Recent advances in catalyst and ligand design for metal-catalysed isomerisation reactions

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Thesis

Reference

Recent advances in catalyst and ligand design for metal-catalysed isomerisation reactions

HUMBERT, Nicolas

Abstract

Le développement des réactions d'isomérisation des époxydes et d'isomérisation des alcools allyliques en aldéhydes, catalysées par un même complexe d'hydrure d'iridium possédant un centre stéréogénique au métal, est dévoilé dans ce manuscrit. Le mécanisme de ces transformations a été étudié et, des synthèses d'analogues du catalyseur permettant de contrôler la stéréochimie au centre métallique ont été mise au point. En complément, un ligand bidentate possédant trois éléments de chiralité, dont un au phosphore étant stéréolabile, a été étudié.

HUMBERT, Nicolas. Recent advances in catalyst and ligand design for metal-catalysed isomerisation reactions. Thèse de doctorat : Univ. Genève, 2015, no. Sc. 4838

URN : urn:nbn:ch:unige-767938

DOI : 10.13097/archive-ouverte/unige:76793

Available at:

http://archive-ouverte.unige.ch/unige:76793

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 biochimie

Département de chimie organique Professeur Clément Mazet

Recent Advances in Catalyst and Ligand Design for Metal- Catalysed Isomerisation Reactions

THÈSE

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

par

Nicolas HUMBERT

de

Avignon (France)

Thèse N^o 4838

GENÈVE

Atelier d’impression ReproMail-Unimail 2015

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Acknowledgments

The work described in this manuscript was carried out in the Department of Organic Chemistry of the University of Geneva, under the supervision of Professor Clément Mazet.

First and foremost I offer my sincerest gratitude to my supervisor, Professor Clément Mazet, who has supported me throughout my thesis with his patience, motivation and knowledge.

I am also grateful to Professor Alexander Adibekian and Professor Marco Bandini for their evaluation of my work as members of the thesis committee.

I would like to thank the different analysis teams: André Pinto, Marion Pupier and Doctor Damien Jeannerat for NMR assistance; Doctor Laure Guénée and Doctor Céline Besnard for X-ray diffraction experiments; Eliane Sandmeier and Doctor Sophie Michalet for high resolution mass spectrometry.

Valuable technical assistance from Pradeep Nareddy and Doctor Devendra Vyas for the synthesis of substrates was widely appreciated.

Professor Jérôme Lacour is also thanked for the discussions of technical aspects of the resolution of racemate by chiral anions and the generous gift of TRISPHAT and BINPHAT

I thank Doctor Evgeny Larionov and Doctor Amalia Poblador-Bahamonde for the theoretical calculations performed on this work.

Doctor Roman Lagoutte, Doctor Vincent Bizet and Doctor Luqing Lin are warmly thanked for their advices and the proofreading of this manuscript.

The University of Geneva and the Swiss National Foundation (Project PP00P2_133482) are acknowledged for their financial support.

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Résumé en français

Le développement des réactions d’isomérisation des époxydes et d’isomérisation des alcools allyliques en aldéhydes, catalysées par un même complexe d’hydrure d’iridium possédant un centre stéréogénique au métal, est dévoilé dans ce manuscrit. Le mécanisme de ces transformations a été étudié et, des synthèses d’analogues du catalyseur permettant de contrôler la stéréochimie au centre métallique ont été mise au point. En complément, un ligand bidentate possédant trois éléments de chiralité, dont un au phosphore étant stéréolabile, a été étudié.

Récemment, ce ligand (P,N) a été utilisé afin d’effectuer l’α-arylation intramoléculaire énantiosélective d’aldéhydes. La diastéréosélectivité lors de la synthèse de ce ligand dépend de la nature des substituants présent sur l’atome de phosphore. Dans certains cas, deux diastéréomères possédant uniquement une configuration opposée au centre phosphoré ont été obtenus. La réaction d’inversion qui prend place entre ces deux diastéréomères a été étudiée. L’influence du centre stéréogénique au phosphore a également été évaluée dans la réaction d’α-arylation catalysée au palladium, ainsi que l’hydrogénation d’alcools allyliques catalysée à l’iridium.

Un complexe d’hydrure d’iridium bien défini et stable à l’air, obtenu dans le groupe, a été utilisé comme catalyseur pour l’isomérisation des époxydes, ainsi que l’isomérisation des alcools allyliques primaires et secondaires. Pour ces deux réactions, le protocole suivi est similaire et consiste en l’activation thermique du précatalyseur. Un mécanisme réactionnel a été proposé, pour chacune de ces transformations, sur la base d’observations expérimentales.

Le complexe d’iridium utilisé dans les précédentes transformations possède un centre stéréogénique au métal. Différentes stratégies ont été utilisées afin de tenter d’isoler des complexes stéréogéniquement purs. La réaction d’inversion observée entre deux stéréoisomères a été étudiée par calculs théoriques.

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1. On the Way to the Development of Catalysis

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6 The concept of “catalysis” was introduced in chemistry by Elizabeth Fulhame in 1794 for her work on redox reactions.¹ The term “catalysis” was later invented by Jöns Jakob Berzelius in 1835 to describe the chemical changes observed in earlier findings:²

“It is then shown that several simple and compound bodies, soluble and insoluble, have the property of exercising on other bodies an action very different from chemical affinity. The body effecting the

changes does not take part in the reaction and remains unaltered through the reaction. This body acts by means of an internal force, whose nature is unknown to us. […], it will be more convenient to

designate the force by a new name. I will therefore call it the “Catalytic Force” and I will call

“Catalysis” the decomposition of bodies by this force, in the same way that we call by “Analysis” the decomposition of bodies by chemical affinity”

– Jöns Jakob Berzelius – The rationale behind this “catalytic force” was vigorously debated during the second half of the 19^th century. In 1894, Wilhelm Ostwald pointed out, in his first definition of the term “catalysis”, the relation between catalysis and the novel area of reaction kinetics:³

“Catalysis is the acceleration of a slow chemical process by the presence of a foreign material”

– Wilhelm Ostwald – Later, he presented his final definition during a lecture at the meeting of the Gesellschaft Deutscher Naturforscher und Ärzte in 1901:⁴

“A catalyst is a material that changes the rates of a chemical reaction without appearing in the final product”

– Wilhelm Ostwald – Wilhelm Ostwald was awarded the Nobel Prize in chemistry in 1909 “in recognition of his work on catalysis and for his investigations into the fundamental principles governing chemical equilibria and rates of reactions”.^5,6

1 (a) E. Fulhame An essay on combustion, with a view to a new art of dying and painting: wherein the phlogistic and antiphlogistic hypotheses are proved erroneous, printed by J. Cooper, sold by J. Johnson; G. G. Robinson; J.

