Synthesis and Study of New Oxazoline-Based Ligands

Mélanie Tilliet

KTH Chemical Science and Engineering

D octoral Thesis

Stockholm 2008

Akademisk avhandling som med tillstånd a v Kungliga Tekniska Högskolan i Stockholm framlägges till offentlig granskning för avläggande av teknologie doktorsexamen i kemi med inriktning mot organisk kemi fredagen den 19e: september kl 10.00 i sal E3, KTH, Osquars Backe 14, Stockholm. Avhandlingen förvaras på engelska. Opponent är D oktor J. H. van Maarseveen, Amsterdam, Nederländerna.

ISBN 978-91-7415-093-3 ISSN 1654-1081 TRITA-CHE Report 2008:54

Abstract

This thesis deals with the study of oxazoline-based ligands in metal-catalyzed asymmetric reactions.

The first part describes the synthesis of six new bifunctinal pyridine-bis(oxazoline) ligands and their applications in asymmetric metal-catalysis. These ligands, in addition to a Lewis acid coordination site, are equipped with a Lewis basic part in the 4-position of the oxazoline rings. D ual activation by means of this system was probed in cyanide addition to aldehydes.

The second part is concerned with the synthesis of two pyridine-bis(oxazoline) ligands bearing bulky triazole groups in the 4-position of the oxazoline rings and a macrocyclic ligand consisting of a pyridine-bis(oxazoline) moiety and a diaza-18-crown-6 ether. The synthesis of these compounds benefits from the use of “click chemistry”. The ligands thus obtained were tested in different asymmetric catalytic reactions. Complexation studies with different bifunctional molecules that could bind into the cavity of the macrocycle were carried out using NMR spectroscopy.

A third chapter is devoted to the synthesis of a supported pyridine-bis(oxazoline) catalyst and its use in catalysis. The pyridine-bis(oxazoline) ligand was efficiently connected to a polystyrene resin via a robust triazole linker. This resin could be employed in different metal- catalyzed asymmetric reactions and good results were obtained in terms of yield and enantioselectivity. Moreover, this polymer-bound ligand could be easily and efficiently recycled.

Finally, the last part deals with the use of a hydroxy-containing phosphinooxazoline ligand in the hydrosilylation of imines and in the asymmetric intermolecular Heck reaction. A cationic iridium complex of this ligand was studied by NMR spectroscopy.

Keywords: asymmetric catalysis, pyridine-bis(oxazoline), phosphinooxazoline, multifunctional ligand, dual activation, secondary interaction, polymer-supported ligand, “click chemistry”, Lewis acid, Lewis base.

Résumé

Le sujet de cette thèse est l’étude de ligands comportant un motif bis(oxazoline) pour la catalyse assymétrique organométallique.

La première partie décrit la synthèse et les applications en catalyse assymétrique de six nouveaux ligands pyridine-bis(oxazoline). Ces ligands, en plus d’un site de complexation pour un acide de Lewis, possèdent des fonctions basiques en position 4 des cycles oxazoliniques. U ne double activation au moyen de ces catalyseurs a été testée pour l’addition de cyanures au benzaldéhyde.

La deuxième partie concerne la synthèse de deux ligands pyridine-bis(oxazoline) présentant des groupement encombrés en position 4 des oxazolines et celle d’un macrocycle composé d’une partie pyridine-bis(oxazoline) et d’un diaza éther couronne. La synthèse de ces trois nouveaux ligands emploie avec profit la « click chemistry ». Ces ligands ont été évalués en catalyse assymétrique. La structure de complexes du macrocycle avec differentes molecules bifonctionelles a également été étudiée en RMN.

Le troisième chapitre a pour sujet la synthèse et l’utilisation en catalyse assymétrique organométallique d’un nouveau ligand supporté à motif pyridine-bis(oxazoline). Le ligand a été connecté de façon efficace sur une résine polymère via un groupement triazole robuste. Cette résine a été employée en combinaison avec différents métaux pour catalyser plusieurs réactions catalytiques assymétriques. D e plus, le ligand supporté a pu être recyclé facilement un grand nombre de fois.

Enfin, la dernière partie traite de l’utilisation d’un ligand phosphinooxazoline possèdant une fonction hydroxy liée à l’oxazoline, pour l’hydrosylilation d’imines et la réaction de Heck intermoléculaire assymétrique. U n complexe cationique d’iridium et de ce liagnd a été étudié en RMN.

M ots-clés : catalyse assymétrique, pyridine-bis(oxazoline), phosphinooxazoline, ligand multifunctionel, double activation, interaction secondaire, ligand supporté sur polymère, “click chemistry”, acide de Lewis, base de Lewis.

List of publications

This thesis is based on the following papers gathered at the end of this document:

I. Polym er-Bound Pyridine-Bis(oxazoline). Preparation through C lick C hem istry and Evaluation in A sym m etric C atalysis. Mélanie Tilliet, Stina Lundgren, Christina Moberg and V incent Levacher. Adv. Synth. Catal. 2007, 349, 2079.

II. C onvenient Preparation of Bifunctional Pybox Ligands. Mélanie Tilliet, Anders Frölander, V incent Levacher and Christina Moberg. Tetrahedron, accepted.

III. Influence of Ligand Secondary Interactions on D ynam ic Processes in A lkene Iridium C om plexes. Mélanie Tilliet, Anders Frölander, Krister Z etteberg, Z oltan Szabo and Christina Moberg. Prelim inary m anuscript.

IV . Evaluation of new pyridine-bis(oxazoline) ligands in asym m etric catalysis. Mélanie Tilliet, Anders Frölander, Stina Lundgren, V incent Levacher and Christina Moberg. Prelim inary m anuscript.

Abbreviations and Acronymes

Å Ångström Abs conf absolute configuration Ac acetyl AMP adenosine monophosphate BINAP 2,2'-bis(diphenylphosphino)-1,1'-binaphthyl BINOL 1,1’-bi-2-naphtol °C degrees Celsius Bn benzyl box bis(oxazoline) COD 1,5-cyclooctadiene Conv conversion D IEA diisopropylethylamine D IOP ((4S,5S)-2,2-dimethyl-1,3-dioxolane-4,5- diyl)bis(methylene)bis(diphenylphosphine) D MAP 4-(N,N-dimethylamino)pyridine D MF dimethylformamide D MSO dimethylsulfoxide ED C-HCl 1-ethyl-3-(3’-dimethylaminopropyl)carbodiimide monohydrochloride ee enantiomeric excess equiv equivalent EX SY exchange spectroscopy FG functional group GC gas chromatography HOBt 1-hydroxybenzotriazole HPLC high performance liquid chromatography i-Pr isopropyl IR infrared LG leaving group Ms mesylate MS mass spectrometry MT magnetization transfer NBD norbornadiene NMM N-methylmorpholine NMR nuclear magnetic resonance NOESY nuclear Overhauser effect spectroscopy Nu nucleophile PEG polyethylene glycol

Ph phenyl PHOX phosphinooxazoline PS polystyrene p-Tol para-tolyl pybox pyridine-bis(oxazoline) rt room temperature s-Bu sec-butyl TASF tris(dimethylamino)sulphonium difluoromethylsiliconate TBAF tetrabutylammonium fluoride t-Bu tert-butyl Tr trityl Tf triflate THF tetrahydrofuran TMSA trimethylsilyl acetylene TMSAN (trimethylsilyl)acetonitrile TMSCN trimethylsilyl cyanide Ts tosyl U V ultraviolet

Table of contents

1) Introduction a. Oxazoline based-ligands in metal-catalyzed asymmetric reactions b. Aim of this thesis 2) New bifunctional pyridine-bis(oxazoline) ligands a. Multifunctional catalysts b. Ligands synthesis c. Catalytic asymmetric addition of cyanides to benzaldehyde d. Conclusion and perspectives 3) New “click” pyridine-bis(oxazoline) ligands a. Background i. Crown ethers ii. Macrocycles and receptors containing a crown ether moiety b. Ligands synthesis c. Complexation studies d. Catalysis i. Asymmetric Mukaiyama aldol reaction ii. Addition of (trimethylsilyl)acetonitrile to benzaldehyde e. Conclusion and perspectives 4) New polymer-supported pyridine-bis(oxazoline) ligand a. Supported ligands b. Ligand synthesis c. Catalysis i. TMSCN epoxide opening ii. Silylcyanation of benzaldehyde iii. Alkynylation of imines d. Conclusion and perspectives 5) Hydroxy-containing phosphinooxazoline ligand a. Phosphinooxazoline ligands b. Catalysis i. Asymmetric hydrosilylation of imines ii. Asymmetric intermolecular Heck reaction c. NMR studies d. Conclusion and perspectives 6) Concluding remarks and outlook 7) Acknowledgements 8) Experimental section 9) References

1) Introduction a. Oxazoline-based ligands in metal-catalyzed asymmetric reactions

Oxazolines are five-membered cyclic iminoesters. They were first synthesized more than hundred and twenty years ago.1 At the beginning they were widely used in organic synthesis, in particular as masked carboxylic acids.2

The first example of a chiral oxazoline ligand was reported in 1986 by Brunner and co-workers.3 Since then, a very large number of chiral ligands containing one, or more, oxazoline rings have been synthesized and applied to a wide range of metal- catalyzed asymmetric transformations.4 These compounds are usually obtained in a few steps from readily available amino alcohols. Most of them have a stereogenic center at the carbon atom adjacent to the coordinating nitrogen. As a consequence, the active metal site is held in close proximity to the chiral center, which can directly influence the stereochemistry of the reaction. Chirality can also be introduced in other positions, for example at the carbon atom adjacent to the oxygen or at one of the substituents. The structure of oxazoline-based ligands can be easily tuned for a specific reaction (scheme 1).

Chiral substituent

*R NH2 O ∗ ∗ HO ∗ R'' R' N ∗ R'' R'

Chiral centers

Schem e 1: General feature of oxazoline ligands.

Among the chiral oxazoline ligands developed, some incorporate only one oxazoline ring (mono(oxazoline) ligands). Others contain two oxazoline rings (bis(oxazoline) ligands). Finally, tris(oxazoline) ligands having three such rings have also been prepared. All of these ligands are usually referred to by mentioning the type of coordinating atoms.4a

As a very large number of structures have been reported, no attempt will be made here to give a comprehensive overview of what has been done in this field, but rather, some representative examples of the most interesting compounds will be given.

Bidentate mono(oxazoline) P,N-ligands have been shown to be useful in many reactions. Among them phosphinooxazolines have been particularly well studied.4c These ligands have one stereogenic center adjacent to the coordinating nitrogen atom (scheme 2, compounds 1-5).5 Some examples with a stereogenic axis (scheme 2, compounds 6-7a)6 or a stereogenic plane (scheme 2, compounds 7b-8)6c,7 have been synthesized and used in various catalytic asymmetric reactions. Examples of oxazoline-phosphinite (scheme 2, compound 9),8 oxazoline-phosphonamidate (scheme 2, compound 11 ),9 oxazoline-phosphoramidate (scheme 2, compound 12),10 oxazoline-phosphite (scheme 2, compound 13)10 and oxazoline ligands having a phosphorus atom bonded to one nitrogen (scheme 2, compound 10)11 have also been described and used with more or less success in catalysis.

