Synthesis, mechanism and applications of azido functionalized and α-imino carbene derived Tröger Bases

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Thesis

Reference

Synthesis, mechanism and applications of azido functionalized and α-imino carbene derived Tröger Bases

BOSMANI, Alessandro

Abstract

Tröger Bases (TB) are chiral bicyclic tertiary amines, which have drawn the interest of the synthetic organic community but only to a limited range of applications. In fact, the difficult functionalization of the main core of the molecule and the configurational lability of TB in acidic conditions have been two limiting factors. The aim of this PhD was to develop synthetic methodologies to overcome these two drawbacks. Therefore, an efficient protocol of C-H functionalization at the benzylic positions was developed to give access to versatile mono- and bis-azido TB derivatives. This allowed the access to a new class of functional anion binding catalysts. Additionally, while exploring the reactivity of N-sulfonyl-1,2,3-triazoles with TB in the aim of synthetizing configurationally stable derivatives via N-ylide chemistry, a route to novel polycyclic indoline-benzodiazepine scaffold was discovered. Through an original cascade of [1,2]-Stevens rearrangement, Friedel-Crafts, Grob fragmentation and aminal formation reactions, polycyclic 5,6,7-membered heterocycles were obtained in good yields and complete [...]

BOSMANI, Alessandro. Synthesis, mechanism and applications of azido functionalized and α-imino carbene derived Tröger Bases. Thèse de doctorat : Univ. Genève, 2019, no.

Sc. 5376

DOI : 10.13097/archive-ouverte/unige:122994 URN : urn:nbn:ch:unige-1229947

Available at:

http://archive-ouverte.unige.ch/unige:122994

Disclaimer: layout of this document may differ from the published version.

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UNIVERSITÉ DE GENÈVE FACULTÉ DES SCIENCES

Section de Chimie et de Biochimie

Département de Chimie Organique Professeur Jérôme Lacour

Synthesis, Mechanism and Applications of Azido Functionalized and α-Imino Carbene Derived

Tröger Bases

THÈSE

Présentée à la Faculté des sciences de l’Université de Genève pour obtenir le grade de Docteur ès sciences, mention chimie

par

Alessandro BOSMANI

de

Bardonnex (Genève)

Thèse N° 5376

GENÈVE

Centre d’impression de l’Université de Genève, ReproMail, Unimail 2019

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I can do this all day.

Cpt. Steve Rogers

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Résumé

Depuis de nombreuses années, la bis-amine tertiaire bicyclique [3.3.1] appelée base de Tröger^[1] attire l’intérêt des chimistes organiques de synthèse pour deux raisons principales:

la géométrie en forme de V adoptée par les sous-unités aromatiques et la chiralité induite par les deux atomes d’azote stéréogènes et stables configurationellement. A l’aide de ce squelette moléculaire, de nombreuses applications ont été développées, principalement dans les domaines de la chimie supramoléculaire et de la science des matériaux.

Cependant, rares sont les applications en tant que ligand pour la chimie organométallique ou l’organocatalyse. L’instabilité configurationnelle en milieu acide et les difficultés à fonctionnaliser le noyau diazocine de manière énantiospécifique peuvent être considérés comme étant à l’origine de ce manque d’applications. Il fallait donc changer cette situation et notre laboratoire a décidé de relever le défi. Par conséquent, dans le cadre de ce travail de thèse, des méthodologies synthétiques ont été développées pour accéder à de nouvelles bases de Tröger fonctionnalisées par des groupes azotures introduits au niveau du noyau central (Schéma 1). De plus, la chimie des carbènes réactifs a été utilisée pour transformer le squelette [3.3.1] de la molécule à un nouveau motif polycyclique de type indoline- benzodiazépine(Schéma 2).

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En effet, l'azidation Csp3-H enantio et régiosélective de la base de Tröger a pu être obtenue avec des rendements élevés et une diastéréosélectivité parfaite (Schéma 1). De plus, la mono- ou la bis-azidation peuvent être réalisés en modifiant les conditions réactionnelles. Ce processus d'oxydation a été réalisé en combinant l’iodosobenzene (PhIO) et l’azidotrimethylsilane (TMSN3) et procède par génération in situ d'un ion iminium en tête de pont. Cette espèce s'est avéré être un intermédiaire de la réaction comme ont pu le montrer des études computationnelles et expérimentales. En utilisant le produit azoturé comme substrat et un acide de Lewis pour l'activation de ce dernier, il a été possible de générer des espèces iminium qui ont été ensuite piégées par des indoles nucléophiles. Ceci a conduit à la génération de nouveaux analogues hétérocycliques de la base de Tröger.

Ensuite, un protocole de cycloaddition 1,3-dipolaire catalysée au cuivre a été appliqué aux produits azoturés pour donner des dérivés de base de Tröger substitués par un ou deux triazoles. Ces composés présentent une affinité pour les anions chlorures et leur application en tant que catalyseurs «anion-binding» a été étudiée.

Schéma 2 Réactivité de la base de Tröger avec les N-sulfonyl-1,2,3-triazoles et transformations du noyau polycyclique.

D'autre part, de nouvelles molécules polycycliques à squelette indoline-benzodiazépines ont été obtenues par la réaction intermoléculaire de la base de Tröger avec les N-sulfonyl-1,2,3- triazoles comme précurseurs réactifs de diazo α-aminés (Schéma 2). Le processus s’effectue

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en une cascade de réactions, incluant un réarrangement [1,2]-Stevens, une Friedel-Crafts, une fragmentation de Grob et une formation de fonction aminal. Cette méthodologie a fourni les composés polycycliques avec de bons rendements et une diastéréosélectivité parfaite. Des études mécanistiques supplémentaires ont mis en évidence l’importance d’intermédiaires de type ylure liés au métal et des composés ethano-«imino» Tröger dérivés de la base de Tröger.

Il a été montré que ces derniers peuvent intervenir dans la racémisation survenue pendant la transformation. Des réactions de dérivatisation du noyau polycyclique ont été également développées. L’ouverture de la fonction aminal conduit à la formation de nouvelles diamines chirales et à des espèces benzodiazepino-indolium fluorescentes sous conditions d’oxydation.