Robinson; T. Cadell, Jr. and W. Davies, London, 1794. (b) K. J. Laidler, A. Cornish-Bowden New Beer in an Old Bottle: Eduard Buchner and the Growth of Biochemical Knowledge, A. Cornish-Bowden Ed., Universitat de València, 1997, 123-126. (c) M. Rayner-Canham, G. Rayner-Caham Women in Chemistry: Their Changing Roles from Alchemical Times to the Mid-Twentieth Century, Chemical Heritage Society, 1998.

2 J. J. Berzelius Annual report on progress in physics and chemistry, Royal Swedish Academy of Sciences, Stockholm, 1835.

3 W. Ostwald Z. Phys. Chem. 1894, 15, 706.

4 W. Ostwald Phys. Z. 1902, 3, 313.

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7 Nowadays, our understanding of the concept of catalysis has become common knowledge and a major topic in advanced chemistry courses.⁷ A catalyst, by interacting with at least one of the reagents, will provide a new attractive pathway towards product formation, requiring lower activation energy. As the catalyst is generally not consumed throughout the transformation, a small amount might be used to transform large quantities of substrates. The turnover number and the turnover frequency are parameters used to quantify the efficiency of a catalyst.

The field of catalysis has grown substantially in the chemical industry over the last century, providing shorter synthetic routes, reduction of the wastes generated and decreased production costs. Over 90% of industrial synthetic processes include at least one catalytic step.⁸ The global catalyst market was evaluated at USD 19.2 billion in 2012 and is forecast to reach USD 24.1 billion by 2018.⁹

Many different species have been employed as catalysts. Brønsted acids, organic molecules, Lewis acids, Lewis bases, transitions metal complexes, zeolites, nanoparticles and enzymes are a short list of examples of the versatile nature of catalysts. Two types of catalytic system can be differentiated.

Heterogeneous catalysis refers to reactions where the catalyst is in a different phase than the reagents and products.¹⁰ Typically, the reagents that are in a liquid or gas phase will be adsorbed at the surface of a solid catalyst and then react to generate the corresponding product that will return to the fluid phase. In contrast, homogeneous catalysis has both the catalyst and the reagents in a single phase.¹¹ Such processes are usually performed in liquid phase. This requires catalysts to be soluble in the media.

5 www.nobelprize.org/nobel_prizes/chemistry/laureates/1909/

6 For an essay on Wilhelm Ostwald, see: G. Ertl Angew. Chem. Int. Ed. 2009, 48, 6600.

7 For recent general books on catalysis, see: (a) G. Rothenberg Catalysis: Concepts and Green Applications, Wiley-VCH Verlag GmbH, Weinheim, 2008. (b) Catalysis: From Principles to Applications, M. Beller, A. Renken, R. A. Van Santen Eds., Wiley-VCH Verlag GmbH, Weinheim, 2012. (c) Organotransition Metal Chemistry: From Bonding to Catalysis, J. F. Hartwig Ed., University Science Books, Sausalito, 2009. (d) The Organometallic Chemistry of the Transition Metals, Sixth Edition, R. H. Crabtree Ed., John Wiley & Sons Inc., New York, 2014.

8 Recognizing the Best in Innovation: Breakthrough Catalyst, R&D Magazine, September 2005, 20.

9Refinery (FCC, Hydrocracking, Catalytic Reforming), Synthesis, Polymer & Environmental Catalyst Market – Global Industry Analysis by Material (Zeolites, Metal, Others), by Type (Homogenous & Heterogeneous), Catalyst Regeneration (Off-site & On-site), Size, Share, Growth, Trends and Forecast 2012-2018, published by Transparency Market Research, February 2013.

10 For books on heterogeneous catalysis, see: (a) Handbook of Heterogeneous Catalysis, G. Ertl, H. Knozinger, F.

Schüth, J. Weitkamp Eds., Wiley-VCH Verlag GmbH, Weinheim, 2008. (b) J. M. Thomas, W. J. Thomas Principles and Practice of Heterogeneous Catalysis, Wiley-VCH Verlag GmbH, Weinheim, 2015.

11 For books on homogeneous catalysis, see: (a) P. W. N. M. Van Leeuwen Homogeneous Catalysis:

Understanding the Art, Kluver Academic Publishers, Dordrecht, The Netherlands, 2005. (b) A. Behr, P. Neubert Applied Homogeneous Catalysis, Wiley-VCH Verlag GmbH, Weinheim, 2012.

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8 Scheme 1-1 Hydrogenation of hexane using Wilkinson’s catalyst

The discovery of chlorotris(triphenylphosphine)rhodium ([Rh(PPh3)3Cl]) as a potent catalyst for hydrogenation reactions by Wilkinson and co-workers in 1965 constitutes a major turning-point in the field of homogeneous catalysis (scheme 1-1).¹² This work has stimulated the investigation of soluble organometallic complexes as catalysts for a tremendous amount of transformations.^7c-d As illustrated on scheme 1-2, several industrial processes have emerged during the 60’s and 70’s. The nickel-catalysed alkene hydrocyanation employed by DuPont for the synthesis of adiponitrile (NC(CH2)4CN), a precursor to hexamethylenediamine used for the production of Nylon;¹³ the synthesis of acetic acid from Monsanto using a rhodium/iodide catalyst;¹⁴ the alkene hydroformylation process of Union Carbide Corporation employing [HRh(CO)(PPh3)2] as catalyst to produce butanal are among the most important.¹⁵ The first industrial asymmetric catalytic synthesis was also developed during this period. Monsanto synthesised L-DOPA, a treatment for Parkinson’s disease, via the enantioselective hydrogenation of 9 using a rhodium catalyst and the chiral ligand (R,R)-DiPAMP.¹⁶ Considerable efforts were made in the development of ligands and catalysts capable of inducing stereoselectivity in catalysed reactions. In 2001, the Nobel Prize in Chemistry was awarded to William Standish Knowles and Ryoji Noyori “for their work on chirally catalysed hydrogenation reactions”, and Karl Barry Sharpless “for his work on chirally catalysed oxidation reactions”.¹⁷

12 (a) J. F. Young, J. A. Osborn, F. H. Jardine, G. Wilkinson Chem. Commun. (London) 1965, 131. (b) J. A. Osborn, F. H. Jardine, J. F. Young, G. Wilkinson J. Chem. Soc. A. 1966, 1711.

