101.6, 57.6, 55.2, 45.2 ppm. IR (ATR):  = 3855, 3458, 3026, 2926, 2750, 2320, 2178, 2082, 1920, 1739, 1599, 1513, 1442, 1218, 1104, 971, 812, 704 cm-1. MS (EI+, 70 eV): m/z (%): 417.1 (5, [M+]), 262.1 (51), 261.1 (100), 218.0 (21), 189.0 (26), 156.0 (21), 141.0 (11), 140.0 (28), 125.0 (22), 97.0 (12), 94.3 (19), 92.1 (56), 91.1 (12), 78.1 (13), 77.1 (82), 65.1 (21), 63.1 (15), 51.1 (55), 50.1 (15). MS (ESI): m/z (%): 440.1 [M+Na]+. HR-MS (ESI+): m/z: calcd. for [M+Na]+ =

+ [C25H23NNaO3S] : 440.1291; found: 440.1293. HPLC: Chiralpack IB, n-heptane/iPrOH 80:20, 0.8

20 mL/min,  = 254.4 nm,  = 15.3 min. OR: [] D = –63.0 (c 0.46, CHCl3, 99% ee).

77 EXPERIMENTAL PART

(S)-(((6-Bromo-2-hydroxynaphthalen-1-yl)(phenyl)methyl)imino)(methyl)(phenyl)-6- sulfanone (62c)

with 10% Et3N). Yield: 87% (combined yield of isolated diastereomers).

d.r. = 55:44. Molecular formula: C24H20BrNO2S. Molecular mass: 466.39 g mol-1

1 (SC,SS)-62ca (white solid): m.p. 128–129 °C. H NMR (600 MHz, CDCl3):  = 11.10 (s, 1H), 7.81 (d, J = 2.1 Hz, 1H), 7.78 – 7.73 (m, 2H), 7.58 (d, J = 8.9 Hz, 1H), 7.45 – 7.42 (m, 1H), 7.37 – 7.33 (m, 2H), 7.31 – 7.28 (m, 2H), 7.26 – 7.16 (m, 6H), 6.02 (s, 1H), 3.23 (s, 3H).ppm. 13C{1H} NMR (151 MHz,

CDCl3):  = 155.0, 147.9, 138.4, 133.7, 131.4, 129.7, 129.7 (2C), 128.9, 128.8, 128.4 (2C), 126.7, 126.6, 124.7, 124.6, 122.7, 121.4, 120.3, 119.1, 52.6, 44.9 ppm. IR (ATR):  = 3856, 3022, 2922, 2328, 2184, 2014, 1753, 1593, 1494, 1447, 1390, 1316, 1224, 1121, 971, 887, 735 cm-1. MS (EI+, 70 eV): m/z (%): 312.0 (12), 310.9 (34), 309.9 (13), 308.9 (34), 231.1 (10), 230.0 (13), 229.0 (11), 203.0 (13), 202.0 (56), 201.0 (19), 200.0 (22), 156.0 (58), 141.0 (17), 140.0 (50), 126.0 (16), 125.0 (36), 155.5 (24), 114.1 (12), 101.1 (26), 100.1 (13), 97.1 (16), 94.1 (14), 92.1 (80), 91.1 (18), 88.1 (15), 78.2 (18), 77.2 (100), 75.2 (12), 74.2 (11), 65.2 (24), 63.2 (15), 51.2 (51), 50.3 (18). MS (CI+, methane): m/z (%): 467.9 (100, [M+H]+). HR-MS (ESI+): m/z: calcd. for

+ + [M+Na] = [C24H20BrNNaO2S] : 490.0269; found: 490.0267. HPLC: Chiralpack IB, n-

20 heptane/iPrOH 70:30, 0.7 mL/min,  = 254.4 nm,  = 10.2 min. OR: [] D = +285.7 (c 1.00, CHCl3, 99% ee).

1 (RC,SS)-62cb (white solid): m.p. 160–161 °C. H NMR (600 MHz, CDCl3): δ 11.44 (s, 1H), 7.85 (d, J = 2.2 Hz, 1H), 7.81 – 7.73 (m, 2H), 7.59 (t, J = 7.7 Hz, 2H), 7.55 (d, J = 9.2 Hz, 1H), 7.47 (t, J = 7.7 Hz, 2H), 7.34 (dd, J = 9.1, 2.2 Hz, 1H), 7.23 – 7.16 (m, 3H), 7.12 – 7.01 (m, 3H), 6.22 (s, 1H), 3.15 (s, 3H)

13 1 ppm. C{ H} NMR (151 MHz, CDCl3):  = 155.8, 142.8, 138.8, 133.5, 130.7, 130.2, 130.1, 129.6, 129.5 (2C), 128.6, 128.5 (2C), 128.3 (2C), 127.5 (2C), 127.2, 123.6, 121.6, 118.9, 116.2, 57.3, 45.2 ppm. IR (ATR):  = 3852, 3745, 3028, 2925, 2740, 2320, 2098, 1910, 1743, 1590, 1492, 1444, 1384, 1323, 1216, 1115, 981, 884, 805, 739, 694 cm-1 MS (EI+, 70 eV): m/z (%): 311.0 (4), 202.0 (20), 156.1 (13), 140.0 (19), 126.0 (12), 125.0 (25), 101.1 (16), 97.1 (13), 94.1 (11), 92.1 (60), 91.1 (15), 88.1 (12), 78.2 (18), 77.2 (100), 75.2 (14), 74.2 (13), 65.2 (29 ), 63.3 (20), 51.4 (71), 50.3 (27). MS (ESI): m/z (%): 490.0 [M+Na]+.HR-MS (ESI+): m/z: calcd. for [M+Na]+ =

78 EXPERIMENTAL PART

+ [C24H20BrNNaO2S] : 490.0269; found: 490.0275. HPLC: Chiralpack IB, n-heptane/iPrOH 70:30, 0.7

20 mL/min,  = 254.4 nm,  = 12.9 min. OR: [] D = −28.8 (c 0.50, CHCl3, 99% ee).

Methyl 3-hydroxy-4-(((methyl(oxo)(phenyl)-6-sulfaneylidene)amino)(phenyl)methyl)-2- naphthoate (62d)

-1 formula: C26H23NO4S. Molecular mass: 445.53 g mol .

1 62da (white solid): m.p. 178–179 °C. H NMR (600 MHz, CDCl3):  = 10.98 (s, 1H), 8.47 (s, 1H), 8.28 (d, J = 8.6 Hz, 1H), 7.94 (d, J = 7.3 Hz, 2H), 7.76 (dd, J = 8.2, 1.3 Hz, 1H), 7.57 (tt, J = 7.4, 1.2 Hz, 1H), 7.52 – 7.45 (m, 4H), 7.34 (ddd, J = 8.5, 6.7, 1.4 Hz, 1H), 7.26 – 7.23 (m, 1H), 7.21 (t, J = 7.6 Hz, 2H), 7.12 (t, J = 7.3 Hz, 1H), 6.73 (s, 1H), 4.04 (s, 3H), 3.03 (s, 3H) ppm. 13C{1H} NMR (151 MHz,

CDCl3):  = 170.7, 152.8, 144.9, 140.2, 135.8, 132.9, 132.7 (2C), 129.9, 129.3 (2C), 128.4 (2C), 128.3, 128.0 (2C), 127.9, 126.7 (2C), 125.9, 124.9, 124.9, 123.6, 113.9, 52.8, 51.7, 44.5 ppm. IR (ATR):  = 3025, 2947, 2650, 2486, 2291, 2161, 2051, 1978, 1911, 1825, 1685, 1621, 1507, 1443, 1305, 1233, 1135, 1076, 955, 877, 838, 788, 744, 706 cm-1. MS (EI+, 70 eV): m/z (%): 445.2 (11 [M]+), 290.1 (50), 289.0 (97), 245.1 (14), 244.0 (11), 231.1 (11), 217.1 (11), 216.0 (13), 202.1 (36), 189.0 (11), 156.0 (89), 142.1 (18), 141.0 (67), 140.0 (40), 126.0 (18), 125.0 (67), 123.9 (16), 114.1 (18), 113.0 (32), 101.1 (16), 97.0 (28), 94.1 (15), 92.0 (48), 91.1 (15), 88.1 (11.5), 78.1 (30), 77.1 (100), 65.1 (22), 63.1 (18), 51.1 (56), 50.1 (10). HR-MS (ESI+): m/z: calcd. for [M+H]+ =

+ [C26H24NO4S] : 446.1421; found: 446.1436. HPLC: Chiralpack IA, n-heptan/iPrOH 85:15, 0.8 mL/min,  = 254.4 nm,  = 10.6 min,  = 13.3 min.

1 62db (offwhite solid): m.p. 123–124 °C. H NMR (600 MHz, CDCl3):  = 10.46 (s, 1H), 8.29 (s, 1H), 8.12 (s, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.51 (d, J = 7.8 Hz, 2H), 7.46 (d, J = 7.8 Hz, 2H), 7.34 – 7.27 (m, 2H), 7.26 – 7.19 (m, 3H), 7.12 (dt, J = 17.4, 7.6 Hz, 3H), 6.62 (s, 1H), 3.99 (s, 3H), 3.18 (s, 3H)

13 1 ppm. C{ H} NMR (151 MHz, CDCl3):  = 170.2, 153.1, 144.9, 140.1, 135.7, 132.4, 132.1, 129.8, 128.4 (2C), 128.3, 128.1 (2C), 128.0 (2C), 127.6, 126.8 (3C), 125.9, 123.9, 123.5, 113.4, 52.7, 50.9, 44.9 ppm. IR (ATR):  = 3182, 3060, 2953, 2891, 2647, 2322, 2176, 2038, 1916, 1674, 1620, 1505, 1440,1319, 1214, 1158, 1118, 1078, 1026, 957, 913, 792, 744, 694 cm-1. MS (EI+, 70 eV): m/z (%): 445.2 (10 [M]+), 305.1 (11), 304.1 (12), 291.1 (10), 290.1 (31), 289.1 (76), 273.1 (13), 272.1 (22), 245.1 (26), 244.1 (22), 231.1 (19), 230.0 (11), 217.1 (26), 216.1 (35), 203.1 (21), 202.1 (90), 201.1 (24), 200.1 (26), 196.0 (13), 195.0 (12), 190.1 (11), 189.1 (29), 167.0 (12),

79 EXPERIMENTAL PART

156.0 (57), 143.0 (15), 142.1 (28), 141.0 (94), 139.9 (63), 138.9 (11), 129.1 (10), 126.0 (27), 124.9 (88), 123.9 (19), 115.1 (13), 114.1 (27), 113.0 (51), 101.1 (20), 97.0 (32), 94.1 (16), 92.1 (45), 91.1 (17), 88.1 (15), 78.1 (30), 77.1 (100), 65.1 (24), 63.1 (19), 51.0 (65). HR-MS (ESI+):

+ + m/z: calcd. for [M+H] = [C26H24NO4S] : 446.1421; found: 446.1434. HPLC: Chiralpack IA, n- heptan/iPrOH 85:15, 0.8 mL/min,  = 254.4 nm,  = 8.9 min,  = 12.1 min.

N-(3-Hydroxy-4-(((methyl(oxo)(phenyl)-6-sulfaneylidene)amino)(phenyl)methyl)naphthalen-2-yl)benzamide (62e)

with 10% Et3N). Yield: 90% (combined yield of isolated diastereomers).

d.r. = 54:46. Molecular formula: C31H26N2O3S. Molecular mass: 506.62 g mol-1.

1 62ea (white solid): m.p. 110–112 °C. H NMR (600 MHz, CDCl3):  = 12.59 (s, 1H), 10.66 (s, 1H), 8.82 (s, 1H), 7.89 – 7.83 (m, 1H), 7.84 – 7.79 (m, 2H), 7.76 – 7.65 (m, 2H), 7.51 – 7.30 (m, 6H), 7.29 – 7.26 (m, 3H), 7.26 – 7.18 (m, 4H), 7.17 – 7.11 (m, 1H), 6.17 (s, 1H), 3.32 (s, 3H) ppm. 13C NMR

(151 MHz, CDCl3):  = 163.8, 152.9, 142.6, 138.8, 137.4, 133.8, 133.7, 133.2, 130.3, 129.6 (2C), 129.1 (2C), 128.6 (2C), 128.6, 128.4 (2C), 127.8, 127.4 (2C), 127.4, 124.9, 123.6, 122.3, 121.4, 120.7 (2C), 119.9, 57.0, 44.9 ppm. IR (ATR):  = 3321, 3057, 2923, 2660, 2325, 2057, 1895, 1660, 1598, 1536, 1442, 1315, 1220, 1117, 976, 843, 740, 689 cm-1. MS (EI+, 70 eV): m/z (%): 353.2 (1), 351.1 (33), 350.1 (12), 259.0 (46), 231.1 (17), 203.1 (19), 202.0 (70), 201.0 (10), 200.0 (11), 140.0 (32), 94.1 (12), 93.1 (17), 92.0 (100), 91.1 (15), 78.1 (12), 77.1 (99), 65.1 (62), 63.1 (13),

+ + + 51.2 (74), 50.1 (26). HR-MS (ESI ): m/z: calcd. for [M+Na] = [C31H26N2NaO3S] : 529.1556; found: 529.1539. HPLC: Chiralpack IB, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4 nm,  = 20.1 min,  = 23.5 min.

1 62eb (white solid): m.p. 139–140 °C. H NMR (600 MHz, CDCl3):  = 13.10 (s, 1H), 10.70 (s, 1H), 8.83 (s, 1H), 7.92 – 7.87 (m, 1H), 7.86 – 7.74 (m, 4H), 7.70 (d, J = 8.5 Hz, 1H), 7.67 – 7.61 (m, 1H), 7.54 – 7.48 (m, 2H), 7.41 – 7.37 (m, 3H), 7.29 (t, J = 7.4 Hz, 1H), 7.26 – 7.23 (m, 2H), 7.19 – 7.01 (m,

13 1 4H), 6.34 (s, 1H), 3.24 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 163.9, 152.9, 142.4, 138.9, 138.3, 133.8, 133.8, 133.1, 130.6, 129.1 (3C), 128.7, 128.5 (2C), 128.4 (3C), 128.1, 127.4 (2C), 127.3, 124.1, 123.7, 121.6, 120.8 (3C), 57.2, 45.1 ppm. IR (ATR):  = 3321, 3058, 2924, 2649, 2315, 2187, 2100, 1818, 1655, 1598, 1538, 1443, 1317, 1223, 1123, 980, 938, 903, 843, 786, 740,

80 EXPERIMENTAL PART

691 cm-1. MS (EI+, 70 eV): m/z (%): 352.2 (5), 351.1 (17), 259.0 (22), 231.1 (11), 203.1 (10), 202.1 (41), 140.0 (27), 97.0 (12), 94.1 (12), 93.1 (16), 92.1 (94), 91.1 (15), 78.1 (12), 77.1 (100), 65.1 (57), 63.1 (12), 57.2 (15), 51.1 (67), 50.2 (22). HR-MS (ESI+): m/z: calcd. for

+ + [M+H] = [C31H27N2O3S] : 507.1737; found: 507.1747. HPLC: Chiralpack IB, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4 nm,  = 29.1 min,  = 36.3 min.