O PAr2 Ph P R O 2 N R O N Ar2P N O N O N PAr2 S N R 3 Boc PAr2 R 1 2 R 4 5

O O N R N O O N R'' N O O PPh2 N Fe R PPh2 N Ph2P R PAr2 Re R' OC CO R CO 6 7a R= H; R' =PPh2 9 10 7b R= PPh2 R' =H 8

NEt Ph Ph Ts O P O O O Ph N O O O P N OH Fe P N O O R Ph N R Ph Ph N Ts O 13 R 12

Schem e 2: Some examples of mono(oxazoline) P,N-ligands.

Mono(oxazoline) N,N-ligands are also a well represented class of compounds. The first mono(oxazoline) ligand with two coordinating nitrogen atoms was described in 1986 (scheme 3, compound 14).3 It was shown later that analogs with a methylene bridge linking the pyridine and the oxazoline rings did not perform equally well in catalysis.12 Some additional mono(oxazoline) N,N-ligands are shown in scheme 3 (compounds 15-17).13

R2 R3

O H2 O R1 N N ∗ H N C N N N R N O N O R ∗ R 14 R 17 15 16 Schem e 3: Some examples of mono(oxazoline) N,N-ligands.

Metal complexes bearing mono(oxazoline) N,O-ligands, such as 18-22 (scheme 4), have been applied in a variety of catalytic asymmetric reactions.14-18 For ligands 19, it was shown that the stereogenic center at the carbon atom bearing the hydroxy group was crucial to achieve high enantioselectivities in certain reactions, such as the addition of diethylzinc to imines.15 Some mono(oxazoline) N,O-ligands containing a ferrocenyl moiety were also employed in catalysis (scheme 4, compound 20).16 An analog bound to a soluble polymer gave good results in catalysis and could be efficiently recycled (scheme 4, compound 21).17 Hiroi also investigated the use of oxazoline sulfoxides of type 22.18

R'' O O HO Ph R HO N N O N O Fe CPh2OH N O S p-Tol ∗ ∗ R R R' 19 20 22 18 O

Fe CPh2OH O ( ) O-MPEG O 6 O O 21

Schem e 4: Some examples of mono(oxazoline) N,O-ligands.

The bidentate mono(oxazoline) N,S-ligands 23-25 were first synthesized and employed in catalysis by Williams (scheme 5).19 Ikeda reported the synthesis of structures 26 but the diastereoisomers were difficult to separate.20 A number of oxazolinylferrocenylthioethers 27a have also proved their efficiency in palladium- catalyzed alkylations.21

O R'S S R'S R'S O N R N O R'' R Fe XR' N O N O N R 27a X = S R R R' 27b X = Se 23 24 25 26

Schem e 5: Some examples of mono(oxazoline) N,S -ligands.

A number of less common structures incorporating a selenium atom were synthesized by Hou but proved inferior to the corresponding oxazolinylferrocenylthioethers (scheme 5, compound 27b).22 Ligands bearing a palladacycle23 or a carbene moiety24 have also been described.

The ligands described so far contain only one oxazoline ring in their structure. However, a vast number of bis(oxazoline) ligands capable of forming bidentate, tridentate or tetradentate metal complexes have been extensively used in catalysis.4b,e,f,h

Bidentate bis(oxazolines), often referred to as “box” ligands (scheme 6, compound 28), were first employed in catalysis in 1991 by Evans, who reported the asymmetric cyclopropanation of alkenes,25 and Corey, who performed enantioselective D iels- Alder reactions.26 Their work paved the way for the development of other bis(oxazoline) ligands.4b,e,h Some examples of bis(oxazoline) ligands synthesized later are shown in scheme 6.

The ferrocenyl-substituted box 29 was prepared by Moyano and co-workers.27 It afforded good enantioselectivities in palladium-catalyzed asymmetric allylations but yields were generally low.

30a-c, bearing respectively, a hydroxy, alkyl or acetyl group at the stereogenic 4- position of the oxazoline rings, were used by Aït-Haddou in palladium-catalyzed alkylations.28 Moderate to high yields were obtained. It was observed that 30a afforded the opposite configuration of the product compared to 30b-c. This phenomenon was explained by the authors by hydrogen bonding of the hydroxy group of 30a to the substrate.

Ligands 31 and 32 which possess second binding sites were assessed in the copper(I)- catalyzed asymmetric cyclopropanation.29 They afforded the product in moderate yields but excellent enantioselectivities. The authors suggested that the hydrogen donor groups (hydroxy and amino groups) could form a hydrogen bond with the substrate thus differentiating the enantiofaces of the double bond and directing the attack of the nucleophile.

O O R'' R'' O O O O N N R'' R' N N N N Ph Ph OR RO R R 28 Fe Fe 30a R=H 30b R =alkyl 29 30c R=COMe

O O O O R' Ph Ph N N N N O N O R R O O N N OH HO R R O O R R 31 NHR RHN 33 R' R' 32 O O N R PPh R N Fe 2 N R PPh2 N R O O

34 35

Schem e 6: Some examples of bidentate bis(oxazoline) ligands.

In 2000, Reiser and co-workers reported the synthesis of aza-bis(oxazoline) ligands 33 (scheme 6) and their use in palladium-catalyzed allylations and copper-catalyzed cyclopropanations.30 Although the allylic allylation reactions only afforded some product when R’ ≠ H, the asymmetric cyclopropanation worked equally well with R = H and with R = alkyl. The authors also used the nitrogen atom to bind their ligand (R = t-Bu) onto a PEG-resin.30 This supported ligand was tested in cyclopropanations and induced high enantioselectivities. Moreover it could be recovered a large number of times without loss of activity.

Ligand 34 (scheme 6) with a binaphtyl backbone was the first bis(oxazoline) ligand with a stereogenic axis to be employed in catalysis. It afforded high enantioselectivities in several reactions.4b,h,31 Many derivatives of 34 have then been synthesized.4a,b,h

Bis(oxazolinyl)biferrocene ligands 35 (scheme 6), with a stereogenic plane, were utilized by Park and co-workers in palladium-catalyzed alkylations.32 The ligands proved to be very efficient, giving the products in quantitative yields and excellent enantioselectivities.

A small revolution took place when Nishiyama, in 1989,33 introduced a pyridine ring as the spacer between the two oxazoline rings: the ligand was no more bidentate but

tridentate. Since then, various pyridine-bis(oxazolines), or pybox, ligands have been synthesized and used in asymmetric catalysis.4f They are very attractive compounds as they can easily be synthesized in a few steps (generally two or three) from readily available starting materials (an amino alcohol and a pyridine derivative). These ligands are able to complex a great variety of metals. As a consequence of these properties, it is easy to tune the catalyst for a specific purpose. A few examples are represented in scheme 7.

O O O O O O N N Ph N Ph N N N N N N R R Ph Ph 36a R=i-Pr 38 36bR =Ph 36c R=t-Bu 37 36dR =s-Bu 36e R=CH2Ph 36f R= CH2OH 36gR =CH2OSiR'3

Schem e 7: Some examples of pyridine-bis(oxazoline) ligands.

Ligands 36a-e (scheme 7) were the first ones to be synthesized. They provided good results in reactions as varied as asymmetric D iels-Alder reactions, cyclopropanations, aziridinations, hydrosilylations, silylcyanations, oxidations of allylic and benzylic compounds and 1,3-dipolar cycloadditions, to mention a few.4f

Pybox 37 (scheme 7) derived from aminoindanol was also synthezised and proved superior to ligands 36a-e in some reactions.34

Ligand 38 (scheme 7) with trans-4,5-diphenyl substitution on the oxazoline rings was prepared by D esimoni and co-workers and assessed in, among others, the Mukaiyama-Michael and D iels-Alder reactions.34d,35 The di-substitution made the ligand more stable and proved to be advantageous in some cases affording better enantioselectivities than pybox ligands such as 36a-e.

Ligands 36g (scheme 7) are obtained by etherification of 36f. For example, they catalyzed 1,3-dipolar cycloadditions, cyclopropanations and D iels-Alder reactions with excellent diastereo- and enantioselectivities.36

Other types of bis(oxazoline) N,N,N-ligands (scheme 8, compounds 39 and 40a),37 N,O,N-ligands (scheme 8, compound 40b),38 N,S,N-ligands (scheme 8, compound 40c)39 and N,P,N-ligands (scheme 8, compounds 41 and 42)40 have also been used in catalysis with more or less success.

O O X N H O O N N N N Ph Ph 39 R R 40a X= NH 40bX =O 40c X= S O O N N i-Pr R P P N i-Pr N R

O O

42 41

Schem e 8: Some examples of bis(oxazoline) N,N,N-ligands, N,O,N-ligands N,S,N-ligands and N,P,N- ligands.

Bis(oxazoline) ligands that bind a metal in a tetradentate manner have been reported

even though more seldom than the other classes described above. The C2-symmetric bis(oxazolinylpiridinyl)dioxolane 43 (scheme 9) was assessed in palladium- catalyzed allylic substitutions and it was shown that only the stereogenic centers of the dioxolane unit were important for the chiral induction in this reaction.41 However the authors could not conclude with certainty whether the ligand behaved as bidentate or tetradentate.

Pfaltz reported that compound 44 (scheme 9) can behave as a tetradentate anionic ligand with Ni(II) and Cu(II). A ruthenium complex of this ligand was also used in asymmetric epoxidations but afforded the products in only moderate yields and ee:s.42

Lee and co-workers investigated the ability of the bisphophinobioxazoline ligand 45 to catalyze the asymmetric hydrosilylation of ketones. Excellent results in terms of both yields and ee:s were obtained.43 Binaphtyl44 and ferrocene45 derived ligands (46 and 47) were also reported and tested in the addition of diethylzinc to benzaldehyde.

O O O O O O NH HN N N N N N N O O PPh Ph P O O 2 2 N N R R 45 R R R' R' 44 O 43 O N R HO Me CPh OH Me N Fe 2 N Me CPh OH Me 2 OH N O R O 47 46

Schem e 9: Some examples of tetradentate bis(oxazoline) ligands.

The first (achiral) tris(oxazolines) were synthesized in 1993 by Sorrell and co- workers.4g,46 Chiral analogs (scheme 10, compound 48a-b) were employed in an asymmetric Kharash-Sosnovsky reaction by Katsuki and co-workers in 1995.47 In 2002, Gade and co-workers reported the synthesis of tris(oxazoline) ligands of the type of 48c-d.48 Noticeably, the hetero substituted tris(oxazoline) 48d performed better in the copper(I)-catalyzed asymmetric cyclopropanation of styrene than 48c. Several other tris(oxazoline) ligands and their use in asymmetric catalysis have been reported (scheme 10, ligands 49 and 50).4g,49

O X O Ox N R Ox R' N Ox R R 3 Me Me N Me 48a X= N 48bX =CH O 50 N O O 49 R O N R' O R Ox = N N N R2 O R1 R2

48c R1 = R2 =iPr 48d R1 = iPr R2 =tBu

Schem e 10: Some examples of tris(oxazoline) ligands.

b. Aim of this thesis

The aim of the work on which this thesis is based was to develop new oxazoline- based ligands for asymmetric metal catalysis. This involves the synthesis of new compounds and their assessment in catalytic asymmetric reactions as well as the study of their behavior by spectroscopic methods. In particular, focus has been put onto two types of oxazoline ligands: the pyridine-bis(oxazoline), i.e. pybox, and the phosphinooxazoline, i.e. PHOX , ligands. This work also includes homogeneous and heterogeneous catalytic systems.