Le noyau polycyclique peut aussi être agrandi en cycle triazonane par l’addition d’une unité de α-imino-carbène supplémentaire.

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Remerciements

Les résultats rapportés dans ce manuscrit ont été obtenus dans le cadre d’un travail de thèse réalisé au sein du laboratoire du Prof. Jérôme Lacour, dans le département de chimie organique de l’Université de Genève, du 1^er octobre 2014 au 28 juin 2019.

Je tiens tout d’abord à remercier le Prof. Jérôme Lacour pour m’avoir accepté dans son groupe de recherche et m’avoir donné l’opportunité de réaliser ce travail de doctorat. Je le remercie énormément pour tous les conseils, ses enseignements, sa confiance et l’autonomie accordés durant toute la thèse.

J’aimerais aussi remercier le Prof. Jérôme Waser (EPFL, Suisse) et le Prof. Nicolas Winssinger (Université de Genève, Suisse) pour avoir accepté de juger ce travail de thèse. Je remercie également le Dr. Nidal Saleh et le Dr. Alexandre Homberg pour les corrections et suggestions constructives apportées lors de la rédaction de la thèse.

Un grand merci aussi au Dr. Amalia Poblador-Bahamonde et au Dr. Fabien Cougnon avec qui j’ai collaboré. Je voudrais remercier les équipes de RMN (Dr. Damien Jeannerat et Marion Pupier), de spectrométrie de masse (Dr. Sopie Michalet, Eliane Sandmeier, Harry Théraulaz), et de cristallographie (Dr. Céline Besnard, Dr. Laure Guenée).

Je remercie très chaleureusement tous les anciens et actuels membres du groupe : Alejandro, Andjela, Antoine, Daniele, Elodie, Federica, Florian, Francesco, Géraldine, Hombi, Irene, Johann, Jojo, Júlia, Julie, Kefeng, Kévin, Kota, Léo, Mahesh, Manon, Margaux, Maya, Michèle, Mireille, Nidal, Olivier, Paupel, Pavol, Rebecca, Romain, Sandip, Sébastien, Shinya, Simon, Sté, Sumit, Zhuang.

Finalement, je tiens à remercier ma famille et Maeva qui ont toujours été à mes côtés durant toutes ces années.

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Abbreviations

Ac: acetate s: singlet

Ar: aryl t: triplet

Bn: benzyl Tf: triflate

Boc: tert-butyloxycarbonyl TFA: trifluoroacetate

C: concentration THF: tetrahydrofuran

Cat.: catalyst TLC: thin layer chromatography

conv.: conversion TMS: trimethyl silane

CSP: chiral stationary phase TPA: triphenlyacetate

CuAAC: Copper-catalyzed azide alkyne cycloaddition Trityl: triphenylmethyl

d: doublet TB: Tröger Base

dd: doublet of doublet

DFT: density functional theory

dr: diastereomeric ratio

Symbols

ee: enantiomeric excess

es: enantiospecificity δ: chemical shift

equiv.: equivalent J: coupling constant

ESI: electrospray ionization T: temperature

Et: ethyl

HPLC: high pressure liquid chromatography

IR: infrared

Units

m: multiplet

Me: methyl °C: degree Celsius

M.p.: melting point g: gram

MS: mass spectrometry mol: mole

Ms: mesyl M: molarity (mol/L)

naphth: naphtyl min: minute

Ns: p-nosyl h: hour

Oct: octanoate ppm: part per million

Ph: phenyl Hz: Hertz

Phth: phthalimide Piv: pivalate q: quartet

Rf: retardation factor

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1. Introduction

Tertiary amines bearing three different substituents are chiral motifs, usually isolated in racemic form due to the configurational instability of the N atoms. The barrier for the nitrogen inversion has been calculated to be typically in the range of 6-7 kcal/mol. A few exceptions to the rule can be observed, especially for mono or polycyclic derivatives which presents configurationally stable stereogenic nitrogen atoms. One particularly important class of such compounds is that of Tröger Bases (TB)^[1] which are [3.3.1] bicyclic tertiary amines characterized by a rigid molecular framework that forbids the pyramidal inversion of the nitrogen atoms.

This class of chiral compounds, that is readily accessible in one-step from simple functionalized materials, has drawn the interest of the synthetic organic community but surprisingly, only a limited range of applications have been developed. In fact, the difficult functionalization of the main core of the molecule and the configurational lability of TBs in acidic conditions have been two limiting factors. In the group of Prof. Lacour, synthetic methodologies have been developed to overcome these two drawbacks. In the context of this thesis, an efficient protocol of C-H functionalizations at the benzylic positions was developed to give access to versatile mono- and bis-azido TB derivatives. This allowed the development of a new class of functional anion binding catalysts. Additionally, while exploring the reactivity of N-sulfonyl- 1,2,3-triazoles with TB in the aim of synthetizing configurationally stable derivatives via N- ylide chemistry, a route to novel polycyclic indoline-benzodiazepine scaffold was discovered.

Through an original cascade of [1,2]-Stevens rearrangement, Friedel-Crafts, Grob fragmentation and aminal formation reactions, polycyclic 5,6,7-membered heterocycles are obtained in good yields and complete diastereoselectivity.

In this chapter, the history and properties of TB will be presented, as well as examples of applications in different fields of chemistry. The specific limitations of TB in the field of catalysis will be discussed in connection with the two drawbacks mentioned previously.