(((10-Hydroxyphenanthren-9-yl)(phenyl)methyl)imino)(methyl)(phenyl)-6-sulfanone (62f)

The title compound was prepared according to GP1 and isolated after FCC on silica gel (pentane/EtOAc 7:1) as a mixture of two diastereomers. The single diastereomers were isolated after second FCC (pentane/EtOAc 5:1

with 10% Et3N). Yield: 54% (combined yield of isolated diastereomers).

d.r. = 53:47. Molecular formula: C28H23NO2S. Molecular mass: 437.55 g mol-1.

1 62fa (pale yellow solid): m.p. 80–81 °C. H NMR (600 MHz, CDCl3):  = 11.85 (s, 1H), 8.65 – 8.61 (m, 1H), 8.57 (d, J = 8.3 Hz, 1H), 8.52 – 8.48 (m, 1H), 7.85 – 7.77 (m, 2H), 7.70 – 7.65 (m, 2H), 7.48 – 7.41 (m, 3H), 7.40 – 7.36 (m, 1H), 7.35 – 7.30 (m, 1H), 7.26 – 7.20 (m, 5H), 7.19 – 7.14 (m, 1H),

13 1 6.12 (s, 1H), 3.26 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 151.6, 143.4, 137.9, 133.6, 131.1, 131.1, 129.6 (2C), 128.6 (2C), 128.6 (2C), 127.8 (2C), 127.2, 127.1, 127.0, 126.9, 126.4, 125.9, 123.2, 123.1, 122.8, 122.3, 122.2, 113.6, 58.0, 45.2 ppm. IR (ATR):  = 3854, 3747, 3627, 3065, 3023, 2924, 2701, 2324, 2211, 2163, 2114, 1911, 1735, 1595, 1533, 1492, 1444, 1351, 1312, 1224, 1118, 976, 842, 742, 695 cm-1 MS (EI+, 70 eV): m/z (%): 437.9 (1 [M]+), 282.6 (22), 281.5 (45), 252.5 (25), 243.3 (22), 165.3 (42), 156.3 (11), 141.2 (22), 140.3 (49), 126.2 (17), 125.2 (27), 113.2 (14), 97.2 (18), 94.2 (13), 92.2 (80), 91.2 (20), 84.2 (11), 78.2 (16), 77.2 (100), 74.2 (12), 70.3 (12), 65.2 (30), 63.2 (16), 51.2 (71), 50.2 (30). HR-MS (ESI+): m/z: calcd. for

+ + [M+Na] = [C28H23NNaO2S] : 460.1342; found: 460.1342. HPLC: Chiralpack IB, n-heptane/iPrOH

80:20, 0.8 mL/min,  = 254.4 nm,  = 10.5 min,  = 12.0 min.

1 62fb (pale yellow solid): m.p. 102–103 °C. H NMR (600 MHz, CDCl3d):  = 12.10 (s, 1H), 8.67 – 8.61 (m, 2H), 8.56 – 8.48 (m, 1H), 7.88 – 7.79 (m, 2H), 7.77 – 7.73 (m, 1H), 7.69 – 7.64 (m, 2H), 7.62 – 7.57 (m, 1H), 7.51 – 7.44 (m, 2H), 7.42 – 7.36 (m, 2H), 7.34 – 7.27 (m, 2H), 7.13 – 6.98 (m,

13 1 3H), 6.37 (s, 1H), 3.17 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 151.5, 142.9, 139.1, 133.4, 131.2, 131.1, 129.5 (2C), 128.5 (2C), 128.3 (2C), 127.8 (2C), 127.2, 127.1, 127.0, 127.0, 126.4, 126.3, 123.3, 123.2, 123.1, 122.4, 122.3, 114.1, 57.7, 45.8 ppm. IR (ATR):  = 3414, 2923, 2859,

81 EXPERIMENTAL PART

2332, 2160, 1911, 1601, 1443, 1312, 1220, 1115, 983, 917, 736 cm-1. MS (EI+, 70 eV): m/z (%): 437.9 (1 [M]+), 282.5 (42), 281.5 (80), 253.5 (11), 252.5 (29), 250.5 (13), 165.3 (13), 155.2 (10), 141.2 (26), 140.3 (58), 126.2 (18), 125.2 (22), 113.2 (18), 97.2 (13), 94.2 (14), 92.2 (100), 91.2 (18), 78.3 (12), 77.3 (93), 65.2 (29), 63.2 (12), 51.3 (56), 50.3 (22). HR-MS (ESI+): m/z: calcd. for

+ + [M+Na] = [C28H23NNaO2S] : 460.1342; found: 460.1349. HPLC: Chiralpack IB, n-heptane/iPrOH

80:20, 0.8 mL/min,  = 254.4 nm,  = 15.5 min,  = 20.1 min.

(S)-(((2-Bromophenyl)(2-hydroxynaphthalen-1-yl)methyl)imino)(methyl)(phenyl)-6- sulfanone (62g)

The title compound was prepared according to GP1 and isolated after FCC on silica gel (pentane/EtOAc 4:1) as an inseparable mixture of two diastereomers. Yield: 90% (offwhite solid). d.r. = 58:42. Molecular

-1 formula: C24H20BrNO2S. Molecular mass: 466.39 g mol .

1 H NMR (400 MHz, CDCl3):  = 12.16 (major, s, 1H), 12.08 (minor, s, 1H), 7.94 – 7.87 (minor, m, 2H), 7.85 (major, d, J = 8.2 Hz, 1H), 7.73 – 7.49 (major and minor, m, 10H), 7.46 – 7.41 (minor, m, 2H), 7.41 – 7.35 (major, m, 2H), 7.35 – 7.30 (major, m, 1H), 7.26 – 7.09 (major and minor, m, 6H), 7.03 – 6.98 (minor, m, 1H), 6.92 – 6.85 (major, m, 1H), 6.77 (major, s,

13 1 1H), 6.44 (minor, s, 1H), 3.23 (minor, s, 3H), 3.19 (major, s, 3H). C{ H} NMR (151 MHz, CDCl3):  = 155.9 (minor), 155.9 (major), 143.1 (minor), 143.1 (major), 139.8 (major), 137.5 (minor), 133.8 (minor), 133.3 (major), 132.9 (minor), 132.5 (major), 131.9 (major), 131.8 (minor), 130.8 (major), 130.7 (minor), 129.7 (minor, 2C), 129.7 (minor), 129.7 (major), 129.2 (major, 2C), 129.0 (minor), 128.8 (minor, 2C), 128.8 (major), 128.7 (major), 128.7 (minor), 128.7 (major), 128.6 (minor), 128.5 (minor), 128.5 (major), 128.3 (major, 2C), 126.7 (major), 126.6 (minor), 122.8 (major), 122.7 (minor), 122.5 (major, 2C), 122.5 (minor), 122.1 (minor), 120.6 (major), 120.5 (minor), 118.6 (major), 118.0 (minor), 58.9 (minor), 57.2 (major), 45.7 (major), 45.6 (minor) ppm. IR (ATR):  = 3882, 3057, 3015, 2925, 2324, 2171, 2106, 2012, 1918, 1811, 1729, 1619, 1516, 1465, 1443, 1407, 1322, 1227, 1125, 1021, 979, 902, 865, 829, 737, 683 cm-1. MS (EI+, 70 eV): m/z (%): 467.3 (1, [M+]), 232.2 (14), 231.2 (75), 202.1 (15), 140.0 (20), 125.0 (11), 115.4 (15), 101.1 (11), 92.1 (65), 91.1 (12), 88.1 (10), 78.2 (14), 77.1 (100), 75.2 (14), 74.1 (11), 65.2 (35), 63.1 (22), 62.1 (10), 51.2 (93), 50.2 (37). HR-MS (ESI+): m/z: calcd. for [M+Na]+ =

+ [C24H20BrNNaO2S] : 490.0269; found: 490.0274. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 254.4 nm, major = 13.6 min minor = 15.3 min.

82 EXPERIMENTAL PART

(S)-(((2-Hydroxynaphthalen-1-yl)(naphthalen-1-yl)methyl)imino)(methyl)(phenyl)-6- sulfanone (62h)

The title compound was prepared according to GP1 and isolated after FCC on silica gel (pentane/EtOAc 4:1) as an inseparable mixture of two diastereomers. Yield: 80% (pale yellow solid). d.r. = 62:38. Molecular

-1 formula: C28H23NO2S. Molecular mass: 437.56 g mol .

1 H NMR (600 MHz, CDCl3):  = 11.82 (major, s, 1H), 11.29 (minor, s, 1H), 8.71 (minor, d, J = 8.6 Hz, 1H), 8.41 (major, d, J = 8.5 Hz, 1H), 7.88 (minor, dd, J = 8.1, 1.3 Hz, 1H), 7.83 – 7.78 (major, m, 1H), 7.75 (major, d, J = 8.9 Hz, 1H), 7.75 – 7.64 (major and minor, m, 4H overlapping), 7.63 (minor, d, J = 8.9 Hz, 1H), 7.59 (minor, dd, J = 8.0, 1.4 Hz, 1H), 7.59 – 7.52 (major and minor, m, 5H overlapping), 7.48 (major, dd, J = 7.2, 1.2 Hz, 1H), 7.43 (major, ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.40 (minor, dd, J = 7.3, 1.2 Hz, 1H), 7.36 (major, ddd, J = 8.0, 6.8, 1.1 Hz, 2H), 7.36 – 7.26 (major and minor, m, 5H overlapping), 7.26 – 7.19 (major and minor, m, 3H overlapping), 7.20 – 7.11 (major and minor, m, 5H overlapping), 7.09 (minor, ddd, J = 8.0, 6.8, 1.1 Hz, 1H), 7.04 (minor, ddd, J = 8.3, 6.8, 1.5 Hz, 1H), 6.98 (minor, s, 1H), 3.19 (minor, s, 2H), 3.06

13 1 (major, s, 3H). C{ H} NMR (151 MHz, CDCl3):  = 155.9 (major), 155.5 (minor), 139.2 (major), 138.3 (major), 138.3 (minor), 137.7 (minor), 134.2 (minor), 133.7 (major), 133.1 (minor), 132.8 (major), 131.8 (major), 131.6 (minor), 130.5 (minor), 130.5 (major), 129.5 (major), 129.4 (minor), 129.1 (major), 128.9 (minor), 128.8 (major), 128.6 (major, 2C), 128.6 (major), 128.6 (minor, 2C), 128.5 (minor), 128.5 (minor), 128.3 (minor), 128.1 (major), 127.5 (minor, 2C), 127.2 (major, 2C), 126.6 (major), 126.4 (major), 126.3 (minor), 126.3 (minor), 126.3 (minor), 126.1 (major), 125.8 (minor), 125.7 (major), 125.5 (minor), 125.1 (major), 123.6 (minor), 123.3 (major), 122.6 (major), 122.4 (minor), 121.9 (major), 121.5 (minor), 120.1 (major), 119.7 (minor), 118.2 (major), 117.7 (minor), 53.4 (minor), 53.1 (major), 45.2 (major), 44.4 (minor). IR (ATR):  = 3057, 2924, 2668, 2323, 2203, 2075, 2015, 1961, 1909, 1810, 1735, 1620, 1598, 1513, 1466, 1444, 1403, 1314, 1271, 1216, 1113, 1079, 1028, 979, 907, 845, 779, 736, 685 cm-1. MS (EI+, 70 eV): m/z (%): 437.0 (3, [M+]), 296.0 (11), 283.1 (11), 282.1 (44), 281.0 (100), 253.0 (12), 252.0 (39), 249.9 (14), 156.0 (16), 139.9 (18). HR-MS (ESI+): m/z: calcd. for [M+H]+ =

+ [C28H24NO2S] : 438.1522; found: 438.1525. HPLC: Chiralpack IB, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4 nm, minor = 10.76 min major = 14.43 min.

83 EXPERIMENTAL PART

(S)-(((2-Hydroxynaphthalen-1-yl)(pyridin-3-yl)methyl)imino)(methyl)(phenyl)-6- sulfanone (62i)

The title compound was prepared according to GP1 and isolated after FCC on silica gel (pentane/EtOAc 6:1) as a mixture of two diastereomers. The single diastereomers were isolated after second FCC (pentane/EtOAc 3:1

with 10% Et3N). Yield: 96% (combined yield of isolated diastereomers).

d.r. = 57:43. Molecular formula: C23H20N2O2S. Molecular mass: 388.49 g mol-1.

1 (SC,SS)-62ia (white solid) m.p. 194–196 °C. H NMR (600 MHz, CDCl3):  = 10.92 (s, 1H), 8.61 (s, 1H), 8.42 (s, 1H), 7.79 – 7.73 (m, 2H), 7.72 – 7.67 (m, 3H), 7.46 – 7.40 (m, 1H), 7.36 – 7.33 (m, 1H), 7.32 – 7.28 (m, 2H), 7.20 – 7.13 (m, 4H), 6.11 (s, 1H), 3.26 (s, 3H) ppm. 13C{1H} NMR (151 MHz,

CDCl3):  = 155.59, 149.21, 148.29, 139.22, 137.67, 135.29, 133.76, 131.38, 129.91, 129.62 (2 C), 128.73, 128.64, 128.58 (2 C), 126.70, 122.79, 121.18, 120.20, 117.08, 55.02, 45.17 ppm. IR (ATR):  = 3248, 3054, 2934, 2523, 2084, 1976, 1911, 1819, 1740, 1615, 1587, 1504, 1436, 1302, 1218, 1115, 973, 851, 802, 742, 696 cm-1. MS (EI+, 70 eV): m/z (%): 388.1 (12 [M]+), 247.1 (30), 233.1 (41), 232.1 (100), 220.1 (12), 205.1 (13), 204.1 (37), 203.1 (12), 177.1 (11), 176.0 (23), 170.0 (12), 156.0 (18), 152.0 (20), 151.0 (14), 141.0 (22), 139.9 (30), 127.1 (11), 126.0 (17), 124.9 (64), 155.0 (56), 114.0 (16), 97.0 (23), 94.1 (10), 92.1 (31), 91.1 (12), 89.1 (11), 78.1 (27), 77.1 (64),

+ + + 76.1 (10), 65.1 (21), 63.1 (17), 51.1 (56). HR-MS (ESI ): m/z: calcd. for [M+H] = [C23H21N2O2S] : 389.1318; found: 389.1317. HPLC: Chiralpack AD-H, n-heptane/EtOH 50:50, 0.5 mL/min,

20  = 254.4 nm,  = 12.2 min. OR: [] D = +353.0 (c 0.50, CHCl3, 99% ee).