13 For book chapters on hydrocyanation, see: (a) A. L. Casalnuovo, T. V. R. Babu Transition Metals for Organic Synthesis: Building Blocks and Fine Chemicals, Second Revised and Enlarged Edition, M. Beller, C. Bolm Eds., Wiley-VCH Verlag GmbH, Weinheim, 2004, chapter 2.6. (b) T. V. RajanBabu Organic Reaction, Vol. 75, S. E.

Denmark Ed., John Wiley & Sons Inc., New York, 2011, chapter 1.

14 (a) For a review on the Monsanto process, see: D. Forster Adv. Organomet. Chem. 1979, 17, 255. (b) For a book chapter on carbonylation of methanol, see: A. Haynes Advances in Catalysis, Vol. 53, B. C. Gates, H.

Knoezinger, F. C. Jentoft Eds., Academic Press Inc., San Diego, 2010, chapter 1.

15 For book chapters on hydroformylation, see: (a) B. Bernhard Topics in Organometallic Chemistry, Vol. 24, J.

M. Brown, P. H. Dixneuf, A. Fürstner, L. S. Hegedus, P. Hofmann, P. Knochel, G. van Koten, S. Murai, M. Reetz Eds., Springer GmbH, 2007, 145-168. (b) L. T. Mika, I. T. Horváth Science of Synthesis: Water in Organic Synthesis, S. Kobayashi Ed., Georg Thieme Verlag, Stuttgart, 2012, chapter 3.3.

16 For a book chapter on asymmetric hydrogenation, see: G. Shang, W. Li, X. Zhang Catalytic Asymmetric Synthesis, Third Edition, I. Ojima Ed., John Wiley & Sons Inc., Hoboken, 2010, chapter 7.

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9 Scheme 1-2 Selection of industrial homogeneous catalysis developed in the 60’s and 70’s Most of d-block elements have found use in catalysis, and astonishing reactions could be achieved in homogeneous catalysis. Among the most prestigious are the olefin metathesis and the palladium- catalysed cross-couplings. The Nobel Prize in Chemistry was awarded in 2005 to Yves Chauvin, Robert Howard Grubbs and Richard Royce Schrock “for the development of the metathesis method in organic chemistry”,¹⁸ and in 2010 to Richard Fred Heck, Ei-ichi Negishi and Akira Suzuki “for palladium-catalysed cross couplings in organic synthesis”.¹⁹ Catalysed C–H activation reactions are

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10 also among the developing new reactivity that might be the topic of a future Nobel Prize in the coming years.

The increasing demand for efficient new catalytic processes has prompted the scientists toward a better comprehension of the reaction mechanisms involved in such transformation. Several tools and techniques have been developed to reach this goal:²⁰

- Kinetic measurements: the rate law of a reaction can be determined experimentally by monitoring the variation of concentration of a reagent or product versus time.

- Electronic spectroscopy: structures and dynamics of atoms and molecules can be studied by observing transitions between different electronic states.

- Vibrational spectroscopy: molecular structures can be elucidated by assessing the vibrational information of a compound.

- X-ray absorption spectroscopy: local geometry and electronic structure can be determined by measuring the linear absorption coefficient.

- Nuclear magnetic resonance: can detect nuclei of diamagnetic compounds (and even some paramagnetic compounds).

- Electron paramagnetic resonance: can be used to study molecules with unpaired electron.

- Theoretical calculations: the density functional theory can model the electronic structure, the exchange and correlation interactions of a given system.

In the Mazet group we place as much importance on the development of new catalytic processes as on the understanding of the reaction mechanism. The following manuscript will detail the work on the synthesis of aldehydes via metal-catalysed isomerisation reactions in homogeneous system and the studies of ligands and catalysts to perform these transformations. Each chapter starts by a presentation of the topic addressed before discussing the results obtained. In chapter 2, an inversion at the stereogenic phosphorus centre of a C1-symmetric (P,N)-ligand is investigated both experimentally and theoretically. Additional characterisations and the influence of the P- stereocentre in catalysis are also detailed. The topic of chapter 3 is the development of a general protocol for the isomerisation of disubstituted terminal epoxides using a well-defined and air-stable iridium hydride catalyst, and the studies of the reaction mechanism. This iridium hydride catalyst was also used in similar conditions for the isomerisation of allylic alcohols. The scope of the reaction and the mechanistic studies that led to the identification of an uncommon mechanism for this transformation are disclosed in chapter 4. The stereoselective synthesis of octahedral stereogenic-

20 E. Roduner Chem. Soc. Rev. 2014, 43, 8226.

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11 at-metal complexes is treated in chapter 5, along with the studies by theoretical calculations of the inversion process between two stereoisomers obtained. A general conclusion on this manuscript is given in chapter 6. Additional experimental details are given in chapter 7.

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2. Study of the inversion of configuration of a stereogenic phosphorus centre in C

1

-symmetric chiral (P,N)-ligands developed for the enantioselective intramolecular α- arylation of aldehydes

Abstract: A new class of ligands was previously synthesised by our group to achieve the enantioselective intramolecular α-arylation of aldehydes. Starting from the binepine-borane adduct, a nucleophilic substitution (SN2) was performed. If the substituent R on the phosphorus is large the reaction produces a single product: (Ra,R,RP)-26•BH3. However, if the substituent R is smaller the reaction becomes less selective and another diastereomer is formed, which possesses the opposite configuration only at the phosphorus centre. These two products are separable by column chromatography. An inversion of configuration occurred when (Ra,R,SP)-26•BH3 was engaged in standard deprotection procedure. New conditions were developed to avoid such process to take place. Once borane-free (Ra,R,SP)-26 isolated, this inversion was studied by NMR spectroscopy. The thermodynamic parameters of the reaction were calculated. The impact of the stereochemistry at the phosphorus centre was evaluated in catalysis. These experimental measurements were further substantiated by DFT calculations in collaboration with Dr Evgeny Larionov.

The results disclosed in this chapter have been published: N. Humbert, E. Larionov, L. Mantilli, P.

Nareddy, C. Besnard, L. Guénée, C. Mazet Chem. Eur. J. 2014, 20, 745.

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2.1 Introduction: from the design of a (P,N)-ligand to inversion at phosphorus

2.1.1 α-Arylation of aldehydes

The first example of α-arylation of α-branched aldehydes was published in 1999 by Muratake and Nakai.²¹ This intramolecular reaction was performed by treatment of aldehyde 15 with 10 mol% of [PdCl2(PPh3)2] in presence of 3.0 equivalents of Cs2CO3 to afford α-arylated aldehyde 16 in 52% yield (scheme 2.1.1-1).