2) New bifunctional pyridine-bis(oxazoline) ligands a. Multifunctional catalysts

Asymmetric catalysis is one the most rapidly evolving fields in organic chemistry. The search for catalysts that are more versatile, more efficient, more economical and more environmentally benign has been driving chemists for many years.50 Some impressive achievements have been made and, in some cases, synthetic chiral catalysts have been claimed to have performances which equal or sometimes surpass Nature’s catalysts, the enzymes.51

Enzymes are able to effect a wide range of transformations under mild conditions with very high levels of enantio- and/or diastereoselectivity. However, they are often extremely specific and do not tolerate a wide range of substrates.52 One major property that often makes enzymes superior to synthetic catalysts is their cooperative mode of action. Enzymes often contain two or more active sites that can act in a synergistic way. This enables the efficient activation of the reaction partners and positions them in a well defined environment favoring a high regio- and stereoselectivity. Therefore, the focus has turned to “imitating” natural catalysts by developing artificial enzymes51 or multifunctional catalysts.53

Many transformations involve the reaction of a nucleophile with an electrophile. These reactions often need an activation. Moreover, a chiral source is needed to induce some stereoselectivity if both reagents are achiral. Activation and chiral induction can be realized by means of a chiral catalyst. Most chiral catalysts work in either of the following two ways: 1) activation of the electrophile by a chiral Lewis or Bronsted acid. The nucleophile can then react with the resulting activated electrophile which is, as well, placed in a chiral environment. 2) coordination of the nucleophile to a chiral base followed by reaction of the nucleophile-catalyst complex with the electrophile to yield optically active products.

In some cases however, single activation of one of the reaction components is not enough. One possible manner to overcome this problem is by dual activation of both the electrophile and the nucleophile, as enzymes sometimes do. D ual activation can promote the reaction of otherwise unreactive substrates under mild conditions. With properly designed catalysts, dual activation can occur in a more constrained position resulting in increased stereoselectivity.

A step in this direction can be the use of two components simultaneously, for example, one that would activate the electrophile and the other one the nucleophile.54 A recent example showed an elegant combination of a Lewis acid, an amine base and a Bronsted acid to catalyze asymmetric Mannich-type reactions.545e The activation of

the Lewis acidic silicon center of SiCl4 by a Lewis base is a special case where a base is needed to activate a Lewis acid.55

It is obvious, however, that dual activation can also lead to unwanted reactions and quenching of the catalysts. Therefore chemists rapidly tried to design new catalysts incorporating the two activating sites on the same molecule. From early reports in the 1990s to today, a plethora of ingenious systems have been created.53, 56

Multifunctional catalysts can schematically be divided into three main classes according to their mode of action.53a,57 One type of multifunctional catalysts incorporate two metals coordinated to the same skeleton which activate the substrate and the reactant (scheme 11, a). These bi-metallic catalysts can be of two types: if the two metals are the same, the catalyst is said to be homometallic,58 on the contrary, if they are different, the catalyst is heterometallic.53e,57,58c,59 Another kind of compounds consist in the combination of a Lewis acid and a base that work in concert to activate an electrophile and a nucleophile (scheme 11, b).60 Finally, a less common class is composed of catalysts that contain a metal center that binds the substrate making it possible for it to undergo the reaction with a second active site (scheme 11, c).61

M1 M2 M B M FG

S R S R S

a b c M1 =M2 : homometallicsystem M1 =M2 : heterometallicsystem

M, M1, M2 = Metal center B=Base FG=Functional Group S=Substrate R=Reactant

Schem e 11: The three different types of dual activation systems.

There are also many bifunctional organocatalysts that have been designed to activate both reaction partners.62 In particular, many of them are derived from proline62a-d or from cinchona alkaloids.62e,f

When the bifunctional catalysis is successful, the activation takes place on neighboring active sites thereby bringing the substrate and the reactant close together in a controlled fashion, in an asymmetric environment promoting a highly selective reaction.

The proximity of the two active sites requires advanced ligand design in order to prevent undesirable interactions between them. The functional groups must be

chosen with care and positioned in the molecule in a proper manner so that they can: 1) recognize the substrates and direct them in a good way, 2) act cooperatively, 3) not interfere with each other. As a consequence, fine-tuning of the catalyst and reaction conditions demand a lot of attention. The linker between the two sites should be short to enable simultaneous activation (the active sites will not cooperate efficiently if they are too far apart) but these two groups should not be too close to prevent them to interact in a detrimental fashion. A Lewis acid, for example, could well react with a Lewis base or the nucleophile if not suitably positioned, thus resulting in quenching of the two functions. This was for example observed by Shibasaki with his bifunctional BINOL system 51a (Compare arm length of 51a and 51b in scheme 12). Interaction of the basic part with the Lewis acid could be prevented by shortening the linker.63 51b promotes efficiently trimethylsilylcyanations whereas 51a does not.

O 51a R = CH P(O)Ph Al Cl 2 2 51b R = P(O)Ph2 O

Schem e 12: Shibasaki’s BINOL systems.

In some cases, the solution to suppress quenching can be as simple as changing the metal. Aggarwal and co-workers found that, in their Baylis-Hillman reaction,

replacing conventional Lewis acids such as BF3·OEt2 or TiCl4 by Sc(OTf)3 or lanthanide triflates was highly efficient. The formation of strong D ABCO-Lewis acid complexes with the former metal salts was indeed responsible for the neutralization of the Lewis acid and the removal some of the D ABCO from the reaction. However,

Sc(OTf)3 and Ln(OTf)3, being much harder, formed weaker and more labile D ABCO- Lewis acid complexes. Moreover, these complexes could still function as Lewis acids as it was proposed that there should still be some free sites on the metal for coordination of the substrate.64

Surprisingly, even though pybox ligands have proven to be useful in a wide range of reactions, their combination with another active site in the same structure has not been investigated. The pybox scaffold has several advantages that make it interesting for the design and synthesis of new bifunctional ligands. First of all, it is easy to adjust: functional groups can be introduced easily at the 4- and 5-positions of the oxazoline rings or on the pyridine nucleus. Moreover, a great range of metals have been reported to form active complexes with this ligand thereby providing a chance to fine-tune the metal/base combination. We therefore undertook the synthesis of new ditopic pybox ligands in the view of applying them to asymmetric catalytic reactions. Our ligands would have a Lewis acidic site (through coordination of a metal to the nitrogen atoms of the pyridine and of the oxazoline rings) and some

Lewis basic parts that we chose to link to the 4-position of the oxazoline rings (scheme 13).

O O Ph N Ph N N M

R R Lewis basic moiety Lewis acidic site

Schem e 13: General structure of bifunctional pybox ligands.

b. Ligands synthesis

Compound 55 was selected as a common intermediate towards the synthesis of our new ditopic pybox ligands since it is easily synthesized from commercially available starting materials and presents two hydroxy functions that can be readily transformed into other functional groups.

Compound 55 was obtained in good yield from 2,6-dicyanopyridine 52 and (1S,2S)-2- amino-1-phenylpropane-1,3-diol 54 via a two-step procedure. First, 2,6- dicyanopyridine was converted to the bis-imidate 53 following a procedure found in the literature.65 With some minor adjustments of this procedure, we could isolate 53 in quantitative yield, in pure form. This compound was then reacted with (1S,2S)-2- amino-1-phenylpropane-1,3-diol 54 as reported by D esimoni (scheme 14).36d

NaOMe cat. (CH2Cl)2,reflux MeOH, rt HN NH Ph O O Ph N 78% N NC N CN 100% O O HO OH N N 52 53 Ph NH OH HO 2 55 54

Schem e 14: Synthesis of intermediate 55.

From the pybox intermediate 55 we considered two ways of introducing new functionalities: 1) by nucleophilic substitution after modification of the hydroxy groups, 2) by esterification of the hydroxy groups of compound 55 (scheme 15).

O O O O Ph N Ph Ph N Ph N N N N

Esterification O O OH HO 55 O O R R

O O O O Ph N Ph Ph N Ph N N N N Nucleophilic LG LG Substitution Nu Nu

LG = Leaving group

Schem e 15: The two general strategies towards ditopic ligands.

Employing the first strategy, we chose four different secondary amines, diethylamine, 1-methylpiperazine, dibenzylamine and pyrrolidine, as nucleophiles, as they would lead to compounds having different structural properties. U sing this strategy, a phosphine oxide could as well be linked to the pybox skeleton. Phosphine oxides and amine bases possess different properties and, in particular, different basicities. As a consequence, we thought that it would be of interest to synthesize those two kinds of ligands.

First we had to find a suitable way to substitute the hydroxy groups. We anticipated that conversion of the hydroxy functions into mesylates, tosylates or triflates would lead to a good precursor for the nucleophilic substitution.

We first attempted the formation of a bis-triflate. D ue to their high reactivity, triflates are usually formed and substituted in a one-pot procedure (scheme 16).

Even though a lot of efforts were put into finding optimal conditions for this reaction, a large amount of by-products, difficult to separate, were formed. The use of different bases instead of 2,6-lutidine did not improve the outcome of the reaction.

O O O O Ph Ph Ph N Ph N 1. Tf 2O, 2,6-lutidine, CH2Cl2, -40°C N N N N 2. R2NH, rt-reflux OH HO R R 55 56a R = Et2N 56b R = N-methylpiperazine 56c R = (PhCH2)2N 56d R = pyrrolidine

Schem e 16: Attempted conversion of 55 to a bis-triflate intermediate followed by one-pot nucleophilic substitutions.

We therefore turned to the formation of the bis-mesylate. As its isolation turned out to be difficult, we attempted the addition of dibenzylamine to the crude mixture. U nfortunately this resulted only in the formation of dibenzylammonium mesylate (scheme 17).

O O Ph Ph Ph O O Ph N 1. MsCl, Et3N, CH2Cl2, rt N N N N N 2. Dibenzylamine, reflux

OH HO N N 55 Ph Ph Ph Ph 56c

Schem e 17: Attempted conversion of 55 to a bis-mesylate intermediate followed by one-pot nucleophilic substitution.

To our great delight, conversion to the bis-tosylate proceeded smoothly. Compound

57 was isolated in 87% yield by reacting 55 with Et3N and TsCl. The bis-tosylate compound 57 could then undergo nucleophilic substitution with the amines mentioned above, in D MF or acetonitrile. These reactions led to the formation of ligands 56a-d in fair to good yields (scheme 18). The tosylate groups could also be

displaced by in-situ generated LiPPh2. The resulting intermediate phosphine was not isolated but directly oxidized using hydrogen peroxide to yield ligand 56e (scheme 18). U nfortunately this ligand was difficult to purify and remained contaminated by some phosphinic acid.

O O Ph N Ph Et NH 2 N N 44% 56a N N

O O N Ph N Ph N N N H N 56b N O O 51% Ph N Ph N N N N

OR RO O O 55 R= H Ph N Ph TsCl 87% N N Et3N Bn2NH 57 R= Ts 56c 45% N N Ph Ph Ph Ph

H O O N Ph N Ph N N

91% N 56d N

O O Ph N Ph N N 1) LiPPh2 56e 2) H2O2 P(O)Ph2 P (O)Ph2

Schem e 18: Synthesis of ligands 56a-e via formation of the bis-tosylate 57.