1 (RC,SS)-62ib (white solid): m.p. 154–156 °C. H NMR (600 MHz, CDCl3):  = 11.20 (s, 1H), 8.44 (s, 1H), 8.32 (s, 1H), 7.83 – 7.78 (m, 2H), 7.76 – 7.68 (m, 2H), 7.67 – 7.57 (m, 3H), 7.55 – 7.48 (m, 2H), 7.33 (ddd, J = 8.4, 6.8, 1.4 Hz, 1H), 7.26 – 7.23 (m, 1H), 7.20 (d, J = 8.8 Hz, 1H), 7.08 – 6.98 (m, 1H),

13 1 6.33 (s, 1H), 3.17 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 155.5, 148.9, 148.2, 138.8, 138.6, 135.2, 133.8, 131.3, 129.9, 129.7 (2C), 128.9, 128.9, 128.2 (2C), 126.8, 123.6, 122.9, 121.2, 120.4, 117.5, 54.7, 44.9 ppm. IR (ATR):  = 3005, 2923, 2325, 2240, 2191, 2145, 2051, 1987, 1915, 1760, 1612, 1512, 1467, 1402, 1308, 1269, 1216, 1117, 1077, 986, 856, 819, 781, 730, 684 cm-1. MS (EI+, 70 eV): m/z (%): 388.1 (9, [M+]), 234.1 (10), 233.1 (55), 232.1 (100), 204.0 (22), 176.0 (16), 156.0 (15), 152.0 (12), 151.0 (11), 140.0 (30), 126.0 (10), 124.9 (29), 115.0 (27), 97.0 (15), 94.1 (10), 92.1 (63), 91.1 (12), 88.1 (15), 78.1 (23), 77.1 (99), 76.1 (20), 75.1 (17), 74.1 (12), 65.2 (32), 63.1 (27), 62.1 (11), 52.2 (11), 51.2 (84), 50.2 (30). HR-MS (ESI+): m/z: calcd. for

84 EXPERIMENTAL PART

+ + [M+H] = [C23H21N2O2S] : 389.1318; found: 389.1299. HPLC: Chiralpack AD-H, n-heptane/EtOH

20 50:50, 0.5 mL/min,  = 254.4 nm,  = 16.7 min. OR: [] D = –70.8 (c 0.5, CHCl3, 99% ee).

(S)-(((2-Hydroxynaphthalen-1-yl)(thien-2-yl)methyl)imino)(methyl)(phenyl)-6-sulfanone (62j)

with 10% Et3N). Yield: 85% (combined yield of isolated diastereomers).

d.r. = 55:45. Molecular formula: C22H19NO2S2. Molecular mass: 393.52 g mol-1.

1 (SC,SS)-62ja (white solid): m.p. 132–133 °C. H NMR (400 MHz, CDCl3):  = 10.74 (s, 1H), 7.81 – 7.69 (m, 2H), 7.69 – 7.63 (m, 2H), 7.49 – 7.43 (m, 1H), 7.42 – 7.36 (m, 1H), 7.28 – 7.23 (m, 2H), 7.23 – 7.16 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 7.11 (dd, J = 5.0, 1.3 Hz, 1H), 6.80 (dd, J = 5.0, 3.5 Hz,

13 1 1H), 6.77 – 6.73 (m, 1H), 6.34 (s, 1H), 3.23 (s, 3H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 155.2, 148.6, 137.9, 133.6, 131.4, 129.7, 129.5 (2C), 128.6, 128.5, 128.4 (2C), 126.8, 126.5, 124.8, 124.7, 122.6, 121.3, 120.1, 118.5, 52.6, 44.9 ppm. IR (ATR):  = 3854, 3066, 3017, 2920, 2324, 2086, 1993, 1913, 1810, 1619, 1517, 1467, 1443, 1402, 1320, 1211, 1141, 1101, 985, 955, 904, 820, 740, 695 cm-1. MS (EI+, 70 eV): m/z (%): 394.2 (2, [M+H]+), 393.2 (8, [M+]), 239.1 (18), 238.1 (76), 237.1 (100), 208.1 (13), 140.0 (23), 92.1 (38), 77.1 (36), 65.1 (10), 51.2 (16). HR-MS (ESI+): m/z:

+ + calcd. for [M+Na] = [C22H19NNaO2S2] : 416.0749 ; found: 416.0747. HPLC: Chiralpack AD-H, n-

20 heptane/iPrOH 80:20, 0.7 mL/min,  = 254.4 nm,  = 17.2 min. OR: [] D = +287.4 (c 0.50, CHCl3, 99% ee).

1 (RC,SS)-62jb (white solid): m.p. 138–140 °C. H NMR (600 MHz, CDCl3):  = 10.84 (s, 1H), 8.05 – 7.86 (m, 2H), 7.74 (dd, J = 8.1, 1.4 Hz, 1H), 7.72 – 7.69 (m, 2H), 7.68 – 7.64 (m, 1H), 7.60 – 7.54 (m, 2H), 7.36 – 7.32 (m, 1H), 7.27 – 7.24 (m, 1H), 7.19 (d, J = 8.9 Hz, 1H), 7.06 (dd, J = 5.1, 1.2 Hz, 1H), 6.68 (dd, J = 5.1, 3.5 Hz, 1H), 6.62 – 6.54 (m, 1H), 6.48 (s, 1H), 3.17 (s, 3H) ppm. 13C{1H} NMR (151

MHz, CDCl3):  = 155.0, 147.9, 138.4, 133.7, 131.4, 129.7, 129.7 (2C), 128.9, 128.8, 128.4 (2C), 126.7, 126.6, 124.7, 124.6, 122.7, 121.4, 120.3, 119.1, 52.6, 44.9 ppm. IR (ATR):  = 3848, 3026, 2924, 2749, 2314, 2192, 2087, 1741, 1598, 1440, 1397, 1329, 1216, 1099, 972, 811, 691 cm-1. MS (EI+, 70 eV): m/z (%): 393.0 (1, [M+]), 251.9 (14), 238.0 (18), 236.9 (30), 207.9 (14), 165.0 (24), 162.9 (14), 152.0 (17), 151.0 (10), 141.0 (18), 140.0 (23), 139.0 (16), 127.0 (10), 126.0 (18),

+ + + 124.9 (59), 115.0 (23). HR-MS (ESI ): m/z: calcd. for [M+Na] = [C22H19NNaO2S2] : 416.0749 ;

85 EXPERIMENTAL PART found: 416.0729. HPLC: Chiralpack AD-H, n-heptane/iPrOH 80:20, 0.7 mL/min,  = 254.4 nm,

20  = 27.4 min. OR: [] D = +1.7 (c 0.90, CHCl3, 99% ee).

(S)-(((5-Bromothien-2-yl)(2-hydroxynaphthalen-1-yl)methyl)imino)(methyl)(phenyl)-6- sulfanone (62k)

The title compound was prepared according to GP1 and isolated after FCC on silica gel (pentane/EtOAc 5:1) as a mixture of two diastereomers. The single diastereomers were isolated after second FCC (pentane/EtOAc 5:1

with 10% Et3N) were separated. Yield: 89% (combined yield of isolated

diastereomers). d.r. = 55:44. Molecular formula: C22H18BrNO2S2. Molecular mass: 472.42 g mol-1.

1 (SC,SS)-62ka (offwhite solid): m.p. 134–135 °C. H NMR (600 MHz, CDCl3):  = 10.60 (s, 1H), 7.81 – 7.70 (m, 2H), 7.71 – 7.64 (m, 2H), 7.44 – 7.38 (m, 2H), 7.31 – 7.26 (m, 2H), 7.24 – 7.18 (m, 2H), 7.15 (d, J = 8.8 Hz, 1H), 6.75 (d, J = 3.8 Hz, 1H), 6.48 (dd, J = 3.9, 1.2 Hz, 1H), 6.23 (s, 1H), 3.27 (s,

13 1 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 155.3, 150.1, 137.7, 133.7, 131.3, 129.9, 129.7, 129.6 (2C), 128.7, 128.5, 128.5 (2C), 126.7, 125.1, 122.8, 121.1, 120.2, 117.7, 111.4, 52.7, 44.9 ppm. IR (ATR):  = 3025, 2923, 2320, 2173, 2051, 1979, 1907, 1728, 1596, 1520, 1414, 1323, 1224, 1125, 961, 901, 860, 797, 740, 686 cm-1. MS (EI+, 70 eV): m/z (%): 237.5 (45), 208.4 (17), 165.4 (11), 140.3 (50), 125.3 (10), 118.7 (13), 104.2 (12). MS (ESI): m/z (%): 495.9 [M+Na]+. HR-

+ + + MS (ESI ): m/z: calcd. for [M+Na] = [C22H18BrNNaO2S2] : 495.9835; found: 495.9834. HPLC:

20 Chiralpack IB, n-heptane/EtOH 80:20, 0.8 mL/min,  = 254.4 nm,  = 10.8 min. OR: [] D = +237.6

(c 1.00, CHCl3, 99% ee).

1 (RC,SS)-62kb (pale yellow solid): m.p. 85–86 °C. H NMR (600 MHz, CDCl3):  = 10.68 (s, 1H), 8.00 – 7.90 (m, 2H), 7.75 (d, J = 8.1 Hz, 1H), 7.72 (d, J = 8.9 Hz, 1H), 7.69 (t, J = 7.5 Hz, 1H), 7.66 (d, J = 8.6 Hz, 1H), 7.63 – 7.58 (m, 2H), 7.39 – 7.32 (m, 1H), 7.28 – 7.24 (m, 1H), 7.18 (d, J = 8.9 Hz, 1H), 6.61 (d, J = 3.8 Hz, 1H), 6.37 (s, 1H), 6.27 (dd, J = 3.8, 1.1 Hz, 1H), 3.18 (s, 3H) ppm. 13C{1H} NMR

(151 MHz, CDCl3):  = 155.1, 149.5, 138.1, 133.9, 131.3, 129.9, 129.8 (2C), 129.5, 129.0, 128.8, 128.3 (2C), 126.9, 124.9, 122.9, 121.1, 120.3, 118.3, 111.3, 52.7, 44.9 ppm. IR (ATR):  = 3854, 3745, 3623, 3019, 2924, 2648, 2487, 2318, 2169, 2074, 2031, 1907, 1739, 1612, 1517, 1443, 1314, 1219, 1113, 964, 796, 739, 688 cm-1. MS (EI+, 70 eV): m/z (%): 238.2 (8), 237.1 (81), 208 (19), 165.0 (12), 163.0 (10), 140.0 (30), 118.5 (16), 104.1 (14), 94.0 (10), 92.1 (95), 91.1 (14), 78.2 (12), 77.1 (100), 69.2 (12.7), 65.1 (23), 63.1 (13), 51.3 (52), 50.2 (20), 45.4 (14). HR-MS

+ + + (ESI ): m/z: calcd. for [M+Na] = [C22H18BrNNaO2S2] : 495.9835; found: 495.9822. HPLC:

86 EXPERIMENTAL PART

20 Chiralpack IB, n-heptane/EtOH 80:20, 0.8 mL/min,  = 254.4 nm,  = 16.2 min. OR: [] D = −18.5

(c 1.00, CHCl3, 99% ee).

(S)-(((2-Hydroxynaphthalen-1-yl)(thien-3-yl)methyl)imino)(methyl)(phenyl)-6-sulfanone (62l)

Et3N). Yield: 76% (combined yield of isolated diastereomers). d.r. = 57:43.

-1 Molecular formula: C22H19NO2S2. Molecular mass: 393.52 g mol .

1 (SC,SS)-62la (white solid): m.p. 137–138 °C. H NMR (600 MHz, CDCl3):  = 10.82 (s, 1H), 7.78 – 7.72 (m, 2H), 7.72 – 7.65 (m, 2H), 7.44 – 7.37 (m, 2H), 7.29 – 7.26 (m, 2H), 7.24 – 7.13 (m, 4H), 7.11 (dd, J = 5.1, 1.3 Hz, 1H), 7.04 – 6.93 (m, 1H), 6.13 (s, 1H), 3.24 (s, 3H) ppm. 13C{1H} NMR (151

MHz, CDCl3):  = 155.3, 144.6, 137.9, 133.6, 131.4, 129.5 (2C), 129.4, 128.6 (2C), 128.6, 128.5, 127.7, 126.4, 125.8, 122.6, 122.1, 121.5, 120.2, 118.3, 53.2, 45.1 ppm. IR (ATR):  = 3879, 3106, 3063, 2922, 2662, 2324, 2168, 2085, 1967, 1906, 1759, 1613, 1514, 1453, 1407, 1320, 1229, 1223, 1083, 983, 822, 783, 740, 684 cm-1. MS (EI+, 70 eV): m/z (%): 393.7 (2 [M+H]+), 238.5 (47), 237.5 (100), 208.4 (12), 165.4 (16), 156.4 (33), 140.3 (16), 125.3 (10), 115.3 (11). HR-MS (ESI+):

+ + m/z: calcd. for [M+Na] = [C22H19NNaO2S2] : 416.0749; found: 416.0749. HPLC: Chiralpack IB, n-

20 heptane/EtOH 80:20, 0.8 mL/min,  = 254.4 nm, major = 10.7 min OR: [] D = +317.2 (c 0.50,

CHCl3, 99% ee).

1 (RC,SS)-62lb (offwhite solid): m.p. 95–96 °C. H NMR (600 MHz, CDCl3):  = 11.11 (s, 1H), 7.90 – 7.82 (m, 2H), 7.77 – 7.72 (m, 2H), 7.70 (d, J = 8.8 Hz, 1H), 7.65 – 7.60 (m, 1H), 7.56 – 7.48 (m, 2H), 7.34 (ddd, J = 8.5, 6.8, 1.4 Hz, 1H), 7.26 – 7.22 (m, 1H), 7.19 (d, J = 8.8 Hz, 1H), 7.05 (dd, J = 5.0, 3.0 Hz, 1H), 6.99 (dd, J = 5.1, 1.4 Hz, 1H), 6.91 (dt, J = 3.0, 1.0 Hz, 1H), 6.40 (s, 1H), 3.13 (s, 3H) ppm.