Scheme 2.1.1-1 First example of palladium-catalysed α-arylation of aldehydes

Later on, Miura and co-workers described an intermolecular Pd-catalysed α-arylation of linear aldehydes with aryl bromides (scheme 2.1.1-2).²² The active catalyst was generated in situ using 5 mol% of [Pd(OAc)2] as palladium source and 10 mol% of tri-tert-butylphosphine (Pt-Bu3) as ligand.

Products were obtained with moderate yields, from 36 to 67%.

Scheme 2.1.1-2 Intermolecular palladium-catalysed α-arylation of aldehydes

Following this report, Martín and Buchwald investigated the intermolecular α-arylation of aldehydes using similar Pd/phosphine systems (scheme 2.1.1-3).²³ Linear aldehydes were coupled with aryl bromide using 2 mol% [Pd(OAc)2] and 3 mol% of rac-BINAP (20). Aryl chlorides were also reacted but bulkier and more electron-rich biaryl ligand 21 was required. The reaction was conducted on α- branched aldehydes using ligand 22.

21 H. Muratake, H. Nakai Tetrahedron Lett. 1999, 40, 2355.

22 Y. Terao, Y. Fukuoka, T. Satoh, M. Miura, M. Nomura Tetrahedron Lett. 2002, 43, 101.

23 R. Martín, S. L. Buchwald Angew. Chem. 2007, 119, 7374.

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14 Scheme 2.1.1-3 Intermolecular α-arylation of linear and α-branched aldehydes

García-Fortanet and Buchwald also developed a procedure for the asymmetric intramolecular α- arylation of α-branched aldehydes.²⁴ During the optimisation process, different ligands were screened. It was found that heterotopic (P,N)-ligands were superior to homotopic diphosphine ligands for this transformation. The best set of conditions delivered the products in 27 to 88% yield and with enantiomeric excesses (ee) from 53 to 98% using 3 mol% of [Pd(OAc)2] and 9 mol% of (S)-25 (scheme 2.1.1-4).

Scheme 2.1.1-4 Asymmetric intramolecular α-arylation of α-branched aldehydes

Based on the observation made by Buchwald, our group designed a novel family of C1-symmetric (P,N)-ligands based on the binepine scaffold to perform the palladium-catalysed asymmetric intramolecular α-arylation of α-branched aldehydes (scheme 2.1.1-5).²⁵ The structure of these ligands features three distinct elements of chirality: 1) an axial chirality on the binaphthyl moiety, 2) a carbon stereocentre in benzylic position, and 3) a phosphorus stereocentre. The synthesis of these ligands will be described in the following part of this manuscript. After extensive ligand optimisation, α-arylated aldehydes were obtained in 6 to >99% yields with 20 to 98% ee using 5 mol% of

24 J. García-Fortanet, S. L. Buchwald Angew. Chem. Int. Ed. 2008, 47, 8108.

25 P. Nareddy, L. Mantilli, L. Guénée, C. Mazet Angew. Chem. Int. Ed. 2012, 51, 3826.

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15 [Pd(OAc)2] and 10 mol% of (Ra,R,RP)-26 (12 examples). When other halides were used instead of bromides yields dropped significantly while maintaining a very high level of enantioselectivity. Six- membered rings were also formed quantitatively; however, the enantiomeric induction of the reaction was drastically reduced.

Scheme 2.1.1-5 Asymmetric intramolecular α-arylation of α-branched aldehydes with a new class of (P,N)-ligands

2.1.2 Synthesis of chiral atropoisomeric (P,N)-ligands

Binepines are monodentate phosphine ligands that possess axial chirality on the binaphthyl moiety.

Gladiali et al. first synthesised this ligand in 1994.²⁶ Starting from 1-bromo-2-metylnaphthalene (27), it was coupled with Grignard reagent 28 under nickel-catalysed Kumada-Corriu cross-coupling conditions. Treatment with butyllithium (n-BuLi) and N,N,N’,N’-tetramethylethylenediamine (TMEDA) of the resulting 2,2’-dimethyl-1,1’-binapthalene (rac-29) followed by a dichlorophenylphosphine quench afforded ligand rac-30. Enantiopure binepine ligand (Sa)-30 was subsequently isolated by resolution using chiral Pd-amine complex 31 (scheme 2.1.2-1).

26 S. Gladiali, A. Dore, D. Fabbri, O. De Lucchi, M. Manassero Tetrahedron: Asymmetry 1994, 5, 511.

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16 Scheme 2.1.2-1 First synthesis of binepine ligands

An improved synthesis was later published by Beller and co-workers (scheme 2.1.2-2).²⁷ The idea was to avoid the use of expensive chiral Pd-amine complex 31. For this reason, enantiopure (Sa)- BINOL ((Sa)-32) was used as starting material. Triflation followed by Ni-catalysed Kumada-Corriu cross-coupling afforded (Sa)-29. After lithiation, intermediate (Sa)-33 was obtained and subsequently quenched with different dichlorophosphine derivatives to provide enantiopure binepine ligands (Sa)- 30. A second strategy was established to overcome the lack of availability of dichlorophosphine reagents. Intermediate (Sa)-33 was reacted in presence of dichloro(diethylamino)phosphine to give diethylaminophosphepine intermediate (Sa)-34. Chlorination using HCl gas delivered chlorophosphepine (Sa)-35 that could be coupled with Grignard or organolithium reagents to form the corresponding enantiopure binepine ligands (Sa)-30.

27 K. Junge, G. Oehme, A. Monsees, T. Riermeier, U. Dingerdissen, M. Beller Tetrahedron Lett. 2002, 43, 4977.

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17 Scheme 2.1.2-2 Improved synthesis of binepine ligands

The possibility to further derivatise the binepine scaffold was demonstrated by the Widhalm group (scheme 2.1.2-3).²⁸ Treatment of 2,2-dimethyl binaphthalene ((Sa)-29) with n-BuLi in presence of TMEDA followed by a quench using dichlorophenylphosphine and then sulfur delivered thiophosphine (Sa)-36. Substituents were introduced at the benzylic position by an electrophilic quench after deprotonation with tert-butyllithium (t-BuLi). This reaction generates two stereogenic centres: one at the benzylic carbon centre, and the second one at the phosphorus centre. Mixtures of two isomers in ratio from 3:1 to 5:1 were obtained and could be separated by column chromatography. The stereochemical identity of (Sa,S,RP)-37 (major) and (Sa,S,SP)-37 (minor) were determined by X-ray crystal structure analysis. The relative accessibility of the hydrogens in pseudo- axial position at the benzylic carbon accounts for the preferential mono-subtitution trans to the P- phenyl group. Desulfuration with Raney nickel gave the corresponding free binepine ligands.