U sing the second strategy L-proline was connected to the pybox scaffold. To avoid a secondary amine, we first converted L-proline to N-methyl-L-proline as described in the literature (scheme 19).66

1. aq CH2O, MeOH 2. 10% Pd on C, H COOH 2 COOH N N H 87% 58

Schem e 19: Synthesis of N-methyl-L-proline 58.

Esterification of pybox intermediate 55 with N-methyl-L-proline 58 was achieved using ED C-HCl and HOBt and afforded the desired ligand 59 in 67% yield (scheme 20).

O O Ph N Ph

EDCòHCl N N COOH 55 N HOBt, NMM O O 67% 58 O O N N

Schem e 20: Synthesis of ligand 59.

With this set of ligands in hand, the next step was to assess them in catalysis.

c. Catalytic asymmetric addition of cyanides to benzaldehyde

The addition of cyanide to aldehydes and ketones leads to cyanohydrins. Optically active cyanohydrins are important building blocks since they can easily be transformed and used in the synthesis of many valuable products.67 The first asymmetric synthesis of cyanohydrins was reported in 1908 by Rosenthaler, who used an enzyme for the chiral induction.68 There are today three types of catalysts used for the enantioselective generation of cyanohydrins: enzymes, peptides and chiral metal complexes. Most common is the use of Lewis acid catalysis and many different systems have been reported.56b,c,g,63

The first pybox-metal mediated addition of trimethylsilyl cyanide to aldehydes 69 (scheme 21) was reported in 1997 using pybox 36a and AlCl3 as a metal catalyst. This catalyst provided a variety of cyanohydrins with high yields but the enantiomeric excess was only reported for the addition to benzaldehyde (90% ee). A more versatile system was then developed in the group of Aspinall.70 They achieved high ee:s for several aldehydes using various lanthanide-pybox complexes, the best

combination being pybox 60 and YbCl3.

O Pybox-Metal complex OSiMe3 + Me3SiCN R H R CN

O O O O N N N N N N Ph Ph 36a 60

Schem e 21: Addition of trimethylsilyl cyanide to aldehydes catalyzed by pybox-metal complexes.

D ual activation has been used with great success in the cyanation of aldehydes and ketones. The first system was reported by Corey and co-workers in 199371 and consisted in the simultaneous use of a magnesium bis(oxazoline) complex 61 and an uncomplexed bis(oxazoline) 62. The bis(oxazoline)-Mg complex acts as a Lewis acid and activates the aldehyde whereas the free bis(oxazoline) behaves as a Lewis base for activation of HCN produced in situ from TMSCN and moisture (scheme 22).

O 61 : 20 mol%; 62 : 12 mol% OSiMe3 + Me3SiCN R H R CN CN O O O O N N N N Ph Ph Ph Mg Ph 62 Cl 61

Schem e 22: Catalytic asymmetric cyanosilylations of aldehydes using Corey’s bis(oxazoline) system.

North’s and Belokon’s titanium salen complexes are other examples in which simultaneous activation of both reaction partners results in high enantioselection (scheme 23).72 They found that the actual precatalyst is a bimetallic complex that activates both the carbonyl function and TMSCN.

N N R = H, tBu, Cl R OH HO R R' = H, Me, tBu, OMe, Cl

R' R' 63

Schem e 23: Salen ligand used by North and Belokon’.

One of the most studied bifunctional catalysts for asymmetric cyanosilylation of aldehydes and ketones is Shibasaki’s Al-BINOL complex 51b (scheme 24). 56b,c,g,63,73 In this system, the aluminum center acts as the Lewis acid and activates the carbonyl group while the phosphine oxide moiety is responsible for the activation of TMSCN. With this catalyst a variety of cyanohydrins were obtained with ee:s ranging between 83 and 99%. A drawback of this system is the need for additional phosphine and slow addition of TMSCN.

Nájera et al. prepared a similar system by replacing the phosphine oxide moiety by diethylamine. Their ligand 64 (scheme 24) catalyzed the asymmetric addition of TMSCN to various aldehydes with modest to good ee:s. This system also presented the advantage to allow the addition of all the reagents at the beginning of the reaction since it was not necessary, as in Shibasaki’s system, to add TMSCN slowly. Moreover, the ligand could be recovered at the end of the reaction by acidic work-up.74

O 51b R = P(O)Ph2 Al Cl 64 R = NEt2 O

Schem e 24: Bifunctional BINOL ligands used in silylcyanations of aldehydes.

U sing ligand 64, both Shibasaki and Nájera could as well use cyanoformates and cyanophosphonates as alternative sources of cyanide anion for the enantioselective synthesis of cyanohydrin derivatives.75

Shibasaki also reported carbohydrate derived ligands in which the Lewis acid and the Lewis base functionalities work cooperatively (Scheme 25).76 These ligands could be combined to various metals to convert aromatic and aliphatic ketones to cyanohydrins in good yields and good enantioselectivities. Worth noting is the observation that changing the metal from titanium to gadolinium resulted in a reversal of the enantioselectivity. This was explained by different arrangements of the transition states: with the titanium complex, Shibasaki suggested that the cyanide is

activated by the phosphine oxide, whereas it is activated by a gadolinium center in the second type of complex.

O X 65a X = Y = H, Ar = Ph Ar2(O)P 65b X = COPh, Y = H, Ar = Ph HO O Y 65c X = Y = F, Ar = p-MeC6H4 65d X = Y = F, Ar = Ph HO

Schem e 25: Shibasaki’s carbohydrate derived ligands.

Some other bifunctional systems were described by Kagan et al. (scheme 26, compounds 66 and 67). These monolithium salts 66 and 67 are thought to react with TMSCN through an hypervalent silicon intermediate which can further activate the aldehyde.77 A peptidic Schiff base ligand 68 complexed to aluminum was also developed by Snapper and Hoveyda (scheme 26).78

O H OLi MeO N OMe N N N N H OH O O tBu OLi HO tBu OH O NHTr tBu tBu 68 66 67 (Tr = trityl)

Schem e 26: Some other ligands used in dual activation in silylcyanations.

Feng and Jiang showed that a titanium catalyst consisting of a pyridine ring equipped with an N-oxide function effectively promoted the asymmetric silylcyanation of ketones (scheme 27, compound 69).79 They found later that the combination of an N- oxide and the titanium complex of the Schiff base 70 gave improved results compared to the use of 69 alone (scheme 27).80

Ph Ph + N OH N N O- N tBu OH HO tBu

tBu tBu 69 70

Schem e 27: Feng and Jiang ligands used for double activation in cyanohydrin formation.

It was found in our group that cyanoformates and acetyl cyanide could add to aldehydes in a highly enantioselective fashion by dual activation by means of a Ti(IV )-salen complex in combination with a tertiary amine base (scheme 28).54b-d

O O O Ti(IV)-salen complex O R NR'3 H R CN CN 71a R = OEt 71b R = Me 72

Schem e 28: Catalytic enantioselective addition of ethyl cyanoformate 71a or acetyl cyanide 71b to benzaldehyde catalyzed by Ti(IV )-salen complex and tertiary amines.

Inspired by those results, we wished to assess our bifunctional pybox ligands having a tertiary amine tethered to the oxazoline rings in the cyanation of aldehydes. A synergic effect on both the reaction rate and the enantioselectivity was thus expected from this dual activation.

We began by testing the YbCl3 complexes of the standard pybox ligands 36a and 60 (scheme 29) in combination with amines in the asymmetric addition of ethyl cyanoformate 71a and acetyl cyanide 71b to benzaldehyde.

O O O O N N N N N N Ph Ph 36a 60

Schem e 29: Pybox ligands 36a and 60.

U sing ethyl cyanoformate as cyanation reagent no reaction took place when pybox 36a or 60 were used alone (entries 1 and 5). In the presence of triethylamine or D MAP, however, the reaction using 36a proceeded smoothly but with quite low enantioselectivity (entries 2 and 3). Pybox 60 also enabled the reaction when combined with D MAP, as well giving the product with low ee (entry 4). When acetyl cyanide was employed, only pybox 36a in combination with triethylamine afforded the cyanohydrin in low yield and modest selectivity (entries 5-7).

T able 1: Addition of cyanoformate and acetyl cyanide to benzaldehyde catalyzed by YbCl3, pybox and amine.[a]

Entry Ligand Amine CN agent Time (h) Conv (%) [b] Ee (%) [c] Abs conf[d] 1 36a / 71a 24 0 / /

2 36a Et3N 71a 1 76 28 R 3 36a D MAP 71a 4 75 58 R 4 60 D MAP 71a 4 90 38 S 5 36a / 71b 24 0 / /

6 36a Et3N 71b 4 38 24 R 7 36a D MAP 71b 24 0 / /

[a] Reaction conditions: 5 mol % YbCl3, 10 mol % ligand, 10 mol % amine, 2 equiv 71a or 71b, 0-25 °C. [b] D etermined by GC/MS. [c] D etermined by chiral GC. [d] Assigned by comparing the sign of optical rotation with literature data.[81,82]

Having established those results, we turned to investigate our bifunctional ligands 56a-d and 59 instead of the simultaneous use of a pybox and an amine base. Table 2 shows the results of the cyanation of benzaldehyde with cyanoformate 71a or acetyl cyanide 71b, in acetonitrile, with these pybox-YbCl3 complexes.

[a] T able 2: Addition of cyanide to benzaldehyde using YbCl3 and a ditopic pybox ligand.

Entry Ligand CN agent T (°C) Conv (%)[b] Ee (%)[c] Abs conf[d] 1 56a 71a 25 100 9 S 2 56b 71a 25 96 28 R 3 56c 71a 60 100 <5 / 4 56d 71a 25 99 <5 / 5ef 59 71a 60 100 0 / 6f 56a 71b 25 44 5 S 7f 56b 71b 25 74 <5 /

[a] Reaction conditions unless otherwise noted: 5 mol % YbCl3, 10 mol % ligand, 2 equiv 71a or 71b, 16 h reaction time. [b] D etermined by GC/MS. [c] D etermined by chiral GC. [d] Assigned by comparing the sign of optical rotation with literature data.[81,82] [e] 5 mol % ligand. [f] 72 h reaction time.

Catalysts derived from YbCl3 and ligands 56a-d and 59 afforded the expected product 72a in very good yield after 16 hours (entries 1-5). For ligands 56c and 59 the

reactions had to be run at 60 °C to afford a complete conversion. The enantioselectivity was generally low. The highest ee was obtained using ligand 56b which gave the product in 28% ee. Changing the cyanation reagent to acetyl cyanide the reaction was somewhat slower and the cyanohydrin 72b was obtained with very low ee (entries 6-7). It is worth noting that the use of ligand 56b afforded product 72a with (S) absolute configuration whereas 56a gave the cyanohydrin 72a with (R)

absolute configuration. The reactions run in D MF or CH2Cl2 proved to be slower and to give racemic products.