13 1 C{ H} NMR (151 MHz, CDCl3):  = 155.1, 144.1, 138.8, 133.5, 131.4, 129.6 (2C), 129.5, 128.9, 128.8, 128.2 (2C), 127.3, 126.6, 125.9, 122.7, 121.8, 121.5, 120.3, 118.7, 52.6, 44.9 ppm. IR (ATR):  = 3019, 2923, 2323,2175, 2106, 2048, 1910, 1731, 1614, 1518, 1458, 1405, 1320, 1222, 1118, 979, 822, 786, 741, 689 cm-1. MS (EI+, 70 eV): m/z (%): 393.2 (2 [M]+), 238.1 (21), 237.0 (42), 208.0 (13), 165.0 (23), 163.0 (10), 156.0 (17), 150.1 (13), 141.0 (18), 140.0 (28), 139.0 (11), 126.1 (13), 124.9 (55), 115.0 (30), 114.0 (11), 109.0 (10), 97.0 (25), 94.1 (11), 93.1 (13), 92.0 (51), 91.0 (19), 82.2 (11), 78.1 (20), 77.1 (100), 76.1 (10), 75.1 (14), 74.1 (14), 69.1 (12), 65.1 (43), 63.1 (35), 62.1 (11), 58.1 (12), 57.1 (13), 52.3 (11), 51.2 (83), 50.2 (32). HR-

87 EXPERIMENTAL PART

+ + + MS (ESI ): m/z: calcd. for [M+H] = [C22H20NO2S2] : 394.0930; found: 394.0916. HPLC: Chiralpack

20 IB, n-heptane/EtOH 80:20, 0.8 mL/min,  = 254.4,  = 14.3 min. OR: [] D = −34.2 (c 0.50, CHCl3, 99% ee).

((Cyclohexyl(2-hydroxynaphthalen-1-yl)methyl)imino)(methyl)(phenyl)-6-sulfanone (62m)

Et3N). Yield: 30% (combined yield of isolated diastereomers). d.r. = 57:43.

-1 Molecular formula: C24H27NO2S. Molecular mass: 393.55 g mol .

1 62ma (white solid): m.p. 133–134 °C. H NMR (400 MHz, CDCl3):  = 10.69 (s, 1H), 7.68 – 7.50 (m, 4H), 7.33 – 7.28 (m, 1H), 7.25 – 7.21 (m, 1H), 7.19 – 6.95 (m, 5H), 4.68 (d, J = 5.8 Hz, 1H), 3.19 (s, 3H), 2.05 – 1.97 (m, 1H), 1.82 – 1.71 (m, 2H), 1.64 – 1.54 (m, 2H), 1.39 – 1.34 (m, 1H), 1.31 –

13 1 1.23 (m, 3H), 1.12 – 1.08 (m, 2H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 144.6, 127.8, 122.6, 121.5, 118.5 (2C), 118.2, 118.0, 117.9, 117.8 (2C), 115.4, 111.7, 111.3, 109.2, 108.7, 48.5, 34.3, 34.0, 20.4, 18.5, 16.1, 16.0, 15.9 ppm. IR (ATR):  = 3067, 3016, 2918, 2847, 2326, 2161, 2076, 2000, 1938, 1718, 1619, 1596, 1517, 1466, 1445, 1404, 1308, 1261, 1225, 1161, 1115, 1081, 1030, 985, 956, 894, 860, 825, 781, 737, 685 cm-1. MS (EI+, 70 eV): m/z (%): 393.1 (10 [M]+), 311.0 (23), 310.0 (100), 181.8 (22), 169.9 (12), 141.0 (24). HR-MS (ESI+): m/z: calcd. for [M+Na]+

+ = [C24H27N2NaO2S] : 416.1655; found: 416.1647. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10,

0.8 mL/min,  = 254.4 nm,  = 7.1 min  = 7.8 min.

1 62mb (offwhite solid): m.p. 144–145 °C. H NMR (400 MHz, CDCl3):  = 10.43 (s, 1H), 8.09 – 7.91 (m, 2H), 7.79 (d, J = 8.6 Hz, 1H), 7.76 (dd, J = 8.1, 1.3 Hz, 1H), 7.73 – 7.63 (m, 2H), 7.61 (dd, J = 8.4, 7.1 Hz, 2H), 7.42 (ddd, J = 8.5, 6.8, 1.5 Hz, 1H), 7.28 (ddd, J = 7.9, 6.8, 1.0 Hz, 1H), 7.15 (d, J = 8.8 Hz, 1H), 5.04 (d, J = 6.4 Hz, 1H), 2.92 (s, 3H), 2.07 – 2.02 (m, 1H), 1.92 – 1.85 (m, 1H), 1.76 – 1.71 (m, 1H), 1.62 – 1.58 (m, 2H), 1.38 – 1.34 (m, 1H), 1.27 – 1.13 (m, 3H), 1.09 (dt, J = 8.5, 2.9 Hz, 2H) ppm.

13 1 C{ H} NMR (151 MHz, CDCl3):  = 155.0, 139.2, 133.6, 132.1, 129.6 (2C), 129.0, 128.9, 128.8, 127.7 (2C), 126.4, 122.6, 121.8, 119.9, 119.4, 58.4, 44.6, 43.5, 30.9, 29.3, 26.5, 26.5, 26.4 ppm. IR (ATR):  = 3061, 2924, 2854, 2668, 2322, 2183, 2062, 2027, 1989, 1944, 1832, 1731, 1619, 1598, 1515, 1446, 1403, 1314, 1259, 1208, 1160, 1115, 979, 954, 907, 862, 827, 791, 748, 690 cm-1. MS (EI+, 70 eV): m/z (%): 393.2 (5 [M]+), 311.1 (20), 310.0 (100), 181.0 (13), 170.0 (33), 157.1 (13), 156.0 (12), 141.0 (65), 125.0 (13), 114.9 (31), 77.1 (11), 55.1 (20). HR-MS (ESI+): m/z: calcd. for

88 EXPERIMENTAL PART

+ + [M+Na] = [C24H27N2NaO2S] : 416.1655; found: 416.1639. HPLC: Chiralpack IB, n-heptane/iPrOH

90:10, 0.8 mL/min,  = 254.4,  = 9.6 min  = 10.5 min.

((1-(2-Hydroxynaphthalen-1-yl)-2-methylpropyl)imino)(methyl)(phenyl)-6-sulfanone (62n)

The title compound was prepared according to GP1 and isolated after FCC on silica gel (pentane/EtOAc 6:1) as an inseparable mixture of two diastereomers. Yield: 20% (offwhite solid). d.r. = 57:43. Molecular

-1 formula: C21H23NO2S. Molecular mass: 353.48 g mol .

1 H NMR (600 MHz, CDCl3):  = 10.88 (major, s, 1H), 10.58 (minor, s, 1H), 8.02 – 7.97 (minor, m, 2H), 7.79 (minor, d, J = 8.6 Hz, 1H), 7.76 (minor, d, J = 8.1 Hz, 1H), 7.70 – 7.66 (minor, m, 2H), 7.65 – 7.58 (major and minor, m, 5H, overlapping), 7.42 (minor, ddd, J = 8.4, 6.7, 1.4 Hz, 1H), 7.34 (major, d, J = 8.4 Hz, 1H), 7.30 – 7.24 (major, m, 2H), 7.20 – 7.07 (major and minor, m, 5H, overlapping), 5.06 (minor, d, J = 5.9 Hz, 1H), 4.72 (major, d, J = 5.3 Hz, 1H), 3.22 (major, s, 3H), 2.94 (minor, s, 3H), 2.25 (minor, dq, J = 13.2, 6.6 Hz, 1H), 2.16 (major, dq, J = 13.4, 6.8 Hz, 1H), 1.09 – 1.04 (major and minor, m, 6H, overlapping), 0.94 (major, d, J = 6.8 Hz, 3H), 0.88

13 1 (minor, d, J = 6.8 Hz, 3H). C{ H} NMR (151 MHz, CDCl3):  = 155.1 (major), 155.1 (minor), 139.3 (minor), 138.3 (major), 133.6 (minor), 133.1 (major), 132.0 (minor), 131.9 (major), 129.6 (minor, 2C), 129.1 (major, 2C), 129.0 (minor), 129.0 (minor), 128.9 (minor), 128.8 (major), 128.5 (major), 128.5 (major), 128.3 (major, 2C), 127.7 (minor, 2C), 126.5 (minor), 125.9 (major), 122.6 (minor), 122.2 (major), 121.8 (minor), 121.7 (major), 119.9 (minor), 119.7 (major), 119.4 (minor), 119.1 (major), 59.7 (major), 58.9 (minor), 44.9 (minor), 43.4 (major), 35.1 (major), 34.9 (major), 20.6 (minor), 20.6 (major), 18.5 (minor), 18.2 (major) ppm. IR (ATR):  = 3058, 2960, 2674, 2331, 2164, 2093, 1907, 1722, 1608, 1515, 1457, 1402, 1315, 1228, 1119, 962, 890, 823, 737, 690 cm-1. MS (EI+, 70 eV): m/z (%): 353.8 (1, [M+]), 310.6 (14), 254.6 (10), 243.5 (13), 170.3 (28), 169.3 (11), 165.3 (31), 156.3 (13), 155.3 (10), 152.2 (11), 143.3 (11), 142.2 (15), 141.2 (100), 140.3 (16), 128.2 (16), 127.2 (12), 126.2 (20), 152.2 (34), 124.2 (17), 116.3 (11), 115.2 (85), 114.2 (16),

+ + + 113.2 (12). HR-MS (ESI ): m/z: calcd. for [M+Na] = [C21H23NNaO2S] : 376.1342 ; found:

376.1340. HPLC: Chiralpack IB, n-heptane/iPrOH 85:15, 0.8 mL/min,  = 254.4 nm, а-1 = 6.8 min,

a-2 = 7.2 min, b-1 = 8.4 min, b-2 = 9.2 min.

89 EXPERIMENTAL PART

(R)-1-Phenylpropan-1-ol (50a)

The title compound was prepared according to GP2 with ligand 62aa and

isolated after FCC on silica gel (pentane/Et2O 5:1) as a colorless oil (82% yield, 72% ee).[148]

1 H NMR (600 MHz, CDCl3):  = 7.37 – 7.26 (m, 5H), 4.61 (t, J = 6.7 Hz, 1H), 1.92 – 1.68 (m, 3H), 0.93 (t, J = 7.4 Hz, 3H) ppm. HPLC: Chiralcel OD-H, n-heptane/iPrOH 95:5, 0.6 mL/min,  = 254.4, major = 13.4 min, minor = 14.7 min.

(R)-1-(2-Methoxyphenyl)propan-1-ol (50b)

The title compound was prepared according to GP2 with ligand 62aa and

isolated after FCC on silica gel (pentane/Et2O 6:1) as a colorless oil (99% yield, 90% ee).[148]

1 H NMR (400 MHz, CDCl3):  = 7.29 (dd, J = 7.5, 1.8 Hz, 1H), 7.26 – 7.21 (m, 1H), 6.96 (td, J = 7.5, 1.1 Hz, 1H), 6.88 (dd, J = 8.2, 1.1 Hz, 1H), 4.78 (t, J = 6.6 Hz, 1H), 3.85 (s, 3H), 2.52 (brs, 1H), 1.90 – 1.74 (m, 2H), 0.95 (t, J = 7.4 Hz, 3H) ppm. HPLC: Chiralcel OD-H, n-heptane/iPrOH 95:5, 0.5 mL/min,  = 254.4 nm, minor= 17.8 min, major = 19.8 min.

1-((1H-indol-3-yl)(phenyl)methyl)naphthalen-2-ol (67a)

The title compound was prepared according to GP3 with C3 as a catalist and isolated after FCC on silica gel (pentane/DCM 1:1) as a white solid in 80% yield with 6% ee. [149]

1 H NMR (400 MHz, CDCl3):  = 8.09 (d, J = 8.6 Hz, 1H), 8.03 (brs, 1H), 7.81 (d, J = 8.1 Hz, 1H), 7.74 (d, J = 8.9 Hz, 1H), 7.46 – 7.14 (m, 10H), 7.04 (d, J = 8.9 Hz, 1H), 6.96 (td, J = 7.5, 6.9, 1.0 Hz, 1H), 6.65 (s, 1H), 6.51 (s, 1H), 6.14 (s, 1H) ppm. . MS (EI+, 70 eV): m/z (%): 349.3 (9, [M+]), 231.1 (17), 135.7 (14), 118.3 (10), 117.2 (100). HPLC: Chiralcel AD-

H, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 230 nm, major= 13.7 min, minor = 17.5 min.

90 EXPERIMENTAL PART

Diethyl 2-(2-chlorobenzylidene)malonate (80b)

Prepared according to GP4 in 20.0 mmol scale. The product was isolated after purification by FCC (pentane/DCM = 1:1) as a pale yellow oil (4.5 g,

1 80%). H NMR (600 MHz, CDCl3):  = 11.00 (s, 1H), 7.80 – 7.70 (m, 2H), 7.69 – 7.64 (m, 2H), 7.42 – 7.35 (m, 4H), 7.28 – 7.22 (m, 4H), 7.21 – 7.09 (m, 4H), 6.10 (s, 1H), 3.22 (s,

13 1 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 165.9, 163.8, 139.4, 134.8, 132.2, 131.3, 129.9, 129.4, 128.9, 126.9, 61.9, 61.8, 14.3, 13.9 ppm.

Diethyl 2-(4-chlorobenzylidene)malonate (80c)

Prepared according to GP4 in 10.0 mmol scale. The product was isolated after purification by FCC (pentane/DCM = 1:1) as a pale yellow oil (2,5 g,

1 89%). H NMR (600 MHz, CDCl3):  = 7.67 (s, 1H), 7.40 – 7.38 (m, 2H), 7.36 – 7.34 (m, 2H), 4.37 – 4.30 (m, 3H), 4.33 – 4.27 (m, 3H), 1.33 (t, J = 7.1 Hz,

13 1 3H), 1.29 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 166.6, 164.1, 140.8, 136.8, 131.5, 130.8 (2C), 129.2 (2C), 126.9, 61.9, 61.9, 14.3, 14.1 ppm.

Diethyl 2-(2-bromobenzylidene)malonate (80d)

Prepared according to GP4 in 10.0 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 10:1) as a pale yellow oil (2,3 g, 70%).

1 H NMR (600 MHz, CDCl3):  = 7.67 (s, 1H), 7.61 (s, 1H), 7.54 (ddd, J = 8.0, 2.0, 1.0 Hz, 1H), 7.39 (d, J = 7.7 Hz, 1H), 7.29 – 7.27 (m, 1H), 4.36 (q, J = 6.6, 6.0 Hz, 2H), 4.33 (q, J = 7.1, 6.5 Hz, 2H), 1.35 (t, J = 7.1 Hz, 3H), 1.33 (t, J = 7.2 Hz, 3H) ppm. 13C{1H} NMR (151 MHz,

CDCl3):  = 166.2, 163.9, 140.4, 135.1, 133.4, 132.1, 130.4, 128.0, 127.9, 122.9, 62.1, 62.0, 14.3, 14.1 ppm.

Diethyl 2-(4-nitrobenzylidene)malonate (80e)

Prepared according to GP4 in 10.0 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 10:1) as a pale yellow solid (2.0

1 g, 69%). H NMR (400 MHz, CDCl3):  = 8.26 – 8.19 (m, 2H), 7.74 (s, 1H),

91 EXPERIMENTAL PART

7.63 – 7.56 (m, 2H), 4.32 (q, J = 7.1 Hz, 4H), 1.33 (t, J = 7.1 Hz, 3H), 1.27 (t, J = 7.1 Hz, 3H) ppm.

13 1 C{ H} NMR (101 MHz, CDCl3):  = 165.7, 163.4, 148.5, 139.4, 139.2, 130.1, 130.1 (2C), 124.0 (2C), 62.3, 62.2, 14.2, 14.0 ppm.