Scheme 2.1.2-3 Synthesis of -substituted binepines

28 P. Kasák, K. Mereiter, M. Widhalm Tetrahedron: Asymmetry 2005, 16, 3416.

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18 Using this methodology, a new type of chiral bidentate ligand bearing a phosphine and an olefinic moiety was synthesised by the same group (scheme 2.1.2-4).²⁹ Borane-protected binepine ligand (Sa)-30a•BH3 was deprotonated at the benzylic position by n-BuLi before undergoing nucleophilic substitution on cinnamyl chloride (38) to form the borane-protected (P,²-olefin)-ligand as a single stereoisomer. Deprotection with diethylamine generates borane-free bidentate ligand (Sa,S,RP)-39.

Scheme 2.1.2-4 Synthesis of binepine-olefin chiral ligand

Inspired by this work, the Mazet group envisaged to create a new type of C1-symmetric chiral bidentate (P,N)-ligand by simply introducing a 2-methylpyridyl unit at the benzylic position of the binepine scaffold.²⁵ With this strategy, the steric and electronic properties of these ligands could be easily tuned through modular assembly of the phosphine- and nitrogen-containing building blocks.

The synthesis of the binepine moiety derived from Beller’s procedure was previously described (scheme 2.1.2-5). Starting with commercially available (Ra)-BINOL ((Ra)-32), 2,2’-dimethyl-1,1’- binapthalene ((Ra)-29) was obtained in two steps using the literature conditions. Treatment with n- BuLi in presence of TMEDA in Et2O delivered dilithiated species (Ra)-33 after three days at 23 °C without stirring of the solution. This salt was reacted with different commercially available bischlorophosphines in hexane at 80 °C. After quenching the reaction, the intermediate was protected using BH3•THF. Binepine products (Ra)-30a-d•BH3 were isolated with good yields (75–82%) after purification by column chromatography.

29 P. Kasák, V. B. Arion, M. Widhalm Tetrahedron: Asymmetry 2006, 17, 3084.

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19 Scheme 2.1.2-5 Synthesis of binepine building blocks

As the variety of commercially available bischlorophosphine is quite limited, a modified procedure inspired by the second strategy reported by Beller was used to introduce electron-rich aromatics on the binepine phosphorus (scheme 2.1.2-6). Starting from dilithiated species (Ra)-33, reaction with diethylaminodichlorophosphine and subsequent treatment by HCl (2 M in Et2O) at room temperature provides chlorophosphepine (Ra)-35. This key intermediate was further reacted with the appropriate Grignard reagents followed by borane protection to produce the corresponding binepine-borane adducts (Ra)-30e-h•BH3 with moderate yields (28–56%).

This library of protected binepines was further derivatised via nucleophilic substitution using t-BuLi to generate a carbanion, which was quenched by addition of the appropriate electrophile (41). A single product (26) with three elements of chirality (an axial chirality, a carbon stereocenter and a phosphorus stereocentre) was afforded in most cases except when the substituent on the phosphorus R¹ was a phenyl ring (scheme 2.1.2-7). In that case, two diastereomers with opposite configuration exclusively at the phosphorus centre were formed with a 2:1 ratio in favour of the (Ra,R,RP) product (scheme 2.1.2-8).

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20 Scheme 2.1.2-6 Synthesis of binepine building blocks with an electron-rich aromatic substituent

on the phosphorus

Entry R¹ R² Product Yield

%

1 Et H (Ra,R,RP)-26ba•BH3 80

2 Cy H (Ra,R,SP)-26ca•BH3 82

3 t-Bu H (Ra,R,RP)-26da•BH3 65

4 t-Bu Me (Ra,R,RP)-26db•BH3 79

5 t-Bu Ph (Ra,R,RP)-26dc•BH3 52

6 2-MeO-C₆H₄ H (R_a,R,R_P)-26ea•BH₃ 39

7 2,4-(MeO)2-C6H3 H (Ra,R,RP)-26fa•BH3 43 8 2,4-(i-PrO)2-C6H3 H (Ra,R,RP)-26ga•BH3 49 9^a 2,4,6-(MeO)3-C6H2 H (Ra,R,RP)-26ha•BH3 19

a reaction performed using n-BuLi instead of t-BuLi

Scheme 2.1.2-7 Nucleophilic substitutions leading to the protected (P,N)-ligands³⁰

30The absolute configuration of the major isomer is (Ra,R,RP) for all ligands except 26ca, which is (Ra,R,SP). This is a formal consequence of the relative priority between all P-substituents according to the CIP rules.

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21 Entry R² Product 1 Yield

% Product 2 Yield

% 1 H (Ra,R,RP)-26aa•BH3 51 (Ra,R,SP)-26aa•BH3 14 2 Me (Ra,R,RP)-26ab•BH3 53 (Ra,R,SP)-26ab•BH3 18

Scheme 2.1.2-8 Nucleophilic substitutions leading to two diastereomeric protected (P,N)-ligands To complete this synthesis, the phosphine-borane adducts were deprotected. Removal of the protecting group was achieved by refluxing 26•BH3 in neat diethylamine for three days^.The corresponding borane-free (P,N)-ligands 26 were isolated in moderate to excellent yields (scheme 2.1.2-9).

Entry Starting Material R¹ R² Product Yield

%

1 (Ra,R,RP)-26aa•BH3 Ph H (Ra,R,RP)-26aa 94

2 (R_a,R,R_P)-26ab•BH₃ Ph Me (R_a,R,R_P)-26ab 85

3 (Ra,R,RP)-26ba•BH3 Et H (Ra,R,RP)-26ba 86

4 (Ra,R,SP)-26ca•BH3 Cy H (Ra,R,SP)-26ca 80

5 (Ra,R,RP)-26da•BH3 t-Bu H (Ra,R,RP)-26da 80

6 (Ra,R,RP)-26db•BH3 t-Bu Me (Ra,R,RP)-26db 60

7 (Ra,R,RP)-26dc•BH3 t-Bu Ph (Ra,R,RP)-26dc 68

8 (R_a,R,R_P)-26ea•BH₃ 2-MeO-C₆H₄ H (R_a,R,R_P)-26ea 83 9 (Ra,R,RP)-26fa•BH3 2,4-(MeO)2-C6H3 H (Ra,R,RP)-26fa 90 10 (R_a,R,R_P)-26ga•BH₃ 2,4-(i-PrO)₂-C₆H₃ H (R_a,R,R_P)-26ga 83 11 (Ra,R,RP)-26ha•BH3 2,4,6-(MeO)3-C6H2 H (Ra,R,RP)-26ha 60