We also evaluated the use of other metal sources (table 3). LuCl3 and CeCl3 catalyzed the addition of ethyl cyanoformate 71a to benzaldehyde in the presence of ligands

56a-c (entries 1-6: 77-100% conversion, ee < 20%). Catalysts prepared from Yb(OTf)3 were less active than those prepared from YbCl3 (entries 7-9). When ligand 59 was used with Yb(OTf)3 no reaction was observed. The product obtained with the

Yb(OTf)3 complex of 56a had the (R) absolute configuration, opposite to what had

been observed when an YbCl3 complex of 56a was used.

T able 3: Addition of ethyl cyanoformate 71a to benzaldehyde using various lanthanide salts and a ditopic pybox.[a]

Entry Metal Ligand T (°C) Conv (%)[b] Ee (%)[c] Abs conf[d]

1 LuCl3 56a 25 100 11 S

2 LuCl3 56b 25 100 10 R

3 LuCl3 56c 60 100 <5 e 4 CeCl3 56a 25 83 <5

5 CeCl3 56b 25 77 0

6 CeCl3 56c 60 100 14 R ef 7 Yb(OTf)3 56a 25 97 18 R ef 8 Yb(OTf)3 56b 60 100 6 R f 9 Yb(OTf)3 56c 60 49 <5 f 10 Yb(OTf)3 59 60 0

[a] Reaction conditions unless otherwise noted: 5 mol % metal salt, 10 mol % ligand, 2 equiv. ethyl cyanoformate 71a, 16 h reaction time. [b] D etermined by GC/MS. [c] D etermined by chiral GC. [d] Assigned by comparing the sign of optical rotation with literature data.[81,82] [e] 72 h reaction time. [f] 5 mol % ligand.

Lastly, AlCl3 was used in place of the lanthanides. When combined with the standard pybox 60 and triethylamine very low conversion was achieved at room temperature. Ligand 56a gave full conversion at 60 °C but the product was racemic. 56b and 56c

did not afford any product even at 60 °C. In contrast, the less sterically hindered pyrrolidine ligand 56d enabled the formation of the desired cyanohydrin at room temperature within 16 hours (98% conversion, 16% ee).

In a control experiment, run with only 56d, without any metal, we could observe the formation of the desired cyanohydrin in yield and enantioselectivity comparable to those obtained when the ditopic pybox-metal complex was used. It is known that amine bases alone can catalyze the addition of ethyl cyanoformate and acetyl cyanide to benzaldehyde.54b-d This result tends to show that the basic part is enough to activate the cyanide source.

To try to understand this behavior and gain insight into the structure of the pybox-

AlCl3 complexes, an NMR study was carried out. This gave us an indication that the metal, instead of coordinating the pyridine and oxazoline nitrogens in its usual tridentate manner, might coordinate one oxazoline nitrogen atom and a pyrrolidine moiety. This situation would result in a decrease in activity and a loss of stereoselectivity.

It was recently shown by Kim and co-workers that trimethylsilylcyanations of several aldehydes could advantageously be performed with an Al(salen) complex and 54a P(O)Ph3 in a double activation process. As expected, the Al(salen) complex functions as a Lewis acid activating the aldehyde while P(O)Ph3 behaves as a Lewis base and is responsible for the activation of TMSCN.

We thus thought that the bifunctional ligand 56e would be a suitable candidate to perform the addition of trimethylsilyl cyanide to benzaldehyde. The results are shown in table 4.

We first started to investigate the reaction with the standard pybox 60. In our hands,

the catalyst prepared from ligand 60 and AlCl3, without additive, provided the cyanohydrin in 95% yield and 84% ee after 4 hours (entry 1). When P(O)Ph3 was used together with this catalyst, the conversion dropped but the ee remained

unchanged (entry 2). Changing to YbCl3 the reaction was slower and only 50% ee was obtained (entry 3). P(O)Ph3 alone catalyzes the reaction to a small extent: after three days 82% conversion was observed whereas in the absence of any catalyst only 12% conversion was recorded.

To explain the slower reaction rate when P(O)Ph3 is added to the reaction, a competitive complexation, between the carbonyl of the aldehyde and the phosphine oxide, to the pybox-metal complex may be envisioned. As a consequence, the reaction proceeds slower while maintaining the same level of enantioselectivity. We hoped that this situation would be avoided with our ligand 56e.

T able 4: Asymmetric trimethylsilylcyanation of benzaldehyde.[a]

O H OTMS Catalyst, solvent H Me3SiCN CN

Entry Catalyst Time Conv (%)[b] Ee (%)[c]

1 60-AlCl3 (10 mol %) 4h 95 84

2 [60-AlCl3 (10 mol %) + 4h 69 84

P(O)Ph3 (20 mol %)]

3 [60-YbCl3 (10 mol %) 4h 33 50

+ P(O)Ph3 (20 mol %)]

4 P(O)Ph3 (20 mol %) 3d 82 / 5 / 3d 12 /

6 56e-AlCl3 (10 mol %) 4h 50 7

[a] All reactions were carried out in acetonitrile at rt for 1.5 h using 1.2 equiv. TMSCN and 10 mol % catalysts. [b] Conversion determined by GC-MS analysis. [c] Enantiomeric excess determined by chiral GC.

U nfortunately this ligand did not give the expected results. When the reaction was run with 10 mol % of our ditopic ligand 56e only 50% yield and 7% ee were observed after 4 hours (entry 6). This shows that ligand 56e probably does not behave as a bifunctional ligand as we expected for this reaction. This result is probably the consequence of a detrimental intra- or intermolecular interaction between the Lewis acid and the phosphine oxide functionalities. It can also ensue from a too important

steric hindrance due to the -P(O)Ph2 groups.

d. Conclusion and perspectives

From the same readily accessible intermediate 55, we have achieved straightforward syntheses of six new pybox ligands 56a-e and 59 bearing different basic moieties on the side arms of the oxazoline rings. These compounds are obtained in a few steps from easily available starting materials.

These compounds were assessed in asymmetric catalysis. U nfortunately our ligands did not show the expected activity in catalysis, probably due to a detrimental interaction between the Lewis acidic part and the basic moiety.

A solution to prevent this situation could be the use of more rigid the side arms so as to avoid intramolecular quenching of the metal by the base. D ue to the flexibily of the

pybox scaffold other positions on this skeleton might as well be good candidates to install a Lewis base. This, however, would mean a complete change in the synthetic strategy to construct the new ditopic pybox ligands. It could also be of interest to try other metal/base combinations. This could help prevent intra- and intermolecular quenching of the Lewis acid by the Lewis base.

Moreover, too high steric hindrance cannot be excluded. Therefore the introduction of less bulky substituents could also be an alternative.

3) New “click” pyridine-bis(oxazoline) ligands a. Background i. Crown ethers

Crown ethers are heterocyclic compounds containing several ether groups.83 The most common crown ethers are oligomers of ethylene oxide and thus present an

ethyleneoxy (-CH2CH2O-) repeating unit. D ioxane, in which the ethyleneoxy unit repeats twice, is, however, generally not considered as a crown ether. The term “crown ether” is usually used for those heterocyclic macrocycles having four or more repeating units.84

Since their accidental discovery by Pedersen in 1967,85 crown ethers have become extremely popular. They have been well studied86 and a large variety of structures have been described.87

Pedersen was looking for a complexing agent for divalent cations. He wanted to link two catechol molecules through one of their hydroxy groups, leaving the two other ones free so that they could be deprotonated at moderate pH and thus neutralize and envelop a divalent cation (scheme 30, a). D uring the isolation of his complexing agent, Pedersen noticed the presence of another species that could complex potassium ions and had no ionizable groups. He called this compound dibenzo-18- crown-6 (scheme 30, b). This discovery was significant since neutral complexers of alkali metals were not common at that time.

a O O O O Ca(OH)2 O O Ca

OH HO O O

b O O O O KCl O O K+ O O O O O O

Schem e 30: a) Pedersen complexing agent for divalent cations; b) dibenzo-18-crown-6.

The name “crown” was given by Pedersen who observed, using molecular models, that the 18-crown-6 ether “crowns” the potassium ion. Pedersen also rapidly realized that the use of systematic names would not be convenient. He proposed a new nomenclature for this class of compounds. He decided to use the ring size, as the first number, and the number of heteroatoms. Thus 3,6,9,12,15,18-hexaoxacyclooctadecane 39

was named 18-crown-6 ether. Even though this nomenclature can sometimes leave some uncertainties when talking about isomers, it is the one commonly used nowadays.

Pedersen tried to expand the number of structures investigating different ring sizes, the type of heteroatoms or substitution on the cyclic framework. He also demonstrated that not only alkali metal cations could be bound by crown ethers. Alkylammonium ions and other species could also be complexed by these heterocyclic systems.85 His discovery prompted a wide interest and many variations in ring size, in heteroatoms, in substitution, in the length of the ethyleneoxy unit, in subunits incorporated in the ring or in the way of linking these macrocycles have been described. By now the number of structures that have been reported probably approaches 10,000.83-85

The most important property of crown ethers is their ability to complex cations.88 It was shown that the binding is optimal when the guest has about the same size as the cavity. As an example, 18-crown-6 binds best K+.84,88d,89 Complexation of the + 90 ammonium ion, NH4 , and of primary alkyl ammonium ions has also been widely studied.91 In particular, receptors that can encapsulate diammonium ions have been developed. Most of them possess two diaza-crown ethers linked by different side arms.

Aza-crowns are crown ethers that contain one or more nitrogen atoms in the macrocyclic ring, but that are not all-nitrogen heterocycles (all-nitrogen heterocycles are called cyclams). They have thus intermediate properties between all-oxygen crowns and cyclams. In particular, they have an enhanced complexing ability for ammonium salts88a,91d and, as such, have found extensive use as synthetic receptors in molecular recognition.92 The nitrogen atoms are often used to link pendent arms93 or to form macrorings.94

ii. Macrocycles and receptors containing a crown ether moiety

Macrocyclic ligands are defined as being cyclic compounds possessing at least three donor atoms incorporated in their ring or, less commonly, attached to their ring. It is admitted that, to be called macrocyclic, these polydentate ligands should consist of at least nine atoms.95

There exist many natural macrocycles. They have been long and well studied and are still a source of inspiration for the chemist.96 A very large number of synthetic macrocycles have also appeared since the 1960s.97 Their mode of action is often inspired by natural macrocycles.51k,95 They have for example been used in molecular recognition,98 as carriers95b and as catalysts.95b,98

Macropolycyclic structures containing one or more crown ethers have received a lot of attention in the recent years.99 Macropolycyclic compounds form a cavity and possess several binding sites thus allowing for the binding of several substrates or of a multifunctional substrate. They can be symmetric or dissymmetric and complex identical or different substrates (homonuclear and heteronuclear complexes respectively). They may act as receptors or effect some transformations. Many structures incorporating an aza-crown ether have been used for binding diammonium cations.

In the 1980s, Lehn described the synthesis and complexation properties of cyclindrical macrotricyclic and macrotetracyclic molecules containing two aza- crown ethers linked by different side arms (scheme 31).100 These macrocycles were + used to complex different alkylammonium ions (RNH3 ) and bis-ammonium ions + + + ( H3N(CH2)nNH3 ) whose binding was compared to that of Na ions. Crystal structures of the inclusion complex formed by 75 and the cadaverine dication, + + H3N(CH2)8NH3 , as well as competition experiments showing selective binding depending on the size of the alkyl chain of the diammonium ion were reported later.101 Stability constants and selectivities of the complexes formed by these macrocycles and ammonium substrates were measured by electrochemical titrations.102

O O 73 R = CH CH OCH CH N N 2 2 2 2 O O R =

R R

74 75 76 O O 77 R = (CH ) N N 2 8 O O

Schem e 31: Some of Lehn’s macrotricyclic ligands.