Diethyl 2-(4-methylbenzylidene)malonate (80f)

Prepared according to GP4 in 12.5 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 15:1) as a pale yellow oil (3.2 g,

1 98%). H NMR (600 MHz, CDCl3):  = 7.66 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.22 – 7.19 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.49 (s,

13 1 3H), 1.32 (dt, J = 8.3, 7.1 Hz, 6H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 167.1, 164.4, 142.9, 141.6, 130.1 (2C), 129.2, 125.8 (2C), 125.2, 61.9, 61.7, 15.1, 14.3, 14.1 ppm.

Diethyl 2-(naphthalen-1-ylmethylene)malonate (80g)

Prepared according to GP4 in 12.5 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 15:1) as a pale yellow oil (3.6 g, 97%).

1 H NMR (600 MHz, CDCl3):  = 8.47 (s, 1H), 8.00 (d, J = 8.9 Hz, 1H), 7.90 – 7.86 (m, 2H), 7.60 – 7.53 (m, 3H), 7.44 (t, J = 7.7 Hz, 1H), 4.37 (q, J = 7.1 Hz, 2H), 4.16 (q, J = 7.1 Hz, 2H), 1.38 (t, J = 7.1 Hz, 3H), 1.06 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (151

MHz, CDCl3):  = 166.2, 164.1, 141.3, 133.5, 131.5, 130.9, 130.6, 129.4, 128.8, 127.0, 126.5, 126.5, 125.3, 124.2, 61.9, 61.6, 14.3, 13.9 ppm.

Diethyl 2-(thiophen-2-ylmethylene)malonate (80h)

Prepared according to GP4 in 25.0 mmol scale. The product was isolated after purification by FCC (Pentane/EtOAc = 15:1) as a pale brown oil (5.9 g, 93%).

1 H NMR (600 MHz, CDCl3):  = 7.84 (d, J = 0.8 Hz, 1H), 7.52 (dt, J = 5.1, 1.0 Hz, 1H), 7.36 (dt, J = 3.8, 0.9 Hz, 1H), 7.07 (dd, J = 5.1, 3.7 Hz, 1H), 4.40 (q, J = 7.1 Hz, 2H), 4.28 (q, J =

13 1 7.1 Hz, 2H), 1.37 (t, J = 7.2 Hz, 3H), 1.32 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 166.4, 164.4, 136.2, 134.8, 134.8, 134.5, 131.7, 127.9, 122.6, 62.0, 61.7, 14.3, 14.1 ppm.

92 EXPERIMENTAL PART

Dimethyl 2-benzylidenemalonate (80i)

Prepared according to GP4 in 13.0 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 15:1) as a colorless oil (2.7 g, 94%).

1 H NMR (400 MHz, CDCl3):  = 7.78 (s, 1H), 7.56 – 7.28 (m, 5H), 3.85 (s, 6H)

13 1 ppm. C{ H} NMR (101 MHz, CDCl3):  = 167.3, 164.6, 143.1, 132.9, 130.8, 129.5 (2C), 129.0 (2C), 125.6, 52.8 (2C) ppm.

Diisopropyl 2-benzylidenemalonate (80j)

Prepared according to GP4 in 10.0 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 15:1) as a colorless oil (2.0 g, 73%).

1 H NMR (600 MHz, CDCl3):  = 7.68 (s, 1H), 7.47 (dd, J = 7.5, 2.1 Hz, 2H), 7.39 – 7.35 (m, 3H), 5.25 (hept, J = 6.3 Hz, 1H), 5.15 (hept, J = 6.3 Hz, 1H), 1.31 (d, J = 6.3 Hz, 6H), 1.28

13 1 (d, J = 6.3 Hz, 6H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 166.4, 163.8, 141.5, 133.1, 130.5, 129.6 (2C), 128.8 (2C), 127.2, 69.4, 69.4, 21.9 (2C), 21.7 (2C) ppm.

Diethyl 2-(4-(methylthio)benzylidene)malonate (80l)

Prepared according to GP4 in 12.5 mmol scale. The product was isolated after purification by FCC (pentane/DCM = 1:1) as a pale yellow oil (3.4 g,

1 91%). H NMR (600 MHz, CDCl3):  = 7.66 (s, 1H), 7.37 (d, J = 8.5 Hz, 2H), 7.22 – 7.19 (m, 2H), 4.35 (q, J = 7.1 Hz, 2H), 4.29 (q, J = 7.1 Hz, 2H), 2.49 (s, 3H), 1.32 (dt, J = 8.3, 7.1

13 1 Hz, 6H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 167.1, 164.4, 142.9, 141.6, 130.1 (2C), 129.2, 125.8 (2C), 125.2, 61.9, 61.7, 15.1, 14.3, 14.1 ppm.

Diethyl 2-(2-methylbenzylidene)malonate (80m)

Prepared according to GP4 in 12.5 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 20:1) as a pale yellow oil (3.0 g, 93%).

1 H NMR (600 MHz, CDCl3):  = 7.97 (s, 1H), 7.33 (d, J = 7.7 Hz, 1H), 7.29 – 7.26 (m, 1H), 7.21 (d, J = 7.5 Hz, 1H), 7.15 (t, J = 7.6 Hz, 1H), 4.32 (q, J = 7.1 Hz, 2H), 4.22 (q, J = 7.1 Hz, 2H), 2.38 (s, 3H), 1.34 (t, J = 7.1 Hz, 3H), 1.16 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (151 MHz,

CDCl3):  = 166.5, 164.2, 141.9, 137.7, 132.8, 130.5, 130.1, 127.9 (2C), 126.1, 77.4, 77.2, 76.9, 61.8, 61.6, 20.1, 14.3, 14.0 ppm.

93 EXPERIMENTAL PART

Dibenzyl 2-benzylidenemalonate (80v)

Prepared according to GP4 in 10.0 mmol scale. The product was isolated after purification by FCC (pentane/EtOAc = 12:1) as a white solid (2.7 g, 73%).

1 H NMR (600 MHz, CDCl3):  = 7.68 (s, 1H), 7.47 (dd, J = 7.5, 2.1 Hz, 2H), 7.39 – 7.35 (m, 3H), 5.25 (hept, J = 6.3 Hz, 1H), 5.15 (hept, J = 6.3 Hz, 1H), 1.31 (d, J = 6.3 Hz, 6H), 1.28

13 1 (d, J = 6.3 Hz, 6H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 166.4, 163.8, 141.5, 133.1, 130.5, 129.6 (2C), 128.8 (2C), 127.2, 69.4, 69.4, 21.9 (2C), 21.7 (2C) ppm.

Diethyl (S)-2-((1H-indol-3-yl)(phenyl)methyl)malonate (81a)

The title compound was prepared according to GP5: The rac-81a was prepared in 16 mmol scale (5.51 g, 92% yield); GP6: Yield : 48%, 86:14 e.r. (S)-81a. GP8: 95% yield, e.r. 91:9.

1 White solid, m.p. 178–179 °C. H NMR (600 MHz, CDCl3):  = 8.03 (brs, 1H), 7.55 (d, J = 8.0 Hz, 1H), 7.41 – 7.34 (m, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.23 (t, J = 7.6 Hz, 2H), 7.18 (d, J = 2.5 Hz, 1H), 7.16 – 7.08 (m, 2H), 7.03 (t, J = 7.5 Hz, 1H), 5.08 (d, J = 11.8 Hz, 1H), 4.29 (d, J = 11.8 Hz, 1H), 3.99 (dq, J = 14.2, 7.1 Hz, 4H), 1.00 (dt, J = 10.1, 7.1 Hz, 6H)

13 1 ppm. C{ H} NMR (151 MHz, CDCl3):  = 168.1, 168.0, 141.5, 136.3, 128.5 (2C), 128.3 (2C), 126.9, 126.8, 122.4, 120.9, 119.6, 119.5, 117.2, 111.1, 61.6, 61.5, 58.5, 43.0, 13.9, 13.9 ppm. HPLC:

Chiralpack IB, n-heptan/iPrOH 90:10, 0.8 mL/min,  = 230, minor = 14.2 min, major = 16.6 min. OR:

20 [131] [] D = +49.1 (c 1.00, CHCl3, 91:9 e.r.)

Diethyl (R)-2-((2-chlorophenyl)(1H-indol-3-yl)methyl)malonate (81b)

The title compound was prepared according to: GP5: The rac-81b was prepared in 5.0 mmol scale (1.52 g, 76% yield); GP6: Yield : 58%, 68:32 e.r. (S)-81b; GP8: 93% yield, 86:14 e.r.

1 Colorless semisolid. H NMR (400 MHz, CDCl3):  = 8.11 (s, 1H), 7.70 (d, J = 7.9 Hz, 1H), 7.41 (d, J = 7.7 Hz, 1H), 7.33 (d, J = 7.8 Hz, 1H), 7.28 (d, J = 8.3 Hz, 1H), 7.21 – 7.02 (m, 5H), 5.67 (d, J = 11.6 Hz, 1H), 4.41 (d, J = 11.7 Hz, 1H), 4.01 (dq, J = 17.8, 7.1 Hz, 4H), 1.04 (t, J = 7.1

13 1 Hz, 3H), 0.97 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 168.0, 167.6, 139.2, 136.1, 134.2, 130.0, 129.1, 128.0, 127.0, 126.8, 122.3, 122.0, 119.7, 119.6, 115.9, 111.1, 61.7, 61.6,

94 EXPERIMENTAL PART

57.7, 38.7, 13.9, 13.8 ppm. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230,

20 [131] minor = 13.9 min, major = 19.0 min. OR: [] D = +30.0 (c 0.50, CHCl3, 86:14 e.r.).

Diethyl (S)-2-((4-chlorophenyl)(1H-indol-3-yl)methyl)malonate (81c)

The title compound was prepared according to: GP5: The rac-81c was prepared in 2.5 mmol scale (0.92 g, 92% yield); GP6: 50% yield, 67:33 e.r, (S)-81c; GP8: 91% yield, 89:11 e.r., (S)-81c.

1 White solid, m.p. 162–163 °C. H NMR (400 MHz, CDCl3):  = 8.09 (s, 1H), 7.49 (d, J = 8.0 Hz, 1H), 7.38 – 7.26 (m, 3H), 7.26 – 7.17 (m, 2H), 7.18 – 7.08 (m, 2H), 7.04 (t, J = 7.6 Hz, 1H), 5.07 (d, J = 11.6 Hz, 1H), 4.25 (d, J = 11.7 Hz, 1H), 4.10 – 3.88 (m,

13 1 4H), 1.06 (t, J = 7.1 Hz, 3H), 1.00 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 167.9, 167.8, 140.1, 136.4, 132.6, 129.7 (2C), 128.6 (2C), 126.6, 122.5, 121.0, 119.8, 119.3, 116.6, 111.2, 61.7 (2C), 58.3, 42.3, 14.0, 13.9 ppm. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.7 mL/min,

20 [131]  = 230, minor = 16.4 min, major = 17.6 min. OR: [] D = +31.6 (c 0.50, CHCl3, 90:10 e.r.).

Diethyl (S)-2-((3-bromophenyl)(1H-indol-3-yl)methyl)malonate (81d)

The title compound was prepared according to: GP5: The rac-81d was prepared in 1.0 mmol scale (0.43 g, 96% yield); GP6: 55% yield, 69:31 e.r, (S)-81d. GP8: 91% yield, 91:9 e.r., (S)-81d.

1 White solid, m.p. 121–122 °C. H NMR (400 MHz, CDCl3):  = 8.13 (s, 1H), 7.58 – 7.46 (m, 2H), 7.35 – 7.26 (m, 3H), 7.21 – 7.02 (m, 4H), 5.06 (d, J = 11.7 Hz, 1H), 4.26 (d, J = 11.7 Hz, 1H), 4.02 (dq, J = 8.3, 7.1 Hz, 4H), 1.07 (t, J = 7.1 Hz, 3H), 1.00 (t, J

13 1 = 7.1 Hz, 3H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 167.8, 167.7, 144.0, 136.3, 131.4, 130.0 (2C), 127.1, 126.6, 122.6, 122.5, 121.1, 119.8, 119.3, 116.3, 111.2, 61.7 (2C), 58.2, 42.6, 14.0, 13.9 ppm. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230 nm, minor = 13.2 min,

20 [131] major = 15.9 min. OR: [] D = +41.4 (c 0.50, CHCl3, 91:9 e.r.).

95 EXPERIMENTAL PART

Diethyl (S)-2-((1H-indol-3-yl)(4-nitrophenyl)methyl)malonate (81e)

The title compound was prepared according to: GP5: The rac-81e was prepared in 1.0 mmol scale (0.37 g, 90% yield); GP6: 92% yield, 50:50 e.r; GP8: 96% yield, 88:12 e.r., (S)-81e.

1 White solid, m.p. 126–127 °C. H NMR (400 MHz, CDCl3):  = 8.20 (brs, 1H), 8.15 – 8.00 (m, 2H), 7.59 – 7.51 (m, 2H), 7.47 (d, J = 8.0 Hz, 1H), 7.32 (dt, J = 8.2, 0.9 Hz, 1H), 7.21 (d, J = 1.8 Hz, 1H), 7.16 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.05 (ddd, J = 8.0, 7.1, 1.0 Hz, 1H), 5.20 (d, J = 11.6 Hz, 1H), 4.33 (d, J = 11.6 Hz, 1H), 4.12 – 3.93 (m, 4H), 1.07 (t, J =

13 1 7.1 Hz, 3H), 1.01 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 167.5, 167.5, 149.3, 146.8, 136.3, 129.2 (2C), 126.4, 123.8 (2C), 122.8, 121.4, 120.0, 119.0, 115.5, 111.4, 61.9 (2C), 57.8, 42.6, 14.0, 13.9 ppm. HPLC: Chiralpack AS-H, n-heptane/iPrOH 85:15, 1.0 mL/min,  = 230,

20 [131] major = 20.6 min, minor = 30.2 min. OR: [] D = +6.6 (c 0.50, CHCl3, 88:12 e.r.).

Diethyl (S)-2-((1H-indol-3-yl)(p-tolyl)methyl)malonate (81f)

The title compound was prepared according to: GP6: 41% yield, 50:50 e.r. GP8: 91% yield, 88:12 e.r., (S)-81f. The rac-81f was prepared according

GP7 using Cu(OTf)2 as a catalyst, without a ligand in 1.3 mmol scale (0.361 g, 75%).