Scheme 2.1.2-9 Deprotection of the borane-protected (P,N)-ligands

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22 Surprisingly, quantitative inversion of the stereogenic phosphorus centre has occurred for the two minor diastereomers (Ra,R,SP)-26aa•BH3 and (Ra,R,SP)-26ab•BH3 previously obtained upon SN2 reaction on (Ra)-30a•BH3 (scheme 2.1.2-10).³¹

Scheme 2.1.2-10 Deprotection and stereoinversion at the phosphorus of the borane-protected (P,N)-ligands

2.1.3 Conformational stability and inversion barrier of the phosphorus atom

Inversion of configuration is a known process of trivalent elements from group 15 (scheme 2.1.3-1).

It has been proposed to generally go through a planar transition state where the lone pair is located in a pure p-orbital. The energy penalty associated with the sp³→sp² rehybridisation is dependant of the s-character of the lone pair. For the third row phosphorus element, the lone pair possesses a strong s-character. Owing to the lower electronegativity of the P atom, the s-character of the bonding orbitals is decreased leading to 1s-3p overlap greater than 1s-3s overlap.³² In contrast, for the more electronegative nitrogen atom, 1s-2p overlap is considerably less favourable than 1s-2s.

Therefore, the energy barrier for the configurational inversion is decreased as a result of the low s- character of the nitrogen lone pair.

In this part of the chapter, emphasis will be placed on the various systems involving a phosphorus inversion that have been previously studied.^33,34

31 Pradeep Narredy PhD Manuscript. University of Geneva, Director: Professor Clément Mazet, 2013.

32 C. C. Levin J. Am. Chem. Soc. 1975, 97, 5649.

33 For recent studies on the nitrogen inversion, see: (a) A. E. Aliev, A. J. Sinclair, S. Zhou, J. D. Wilden, S.

Caddick, D. M. Kullmann, D. A. Rusakov J. Phys. Org. Chem. 2009, 22, 607. (b) O. Trapp, L. Sahraoui, W.

Hofstadt, W. Könen Chirality 2010, 22, 284. (c) L. Degennaro, R. Mansueto, E. Carenza, R. Rizzi, S. Florio, L. M.

Pratt, R. Luisi Chem. Eur. J. 2011, 17, 4992. (d) P. K. Eckert, V. H. Gessner, M. Knorr, C. Strohmann Inorg. Chem.

2012, 51, 8516. (e) V. V. Kuznetsov Russian J. Org. Chem. 2014, 50, 143.

34 For report on arsenic inversion, see: (a) G. H. Senkler, Jr., K. Mislow J. Am. Chem. Soc. 1972, 94, 291. (b) R. D.

Baechler, J. P. Casey, R. J. Cook, G. H. Senkler, Jr., K Mislow J. Am. Chem. Soc. 1972, 94, 2859. (c) R. H. Bowman, K. Mislow J. Am. Chem. Soc. 1972, 94, 2861.

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23 Scheme 2.1.3-1 General information and inversion barrier energies of group 15 elements³⁵ The parameters influencing the conformational stability of stereogenic trivalent alkyl and aryl phosphine compounds have been extensively studied by Mislow in the early 70’s. The observations he made are now considered as the standard rules for pyramidal inversion and will be detailed below:

 No significant influence can be attributed to the steric parameter of the phosphorus substituents (scheme 2.1.3-2).³⁶ Indeed, increasing the steric bulk by going from a linear propyl group to a tert-butyl group (entries 1 and 2) gives only a 0.6 kcal.mol^1 increase of the energy barrier for pyramidal inversion.

Entry R G^ǂ₄₀₃

kcal.mol^–1

1 n-Pr 32.1

2 t-Bu 32.7

3 -CH2-CH=CH2 32.8

Scheme 2.1.3-2 Influence of steric parameters on phosphorus inversion

 Delocalisation of the lone pair of electron of the phosphorus stabilises the transition state, and therefore decreases the energy penalty of the inversion process (scheme 2.1.3-3).³⁶Allowing (p- p) movement of electrons by replacement of a cyclohexyl ring by phenyl group (entries 1 and 2) results in a 3.5 kcal.mol^–1 drop on the inversion barrier. Electron-withdrawing substituents on the para position of the aromatic permit better delocalisation than electron-rich aryls (entries 3 and 5).

35 (a) R. E. Weston, Jr. J. Am. Chem. Soc. 1954, 76, 2645. (b) G. W. Koeppl, D. S. Sagatys, G. S. Krishnamurthy, S.

I. Miller J. Am. Chem. Soc. 1967, 89, 3396.

36 R. D. Baechler, K. Mislow J. Am. Chem. Soc. 1970, 92, 3090.

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24

Entry R¹ R² G^ǂ₄₀₃

kcal.mol^1

1 C6H11 n-Pr 35.6

2 C6H5 n-Pr 32.1

3 C6H5 p-MeOC6H4 30.8 4 C6H5 p-CH3C6H4 30.3 5 C6H5 p-CF3C6H4 29.1

Scheme 2.1.3-3 Influence of the delocalisation of the lone pair on phosphorus inversion

 The energy associated with the pyramidal inversion increases proportionally with the electronegativity of the substituents (scheme 2.1.3-4).³⁷

Entry R Y _y^a G^ǂ

kcal.mol^–1

1 Me C 2.55 32.7

2 i-Pr Si 1.90 18.9

3 i-Pr Ge 2.01 21.4

4 i-Pr Sn 1.96 19.3

a Allred electronegativity of the element.³⁸

Scheme 2.1.3-4 Influence of the substituent electronegativity on phosphorus inversion

37 R. D. Baechler, K. Mislow J. Am. Chem. Soc. 1971, 93, 773.

38 A. L. Allred J. Inorg. Nucl. Chem. 1961, 17, 215.

Si Sn Ge

C

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25 Additional observations were made for cyclic phosphorus containing systems by Cremer, and later by Bachrach:

 The energy barrier for the inversion of phosphorus increases along with the angle-strain imposed by the ring in the transition state (scheme 2.1.3-5).³⁹ Due to the geometric restriction in a three-membered ring compared to an acyclic analogue, the energetic penalty raises from 41.5 to 68.3 kcal.mol^–1. Going from a three-membered to a four-membered ring lowers this barrier to 42.7 kcal.mol^–1.