Metalloreceptors containing porphyrin subunits that worked as heterotopic co- receptors capable of binding organic substrates and metal ions were also designed.103 A bis-anthracenyl macrotricyclic receptor 77 (scheme 32, a) was shown to undergo changes in its optical properties (U V -visible absorption and fluorescence) upon complexation with bis-ammonium cations. This was the first example of optical detection of a linear diammonium guest by fluorescence spectroscopy.104

Sutherland and co-workers presented several macrotricyclic host molecules containing side arms of different rigidity such as 78.98a,105 They showed that, depending on the flexibility of the bridge between the two aza-crown moieties, the

selectivity towards bis-ammonium ions of various lengths was more or less pronounced. They also noticed that dissymmetry in the host structure influenced the binding of the guest (scheme 32, b).

a) b) O O N N O O O O N N O O O O O

O O O O O O O N N N N O O O O

77 78

Schem e 32: a) Bis-anthracenyl receptor for optical detection of linear diammonium ions; b) one of Sutherland’s dissymmetric hosts for bisammonium cation recognition.

Already from the beginning of the development of crown ethers, Cram had realized that selective complexation of chiral ammonium cations could be achieved if the crown was incorporated in a rigid structure. He synthesized system 79 consisting of two naphthalene rings attached at the -position. This system was used to resolve ammonium salts (scheme 33).106 Some other examples have thereafter been reported.107

O O O O + H3N OCH3 O O H O

79 80

Schem e 33: Cram’s bisnaphtyl crown 79 and the phenylethylene ammonium ion 80 that was resolved.

Another type of receptors consist of systems formed by a central core bearing two crown ethers on its pendant arms. These systems have been used to complex bis- ammonium and bipyridinium guests. Shinkai and co-workers synthesized a system containing two crown ethers, connected by an azo linkage that could be switched to bind or release diammonium ions under photochemical control.108 A porphyrin-based receptor having two benzo-crown ether side arms was developed to bind different bipyridinium guests.109 A ternaphtalene derivative 81 was also used for chain length recognition of diamines (scheme 34).110

O O O

OH O O

OMe OMe H2N(CH2)9NH2

OMe H2N(CH2)10NH2 OMe

O O OH

O O O 81

Schem e 34: Ternaphtalene receptor 81 with its two optimal guests.

Hamilton and co-workers prepared a Ru-terpyridine complex possessing two pendant aza-18-crown-6 ether rings and showed that this metal template could be used for solid-liquid extraction of bis-ammonium ions.111 Weiss and co-workers, in turn, reported symmetrical molybdenum complexes having two crown ether subunits that showed good binding abilities towards different diammonium ions but low selectivity, probably due to the too high flexibility of this structure.112 A ditopic host based on a nickel(II) cyclidene platform bearing two crown ethers was shown to behave as tweezers and to selectively bind trimethylene- and tetramethylenediammonium ions.113

Other systems possessing two binding sites, only one of which is a crown ether, have been designed. They offer the possibility to bind bifunctional guests. Some of them incorporate a metal center, which could be useful for catalytic reactions.

Two interesting macrocyclic systems 82 and 83, shown in scheme 35, that contain two potential binding sites with different coordination features, have been synthesized. Mononuclear palladium and copper complexes of 82 were studied but no complexation study was reported using receptor 83.114

CH3 H C a) 3 b) N N N CH3 N N

O O N N O O O O N N 82 O O

Schem e 35: Two macrocyclic receptors presenting two different binding sites.

Two heteroditopic bis-macrocycles 84a-b containing a crown thioether and a crown ether separated by a benzene ring were prepared (scheme 36, a).115 These structures are interesting as it is known that thiacyclophanes are good coordinating agents for transition metals116 whereas all-oxygen crown ethers bind alkali metal ions.84 U sing these properties, a complex of the type [Cu(I)(AMP)(Na+)] was studied.

Mixed complexes 85 of alkaline earth metal ions and proton, Ag+ or Hg2+ are also worth noting (scheme 36, b).117 Alkaline earth metal cations form complexes with the 15-crown-5 while the nitrogen atom of the benzothiazole can be protonated. Ag+ and Hg2+ bind both to the crown and to the heterocyclic residue.

b) a) O S O Mg2+, Ca2+, Ba2+ S O O O S O O O O 84a + Cu S O O O N 85 S O O S S O O H+ O Ag+, Hg2+ 84b

Schem e 36: Heteroditopic systems containing a crown ether moiety.

The systems described above, even though ingenious, have not yet found any use in catalysis. Moreover, apart from Cram’s binaphtyl system used for resolution of primary amines (scheme 33),106 those systems are achiral. There are however a few

chiral systems that have been synthesized and assessed in asymmetric catalytic reactions.

Two heterobimetallic systems 86 and 87 bearing a crown ether side arm and a Lewis acidic site have been previously reported by our group (scheme 37).118 These systems are interesting candidates to effect asymmetric transformations where a secondary interaction can be beneficial. However, only complexation studies have been carried out so far.

O O O O O K+ O O O O + O O O K O O O O O MeO O N N Ph Cu Ph N N - Pd O O Cl Cl 86 87

Schem e 37: Moberg’s heterobimetallic systems.

Ito and co-workers reported the first ferrocenylphosphine ligands 88 modified by crown ethers of different ring sizes and their applications in the palladium-catalyzed asymmetric allylation of -diketones (scheme 38).119 The reaction proved to be very sensitive to the crown ether ring size, the length of the linker chain and the reaction conditions. This is a good example of a multifunctional catalyst where both the nucleophile and the electrophile are activated simultaneously.

O O

N O O O O O ∗ CH Pd2(dba)3.CHCl3, 88 3 PPhH Fe 2 CH2=CHCH2OAc, KF PPh2 88

Schem e 38: Palladium-catalyzed asymmetric allylation of -diketones using ferrocenylphosphine ligand 88 possessing a crown ether moiety.

A similar system 89 composed of a ferrocenyl complex bearing a benzo-aza-15- crown-5 was reported.120 This ligand forms stable complexes with Pt(II). Moreover, a rhodium catalyst formed with this ligand could effect the hydrogenation of simple substrates. Kinetic acceleration of the reaction due to secondary interactions with the crown ether was attempted but failed as only substitution of the crown moiety by allyl ammonium triflate was observed (scheme 39).

O O

H3C N O OTf H3C O N O + - PPh2 NH3 OTf H H Fe PPh O N H Fe 2 PPh2 PPh2 O O 89

Schem e 39: Substitution of the crown ether moiety of ligand 89.

D ue to our interest in bifunctional systems, we wished to synthesize a macrocylic ligand which would incorporate a crown ether and a pybox moiety thus having a hard and a soft binding sites that could be used in asymmetric catalysis (scheme 40).

O O Ph N Ph N N M

Soft binding site

Hard binding site

N O O N O O

Schem e 40: General structure of the macrocyclic ligand.

b. Ligands synthesis

Triazoles are robust linkers that can be made under mild conditions in a regioselective manner using the “click chemistry”.121 We therefore thought that this would be a suitable way of linking the pybox skeleton and the crown ether part together.

Before undertaking the synthesis of a macrocyclic compound, we first probed the attachment by “click chemistry”, on the 4-position of the oxazoline rings, of groups that would resemble the final macrocycle, without the difficulty of the macrocyclization step. We therefore started by preparing the two ligands 91a and 91b (scheme 42). We first had to introduce the azide groups that would then undergo the Huisgen [3+2] cycloaddition. For this purpose, intermediate 57 was subjected to nucleophilic substitution with sodium azide to yield compound 90 in quantitative yield (scheme 41).

O O O O Ph N Ph Ph N Ph NaN3 N N N N 100%

OTs TsO N3 N3 57 90

Schem e 41: Synthesis of intermediate 90.

Compound 90 was then reacted with diphenylacetylene under the thermal conditions of the Huisgen cycloaddition to yield 91a in 88% yield (scheme 42). Ligand 91b was synthesized in 64% yield, using the “click chemistry”, thus resulting in regioselective formation of the 1,3-triazole rings (scheme 42). The use of copper(I) to catalyze the reaction also enabled to shorten the reaction time in comparison with the thermal conditions.

O O Ph N Ph Ph Ph N N 88% N N N N Ph N N Ph

O O Ph Ph N Ph Ph 91a N N

N3 N3 O O 90 Ph N Ph N N

N N N N Ph N N 64% Ph Ph 91b

Schem e 42: Synthesis of ligands 91a and 91b.

With this methodology in hand, the next step was to functionalize a diaza-crown ether to make it a suitable precursor for the Huisgen [3+2] addition (scheme 43). 4- Bromobenzyl groups were installed on the diaza-18-crown-6 by nucleophilic displacement (91% yield). The intermediate 92 thus obtained was then subjected to Sonogoshira coupling to yield compound 93. This compound was not isolated and removal of the silyl protecting groups was effected on the crude mixture. After purification, compound 94 could be isolated in 72% yield over two steps.

O O H N O N O Br Br O N Cl O N H O O Na2CO3, MeCN 91% 92

O SiMe3 SiMe3 N O

Pd(PPh3)Cl2, CuI, Et N O N 3 Me Si 3 O 93

O N O TBAF, THF O N 72%over 2 steps O 94

Schem e 43: Synthesis of intermediate 94.

The two intermediates 90 and 94 were then subjected to the Cu(I)-catalyzed [3+2] cycloaddition. This reaction was performed under high dilution conditions in order to favor macrocyclization over oligomerization (scheme 44). After two days at room temperature, the reaction mixture did not seem to change anymore. Some oligomers had precipitated during the reaction whereas the macrocycle was found to be soluble in the reaction solvent. It could therefore be separated from the oligomeric mixture by simple filtration and further purified by column chromatography. After optimization of the reaction and purification conditions, we were able to isolate macrocycle 95 in 21% yield from 91 and 94.

O O Ph N Ph O O N N N Ph Ph N N

N3 N3 N N 90 N N "Click" N N CuI, DIEA, DCM/MeCN 21%

N O O N O O N O O N O O 95 94

Schem e 44: Synthesis of macrocycle 95.

c. Complexation studies

It has been shown that pybox ligands can bind secondary dialkylammonium ions through hydrogen bonding.122 On the other hand diaza-crown ethers possess good complexing abilities towards primary ammonium ions.88a,91d We hypothesized that primary ammonium ions should also be able to form hydrogen bonds with the pybox moiety and therefore we envisaged the encapsulation in our macrocycle of bis- primary ammonium cations of suitable size.

We first verified our hypothesis that primary ammonium cations bind to a pybox ligand (scheme 45). For this purpose, pybox 60 and benzylammonium chloride were stirred for two hours in deuterated methanol. The 1H NMR spectrum showed complexation of the ammonium cation to the nitrogen atoms on the pyridine and the oxazoline rings. The experiment was repeated with 1,4-dibenzylammonium dichloride but two equivalents of pybox ligand were used. We could observe the binding of one pybox on each ammonium function of the diammonium salt.