1 White solid, m.p. 140–141 °C. H NMR (600 MHz, CDCl3):  = 8.04 (brs, 1H), 7.56 (d, J = 9.0 Hz, 1H), 7.28 (dt, J = 8.2, 1.0 Hz, 1H), 7.26 – 7.23 (m, 2H), 7.17 – 7.10 (m, 2H), 7.07 – 6.97 (m, 3H), 5.05 (d, J = 11.8 Hz, 1H), 4.28 (d, J = 11.8 Hz, 1H), 4.07 – 3.92 (m, 4H), 2.25 (s,

13 1 3H), 1.04 (t, J = 7.1 Hz, 3H), 0.98 (t, J = 7.1 Hz, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 168.2, 168.0, 138.5, 136.4, 136.4, 129.1 (2C), 128.1 (2C), 126.8, 122.3, 120.9, 119.6, 119.5, 117.3, 111.1, 61.6, 61.5, 58.5, 42.6, 21.1, 13.9, 13.9 ppm. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8

20 [131] mL/min,  = 230, minor = 7.6 min, major = 6.3 min. OR: [] D = +28.2 (c 0.50, CHCl3, 88:12 e.r.).

96 EXPERIMENTAL PART

Diethyl (S)-2-((1H-indol-3-yl)(naphthalen-1-yl)methyl)malonate (81g)

The title compound was prepared according to: GP5: The rac-81g was prepared in 3.8 mmol scale (0.33 g, 21% yield); GP6: 42% yield, 50:50 e.r. GP8: 98% yield, 91:9 e.r., (S)-81g.

1 Pale yellow semisolid. H NMR (600 MHz, CDCl3):  = 8.44 (d, J = 8.5 Hz, 1H), 8.05 (brs, 1H), 7.80 (d, J = 6.7 Hz, 1H), 7.70 (d, J = 8.2 Hz, 1H), 7.62 (d, J = 8.0 Hz, 1H), 7.55 (dd, J = 7.3, 1.2 Hz, 1H), 7.51 – 7.46 (m, 1H), 7.46 – 7.36 (m, 2H), 7.23 (d, J = 8.1 Hz, 1H), 7.14 – 7.07 (m, 1H), 7.06 – 6.95 (m, 2H), 6.00 (d, J = 11.6 Hz, 1H), 4.52 (d, J = 11.6 Hz, 1H), 3.96 (q, J = 7.1 Hz, 2H), 3.89 – 3.72 (m, 2H), 0.96 (t, J = 7.1 Hz, 3H), 0.82 (t, J = 7.1 Hz, 3H) ppm.

13 1 C{ H} NMR (151 MHz, CDCl3):  = 168.7, 168.0, 137.9, 136.2, 134.1, 131.7, 128.8, 127.5, 126.6, 126.2, 125.6, 125.3, 124.2, 123.8, 122.4, 122.2, 119.6, 119.5, 116.9, 111.2, 61.8, 61.5, 58.8, 37.5, 13.8, 13.6 ppm. IR (ATR)  = 3398, 3054, 2982, 2933, 2673, 2165, 2013, 1924, 1726, 1621, 1598, 1517, 1458, 1369, 1248, 1148, 1097, 1019, 859, 781, 741, 680 cm-1. MS (CI+, methane) m/z (%): 415.3 (33, M+), 257.0 (20), 256.0 (100), 255.2 (15), 254.0 (26). HR-MS (ESI+) m/z: calcd. for

+ + [M+Na] = [C23H25NNaO4S] : 438.1676; found: 438.1676. HPLC: Chiralpack IB, n-heptane/iPrOH

20 90:10, 0.8 mL/min,  = 230 nm, minor = 10.9 min, major = 13.1 min. OR: [] D = +3.60 (c 1.00,

CHCl3, 91:9 e.r.).

Diethyl (R)-2-((1H-indol-3-yl)(thien-2-yl)methyl)malonate (81h)

The title compound was prepared according to: GP5: The rac-81h was prepared in 2.5 mmol scale (0.26 g, 28% yield); GP6: 39% yield, 50:50 e.r. GP8: 90% yield, 83:17 e.r., (S)-81h.

1 White solid, m.p. 128–129 °C. H NMR (600 MHz, CDCl3):  = 8.10 (brs, 1H), 7.62 (d, J = 7.9 Hz, 1H), 7.31 (d, J = 8.1 Hz, 1H), 7.21 – 7.12 (m, 2H), 7.11 – 7.01 (m, 2H), 7.01 – 6.91 (m, 1H), 6.86 (dd, J = 5.1, 3.6 Hz, 1H), 5.39 (d, J = 11.4 Hz, 1H), 4.31 (d, J = 11.5 Hz, 1H), 4.16 – 4.05 (m, 2H), 3.94 (q, J = 7.1 Hz, 2H), 1.14 (t, J = 7.1 Hz, 3H), 0.92 (t, J =

13 1 7.1 Hz, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 167.9, 167.6, 145.8, 136.2, 126.5, 126.5, 125.2, 124.4, 122.4, 121.7, 119.8, 119.5, 116.6, 111.2, 61.8, 61.6, 59.4, 38.1, 14.0, 13.8 ppm. HPLC:

Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230 nm, minor = 15.2 min, major = 16.7 min.

20 [131] OR: [] D = +45.4 (c 1.00, CHCl3, 83:17 e.r.).

97 EXPERIMENTAL PART

Dimethyl (S)-2-((1H-indol-3-yl)(phenyl)methyl)malonate (81i)

The title compound was prepared according to: GP5: The rac-81i was prepared in 4.1 mmol scale (1.11 g, 80% yield); GP6: 40% yield, 55:45 e.r, (S)-81i. GP8: 92% yield, 85:15 e.r., (S)-81i.

1 White solid, m.p. 149–150 °C. H NMR (400 MHz, CDCl3):  = 8.04 (brs, 1H), 7.50 (d, J = 8.0 Hz, 1H), 7.33 (d, J = 7.6 Hz, 2H), 7.27 (d, J = 8.1 Hz, 1H), 7.24 – 7.20 (m, 2H), 7.19 – 7.06 (m, 3H), 7.02 (t, J = 7.5 Hz, 1H), 5.08 (d, J = 11.7 Hz, 1H), 4.31 (d, J = 11.7 Hz, 1H), 3.52

13 1 (d, J = 12.1 Hz, 6H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 168.6, 168.3, 141.3, 136.4, 128.5 (2C), 128.2 (2C), 127.0, 126.7, 122.4, 120.9, 119.7, 119.5, 116.9, 111.2, 58.3, 52.8, 52.6, 43.0 ppm.

HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230, minor = 17.3 min, major =

20 [150] 20.2 min. OR: [] D = +48.4 (c 0.50, CHCl3, 85:15 e.r.).

Diisopropyl (S)-2-((1H-indol-3-yl)(phenyl)methyl)malonate (81j)

The title compound was prepared according to: GP6: 45% yield, 72:28 e.r, (S)-81j. GP8: 97% yield, 83:17 e.r., (S)-81j. The rac-81j was prepared according to a reported procedure.[151]

1 White solid, m.p. 149–150 °C. H NMR (400 MHz, CDCl3):  = 8.06 (brs, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.42 – 7.35 (m, 2H), 7.28 (d, J = 8.0 Hz, 1H), 7.22 (t, J = 7.6 Hz, 2H), 7.18 – 7.08 (m, 3H), 7.04 (td, J = 7.5, 7.0, 1.1 Hz, 1H), 5.06 (d, J = 11.8 Hz, 1H), 4.85 (hept, J = 6.3 Hz, 2H), 4.26 (d, J = 11.8 Hz, 1H), 1.10 (d, J = 6.3 Hz, 3H), 1.05 – 0.88 (m, 9H) ppm. 13C{1H} NMR (101

MHz, CDCl3):  = 167.7, 167.5, 141.7, 136.3, 128.4 (4C), 126.9, 126.8, 122.3, 121.0, 119.6, 119.5, 117.3, 111.1, 69.0 (2C), 58.8, 42.9, 21.5, 21.4, 21.4, 21.4 ppm. HPLC: Chiralpack IB, n-

20 heptane/iPrOH 90:10, 0.8 mL/min,  = 230, minor = 9.8 min, major = 11.9 min. OR: [] D = +38.0 (c

[150] 1.00, CHCl3, 83:17 e.r.).

Ditertbutyl 2-((1H-indol-3-yl)(phenyl)methyl)malonate (81k)

The title compound was prepared according to: GP6: 95% yield, 50:50 e.r. The rac-81k was prepared according to a reported procedure.[151]

1 Pale pink solid. H NMR (400 MHz, CDCl3):  = 8.04 (s, 1H), 7.59 (d, J = 7.9 Hz, 1H), 7.39 (d, J = 7.3 Hz, 2H), 7.29 (d, J = 8.1 Hz, 1H), 7.22 (t, J = 7.7 Hz, 2H), 7.16 (d, J = 2.5 Hz, 1H), 7.16 – 7.10 (m, 2H), 7.06 – 7.00 (m, 1H), 4.96 (d, J = 11.7 Hz, 1H), 4.14 (d, J

98 EXPERIMENTAL PART

= 11.7 Hz, 1H), 1.25 (s, 6H), 1.19 (s, 6H) ppm. HPLC: Chiralpack IB, n-heptan/iPrOH 85:15, 0.8 mL/min,  = 230 nm, major = 6.2 min, minor = 7.1 min.

Diethyl (S)-2-((1H-indol-3-yl)(4-(methylthio)phenyl)methyl)malonate (81l)

The title compound was prepared according to: GP5: The rac-81l was prepared in 1.3 mmol scale (0.30 g, 57% yield); GP8: 60% yield, 84:16 e.r., (S)-81l.

1 White solid, m.p. 166–167 °C. H NMR (400 MHz, CDCl3):  = 8.05 (brs, 1H), 7.53 (d, J = 7.9 Hz, 1H), 7.29 (d, J = 8.1 Hz, 3H), 7.21 – 7.07 (m, 4H), 7.03 (t, J = 7.5 Hz, 1H), 5.05 (d, J = 11.7 Hz, 1H), 4.26 (d, J = 11.7 Hz, 1H), 4.01 (qd, J = 7.2, 2.5 Hz, 4H), 2.40 (s, 3H), 1.05 (t, J = 7.1 Hz, 3H), 0.99 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz,

CDCl3):  = 168.1, 167.9, 138.6, 136.6, 136.3, 128.8 (2C), 126.9 (2C), 126.7, 122.4, 120.9, 119.7, 119.5, 117.0, 111.1, 61.6 (2C), 58.4, 42.5, 16.1, 14.0, 13.9 ppm. IR (ATR)  = 3901, 3529, 3407, 3128, 3075, 3026, 2928, 2693, 2491, 2323, 2206, 2178, 2147, 2047, 2010, 1942, 1744, 1597, 1547, 1491, 1456, 1421, 1369, 1334, 1270, 1246, 1185, 1149, 1106, 1038, 925, 859, 800, 742, 698 cm-1. MS (CI+, methane) m/z (%): 412.2 (28, [M+H]+), 411.2 (19), 295.0 (18), 253.0 (20), 252.0

+ + + (100). HR-MS (ESI ) m/z: calcd. for [M+Na] = [C23H25NNaO4S] : 434.1397.; found: 434.1397.

HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230, minor = 20.0, min

20 major = 21.9 min. OR: [] D = +15.8 (c 0.50, CHCl3, 84:16 e.r.).

Diethyl (S)-2-((1H-indol-3-yl)(o-tolyl)methyl)malonate (81m)

The title compound was prepared according to: GP5: The rac-81m was prepared in 1.3 mmol scale (0.15 g, 31% yield); GP8: 83% yield, 85:15 e.r., (S)-81m.

1 Pale yellow semisolid. H NMR (400 MHz, CDCl3):  = 8.04 (s, 1H), 7.62 (d, J = 8.2 Hz, 1H), 7.42 –7.35 (m, 1H), 7.27 (d, J = 7.2 Hz, 1H), 7.21 – 6.94 (m, 6H), 5.33 (d, J = 11.8 Hz, 1H), 4.35 (d, J = 11.8 Hz, 1H), 3.99 (q, J = 7.1 Hz, 2H), 3.90 (q, J = 7.1 Hz, 2H), 2.48 (s, 3H), 1.00 (t, J = 7.1 Hz, 3H), 0.91 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101 MHz,

CDCl3):  = 168.5, 168.0, 140.2, 136.4, 136.1, 130.8, 126.9, 126.6, 126.4, 126.1, 122.4, 122.2, 119.6, 119.5, 116.7, 111.1, 61.6, 61.5, 58.6, 38.2, 20.1, 13.9, 13.8 ppm. HPLC: Chiralpack IB, n-

20 heptane/iPrOH 90:10, 0.8 mL/min,  = 230, minor = 11.2 min, major = 12.8 min. OR: [] D = –52.6

(c 0.50, CHCl3, 85:15 e.r.).

99 EXPERIMENTAL PART

Diethyl (R)-2-(1-(1H-indol-3-yl)ethyl)malonate (81n)

The title compound was prepared according to GP8: 88% yield, 71:29 e.r.,

(S)-81n. The rac-81n was prepared according to GP7 using Cu(OTf)2 as a catalyst, without a ligand in 0.3 mmol scale (58 mg, 64%).

1 Colorless semisolid. H NMR (400 MHz, CDCl3):  = 8.09 (brs, 1H), 7.7 (d, J = 7.8 Hz, 1H), 7.33 (d, J = 8.0 Hz, 1H), 7.17 (ddd, J = 8.2, 7.0, 1.3 Hz, 1H), 7.11 (ddd, J = 8.1, 7.0, 1.2 Hz, 1H), 7.04 (d, J = 2.5 Hz, 1H), 4.23 (q, J = 7.1 Hz, 2H), 3.97 – 3.85 (m, 3H), 3.82 (d, J = 9.9 Hz, 1H), 1.47 (d, J = 6.9 Hz, 3H), 1.28 (t, J = 7.1 Hz, 3H), 0.93 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR (101

MHz, CDCl3):  = 168.9, 168.8, 136.3, 126.4, 122.1, 121.6, 119.4 (2C), 118.1, 111.3, 61.5, 61.3, 58.9, 31.8, 19.8, 14.2, 13.8 ppm. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230 nm,

20 [129a] major = 10.8 min, minor = 11.6 min. OR: [] D = +2.2 (c 0.50, CHCl3, 84:16 e.r.).

Diethyl (S)-2-((1-methyl-1H-indol-3-yl)(phenyl)methyl)malonate (81o)

The title compound was prepared according to: GP5: The rac-81o was prepared in 3.0 mmol scale (0.63 g, 55% yield); GP8: 87% yield, 86:14 e.r., (S)-81o.

1 White solid, m.p. 90–91 °C. H NMR (600 MHz, CDCl3):  = 7.56 (d, J = 8.0 Hz, 1H), 7.41 – 7.33 (m, 2H), 7.26 – 7.19 (m, 3H), 7.19 – 7.10 (m, 2H), 7.07 – 6.99 (m, 2H), 5.07 (d, J = 11.8 Hz, 1H), 4.29 (d, J = 11.8 Hz, 1H), 4.06 – 3.89 (m, 4H), 3.73 (s, 3H),

13 1 1.12 – 0.89 (m, 6H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 168.1, 167.9, 141.8, 137.0, 128.4 (2C), 128.2 (2C), 127.2, 126.8, 125.8, 121.9, 119.6, 119.1, 115.5, 109.2, 61.5, 61.5, 58.5, 43.0, 32.9, 13.9, 13.9 ppm. HPLC: Chiralpack AD-H, n-heptane/iPrOH 90:10, 1.0 mL/min,  = 230,

20 [131] major = 25.5 min, minor = 32.3 min. OR: [] D = +40.1 (c 1.00, CHCl3, 86:14 e.r.).