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Introduction

1.1 Tröger Base: History and Properties 1.1.1 Structural Overview

Tröger Base (TB)^[1] is a tertiary bicyclic amine first synthetized by Julius Tröger in 1887 by the treatment of methylal with p-toluidine in aqueous HCl.^[2] However, the correct structure was only assigned in 1935 by Spielman^[3] (Figure 1.1) and several years later by X-ray diffraction analysis.^[4] Over the years, this compound has drawn the attention of the chemistry community thanks to two main features: an original V-shape geometry adopted by the two aromatic subunits and the occurrence of a chirality induced by the two stereogenic nitrogen atoms. In Figure 1.1 are drawn two different representations of these compounds. While the structures on the top emphasize the connections between atoms and functional groups, including the resulting stereochemistry, the drawing at the bottom represent the 3-D aspect of the molecules and the V-shape geometry in particular as evidenced by Wilcox and coworkers by X-Ray analysis. ^[4]

Figure 1.1 Typical drawing representations of TB 1. The bold bonds are used to represents a single enantiomer.

Overall, TBs are [3.3.1] bridged bicyclic molecules characterized by two bridgehead nitrogen atoms. The main core of the molecule is composed of a diazocine and an aminal bridge.

Additionally, the aromatic rings are imbedded within the bicyclic core of the molecule and adopt a nearly orthogonal orientation induced by the strain of the aminal bridge and the pyramidal conformation of the nitrogen atoms in particular. In such a geometry, the lone pairs of the N-atoms pointing in opposite directions from each other. The size of the bridge can be

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increased by 1 carbon atom (see section 1.4.2), and hence the methano or ethano bridge denomination that will be adopted throughout the manuscript (Figure 1.2). This V-shape geometry and the ease of preparation are to date the main reason why TBs are used in various applications. Direct applications of TBs in supramolecular chemistry and material science will be presented later in section 1.2.1.

Figure 1.2 Typical drawing representation of methano and ethano-TBs.

1.1.2 Stereogenic Nitrogen Atoms

As already mentioned, in addition to the orthogonal geometry, the chirality of TBs is a salient feature. In this context, it is important to remember that tertiary amines with three different substituents are chiral owing to their tetrahedral geometry, the lone pair being the fourth substituent. The barrier for the nitrogen inversion (enantiomerization) is however low, in the range of 6-7 kcal/mol, making the separation of the enantiomers impossible at room and even lower temperatures.^[5] Nevertheless, some mono- or polycyclic compounds presenting bridged or fused nitrogen atoms can be an exception; the presence of cyclic structures and certain electronic contribution can prevent the inversion, and hence increase the barrier of the enantiomerization process (Scheme 1.1).^[5-6] As a rule, quaternary nitrogen atoms with different substituents are also stereogenic but are configurationally stable; a noticeable exception being the Wedekind-Fock-Havinga salt.^[7] In the case of TB, the presence of a methano or ethano bridge confers a rigidity to the whole molecule and thus prevents the pyramidal inversion of the nitrogen atoms.

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Introduction

Scheme 1.1 Barrier of nitrogen inversion for a selection of reported tertiary amines (top). Example of a quaternary chiral, yet configurationally labile, ammonium salt (bottom).

In 1944, Prelog and Wieland were able to separate the two enantiomers of 1a by chromatography using α-ᴅ-lactose as a chiral stationary phase (CSP).^[8] This result marked a fundamental advance in the field of chiral separation, as it was the first key example of the use of an enantiopure stationary phase for resolution of a racemic mixture. Moreover, it was the first case of the resolution of a molecule for which the chirality was exclusively due to the presence of stereogenic N-atoms.

1.1.3 Racemization of Tröger Base

Somewhat surprisingly, in view of the facile preparation and chirality of TBs, one can but notice a certain lack of applications in the fields of organometallic chemistry and organocatalysis. In term of stereochemistry, TBs are configurational labile in acidic media (Brønsted or Lewis). In fact, Prelog and Wieland^[8] reported that 1a slowly racemizes in diluted acidic media and a mechanism via the reversible formation of an achiral iminium ion was later proposed (Scheme 1.2).^[9] In presence of a Brønsted acid, the initial quaternization of the nitrogen atom of 1a leads to intermediate A, which readily undergoes aminal opening.

Iminium of type B will then planarize to form achiral iminium C, whose aminal reformation can occur with equal probability from either the top or the bottom of the plane axis, leading to the final racemic mixture of 1a.

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Scheme 1.2 Proposed mechanism for the acid-catalyzed racemization of 1a.

The energy barrier for the racemization of 1a at 25 °C was reported to be 24.1 kcal/mol (t1/2 = 886 min) under acidic conditions (pH = 2.2) and of 21.6 kcal/mol (t1/2 = 12 min) after introduction of a permanent positive charge by quaternization of the N-atom. It is also important to mention that the racemization of 1a occurs only in a diluted acidic media as the racemization via iminium intermediate can occur only if a single N-atom is protonated.^[9a] At lower pH, the double protonation of TB leads to intermediates that are configurationally stable since the lone pairs are necessary for the animal opening and subsequent iminium formation.

Schurig et al. also proposed an alternative pathway for the racemization of 1a occurring in the gas phase via a degenerated retro-hetero Diels-Alder and subsequent hetero-Diels Alder proceeding without quaternization of the N-atom and formation of planar intermediate D (Scheme 1.3).^[9b] In this case, the barrier of inversion was calculated to be 28.2 kcal/mol in solution, therefore demonstrating that the racemization can occur also without the formation of a positive charge. However, this mechanistic proposition has never been supported by experimental evidences and^[10] recent studies indicate that the racemization through iminium C is the most likely pathway.

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Introduction

Scheme 1.3 Proposed mechanism for the retro-hetero Diels-Alder racemization of 1a.

In any case, 1a can be easily resolved by precipitation/filtration protocols on gram scale using dibenzoyl tartaric acid as a chiral resolving agent.^[11] Interestingly, in contrast to the resolution of regular chiral amines, Periasamy et al. proposed the formation of a diastereomeric complex with no direct protonation of the N-atoms. As mentioned above, the protonation of the TB would be indeed problematic as the racemization barrier would be drastically lowered and the resolution would be ineffective. This can be explained by the pKa of 1a. In fact, Wepster et al. determined a pKa value of 3.2 for monoprotonated salt A in 50% aqueous solution of ethanol.^[12] In this same study, it was proposed that this unusually low pKa compared to regular anilinium ions (typically pKa 4-5) is due to the presence of the adjacent methylenediamine and benzylamines groups. Wärnmark and coworkers^[1c] also proposed that this lower pKa is a direct consequence of the specific geometry of the molecule. In fact, as showed in Figure 1.3, the lone pair of the nitrogen overlaps with the σ* antibonding orbital of the adjacent methylene C-N bond. This stabilization by anomeric effect decrease the nucleophilicity/basicity of the lone pair of the nitrogen atoms.