Scheme 2.1.3-5 Influence of the angle-strain on phosphorus inversion⁴⁰

 Steric parameters play a more important role in cyclic systems. More sterically demanding groups tend to lower the energy required by destabilisation of the ground state (scheme 2.1.3- 6).⁴¹ Replacement of the phosphorus-R substituent on 2,2,3,4,4-pentamethylphosphetane 46b(R) from a methyl group to a tert-butyl group enables the inversion process to take place (entries 1 and 3). The equilibrium between the two conformations is displaced in favour of the compound where the methyl in position 3 and the substituent on the phosphorus are trans to each other.

Entry R H^ǂ

kcal.mol^–1

S^ǂ

cal.K^–1.mol^–1 G^ǂ

kcal.mol^–1 k1/k–1

1^a Me - - - -

2^b Ph 29.8 8 33.0 1.5

3^c t-Bu 28.2 8 31.4 1.3

a No inversion after 4 days at 162 °C

b Inversion monitored at 112.0, 143.2, 165.4 and 190.2 °C.

c Inversion monitored at 118.8, 131.6, 145.0 and 157.0 °C.

Scheme 2.1.3-6 Influence of steric parameters on phosphorus inversion in cyclic system

39 S. M. Bachrach J. Phys. Chem. 1989, 93, 7780.

40 Calculated energies. MP2/6-31G*//HF/6-31G* + ZPE(3-21G(*)).

41 S. E. Cremer, R. J. Chorvat, C. H. Chang, D. W. Davis Tetrahedron Lett. 1968, 55, 5799.

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26 An abnormally low inversion barrier was measured by the Gladysz group in the case of a macrobicycle aliphatic dibridgehead diphosphine (47).⁴² When recorded at low temperature in toluene-d8, ³¹P EXSY NMR experiment gave evidence for an equilibrium with a 97:3 ratio between two conformers of the compound. The energy barrier of the process has been calculated by line- broadening analyses: 11.5 kcal.mol^–1 from major to minor and 10.4 kcal.mol^–1 from minor to major.

These values are notably lower than the usual range for pyramidal inversion barrier of trialkylphosphines (29–36 kcal.mol^–1) indicating that another mechanism is involved here. An exclusive conformational process, allowing to invert from the in,in to the out,out isomer, achieved by simply puling one of the three chains through the macrocycle defined by the two remaining chains accounts for this low energy penalty (scheme 2.1.3-7). Upon heating at 150 °C, a classical inversion via a planar intermediate takes place with a 33.8 kcal.mol^–1 energy barrier and results in a 51:49 mixture between [in,in-47/out,out-47] and in,out-47.

Scheme 2.1.3-7 Conformational and pyramidal inversion of the phosphorus in dibridgehead macrobicycle

Recently, Radosevich and co-workers have reported a decrease in the inversion barrier of stereogenic tertiary phosphines by catalysed single-electron oxidation (scheme 2.1.3-8).⁴³ Racemisation of enantioenriched mixtures of phosphine could be achieved at room temperature in

42 M. Stollenz, M. Barbasiewicz, A. J. Nawara-Hultzsch, T. Fiedler, R. M. Laddusaw, N. Bhuvanesh, J. A. Gladysz Angew. Chem. Int. Ed. 2011, 50, 6647.

43 K. D. Reichl, D. H. Ess, A. T. Radosevich J. Am. Chem. Soc. 2013, 135, 9354.

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27 30 minutes. Computation of the transition state for the inversion of phosphoniumyl radical cations was found to be geometrically almost identical to the phosphine planar transition states but with considerably reduced levels of energy (4–5 kcal.mol^–1).⁴⁴

Scheme 2.1.3-8 Racemisation of stereogenic phosphines by single-electron transfer catalysis The configurational stability resulting from the high inversion barrier for tertiary phosphines has permitted the development of a vast range of ligands containing at least one stereogenic phosphorus centre (scheme 2.1.3-9). Their uses in asymmetric catalysis have revealed to be essential to induce selectivity in some reactions.

45,46,47,48 = 45,46,47,48

Scheme 2.1.3-9 Non-exhaustive list of monodentate and bidentate (P,P)- or (P,N)-ligands containing a phosphorus stereogenic centre

44 (U)M06-2X/6-31G(d,p) in SMD acetonitrile.

45 A. M. Taylor, R. A. Altman, S. L. Buchwald J. Am. Chem. Soc. 2009, 131, 9900.

46 E. Vedejs, O. Daugulis J. Am. Chem. Soc. 2003, 125, 4166.

47 M. L. Christ, M. Zablocka, S. Spencer, R. J. Lavender, M. Lemaire, J. P. Majoral J. Mol. Catal. A 2006, 245, 210.

48 L. Fanfoni, A. Meduri, E. Zangrando, S. Castillon, F. Felluga, B. Milani Molecules 2011, 16, 1804.

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28

2.2 Mazet’s (P,N)-ligands: large scale synthesis and physical characterisation

Considering the latent possibility to further tune the steric and electronic properties of Mazet’s C1- symmetric chiral (P,N)-ligand, our group grows convinced of the great potential of this scaffold in mechanistically non-related asymmetric reactions.

2.2.1 Multi-gram synthesis of (Ra,R,RP)-12da•BH3

The increasing use of the C1-symmetric chiral (P,N)-ligand to induce selectivity in the reactions developed by the Mazet group⁴⁹ has prompted us to challenge the scalability of its initial synthetic route.

Synthesis of the pivotal binepine (30) has been previously reported has highly scalable.

A 201 g scale synthesis of (Sa)-2,2’-dimethyl-1,1’binaphtyl ((Sa)-29) was achieved by Zhang and co- workers starting from 344 g of commercially available (Sa)-BINOL ((Sa)-32) (scheme 2.2.1-1).⁵⁰ The product was obtained with 88% yield after triflation and subsequent Kumada-Corriu coupling.

Scheme 2.2.1-1 200 g scale synthesis of (Sa)-2,2’-dimethyl-1,1’binaphtyl

After dilithiation of 21 g of (Sa)-29 followed by an electrophilic quench with tert- butyldichlorophosphine, the Beller group was able to synthesise a 13.2 g batch of tert-butylbinepine (Sa)-30d (scheme 2.2.1-2).⁵¹ This two steps sequence has an overall yield of 49 to 65%.