Diethyl (S)-2-((2-methyl-1H-indol-3-yl)(phenyl)methyl)malonate (81p)

The title compound was prepared according to GP8: 91% yield, 74:26 e.r.,

(S)-81p. The rac-81p was prepared according to GP7 using Cu(OTf)2 as a catalyst, without a ligand in 0.3 mmol scale (59 mg, 52%).

1 Pale yellow solid, m.p. 135–136 °C. H NMR (600 MHz, CDCl3):  = 7.77 (brs, 1H), 7.69 – 7.64 (m, 1H), 7.41 – 7.35 (m, 2H), 7.25 – 7.20 (m, 2H), 7.20 – 7.16 (m, 1H), 7.15 – 7.10 (m, 1H), 7.08 – 7.00 (m, 2H), 5.06 (d, J = 12.2 Hz, 1H), 4.70 (d, J = 12.2 Hz, 1H), 4.10 (q, J = 7.1

100 EXPERIMENTAL PART

Hz, 2H), 3.91 – 3.77 (m, 2H), 2.45 (s, 3H), 1.11 (t, J = 7.1 Hz, 3H), 0.78 (t, J = 7.1 Hz, 3H) ppm.

13 1 C{ H} NMR (151 MHz, CDCl3):  = 168.4, 168.2, 141.9, 135.3, 132.2, 128.5 (2C), 127.7 (2C), 127.4, 126.5, 120.9, 119.5, 119.3, 111.5, 110.4, 61.6, 61.3, 55.9, 42.6, 14.0, 13.6, 12.5 ppm. HPLC:

Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230 nm, major = 10.9 min, minor = 17.4 min.

20 [127d, 152] OR: [] D = −11.0 (c 0.50, CHCl3, 74:26 e.r.).

Diethyl (S)-2-(phenyl(2-phenyl-1H-indol-3-yl)methyl)malonate (81q)[153]

The title compound was prepared according to GP8: 52% yield, 57:43 e.r.,

(S)-81q. The rac-81q was prepared according to GP7 using Cu(OTf)2 as a catalyst, without a ligand in 0.3 mmol scale (14 mg, 10%).

1 Pale yellow solid, m.p. 110–111 °C. H NMR (400 MHz, CDCl3):  = 8.03 (brs, 1H), 7.87 (d, J = 7.5 Hz, 1H), 7.60 (d, J = 7.4 Hz, 2H), 7.55 – 7.37 (m, 3H), 7.37 – 7.20 (m, 4H), 7.20 – 7.06 (m, 4H), 5.26 (d, J = 12.1 Hz, 1H), 4.78 (d, J = 12.1 Hz, 1H), 4.04 (q, J = 7.1 Hz, 2H), 3.92 – 3.73 (m, 2H), 1.07 (t, J = 7.1 Hz, 3H), 0.73 (t, J = 7.1 Hz, 3H) ppm. 13C{1H} NMR

(101 MHz, CDCl3):  = 168.4, 168.1, 142.3, 136.2, 136.0, 133.0, 129.2 (2C), 128.9 (2C), 128.5 (2C), 128.4, 127.8 (2C), 127.5, 126.5, 122.1, 120.9, 120.0, 112.4, 111.1, 61.6, 61.3, 56.5, 42.6, 14.0, 13.5 ppm. HPLC: Chiralpack IA, n-heptane/iPrOH 85:15, 1.0 mL/min,  = 230 nm, major = 13.2 min,

20 minor = 32.9 min. OR: [] D = −3.6 (c 0.80, CHCl3, 57:43 e.r.).

Diethyl (S)-2-((6-chloro-1H-indol-3-yl)(phenyl)methyl)malonate (81r)

The title compound was prepared according to GP8: 95% yield, 86:14 e.r.,

(S)-81r. The rac-81r was prepared according to GP7 using Cu(OTf)2 as a catalyst, without a ligand in 0.3 mmol scale (81 mg, 68%).

1 White solid, m.p. 207–208 °C. H NMR (600 MHz, CDCl3):  = 8.05 (brs, 1H), 7.43 (d, J = 8.5 Hz, 1H), 7.33 (d, J = 7.0 Hz, 2H), 7.28 (d, J = 1.8 Hz, 1H), 7.24 (t, J = 7.6 Hz, 2H), 7.18 – 7.09 (m, 2H), 7.00 (dd, J = 8.5, 1.8 Hz, 1H), 5.03 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 11.8 Hz, 1H), 4.00 (dq, J = 19.7, 7.1 Hz, 4H), 1.11 – 0.81 (m, 6H) ppm. 13C{1H} NMR

(151 MHz, CDCl3):  = 168.1, 167.8, 141.2, 136.6, 128.6 (2C), 128.4, 128.2 (2C), 127.0, 125.4, 121.6, 120.5, 120.4, 117.4, 111.1, 61.7, 61.6, 58.4, 42.8, 13.9, 13.9 ppm. HPLC: Chiralpack IB, n-

20 heptane/iPrOH 90:10, 0.8 mL/min,  = 230 nm, minor = 12.5 min, major = 14.1 min. OR: [] D =

[129a] +35.0 (c 1.00, CHCl3, 86:14 e.r.).

101 EXPERIMENTAL PART

Diethyl (S)-2-((5-bromo-1H-indol-3-yl)(phenyl)methyl)malonate (81s)

The title compound was prepared according to: GP5: The rac-81s was prepared in 3.8 mmol scale (1.50 g, 89% yield); GP8: 95% yield, 87:13 e.r., (S)-81s.

1 Off-white solid, m.p. 190–191 °C. H NMR (600 MHz, CDCl3):  = 8.09 (brs, 1H), 7.68 (d, J = 1.9 Hz, 1H), 7.35 (dd, J = 8.2, 1.4 Hz, 2H), 7.26 – 7.23 (m, 2H), 7.21 (dd, J = 8.6, 1.9 Hz, 1H), 7.19 – 7.07 (m, 3H), 5.00 (d, J = 11.7 Hz, 1H), 4.25 (d, J = 11.8

13 1 Hz, 1H), 4.08 – 3.89 (m, 4H), 1.11 – 0.88 (m, 6H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 168.0, 167.7, 141.1, 134.9, 128.6 (2C), 128.5, 128.2 (2C), 127.1, 125.4, 122.3, 122.0, 116.9, 113.1, 112.6, 61.7, 61.6, 58.5, 42.7, 13.9, 13.9 ppm. HPLC: Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,

20 [150]  = 230, minor = 13.1 min, major = 15.7 min. OR: [] D = –11.7 (c 1.00, CHCl3, 87:13 e.r.).

Diethyl (S)-2-((5-methyl-1H-indol-3-yl)(phenyl)methyl)malonate (81t)

The title compound was prepared according to GP8: 48% yield, 71:29 e.r., (S)-81t.

1 White solid, m.p. 174–175 °C. H NMR (600 MHz, CDCl3):  = 7.96 (s, 1H), 7.42 – 7.33 (m, 3H), 7.25 – 7.21 (m, 2H), 7.17 (d, J = 8.2 Hz, 1H), 7.16 – 7.11 (m, 2H), 6.95 (dd, J = 8.3, 1.6 Hz, 1H), 5.05 (d, J = 11.8 Hz, 1H), 4.28 (d, J = 11.8 Hz, 1H), 3.99 (dqd, J = 10.0, 7.1, 1.4 Hz, 4H), 2.39 (s, 3H), 1.00 (dt, J = 9.6, 7.1 Hz, 6H).

13 1 ppm. C{ H} NMR (151 MHz, CDCl3):  = 168.1, 168.0, 141.6, 134.6, 128.8, 128.4 (d), 128.3 (d), 127.0, 126.8, 124.0, 121.1, 119.1, 116.6, 110.7, 61.6, 61.5, 58.6, 42.9, 21.7, 13.9, 13.9. ppm. HPLC:

Chiralpack IB, n-heptane/iPrOH 90:10, 0.8 mL/min,  = 230, minor = 11.4 min, major = 13.6 min.

20 [150] OR: [] D = +12.0 (c 0.50, CHCl3, 71:29 e.r.).

Dibenzyl (S)-2-((1H-indol-3-yl)(phenyl)methyl)malonate (81v)

The title compound was prepared according to GP8: 95% yield, 91:9 e.r., (S)-

81v. The rac-81v was prepared according to GP7 using Cu(OTf)2 as a catalyst, without a ligand in 0.3 mmol scale (125 mg, 85%).

1 White solid, m.p. 137–138 °C. H NMR (400 MHz, CDCl3):  = 7.88 (brs, 1H), 7.51 (d, J = 8.0 Hz, 1H), 7.32 (d, J = 7.5 Hz, 2H), 7.28 – 7.10 (m, 11H), 7.06 – 6.99 (m, 4H), 6.94 (d, J = 7.5 Hz, 2H), 5.12 (d, J = 11.8 Hz, 1H), 4.97 – 4.91 (m, 4H), 4.41 (d, J = 11.8 Hz, 1H) ppm.13C{1H}

102 EXPERIMENTAL PART

NMR (101 MHz, CDCl3):  = 167.8, 167.7, 141.3, 136.3, 135.3, 135.2, 128.6 (4C), 128.4 (2C), 128.3, 128.3 (2C), 128.2 (2C), 128.2, 128.1 (2C), 126.9, 126.7, 122.4, 121.1, 119.7, 119.5, 116.8, 111.2, 67.3, 67.3, 58.4, 43.1 ppm. HPLC: Chiralpack IB, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 230,

20 [150] minor = 11.6 min, major = 18.0 min. OR: [] D = +44.8 (c 1.00, CHCl3, 91:9 e.r.).

3,3'-(phenylmethylene)bis(1H-indole) (84a)

The title compound was prepared according to GP6: obtained as a pink foam in 53% yield.

1 H NMR (600 MHz, CDCl3):  = 7.79 (s, 2H), 7.41 (dd, J = 8.0, 1.1 Hz, 2H), 7.39 – 7.32 (m, 4H), 7.30 (dd, J = 8.3, 6.8 Hz, 2H), 7.25 – 7.22 (m, 1H), 7.19 (ddd, J = 8.2, 7.0, 1.1 Hz, 2H), 7.03 (ddd, J = 8.0, 7.0, 1.0 Hz, 2H), 6.62 (d, J =

13 1 1.4 Hz, 2H), 5.90 (s, 1H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 144.1, 136.8 (2C), 128.8 (2C), 128.3 (2C), 127.2 (2C), 126.3, 123.7 (2C), 122.0 (2C), 120.1 (2C), 119.8 (2C), 119.3 (2C), 111.2 (2C), 40.3 ppm. HPLC: Chiralpack IA, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4,  = 24.5 min.

3,3'-((2-chlorophenyl)methylene)bis(1H-indole) (84b)

The title compound was prepared according to GP6 and obtained as a pink semisolid in 41% yield.

1 H NMR (600 MHz, CDCl3):  = 7.89 (s, 2H), 7.45 – 7.39 (m, 3H), 7.35 (dd, J = 8.2, 0.9 Hz, 2H), 7.22 (dd, J = 7.7, 1.8 Hz, 1H), 7.17 (dtd, J = 13.7, 7.4, 1.5 Hz, 3H), 7.12 – 7.07 (m, 1H), 7.03 (ddd, J = 7.9, 7.0, 1.0 Hz, 2H), 6.60 (d, J = 2.0 Hz,

13 1 2H), 6.35 (s, 1H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 141.4, 136.8 (2C), 134.1, 130.4, 129.6, 127.6, 127.1 (2C), 126.8, 123.9 (2C), 122.1 (2C), 120.0 (2C), 119.4 (2C), 118.4 (2C), 111.2 (2C), 36.7 ppm.

103 EXPERIMENTAL PART

3,3'-((4-chlorophenyl)methylene)bis(1H-indole) (84c)

The title compound was prepared according to GP6 and obtained as a pink semisolid in 48% yield.

1 H NMR (400 MHz, CDCl3):  =7.86 (s, 2H), 7.35 (t, J = 8.1 Hz, 4H), 7.28 – 7.20 (m, 4H), 7.17 (ddd, J = 8.2, 7.0, 1.2 Hz, 2H), 7.01 (td, J = 7.4, 7.0, 1.0 Hz, 2H), 6.60 (dd, J = 2.2, 1.1 Hz, 2H), 5.85 (s, 1H) ppm. 13C{1H} NMR (101 MHz,

CDCl3):  = 142.7, 136.8 (2C), 131.9, 130.2 (2C), 128.5 (2C), 127.0 (2C), 123.7 (2C), 122.2 (2C), 119.9 (2C), 119.5 (2C), 119.3 (2C), 111.2 (2C), 39.7 ppm.

3,3'-((3-bromophenyl)methylene)bis(1H-indole) (84d)

The title compound was prepared according to GP6 and obtained as a pink semisolid in 45% yield.

1 H NMR (400 MHz, CDCl3):  = 7.89 (s, 2H), 7.51 (t, J = 1.9 Hz, 1H), 7.37 (dd, J = 10.8, 8.0 Hz, 5H), 7.31 – 7.26 (m, 1H), 7.23 – 7.10 (m, 3H), 7.07 – 6.98 (m,

13 1 2H), 6.67 – 6.59 (m, 2H), 5.86 (s, 1H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 146.6, 136.8 (2C), 131.8, 129.9, 129.5, 127.5, 126.9 (2C), 123.8 (2C), 122.5, 122.2 (2C), 119.9 (2C), 119.5 (2C), 119.1 (2C), 111.3 (2C), 40.1 ppm.

3,3'-(p-tolylmethylene)bis(1H-indole) (84f)

The title compound was prepared according to GP6 and obtained as a pink semisolid in 45% yield.

1 H NMR (600 MHz, CDCl3):  = 7.87 (s, 2H), 7.44 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.9 Hz, 2H), 7.22 – 7.18 (m, 2H), 7.12 (d, J = 7.8 Hz, 2H), 7.04 (td, J = 7.5, 7.0, 1.0 Hz, 2H), 6.64 (dd, J = 2.5, 1.1 Hz, 2H), 5.89 (s,

13 1 1H), 2.37 (s, 3H) ppm. C{ H} NMR (151 MHz, CDCl3):  = 141.1, 136.8 (2C), 135.6, 129.0 (2C), 128.7 (2C), 127.2 (2C), 123.7 (2C), 121.9 (2C), 120.0 (2C), 119.9 (2C), 119.3 (2C), 111.2 (2C), 39.9, 21.2.