+ - NH3 Cl 1:1 complex O O N CD3OD N N CD3OD Ph Ph + 60 NH3 1:2 complex 2 Cl- + H3N

Schem e 45: Preliminary complexation studies with pybox 60 and two benzylammonium chloride salts.

We then investigated binding in the macrocycle 95 (scheme 46). 1,4- D ibenzylammonium dichloride was mixed with one equivalent of our macrocycle and the mixture stirred in deuterated methanol for two hours. The 1H NMR spectrum showed weak shifts of the macrocycle and ammonium protons in comparison to the free species. A NOESY experiment confirmed the presence of the diammonium inside the cavity of the macrocycle. To account for the fact that only weak shifts were observed on the 1H NMR spectrum, we propose that the 1,4-dibenzylammonium guest could be somewhat too short for the cavity and thus would be in rapid exchange between the two coordination sites.

O O N - + Ph Ph Cl H3N N N

N N N N N N

+ - NH3 Cl 1:1 complex CD3OD N O O N O O

Schem e 46: Complex formation of macrocycle 95 and 1,4-dibenzylammonium dichloride.

A longer guest, 1,7-heptanediammonium dichloride, was therefore selected and we started to investigate its complexation. First, we prepared a complex of ligand 60 and 1,7-heptanediammonium dichloride (scheme 47). As expected, we could observe a 1:2 complex with one pybox binding each ammonium function (scheme 47).

+ + H3N ( )5 NH3 O O N 2 Cl- N N 1:2 complex CDCl3/CD3OD 3:1 Ph Ph 60

Schem e 47: Preliminary complexation study with pybox 60 and 1,7-heptanediammonium dichloride.

We then attempted binding of 1,7-heptanediammonium dichloride into the macrocycle 95. The 1H NMR spectrum clearly showed complexation of both ammonium functions in the macrocycle (one to the pybox moiety and the other one in the crown ether), with marked shifts for the protons of the pybox moiety and of the diaza-crown ether. A weak NOE effect could be seen between the protons of the

alkyl chain of the diammonium guest and the phenyl rings on the linker arms of the macrocycle.

O O N Ph Ph N N

N N N N + + N N H3N ( )5 NH3 2 Cl- 1:1 complex CDCl3/CD3OD 3:1

N O O N O O

Schem e 48: Complex formation of macrocycle 95 and 1,7-heptanediammonium dichloride.

Our macrocycle 95 presents two binding sites with different features. Therefore, another possibility is to encapsulate a substrate having two different functional groups that could selectively bind to the pybox-metal complex on one end and to the crown ether on the other end. We thus thought that it would be of interest to study complexes formed by macrocycle 95 and some bifunctional molecules that could fit in the cavity. This approach opens interesting perspectives in the design of selective catalysts for the recognition of functionalized substrates (scheme 49).

O O N Ph Ph N N

N N N N N N

N O O N Catalysis O O Molecular recognition 95

Schem e 49: Possible uses of macrocyclic ligand 95 in chiral recognition and selective substrate binding and reaction.

Ru-pybox-olefin complexes have been described.123 It was shown that only one

enantioface of the different olefins studied binds to the chiral (pybox)RuCl2 fragment. Ab initio calculations and X -ray analysis showed that the C=C bond is coordinated parallel to the pybox plane. This was explained by back-donation of electrons of the filled metal d orbital in the pybox plane to the vacant p orbital of the coordinated carbon atoms in the olefin.

We therefore wished to try to bind an olefin of suitable length bearing another functional group that could fit in the crown pocket. To this end, complexation of 10- undecanoic acid and macrocycle 95 was undertaken.

O O ( ) COOH N 6 N N 1:1 complex [Ru(p-cymene)Cl2]2 Ph Ph 60

Schem e 50: Preliminary complexation study with pybox 60 and 10-undecanoic acid.

Preliminary experiments were carried out using pybox 60 and 10-undecanoic acid (scheme 50). U sing the procedure described by Nishiyama and co-workers,123e the complex formed smoothly in dichloromethane. As shown by 1H NMR, only one complex was formed. This is consistent with the results reported in the literature,123 as it has previously been observed that only one enatioface of the olefin binds to the bis(oxazolinyl)pyridineruthenium fragment.

O O N Ph Ph N N

N N N N ( ) COOH N N 1) 6 [Ru(p-cymene)Cl2]2 1:1 Ru-carboxylate complex 2) NaH

N O O N O O

Schem e 51: Complex formation of macrocycle 95 and sodium 10-undecenoate.

Carboxylates are known to be easily complexed by Ru(II).124 To try to avoid complexation of the carboxylate function of 10-undecenoate to ruthenium, we first formed the Ru-olefin complex of macrocycle 95 using 10-undecanoic acid, as it had

been done for pybox 60 except that THF was used instead of dichloromethane. Sodium hydride was then added. We hoped that the carboxylic acid function would be placed inside the cavity towards the crown ether and would be deprotonated by sodium hydride thus forming a carboxylate which counter ion would be bound to the crown ether. To our disappointment, upon doing this, we could observe that only Ru- carboxylate complexes were formed. D ecomplexation of the olefin and of a chloride ion and their replacement by the carboxylate, forming a chelate, is thought to occur.

d. Catalysis i. Asymmetric Mukaiyama aldol reaction

The aldol reaction, i.e. the addition of an enolizable carbonyl compound to an aldehyde or a ketone, is considered as one of the most important carbon-carbon bond forming reactions.125 Because up to two new adjacent stereogenic centers can be created, providing interesting chiral structural motifs, the aldol reaction has been widely used for the synthesis of natural and unnatural products126 and many methodologies involving chiral catalysts have been developed.127

The Lewis acid catalyzed addition of enolsilanes to aldehydes, the Mukaiyama aldol reaction, is an important variant of the aldol reaction that has attracted a wide interest.128 The introduction of pybox ligands in this reaction is mainly due to Evans.129 The use of various pybox complexes has later been reported.35a,130 In particular, some recent examples suggest that the use of bulky silyl ether substituents on the 4-position of the oxazoline rings, such as in compound 96 (scheme 52), leads to improved enantioselectivities.36d,131 Therefore we thought that our pybox ligands 91a and 91b, bearing more stable bulky triazole groups, could be used in a similar way.

O O O O Ph N Ph Ph N Ph N N N N

N N N N N N N N Ph N N Ph N N

Ph Ph Ph Ph 91a 91b

O O Ph N Ph N N

OSiiPr3 OSiiPr3 96

Schem e 52: Pybox ligands used in the Mukaiyama aldol reaction.

We thus undertook to test these two ligands in the Mukaiyama aldol reaction. D esimoni and co-workers showed that, in the reaction of 1-phenyl-1- trimethylsilyloxyethene 97 and ethyl pyruvate 98, the best results were obtained 131a using a Sc(OTf)3 complex of pybox 96. They reported 92% yield and 92% ee for the reaction run at -50 °C during 3 days. In our hands, this catalyst afforded ethyl 2- hydroxy-2-methyl-4-oxo-4-phenylbutanoate 99 in 90% yield and 84% ee after 65 hours at -50 °C (table 5, entry 1). We then run the reaction under the same conditions using our ligand 91b. The desired product was obtained in 80% yield and 38% ee (entry 2). When using the more hindered ligand 91a, the reaction had to be run at -20 °C. These conditions afforded product 99 in 49% yield and a somewhat better ee (54% ee, entry 3) than when ligand 91b was used. For comparison, the reaction was run at -50°C with ligand 60: this afforded product 99 in 92% yield and low ee (29% ee, entry 4).

T able 5: Mukaiyama aldol reaction of 1-phenyl-1-trimethylsilyloxyethene 97 and ethyl pyruvate 98.[a]

O OTMS 1) Ligand, Sc(OTf)3, DCM OMe OH O 2) CF3COOH O Ph Ph 97 O 98 99 O

Entry Ligand Yield (%)[b] Ee (%)[c] 1 96 90 84 2 91b 80 38 3[d] 91a 49 54 4 60 92 29

[a] All reactions were run in CH2Cl2 at -50 °C in the presence of 10 mol % of complex for 65 h. [b] Isolated yields.

[c] Enantiomeric excess determined by HPLC (OD -H column, Hex/iPrOH 96:4, 0.7 mL/min tr1 = 19

min, tr2 = 21 min). [d] Reaction run at –20 °C for one day.

As can be seen from those results, our ligands 91a and 91b did not perform as well as ligand 96 reported by D esimoni and co-workers. The structure of the catalyst therefore seems very important to achieve good results in this reaction and it appears that a good balance between sufficiently but not too sterically hindered arms is crucial here. Comparison of the results obtained with our ligands 91a and 91b and those furnished using ligand 96 indicates that our ligands might be too bulky for this peculiar reaction.

ii. Addition of (trimethylsilyl)acetonitrile to benzaldehyde

-Hydroxynitriles are useful intermediates in organic synthesis and are particularly interesting as they can easily be transformed into 1;3-amino alcohols.132 The opening of epoxides with a cyanide source, such HCN,132b,133a-c LiCN,133c NaCN,132a,133d-g KCN,133h-l TMSCN133m-s or acetone cyanohydrin132d,133t-u represents one of the most common ways to obtain these compounds. TMSCN has the advantage to yield the protected -hydroxynitriles.

Interestingly the synthesis of 3-phenyl-3-(trimethylsilyloxy)propanenitrile 100 has seldom been reported and no enantioselective version has yet been successful. This product has been synthesized via epoxide ring opening using TMSCN (scheme 53, a).134 U sing this method, Wheeler reported the synthesis of the (R)-3-phenyl-3- (trimethylsilyloxy)propanenitrile 100 but starting from the (R)-phenyloxirane.135b Apart from this synthesis, no attempt to obtain 100 in an enantiomerically pure form has been made. 3-Phenyl-3-(trimethylsilyloxy)propanenitrile 100 has also been obtained as a racemate by addition of -haloacetonitrile to benzaldehyde catalyzed by zinc-trimethylchlorosilane (scheme 53, b).135 Another racemic synthesis (scheme 53, c) requires heating of isoxazolines at 100 °C for prolonged times.136 Finally, addition of (trimethylsilyl)acetonitrile (TMSAN) to benzaldehyde, catalyzed by the KCN-18-crown-6 complex137a or different fluoride sources such as tris(dimethylamino)sulphonium difluoromethylsiliconate (TASF)137b or KF and CsF,137c-f has been reported (scheme 53, d).

a) OSiMe O 3 Catalyst CN TMSCN 100 b) OSiMe O 3 CN ClSiMe3 H XZnCH2CN 100

c) OSiMe3 Me3Si 100°C, 24h CN N Ph O 100

d) O OSiMe3 CN H Catalyst Me3SiCH2CN 100

Schem e 53: D ifferent syntheses of compound 100.