Figure 1.3 Anomeric effect in the TB 1. On the right, zoomed representation of the methylene bridge.

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1.1.4 Synthesis of Tröger Base

Currently, the methodology to synthesize TBs involves the use of paraformaldehyde as methylene group precursor and regular anilines as reactant in trifluoroacetic acid (TFA). In 1935, Wagner proposed the first mechanistic rationale for this transformation,^[13] which was later reexamined by both Wagner and Farrar to lead to the final proposed mechanism describes in Scheme 1.4.^[14] This proposal involves the acid-mediated condensation between a para substituted aniline and formaldehyde (aniline→E, F→G, G→H) and a subsequent series of electrophilic aromatic substitutions (E→F, H→1). It is worth mentioning that the presence of the para substituent is essential to a avoid polymerization. Nowadays, the reaction conditions have been optimized to extend the scope to a wide range of anilines with various ortho, meta and para substituents.^[15] However, the use of strong electron withdrawing groups in para position can be problematic; these groups disfavored steps E→F and H→1 for instance.

Scheme 1.4 Proposed mechanism for the synthesis of TB 1.

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Introduction

This direct condensation of anilines with paraformaldehyde is used to access to symmetrically- substituted TBs exclusively. A stepwise and efficient synthesis of unsymmetrical TB was reported by Wilcox et al. (Scheme 1.5).^[16] Nucleophilic addition of anilines to benzo-oxazine- diones, that present different substituents of the aromatic groups, affords diamines I upon reduction with BH3 of the coupling product. Afterwards, treatment of I with formaldehyde in aqueous acidic media afforded the unsymmetrically substituted TB. This synthetic method is however limited to the use of anilines with a strong nucleophilic character (R¹ = EDG);

electron-poor benzo-oxazine diones being on the other hand suitable partners. TB analogues with strong difference in electronic character for the two N-atoms will be of particular interest in this PhD thesis as they provided key information on mechanisms and global reactivity.

Scheme 1.5 Alternative pathway to access unsymmetrically substituted TB.

1.2 Applications of Tröger Base

As mentioned previously, TBs presents a rigid V-shape geometry which is quite unusual for small organic molecules. The straightforward synthesis starting from easily available anilines and paraformaldehyde makes it even more interesting. In 1985, Wilcox et al. proposed the first use of TB analogues as chiral hosts and metal ligands.^[17] Since then, TB has been derivatized into several building blocks for applications in the field of supramolecular

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chemistry and material science. Some relevant examples of such applications will be presented in the following section.

1.2.1 Supramolecular Chemistry and Material Science

For the making of molecular receptors, for instance, the synthesis of carboxylic acid derivatives of TB was performed by the group of Wilcox (Figure 1.4, left).^[18] The researchers harvested the H-bond ability of such derivatives towards biotin and adenine. The binding interactions were studied by ¹H-NMR and UV spectroscopies in different solvent systems. In every case, the influence of water for the efficient binding abilities was demonstrated. Similar motifs were reported by the group of Goswami, in which the di-carboxylic acid units were replaced by 2-aminopyridine substituents (Figure 1.4, right).^[19] This new receptor was used for binding with di-carboxylic acids and with a particular selectivity for suberic acid.

Figure 1.4 (Right) Tetra-carboxylic acid TB, (left) bis-2-aminopyridine amide TB and subsequent host-guest chemistry.

In the 1990’s, to study weak molecular interactions, Wilcox et al. also reported the novel

“Molecular Torsion Balance (MTB)” concept (Scheme 1.6) based on the TB as structural anchor to study weak molecular interactions.^[20] In the first report, edge-to-face interactions between aromatic units were investigated thanks to the V-shape geometry of TB that affords either folded or unfolded geometries. Later,^[21] the same group used similar motifs to study CH-π interactions, which are known to play a role in protein folding.^[22]

In fact, the MTB system correlates weak edge-to-face and/or CH-π forces with the difference in free energy between folded and unfolded conformers. Such quantification can be done using NMR spectroscopy as an experimental tool. Some water-soluble variants of these motifs were prepared as well in order to avoid corrections for the change of dipole moments

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Introduction

between folded and unfolded conformers.^[23] Similarly, Diederich and coworkers extended the use of MTB for the study of weak interactions between organic fluorine and amide functional groups.^[24]

Scheme 1.6 MTB based on TB skeleton.

Later on, both Diederich and Saigo independently reported the use of TB analogues for the tether-directed double Bingel cyclopropanation^[25] of C60 with excellent regiocontrol and diastereoselectivity (Scheme 1.7).^[26] Starting from enantiopure TBs, it is then possible to access enantiomerically pure fullerene derivatives. This was the first example of the use of TB as chiral auxiliary for asymmetric synthesis. Shortly after, the same reactivity was also performed on C70.^[27]

Scheme 1.7 Double Bingel cyclopropanation tailored by the TB skeleton.

In 1998, Wärnmark et al. exploited the V-shape geometry of TB to prepare a novel C2- symmetric bis crown ether and studied the recognition abilities for this new receptor towards chiral and achiral bis-ammonium salts (Figure 1.5, left).^[28]It was reported that the highest binding affinity was obtained with heptane-1,7-diylbis(ammonium chloride) and moderate stereoselective recognition was observed in the complexation of racemic bis crown ether with

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dimethyl ester dihydrochlorides of ʟ-Cystine. In a similar manner, the group of Crossley reported the synthesis of tetraarylporphyrins fused by a TB unit (Figure 1.5, right), forming as such a chiral cleft molecule.^[29] Interestingly, this novel bisporphyrino-TB presented strong affinities with diaminoalkanes, lysine esters and histidine when Zn^II is complexed within the core of the porphyrin units. In addition, this receptor was reported for the encapsulation of tetraamine dendrimers to self-assemble into a spherical cage.^[29c]

Figure 1.5 Macrocyclic scaffolds linked by a TB unit.