104 EXPERIMENTAL PART

3,3'-(naphthalen-1-ylmethylene)bis(1H-indole) (84g)

The title compound was prepared according to GP6 and obtained as a white solid in 57% yield.

1 H NMR (400 MHz, CDCl3):  = 9.98 (s, 2H), 8.31 (d, J = 8.3 Hz, 1H), 7.92 (dd, J = 7.8, 1.7 Hz, 1H), 7.78 (dd, J = 7.5, 1.9 Hz, 1H), 7.52 – 7.27 (m, 8H), 7.12 – 7.05 (m, 2H), 6.90 (t, J = 7.5 Hz, 2H), 6.75 (s, 1H), 6.74 (d, J = 2.4 Hz, 2H)

13 1 ppm. C{ H} NMR (101 MHz, CDCl3):  = 140.5, 137.2 (2C), 134.2, 132.0, 128.6, 127.2 (2C), 126.7, 125.8, 125.7, 125.2, 125.2, 124.3 (2C), 124.2, 121.2 (2C), 119.2 (2C), 118.6 (2C), 118.5 (2C), 111.3 (2C), 35.7 ppm.

3,3'-(thien-2-ylmethylene)bis(1H-indole) (84h)

The title compound was prepared according to GP6 and obtained as a pink semisolid in 58% yield.

1 H NMR (400 MHz, CDCl3):  = 7.90 (s, 2H), 7.47 (d, J = 8.0 Hz, 2H), 7.35 (d, J = 8.1 Hz, 2H), 7.22 – 7.12 (m, 3H), 7.04 (t, J = 7.5 Hz, 2H), 6.92 (p, J = 3.2, 2.8 Hz, 2H), 6.81 (d, J = 2.4 Hz, 2H), 6.17 (s, 1H) ppm. 13C{1H} NMR (101

MHz, CDCl3):  = 148.8, 136.7 (2C), 126.9 (2C), 126.5, 125.2, 123.7, 123.3 (2C), 122.1 (2C), 119.9 (2C), 119.8 (2C), 119.5 (2C), 111.3 (2C), 35.4 ppm.

3-((1H-indol-3-yl)(phenyl)methyl)-5-bromo-1H-indole (86b)

The title compound was prepared according to GP6 and obtained as a pink semisolid in a mixture with 87b and 84a (86b:87b:84a = 1.0:0.2:0.4, 86b with 50:50 e.r.). The three compounds could be partly separated by a second FCC (pentane/EtOAc = 4:1).

1 H NMR (600 MHz, CDCl3):  = 7.98 – 7.83 (m, 3.1H, overlapping), 7.53 (d, J = 1.8 Hz, 1H), 7.48 (d, J = 1.8 Hz, 0.4H), 7.40 (dd, J = 8.0, 1.0 Hz, 1H), 7.37 – 7.34 (m, 3.3H, overlapping), 7.34 – 7.27 (m, 5.4H, overlapping), 7.25 – 7.14 (m, 5.8H, overlapping), 7.01 (td, J = 7.5, 7.0, 0.9 Hz, 1.8H, overlapping), 6.63 (ddd, J = 12.4, 2.4, 1.0 Hz, 3H, overlapping), 5.89 (s, 0.4H,

13 1 84a), 5.82 (s, 1H, 86b), 5.75 (s, 0.2H, 87b) ppm. C{ H} NMR (151 MHz, CDCl3):  = 144.1, 143.6*, 143.2, 136.8*, 136.8, 135.4, 135.4*, 128.9, 128.8, 128.7*, 128.7, 128.6, 128.5*, 128.3, 127.2, 127.0, 126.7*, 126.5, 126.3, 125.1, 125.0, 124.9*, 124.9, 123.7, 123.7, 122.5, 122.4, 122.2, 122.1,

105 EXPERIMENTAL PART

120.1, 120.0, 119.8, 119.6, 119.4, 119.4, 119.2, 112.8, 112.7, 112.6*, 111.2*, 111.2, 40.3, 40.2*, 40.0 ppm. MS (EI+, 70 eV) (86b): m/z (%): 403.4 (19), 402.4 (81), 401.4 (39), 400.4 (90), 399.5 (19), 325.3 (16), 323.4 (24), 319.4 (16), 244.3 (13), 243.3 (57), 242.3 (13), 205.3 (12), 204.3 (47), 203.3 (15), 177.3 (11), 176.2 (21), 117.2 (41), 79.2 (10), 78.2 (46), 77.1 (100), 51.2 (30). HPLC:

Chiralpack IA, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4, 87b = 10.9 min, 86b = 14.7 min,

86b = 16.2 min, 84a = 24.5 min.

3-((1H-indol-3-yl)(phenyl)methyl)-6-chloro-1H-indole (86c)

The title compound was prepared according to GP6 and obtained after FCC (pentane/DCM = 2:1) as a pink semisolid in a mixture with 87c and 84a (86c:87c:84a = 1.0:0.1:0.1, 86c with 50:50 e.r.).

1 H NMR (400 MHz, CDCl3):  = 7.92 (s, 1.2H, overlapping), 7.89 (s, 1.2H, overlapping), 7.37 (dd, J = 8.3, 6.4 Hz, 2H), 7.34 – 7.32 (m, 2.5H, overlapping), 7.30 – 7.26 (m, 3H), 7.26 (d, J = 0.7 Hz, 1H), 7.25 – 7.18 (m, 2H), 7.21 – 7.13 (m, 1.2H, overlapping), 7.03 – 6.98 (m, 1.4H, overlapping), 6.96 (dd, J = 8.5, 1.8 Hz, 1.2H, overlapping), 6.68 – 6.62 (m, 2.2H, overlapping), 5.89 (s, 0.1 H, 84a). 5.85 (s, 1H, 86c ), 5.80 (s, 0.1 H, 87c) ppm.

13 1 C{ H} NMR (101 MHz, CDCl3):  = 143.8, 137.2, 136.8, 128.8 (2C), 128.4 (2C), 128.0, 127.1, 126.4, 125.8, 124.3, 123.6, 122.2, 121.0, 120.2, 120.1, 120.0, 119.6, 119.5, 111.2, 111.1, 40.3 ppm. MS (CI+, methane): m/z (%): 356.4 (4, [M]+), 284.4 (17), 258.3 (35), 257.3 (20), 256.3 (100), 250.4 (13), 240.3 (11), 223.4 (14), 222.4 (76), 207.3 (12), 206.3 (58), 134.2 (14), 118.2 (15),

105.2 (25). HPLC: Chiralpack IA, n-heptane/iPrOH 80:20, 0.8 mL/min,  = 254.4 nm, 86a = 24.5 min, 86c = 26.0 min, 87c = 28.3 min, 86c = 33.7 min.

3-((1H-indol-3-yl)(phenyl)methyl)-7-bromo-1H-indole (86d)

The title compound was prepared according to GP6 and obtained after FCC (pentane/DCM = 2:1) as a pink semisolid in a mixture with 87d and 84a (the ratio between the three compounds was not determined). After a second FCC, 86d was isolated in 22% yield with 50:50 e.r.

1 H NMR (400 MHz, CDCl3):  = 8.06 (s, 1H), 7.89 (s, 1H), 7.45 – 7.10 (m, 10H), 7.04 – 6.96 (m, 1H), 6.86 (t, J = 7.8 Hz, 1H), 6.70 (d, J = 2.3 Hz, 1H), 6.61 (d, J = 2.3 Hz, 1H),

13 1 5.85 (s, 1H) ppm. C{ H} NMR (101 MHz, CDCl3):  = 143.7, 136.8, 135.5, 128.8 (2C), 128.4 (2C), 128.4, 127.1, 126.4, 124.4, 124.3, 123.7, 122.2, 121.1, 120.6, 120.0, 119.5, 119.5, 119.5, 119.3,

106 EXPERIMENTAL PART

119.3, 111.2, 104.7, 40.5 ppm. HPLC: AD-H, n-heptane/EtOH 70:30, 0.6 mL/min,  = 230 nm,

 = 13.4 min,  = 15.5 min.

(R)-3-(2-nitro-1-phenylethyl)-1H-indole (91a)[154]

The product 91a was prepared from indole (66a) and -nitrostyrene (90a),

following GP7 with a catalyst prepared from Cu(OTf)2 and L5 and was isolated after FCC on silica gel (pentane/DCM = 1:1) as a pale yellow semisolid (48.4 mg, 61% yield, 54:46 e.r.).

1 H NMR (400 MHz, CDCl3):  = 8.08 (s, 1H), 7.45 (d, J = 7.9 Hz, 1H), 7.40 – 7.23 (m, 6H), 7.20 (ddd, J = 8.1, 7.1, 1.2 Hz, 1H), 7.08 (ddd, J = 8.1, 7.1, 1.0 Hz, 1H), 7.03 (d, J = 1.7 Hz, 1H), 5.20 (t, J = 8.0 Hz, 1H), 5.07 (dd, J = 12.5, 7.6 Hz, 1H), 4.95 (dd, J = 12.5, 8.4 Hz, 1H) ppm. HPLC: Chiralpack AD-H, n- heptane/iPrOH 90:10, 1.0 mL/min,  = 230, major = 28.0 min, minor = 31.4 min.

107

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115

ABBREVIATIONS

6. ABBREVIATIONS

Ac acetyl

Ar aryl

Bn benzyl

BOX bis(oxazoline) brs broad singlet

Bu butyl

CDC cross-dehydrogenative coupling

CI MS chemical ionization mass spectrometry

CSP chiral stationary phase d doublet

DCM dichloromethane dd doublet of doublet ddt doublet of doublet of triplet

DDQ 2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DIMPEG dimethyl polyethylene glycol

DMSO dimethyl sulfoxide d.r. diastereomeric ratio ee enantiomeric excess

EI MS electron ionization mass spectrometry

Et ethyl e.r. enantiomeric ratio

EWG electron-withdrawing group equiv equivalent

FCC flash column chromatography h hour(s)

117 ABBREVIATIONS

HFIP hexafluoroisopropanol

HPLC high performance liquid chromatography

HRMS high-resolution mass spectrometry

HSBM high speed ball milling iPr isopropyl

IUPAC International Union of Pure and Applied Chemistry

Lg leaving group m meta m multiplet

Me methyl min minute(s)

MM mixer mill mmol milimol(s) mp melting point

MS molecular sieves n.d. not determind

NMR nuclear magnetic resonance

Np naphthyl n.r. no reaction o ortho o-QM ortho-quinone methides

OR optical rotation p para

PFP pentafluorophenol

Ph phenyl

PM planetary mill

Pr propyl

118 ABBREVIATIONS

Py pyridine q quartet rac racemic r.t. room temperature s singlet t triplet

T temperature tBu tertbutyl

TBHP tertbutyl hydroperoxide tdd triplet of doublet of doublet

TFA trifluoroacetic acid

TFE trifluoroethanol

THF tetrahydrofuran

119

CURRICULUM VITAE

Personal information

Name Plamena Krasimirova Staleva

Date of birth 07.11.1987

Place of birth Sliven

Nationality Bulgarian

Education

Since 03/2014 Doctoral studies in the group of Prof. Dr. C. Bolm, Institute of Organic Chemistry, RWTH Aachen University, Germany

10/2010 – 07/2012 Master degree in Chemistry, Faculty of Chemistry, Sofia University

Master program: Modern methods for synthesis and analysis of organic

compounds

Master thesis in the group of Prof. V. Dimitrov Institute of Organic Chemistry with Centre of Phytochemistry, Bulgarian Academy of Science.

„Synthesis of functionalized chiral aminoalcohols - structure, configuration and application “

10/2006 – 07/2010 Bachelor degree in Chemistry, Faculty of Chemistry, Sofia University

Publications

P. Staleva, J. G. Hernández, C. Bolm, Chem. Eur. J. 2019, 25, 9202.

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ACKNOWLEDGMENTS

Firstly, I would like to express my deep gratitude to Prof. Dr. Carsten Bolm for giving me the opportunity to join his research group and pursue with my doctoral studies. His tremendous expertise, commitment and supportive nature are constantly gathering around him talented and thoughtful young people – a real team I was honored to be part of.

I wish to acknowledge Prof. Dr. Markus Albrecht for his willingness to be my second referee. Furthermore, I would like to thank Prof. Dr. Vladimir Dimitrov and Assoc. Prof. Dr. Kalina Kostova for their profound support in the early stage of my scientific career.

Ingrid Voss, Daniela Gorissen, Ina Groß and especially Dr. Ingo Schiffers deserve a big thank you for their help in all kinds of administrative affairs. Thanks to Susanne Grünebaum and Pierre Winandy for their assistance in the syntheses and the organisation of supplies. Additionally, I appreciate all coworkers involved in analytical measurements and practical affairs in the IOC. I would like to thank Marcus Frings for his assistance and dedication during our collaborations.

I am very grateful that I had the opportunity to spend my time in the last years in lab 5.07 with the best labmates possible. Special thanks go to Dr. Hannah Baars, Timon Ortloff and Arno Claßen for their warm welcoming and guidance in the beginning of my doctoral studies. Sharing the lab with Dr. Anne-Katrin Bachon and Maximilian Bremerich was both educational and fun. I would like to thank them for their unlimited willingness to share all kind of wisdom and small facts with me, their understanding, the countless discussions, and foremost for their friendship.

I am fortunate to have good and smart friends, which were by my side in process of writing this thesis and assisting me with their expertise and helpful advises. Special thanks go to Dr. Anne- Katrin Bachon, Dr. Fabrizio Vetica, Dr. Saumya Dabral, Dr. José G. Hernández, Hannah Fergen, Ulla Weißbach and Stefan Wiezorek for proofreading parts of the thesis.

To AK Bolm – all current and former members and my friends and colleagues from the other research groups in IOC I would like to say a big thank you for the stimulating and nice work atmosphere. I do not believe there is a better group of people I could have encountered. Being away from family and friends and living in a foreign country is a challenge, but also gives the chance for building strong and special connections with the people you share that experience with. Thank you all for making Aachen my home, celebrating with me my successes and supporting me in my failures, making my PhD a unique experience. Special thanks to Dr. Laura Buglioni, Dr. Saumya Dabral, Dr. Hannah Baars, Dr. Philip Lamers, Dr. José G. Hernández, Dr. Karen

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J. Ardila-Fierro, Stefan Wiezorek, Dr. Anne-Katrin Bachon, Dr. Fabrizio Vetica, Dr. Laure Konnert, Maximilian Bremerich, Hannah Fergen, Felix Krauskopf, Marc Calin and Francesco Puccetti.

I would like to thank all my friends in Bulgaria, especially Dr. Mariana Kamenova-Nacheva, for their constant support and encouragement, for always welcoming me warmly when I went back home and for simply staying my friends, despite my absence.

Finally, I would like to express my endless gratitude to my family. I wish to thank my grandfather Georgi for the care and for teaching me the importance of achievement and excellence. Deepest thanks to my mother Reni for being always there and wishing the best for me. My sister Gloria and Vaseto I thank for never losing faith in me and for their limitless support, without which this thesis would not be possible.

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