49 G. M. Borrajo-Calleja, V. Bizet, T. Buergi, C. Mazet Chem. Sci. 2015, 6, 4807.

50 W. Tang, W. Wang, Y. Chi, X. Zhang Angew. Chem. Int. Ed. 2003, 42, 3509.

51 S. Enthaler, G. Erre, K. Junge, J. Holz, A. Börner, E. Alberico, I. Nieddu, S. Gladiali, M. Beller Org. Process R&D 2007, 11, 568.

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29 Scheme 2.2.1-2 13.2 g scale synthesis of (Sa)-tert-butylbinepine

Following the procedure reported by the Mazet group,²⁵ 3.3 g of tert-butylbinepine-borane adduct ((Ra)-30d•BH3) were synthesised in 60% yield after five steps. Binepine (Ra)-30d•BH3 was further treated with tert-butyllithium at 78 °C followed by reaction with 2-bromomethylpyridine (41) to afford the corresponding borane-protected (P,N)-ligand (Ra,R,RP)-26da•BH3 as a single product in 79% yield after standard purification by column chromatography. Removal of the protecting group by refluxing in neat diethylamine for three days yielded 3.0 g (96% yield) of ligand (Ra,R,RP)-26da (scheme 2.2.1-3).

Scheme 2.2.1-3 3.0 g scale synthesis of (Ra,R,RP)-26da

A rationale for the high levels of stereoselectivity (>20:1) observed in the nucleophilic substitution reaction has been proposed based on X-ray crystallography analysis. A front view of cyclohexylbinepine ((Ra)-30c) shows that out of the two hydrogens in a pseudo-apical position susceptible to deprotonation upon basic treatment, one is clearly more accessible whereas the second is shielded by the large substituent on the phosphorus and the binaphthyl moiety. A view along the same axis of the corresponding (Ra,R,SP)-26ca•BH3 crystal structure clearly indicates that substitution has occurred on the more accessible position (scheme 2.2.1-4).

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30 Scheme 2.2.1-4 Rationale for the high level of stereoselectivity observed during ligand synthesis⁵² Gram scale reaction starting from protected phenylbinepine (Ra)-30a•BH3 (1.6 g) was also performed (scheme 2.2.1-5). Following the same procedure as before, two diastereomers that differed only in the absolute configuration of the phosphorus stereocentre were obtained with a 1.4:1 ((Ra,R,RP):(Ra,R,SP)) ratio by NMR of the crude product. Separation of the two (P,N)-ligand precursors by column chromatography proved to be particularly challenging due to the overlap of the isomers and the presence of decomposition products derived from the electrophile. While 743 mg of (Ra,R,RP)-26aa•BH3 were isolated, only 260 mg of (Ra,R,SP)-26aa•BH3 were obtained in pure form.

Inspection of the front views of the molecular structure of each protected diastereomeric ligand indicates that, indeed, both pseudo-apical protons in phenylbinepine precursor (Ra)-30a•BH3 must have been almost equally susceptible to deprotonation upon rotation of the phenyl ring along the PCipso axis. Attempts to identify the reaction parameters that could influence the outcome of the reaction in favour of the (Ra,R,SP) product (temperature at addition, duration and rate of the temperature gradient, reaction time, …) were unsuccessful.

The major compound was engaged with another batch (880 mg) in deprotection reaction affording after three days 753 mg (88% yield) of borane-free (Ra,R,RP)-26aa. Submitting (Ra,R,SP)-26aa•BH3 to the exact same conditions gave quantitative inversion of the stereogenic phosphorus centre.

Another protocol to conduct the deprotection of (Ra,R,SP)-26aa without any stereoinversion had to be identified.

52 X-Ray solved by Dr Laure Guénée and Dr Céline Besnard.

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31 Scheme 2.2.1-5 Gram scale reaction on the protected (Ra)-phenylbinepine and X-ray structures

of the two diastereomers formed upon nucleophilic substitution⁵³

An attempt to perform the deprotection step with diethylamine at room temperature resulted in a considerable increase in reaction time. Monitoring of the reaction indicated complete conversion was reached after 30 days. Unfortunately, removal of the volatiles under vacuum to isolate the product led to partial re-protection of the phosphine (ca. 20%). This might be due to the higher accessibility of the lone pair of electron of the phosphorus in (Ra,R,SP)-26aa.

Using excess 1,4-diazabicyclo[2.2.2]octane (DABCO) at room temperature in toluene led to quantitative deprotection after seven days (scheme 2.2.1-6). Borane-free (P,N)-ligand (Ra,R,SP)-26aa was isolated in 59% yield after a rapid filtration over degassed silica under inert atmosphere in the glove box.

53 X-Ray solved by Dr Laure Guénée.

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32 Scheme 2.2.1-6 DABCO deprotection of (Ra,R,SP)-26aa•BH3

2.2.2 Physical characterisation of (P,N)-ligand derivatives 26

With the two diastereomers of 26aa in hand, we sought to carry out the study of the phosphorus inversion in this system in more details along with further physical characterisation.

2.2.2.1 Oxidation

It has been observed that ligand (Ra,R,RP)-26da is resistant to oxidation both in the solid state and in solution for weeks. It can therefore be conveniently handled in usual laboratory atmosphere. On the other hand, while the major phenyl derivative (Ra,R,RP)-26aa was slowly oxidised in solution (CDCl3), (Ra,R,SP)-26aa displayed a faster oxidation rate under the same conditions (scheme 2.2.2.1-1). This strong difference has been attributed to the increased availability of the phosphorus lone pair in the minor isomer, as can be deduced from the comparative X-ray analyses of the two borane-protected precurssors (scheme 2.2.1-5).

Scheme 2.2.2.1-1 Oxidation profile of (P,N)-ligands 26 in a CDCl3 solution measured by ³¹P{¹H} NMR

Recent advances in catalyst and ligand design for metal-catalysed isomerisation reactions

Thesis

Reference

Recent advances in catalyst and ligand design for metal-catalysed isomerisation reactions

Recent Advances in Catalyst and Ligand Design for Metal- Catalysed Isomerisation Reactions

THÈSE

Nicolas HUMBERT

Table of Contents

Acknowledgments

Résumé en français

1. On the Way to the Development of Catalysis

2. Study of the inversion of configuration of a stereogenic phosphorus centre in C

-symmetric chiral (P,N)-ligands developed for the enantioselective intramolecular α- arylation of aldehydes

2.1 Introduction: from the design of a (P,N)-ligand to inversion at phosphorus

2.2 Mazet’s (P,N)-ligands: large scale synthesis and physical characterisation