Others TB analogues based on cyclophanes have also been investigated. Fukae et al. proposed the synthesis of dimeric TB, which was obtained in moderate yield (45%) as a mixture of meso and racemic compounds (Figure 1.6, left, only racemic shown).^[30] Others reports of similar scaffolds can be found in the literature.^[31] Remarkably, the group of Wilcox developed a series of water soluble cyclophanes that included either ammonium or carboxylic acid groups for solubility (Figure 1.6, middle and right).^[32] Those scaffolds presented some selectivity for several small organic molecules, benzenoid and acyclic substrates, and interestingly an unprecedented high affinity with isomeric menthols. It is important to notice that all the binding studies were performed by ¹H-NMR titrations.

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Introduction

Figure 1.6 Cyclophanes based on the TB skeleton.

Several other supramolecular structures were designed based on the TB skeleton. Lützen et al. reported the highly stereoselective self-assembly of metallohelicates.^[33] In 2007, Dolensky, Král et al reported the synthesis of calix-shaped tris-TB for the design of molecular capsules.

In this particular case, the ability of TBs to racemize under acidic conditions was seen as a feature of interest as it could be a possible pathway for targeted drug delivery (opening of the capsule).^[34] Demeunynck et al. reported the interaction of proflavine- and phenanthroline- based TB with calf-thymus DNA.^[35] It was shown that proflavine derivative prefer to bind by intercalation between the DNA pairs whereas the phenanthroline derivative resides in the DNA minor-groove.^[35c] More recently, the group of Gunnlaugsson reported the synthesis and photophysical properties of naphthalimides derivatives of TB (Figure 1.7).^[36] These analogues self-assemble in solution to give rise to spherical nanostructures that demonstrated an ability to function as fluorescent probes for Concanavalin A.^[36d]

Figure 1.7 Example of a naphthalimide derivative of TB.

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In the past decade, TB research has made significant advances in the field of polymer chemistry and material science.^{[36a, 37]} Once again, the V-shape geometry of the compounds represented a unique and attractive feature for molecular design. As a representative example, the group of McKeown developed molecular sieves based on TB, for high gas permeability and selectivity for small molecules such as oxygen and hydrogen (Figure 1.8, J and K).^[37d] Classical permeable microporous polymers often demonstrate poor selectivity due to chain flexibility which causes ill-defined and size-fluctuating voids.^[38] To overcome this issue, McKeown and coworkers conceived a rigid microporous polymer based on bridged TB moieties whose rigidity could avoid the fluctuation in size (Figure 1.8, L).

Figure 1.8 Molecular sieve constructed on a polymeric network of TB.

1.2.2 Organometallic Chemistry and Organocatalysis

There have been several attempts to exploit the chirality of TB in asymmetric transformations and organocatalysis. However, only few cases led to an efficient transformation with good enantioselectivity, mainly because of the racemization issue that can be encountered (see section 1.1.3). Some of the reported examples will be presented in the following section.

The first isolated TB metal complex was reported by Alper et al. in 1995.^[39] The resulting 1a•[RhCl3]2 complex successfully catalyzed the hydrosilylation of alkynes affording products with high regioselectivity, and in some cases, stereoselectivity. Herrmann and coworkers later

J K

L

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Introduction

reported a methyltrioxorhenium-(VII) (MTO) complex with 1a in order to investigated enantioselective epoxidations in presence of H2O2.^[40] The reaction proceeded efficiently towards the epoxide but no enantioselectivity was induced by enantiopure 1a. In the latter case, and contrary to what has been reported, complexation of enantiopure 1a with metal complexes like MTO leads to a full racemization of the TB skeleton. In fact, the space group of the obtained crystallographic structure is P21/c, which is centrosymmetric. Thus, MTO complex is thus racemic and not enantiopure. This example illustrates how the TB moieties can racemize not only in aqueous acidic media, but as well by coordination to a Lewis acid.

Baiker and coworkers investigated the enantioselective heterogeneous hydrogenation of ethyl pyruvate into optically active ethyl lactate in 65% ee.^[41] This reaction was performed using Pt/alumina modified by 1a as catalyst (Scheme 1.8).

Scheme 1.8 Heterogeneous hydrogenation of ethyl pyruvate.

The group of Xu reported the enantioselective 1,4-addition of aryllithium reagents to α,β- unsaturated tert-butyl esters with the addition of chiral additives, mainly diamines or amino ethers (Scheme 1.9).^[42] The corresponding 1,4-addition product was obtained in 57% ee when (‒)-1a was used as chiral additive. Interestingly, similar results were obtained using (‒)- sparteine despite rather different geometries and electronic character for the N-atoms.

Scheme 1.9 Enantioselective 1,4-addition of aryllithium reagents to α,β-unsaturated tert-butyl esters.

Several years later, Sigman et al. reported the use of (+)-1a and (–)-sparteine as ligands for palladium catalyzed kinetic resolution of benzyl alcohol (Scheme 1.10).^[43] Unlike sparteine,

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the bridgehead nature of the N-atoms of TB constraints the lone pairs in opposite directions.

As a consequence, the molecule cannot behave as a bidentate ligand towards a unique metal center. This characteristic can be considered as a limitation for the direct applications of TB in organometallic chemistry as surrogate to sparteine or other dinitrogen ligands.

Scheme 1.10 Palladium catalyzed kinetic resolution of benzyl alcohol. Drawing of (+)-1a and (–)-sparteine.

Harmata et al. proposed new derivatives of TB substituted at the benzylic position as ligands for the asymmetric addition of Et2Zn to aromatic aldehydes (Scheme 1.11).^[44] These functionalized ligands were accessed by deprotonation of a 1a•BF3 complex and alkylation at the benzylic position (see section 1.3). The authors proposed a chelation of the Zn by the OH group and adjacent nitrogen atom. In this work the unsubstituted 1a was also tested but a low enantioselectivity was observed (10% ee vs 86% ee for p-BrPhCHO). A modification of the main core was thus necessary to design an effective chiral ligand for the transformation.

Scheme 1.11 Asymmetric addition of Et2Zn to aromatic aldehydes

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Introduction

Other modifications of the aromatic units of the TB were reported in order to perform heterogenous catalysis and cross coupling reactions.^{[37a, 45]} In the field of organocatalysis few examples can be found. The group of Shi reported in 2006 amine-promoted aziridinations of chalcones.^[46] In this work, O-mesitylenesulfonylhydroxylamine (MSH) was used as amination reagent with tertiary amines as catalysts. Formation of corresponding hydrazinium salts and further reactions with chalcones afforded indeed aziridines (Scheme 1.12). Herein, (+)-TB-1 was used as a chiral tertiary amine for the asymmetric version of the reaction, affording aziridine derivatives in 67% ee.

Scheme 1.12 TB promoted aziridination of chalcones

Wu et al. recently reported a stereoselective Mannich reaction in aqueous media catalyzed by pyrazole derived Pyr-TB (Scheme 1.13).^[47] The process was very high yielding with good stereoselectivities. It is promoted by H-bonding interactions between the Pyr-TB and both the enol form of the cyclohexanone and the aryl amine. This shape of the TB is thus thought to be crucial to induce the diastereoselectivity on the transformation.

Scheme 1.13 Stereoselective Mannich reaction in aqueous media catalyzed by Pyr-TB.

In 2009, Sergeyev and coworkers reported a novel thiourea derivative of TB as a potential organocatalyst for Michael addition of malonate to trans-β-nitrostyrene.^[48] The process was successfully catalyzed by Thiourea-TB, however no enantioselectivity was observed when

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using enantiopure catalyst (Scheme 1.14). The reaction was performed also with regular TB and the authors observed a partial racemization of the catalyst with no conversion towards the final product.

Scheme 1.14 Michael addition of malonate to trans-β-nitrostyrene catalyzed by Thiourea-TB.

As a general trend, TB was not widely investigated for its potential as ligand for organometallic chemistry or organocatalysis. The facile racemization of the compound and the limited access to functionalized derivatives are issues that require to be solved to render TB more attractive.

1.3 Functionalization of the Diazocine Ring

As presented in the previous sections of this manuscript, the TB skeleton has been widely functionalized on the aromatic units giving access to a variety of building blocks for supramolecular or polymer chemistry. However, only very few examples of direct functionalization of the main core of the molecule (diazocine ring) can be found in the literature. This section will treat about the functionalization at the benzylic positions of TB, then the modification at the aminal bridge will be treated in the section 1.4

The group of Harmata investigated different strategies to afford selective benzylic substitution reactions. In 1996, they reported a methodology that proceeds by the pre-complexation of one tertiary amine with boron trifluoride (Scheme 1.15)^[49]. This step facilitates the deprotonation/metalation of the adjacent carbon.^[50] The process is not only regio- but also stereoselective as the subsequent alkylation occurs only on the exo face (convex). Surprisingly, this protocol has not been reported in the enantiopure TB series and it is limited to the mono substitution of the benzylic positions.

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Introduction

Scheme 1.15 Direct mono-alkylation of the benzylic position of 1a.

Several years later, Snieckus, Harmata and Wärnmark reported improved metalation conditions to give access to both mono and bis substituted products.^[51] Moreover, in the case of bis-additions, two different electrophiles can be introduced leading to unsymmetrical TB derivatives. The reaction is strongly sensitive to the number of equivalents of sBuLi/TMEDA and to the order of addition of each electrophile. In another report, both groups collaborated again for the synthesis of novel twisted bis amides (Scheme 1.16).^[52] In this work, it was shown that TB can be directly functionalized in one step under strongly oxidative conditions.

Interestingly, due to the geometry of the bicyclic system, the resulting amide is twisted, meaning that the amide bond resonance is no longer possible due to the torsion angle of 43.7°

between the carbonyl π orbital and the lone pair of the nitrogen atom. This type of amide behaves as a highly reactive amino-ketone thus allowing derivatization that could not be accessed otherwise. Several years later, Cvengroš and coworkers optimized the reactions conditions for the oxidation of ethano-TB (see section 1.4.2 for this class of derivatives) to give access to similar twisted amide derivatives.^[53]

Scheme 1.16 Synthesis of twisted bis-amides derivatives of TB.

Snieckus, Harmata and Wärnmark continued to investigate the reactivity of the novel TB twisted amide and successfully reported the synthesis of inverted crown ethers based on that skeleton.^[54] Interestingly, it is also the first report of successful synthesis of an endo-

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substituted TB, achieved by Wittig olefination of the carbonyl groups followed by the hydrogenation of the double bonds (Scheme 1.17). This reactivity was never attempted on the enantiopure series of TB as the authors developed a methodology to efficiently separate the final product by CSP-HPLC.

Scheme 1.17 Synthesis of endo-substituted TB.

Recently, the group of Cvengroš reported a protocol to perform the C-H acetoxylation of TB using the combination of NBS and Pd(OAc)2 as oxidizing agents (Scheme 1.18).^[55] This process is reported to be highly stereospecific and enantiospecific, however, no control of mono- versus bis-addition was obtained, leading to a mixture of products yet separable. Interestingly, the authors of this work propose that the mechanism goes through the formation of an iminium ion but no evidence was found to support this hypothesis. The same methodology was extended to the addition of azido groups in the benzylic positions of TB.^[55]

Scheme 1.18 Mono and bis C-H acetoxylation of TB.

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Introduction

1.4 Configurationally Stable Tröger Bases

As previously mentioned, the racemization induced by the quaternization of one of the N atoms is a main issue in TB chemistry. In the synthetic community, several solutions have been proposed to overcome this problem. The main objective in this section is to detail structural modifications of TB that increase the energy barrier of racemization. Such compounds will be identified as being configurationally stable, in acidic conditions in particular.

1.4.1 Modulation of the Aromatic Units

As discussed, the racemization of TB takes often place when there is a quaternization of one of the nitrogen atoms, most of time by the presence of Brønsted or Lewis acids. Demeunynck et al. reported acridine and proflavine derivatives of TB which possesses extra sp² nitrogen atoms that are more basic than the bridgehead nitrogens and can act as intramolecular proton scavengers (Figure 1.9, left).^[35a] The protonation of the acridine nitrogen causes the molecule to be more electron deficient thus preventing the protonation of the bridgehead nitrogen and subsequent racemization.

More recently, Kostyanovsky and coworkers reported a TB derivative substituted at the ortho positions relative to the N-atoms (Figure 1.9, right).^[56] This type of analogues turned out to be highly configurationally stable. The presence of the ortho-substituents adds a large steric hindrance that disfavors the planarization of the iminium intermediate. (see Scheme 1.2, section 1.1, B→C). At pH = 1, the racemization barrier of the protonated tetra methyl derivative was thus calculated to be of 31.2 kcal/mol compared to 24.1 kcal/mol for 1a.

Figure 1.9 Configurationally stable TB analogues.

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However, these proposed solutions imply that the skeletal modifications remain present;

some of these modifications limiting strongly the type of possible applications. For instance, the hindrance created by ortho-substituents reduces the accessibility to the lone pair of the N-atoms and limit applications that involve those centers.

1.4.2 Modifications at the Methano-Bridge

In 1996, the synthesis of a novel ethano-TB analogue was reported by Hamada et al. using a formal ring expansion of the methano-bridge (see below). Of crucial importance for this PhD thesis, the presence of this ethano-bridge does not allow the formation of an iminium intermediate under acidic conditions (e.g. species B, see Scheme 1.2, section 1.1). In fact, Lenev and Kostyanovsky reported that such a ethano-TB does not racemize after methylation of one N-atom.^[57] Subsequent heating in DMF at 100 °C does not reduce configurational stability of the compound.

Despite the elongation of the bridge by one carbon, the compound preserves the nearly orthogonal geometry between the aromatic rings. The already reported applications in supramolecular chemistry or synthesis should thus be amenable. However, the direct synthesis of ethano-TB 2. In fact, the procedure reported by Hamada and coworkers involves the treatment of 1a by 1,2-dibromoethane that leads to the aminal opening and subsequent intramolecular nucleophilic substitution to afford ethano-TB (Scheme 1.19). As this process occurs via the quaternization of a N-atom, it is unfortunately leading to racemic 2 in the enantiopure series.

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Introduction

Scheme 1.19 Synthesis of ethano-TB.

In the past few years, the group of Cvengroš was highly interested in the functionalization of ethano-TB and reported the C-H oxygenation and nitrogenation via a Ritter type reaction at the α position of the N-atom (Scheme 1.20).^[58] This process is proposed to occur via the formation of an iminium ion by an oxidative process at the bridge position. The stereoselectivity is rationalized by the stabilization of the iminium intermediate that give rise to a non-classical carbocation.^[59] The obtained stereoisomer was confirmed by X-Ray analysis, but no further investigations (for example computational studies) were performed to determine the viability of a non-classical carbocation approach.

Scheme 1.20 C-H oxygenation and nitrogenation of ethano-TB-2.

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Ethano-TB 2 can nonetheless be resolved using (‒) or (+)-di-p-toluoyl-ʟ-tartaric acid as reported by Hamada et al.^[60] However, this procedure is reported to work only on ethano-TB containing unsubstituted diazocine ring. Synthetic pathways to access these derivatives in enantiopure form were therefore a challenge and a topic of interest in our group. Remarkable advances were achieved by the means of [1,2]-Stevens rearrangements.

In fact, getting ahead of ourselves (see section 1.4.3), it is possible to generate highly enantioenriched disubstituted ethano-TB by ring-expansion of methano derivatives. With these derivatives of type 2a and 2b, our group reported an original and enantiospecific ring contraction with DDQ as oxidant.^[61] The methylene extrusion is performed in mild conditions and affords methano-TB derivatives with a complete retention of the chiral information (Scheme 1.21, es ≥ 98%).Interestingly, this study revealed that the CH2 group is released as a molecule of formaldehyde which could be observed by ¹H-NMR spectroscopy. This process is indeed highly enantiospecific despite the necessary C-C and C-N bond cleavage and the resulting derivatives are configurationally stable even under acidic conditions.

Scheme 1.21 Methylene extrusion of ethano-TB to afford methano-TB.

More recently, Cvengroš et al. developed the synthesis of TB functionalized at the methano bridge by double aza-Michael reaction starting from the diazocine ring (Scheme 1.22).^[62]

However, when R² was a chiral moiety, (‒)-menthol for example, only a poor diastereoselectivity was observed. Moreover, the diazocine substrate is prepared from 1a by treatment with trifluoroacetic anhydride to remove the aminal bridge.^[63]

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Introduction

Scheme 1.22 Double aza-Michael reaction to access TB functionalized in the methylene bridge.

1.4.3 [1,2]-Stevens Rearrangement of Nitrogen Ylides

1.4.3.1 Definition and Mechanism

As a general definition, an ylide is a neutral “compound in which an anionic site Y⁻ is attached directly to a heteroatom X⁺ carrying a formal positive charge”.^[64] In 1928, Stevens and coworkers discovered an unprecedented [1,2]-shift reaction of a quaternary ammonium salt when treated with sodium hydroxide (Scheme 1.23).^[65] From the start, initial propositions involved the formation of an ammonium ylide intermediate by deprotonation in alpha position to the nitrogen atom followed by the migration, here of a benzyl group on the before- mentioned carbon. Since then, the [1,2]-Stevens rearrangements of quaternary ammonium ions have provided an unique access to different types of natural and unnatural products, some of them belonging to the class of alkaloids and other complex molecules.^[66]

Scheme 1.23 First reported [1,2]-Stevens rearrangement.

A comparable reactivity is observed with the allylic derivatives which undergo this time [2,3]- sigmatropic rearrangements involving analogous ylide intermediates.^[67] In this section, only the mechanism and ylide generation related to the [1,2]-Stevens rearrangement of quaternary ammonium ions will be discussed.

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From a mechanistic point of view, the [1,2]-Stevens rearrangement of ammonium ylides has been a source of debate since its discovery. Several studies were conducted to determine the possible mechanistic pathway(s) and the nature of the species involved. Initially, Stevens and coworkers proposed an ion-pair mechanism (Scheme 1.24, top) which proceeded via the heterolytic cleavage of the ammonium ylide forming an iminium ion and the anionic counterpart N, which then recombine to give the rearranged product.^[68] This proposition was based on the lack of cross-over experiments when a 1:1 mixture of labeled starting materials was involved in the reaction.^{[68b, 69]} However, the resulting absence of chirality transfer by this mechanistic proposal was in contradiction with the enantiospecific transformations reported in the literature.^[70] Hauser^[71] and Wittig^[72] postulated then that the mechanism should proceed via an intramolecularly concerted pathway based on these results (Scheme 1.24, middle).

Scheme 1.24 Proposed mechanisms for the [1,2]-Stevens rearrangement of ammonium ylides.

Nevertheless, this proposed mechanism involves a four-electrons [1,2]-shift in suprafacial- suprafacial mode which should be symmetry forbidden according to the Woodward- Hoffmann rules.^[73] Under thermal conditions, a suprafacial-antarafacial approach should thus be favored but, in specific cases, it could lead to a high degree of strain in the transition state O, thus making the overall process disfavorable. Therefore, another mechanistic proposition was put forward by Ollis et al. who suggested a non-concerted mechanism proceeding via homolytic cleavage to form radical species P (Scheme 1.24, bottom).^[74] According to what is

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Introduction

proposed by Ollis, the radical species are held closely together in a “solvent cage”, which results in the retention of the absolute stereochemistry upon recombination of the radical pair. Nowadays the diradical mechanism is the most considered in the literature, yet the other mechanistic propositions still have to be considered and could be implicated depending on the substrate and reaction conditions.^[75]

1.4.3.2 Generation of Ylides and Subsequent Reactivity

Several ylide generation methods are reported in the literature: (i) the base-induced deprotonation of ammonium salts and (ii) the carbene addition to tertiary amine being the most reliable and practiced methods (Scheme 1.25).^[66c]

Scheme 1.25 Base-induced generation of nitrogen ylides.

The first acid-base approach is easily accessible, however, to be performed readily and selectively, the presence of EWG is necessary. In fact, such groups enhance the acidity of the hydrogen atoms in α position and they participate to the regioselective formation of the ylide.

Yet, despite these groups, the use of strong bases such as NaOH or tBuOK is often necessary.^[76] If more than one acidic site is present in the molecule, then a complex mixture of product results. ^[77] To overcome this limitation, the fluoride-mediated desilylations of trimethylsilyl substituted ammoniums ions was developed by Vedejs^[78] and Sato^[79] and it allowed a straightforward access to highly reactive ylide intermediates.

Stevens and coworkers^[80] discovered another viable alternative for ylide generation via the decomposition of diazo-compound which may occur under thermal, photochemical or metal catalyzed conditions. ^[81] This latter method is of principal interest for our group. Over the last few years, several reactivities were discovered using in situ generated nitrogen or oxygen ylides by metal catalyzed decomposition of diazo compounds. Concerning the nitrogen ylide chemistry specifically, our group reported the copper-catalyzed [1,2]-Stevens rearrangement of binaphthyl and biphenyl azepines (Scheme 1.26, top).^[82] More recently, the

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dearomatization of pyridines and isoquinolines via the formation of nitrogen ylides (Scheme 1.26, bottom) has also been studied; this transformation will be soon reported.^[83]

Scheme 1.26 Examples of reactivity of nitrogen ylides described in our group.

As just shown above, the metal-catalyzed decompositions of diazo compounds in presence of tertiary amines is a mild and efficient access to reactive nitrogen ylides. In presence of transition metal salts and complexes based on Rh,^[84] Ru,^[85] Cu,^[86] or Pd^[87], diazo compounds^{[81, 88]} react with these Lewis acidic moieties to generate, after release of molecular N2, an electrophilic metal carbene of type Q (Scheme 1.27). In several C-H insertion processes, it has been observed that the release of N2 is the rate determining step of the reaction.^[89]

Once generated, the electrophilic carbene reacts rapidly in presence of electron-rich σ or π bonds and Lewis bases. The metal is afterwards released and reacts with another diazo compound thus allowing the catalytic cycle to proceed.

Synthesis, mechanism and applications of azido functionalized and α-imino carbene derived Tröger Bases

Thesis

Reference

Synthesis, mechanism and applications of azido functionalized and α-imino carbene derived Tröger Bases

Synthesis, Mechanism and Applications of Azido Functionalized and α-Imino Carbene Derived

Tröger Bases

THÈSE

Alessandro BOSMANI

Résumé

Remerciements

Abbreviations

Symbols

Units

Table of Contents

1. Introduction

1.1 Tröger Base: History and Properties 1.1.1 Structural Overview

1.1.2 Stereogenic Nitrogen Atoms

1.1.3 Racemization of Tröger Base

1.1.4 Synthesis of Tröger Base

1.2 Applications of Tröger Base

1.2.1 Supramolecular Chemistry and Material Science

1.2.2 Organometallic Chemistry and Organocatalysis

1.3 Functionalization of the Diazocine Ring

1.4 Configurationally Stable Tröger Bases

1.4.1 Modulation of the Aromatic Units

1.4.2 Modifications at the Methano-Bridge

1.4.3 [1,2]-Stevens Rearrangement of Nitrogen Ylides

1.4.3.1 Definition and Mechanism

1.4.3.2 Generation of Ylides and Subsequent Reactivity