The last method attracted our attention since we thought that our macrocycle could act as a bifunctional catalyst and enable to perform an asymmetric version of this reaction. Benzaldehyde could be activated by a Lewis acid coordinated to the pybox moiety. The crown ether part could be used to activate potassium fluoride which would in turn activate (trimethylsilyl)acetonitrile. It is well known that fluorides can be used to generate the acetonitrile anion.137b-f, 138

We therefore started to screen different reaction conditions (table 6). We first verified that TMSAN and benzaldehyde do not react in the absence of an activator (entry 1). We also checked that KF alone did not promote the reaction (entry 2). However, as expected, the use of a catalytic amount of the KF-18-crown-6 complex enables complete conversion of the starting materials to the desired product within 6 hours at room temperature (entry 3).

T able 6: Addition of (trimethylsilyl)acetonitrile to benzaldehyde.[a]

O OSiMe3 CN H Catalyst Me3SiCH2CN 101

Entry Catalyst Time Yield (%)[b] Ee (%)[c] 1 / 1 day 0 / 2 KF 1 day 0 / 3 KF-18-crown-6 6 h > 99 /

4 KF-18-crown-6 + 60-CuF2 6 h 22 < 5

5 KF-18-crown-6 + 60-YbF3 5 min > 99 < 5

6 60-YbF3 1 day 0 / [d] 7 KF-18-crown-6 + 60-YbF3 2 h 35 < 5 [e] 8 KF-18-crown-6 + 60-YbF3 2 h 72 < 5 [f] 9 KF-18-crown-6 + 60-YbF3 2 h < 5 / [g] 10 KF-18-crown-6 + 60-YbF3 15 min > 99 < 5

11 95- YbF3-KF 15 min 95 < 5 [h] 12 95- YbF3-KF 2 h 0 /

[a] All reactions were carried out in CH2Cl2 at rt using 10 mol % of catalyst, 1.2 equiv. TMSAN. [b] Conversion determined by GC-MS analysis. [c] Enantiomeric excess determined by GC-MS. [d] Reaction run in THF. [e] Reaction run in D MF.

[f] Reaction run in CH2Cl2. [g] Reaction run at -20 °C. [h] Reaction run at 0 °C.

As we wished to develop an enantioselective version of this reaction, we investigated the use of different metal complexes of pybox 60, in combination with the KF-18- crown-6 complex. This was expected to lead to a dual activation, also mimicking the situation that would be obtained using the macrocycle, a metal salt and KF.

We thus performed the reaction using different metal complexes of pybox 60. The counter ions on the metal salt proved to be determining as all metal sources except those having fluorides as counter ions completely inhibited the reaction. It had been earlier reported by Palomo and co-workers that the reaction did not work under 137b Lewis acid conditions, when catalyzed by Z nI2 or TiCl4 among others. However, we were pleased to observe that the pybox-CuF2 complex, used in combination with the KF-18-crown-6 complex, afforded, after 6 hours at room temperature, the protected -hydroxynitrile 101 in a modest 22% yield and with low enantioselectivity

(entry 4). When YbF3 was used instead of CuF2, a tremendous increase in the reaction rate was observed: the reaction was complete after 5 minutes at room temperature, but unfortunately, this system also failed to afford any

enantioselectivity (entry 5). When a complex of pybox 60 and YbF3 was used in the absence of KF-18-crown-6 complex, no reaction took place (entry 6).

The influence of the solvent was also investigated (entries 7-9). The reaction was slower in all other solvents and none of them afforded any improvement in enantioselectivity. The reaction performed in THF gave the product in 35% yield and less than 5% ee after 2 hours (entry 7). D MF gave a somewhat faster reaction (72% yield in 2 hours) but with the same level of enantioselectvity as THF (< 5% ee) (entry

8). The use of CH2Cl2 almost inhibited the reaction (entry 9).

Attempts to improve the enantioselectivity by carrying out the reaction at lower temperatures failed, leading to the same level of enantioselectivity (< 5% ee) and a slightly lower reaction rate (99% yield in 15 minutes) (entry 10).

However, we hoped that our macrocycle 95 would provide a more favorable environment leading to better levels of enantioselection. We thus carried out the

reaction using this ligand in combination with YbF3 and KF (entries 11 and 12). U nfortunately, the reaction carried out under these conditions, at room temperature, was somewhat slower and only provided the same result in terms of

enantioselectivity (< 5% ee). At -20 °C or 0 °C, using the macrocycle-YbF3-KF complex, no reaction was observed. This decrease in reactivity could be due a more difficult approach of the benzaldehyde due to increased steric hindrance around the metal center compare to the situation where pybox 60 was used in combination with the KF-18-crown-6 complex.

e. Conclusion and perspectives

Two new pybox ligands 91a and 91b, bearing bulky substituents, and a macrocyclic ligand 95, consisting of a pybox unit and a diaza-18-crown-6, have conveniently been synthesized using the “click chemistry”.

Complexes of the macrocyclic ligand 95 with different bifunctional substrates have been studied by NMR. It was shown that substrates are able to bind to both coordinating sites of the macrocycle: one end at the pybox unit and the other one in the diaza-crown ether. This opens the way to new reactions in which our macrocyclic ligand 95 could be used for molecular recognition or selective activation of multifunctional substrates. By holding substrates in close proximity, this macrocycle could enhance the rate and enantioselectivity of catalytic asymmetric reactions. It could also be used to regioselectively react one function of a multifunctional substrate.

The potential of ligands 91a and 91b has also been examined in the Mukaiyama aldol reaction. The macrocyclic ligand 95 has been assessed in the enantioselective synthesis of -hydroxynitriles. U nfortunately the results remained quite disappointing. Ligands 91a and 91b afforded inferior results in the Mukaiyama aldol reaction than previously reported ligands. Addition of TMSAN to benzaldehyde could be effected using the macrocyclic ligand 95 but no chiral induction was observed. It would therefore be of interest to assess those compounds in other types of reactions.

4) New polymer-supported pyridine-bis(oxazoline) ligand a. Supported ligands

Ligand design is often a time-consuming and expensive process, but even more so is the synthesis of these molecules. It can therefore be of interest to be able to recover the catalyst at the end of a reaction. Separation from a complex reaction mixture can sometimes be difficult and demand long and costly procedures. As a solution to these issues a wide range of methods have been developed to attach homogeneous catalysts onto various supports.139 Heterogenization of a given catalyst not only allows for its simple and efficient reuse, but it is also more environmentally benign.

The most common strategy to allow heterogeneous chiral catalysis is to bind a chiral ligand or complex onto an insoluble support. This support can be either inorganic (such as clay, silica and zeolites) or organic (polymeric). Both types of supports have their own advantages and drawbacks. For example, inorganic supports are more thermically and mechanically stable whereas organic supports are more flexible and allow for more freedom in the design of the final system. There are essentially two ways of making polymeric supported ligands: either via co-polymerization or via grafting onto a preformed resin.

In many cases the support can influence the activity of an immobilized catalyst due to the presence of additional functionalities or an increased steric bulk. As a consequence, special attention has to be paid to the linker and type of support. In particular, the cross-linking degree of a polymeric resin can be crucial for the outcome of the reaction as it affects the accessibility of functional sites and thus the catalyst performances.

As we have seen before, pybox ligands have a wide applicability.4f Interestingly, however, methods for the immobilization of pybox ligands have been developed quite recently while supported bis(oxaline) ligands have attracted a lot of attention in the past years.4e Mayoral and co-workers described the first polymer-supported pybox 102.140 This compound was obtained via co-polymerization of 4-vinylpybox derivatives with styrene and divinylbenzene (scheme 54).

O O Co-polymerization O O N + + N N N N N

102

Schem e 54: Immobilization of a pybox ligand via co-polymerization.

O a) (CH2)nCOOH ( )n O

O O O O N Esterification N N N N N Ph Ph Ph 103a Ph

(CH ) OH O 2 n ( )n O

COOH

O O O O N Esterification N N N N N Ph Ph Ph 103b Ph

b) Cl

1) Nucleophilic aromatic substitution 2) Grafting O O O O N N N N N N

104

O ( ) O c) n 5 steps O CCl3 O O N NH N N R 105 R

Schem e 55: Some examples of immobilization of pybox ligands: a) on a TentaGel resin via esterification, b) on a Merrifield resin via nucleophilic substitution, c) on a Wang resin by stepwise solid phase synthesis.

Shortly after, Moberg and co-workers reported the attachment of the same type of ligands onto silicon chips.141 Pybox ligands were then immobilized on various silica supports by different means and the influence of different parameters was studied by the group of Mayoral.142 Subsequently, pybox ligands were grafted on a TentaGel resin via an ester bond143 (scheme 55a, compounds 103a and 103b), on a Merrifield resin via nucleophilic substitution144 (scheme 55b, compound 104), on a Wang resin possessing a long spacer via an ether bond145 (scheme 55c, compound 105), and on

modified starch.146 The first electrostatic immobilization on silica of pybox-copper complexes was recently reported by O’Leary.147

These different strategies led to interesting results and a better understanding of the factors that are critical to obtain an efficient system. However, those polymeric catalysts showed some drawbacks. For instance, some suffer from a long and quite low yielding synthesis140,145 or from a low stability of the linker that connects the ligand to the resin.141,143 Sometimes, leaching of the metal can also occur, leading to a decrease in catalytic activity.147

We therefore thought that developing a more straightforward synthesis of a polymer- bound pybox in which the linker would be more robust would be of interest.

b. Ligand synthesis

We chose to immobilize the pybox ligand onto a Merrifield resin, a poly(styrene- divinylbenzene) polymer with a low cross-linking degree, that is widely used. A low cross-linking is known to be favorable as it allows for a better functionalization degree and a higher reactivity of the resulting reagent. By direct grafting of the ligand onto the resin we would be able to control the cross linking degree of our supported catalyst. The linker type and length are also crucial for the success of the system. Triazoles can be made easily under mild conditions using the “click chemistry” and they are resistant to most reaction conditions.121 We thus thought that this would be a convenient way to link a pybox onto the resin. Moreover, the triazole ring was expected to be of suitable length. There are now many examples in the literature where a triazole has been used to simply attach in a solid way catalysts on resins.148

O Br

1) PBr5, 90°C HO OH 2) MeOH, 0°C MeO OMe N N H 86% O O O O 106 107 Br NH HO 2 Ph N 80% O O HO 108 OH Br

TsCl, Et3N O O 71% N N N Ph Ph 109

Schem e 56: Synthesis of 4-bromo-substituted pybox 109. 61

First, the Merrifield resin needed to be modified by nucleophilic substitution with 149 NaN3. This was realized according to a procedure reported by Mioskowski et al. 4- Bromo-substituted pybox 109 was selected as a good precursor to install the acetylene function. 4-Bromo-substituted phenyl-pybox 109 can be readily obtained in two steps from chelidamic acid 106 (scheme 56).143

The intermediate 109 was then subjected to Sonogashira cross-coupling with

trimethylsilyl acetylene in refluxing CH2Cl2 in the presence of Pd(PPh3)2Cl2, CuI and a large excess of Et3N (scheme 57). The resulting 4-[(trimethylsilyl)ethynyl]-pybox 110 was subsequently desilylated, without further purification, using TBAF to yield the 4-ethynyl pybox 111 in 50% yield over two steps from the 4-bromo-substituted phenyl-pybox 109. Finally, immobilization of this pybox onto the modified Merrifield resin 112 was accomplished in THF at 35 °C in the presence of a catalytic amount of CuI and an excess of D IEA over 3 days.

Me3Si H O O O O N N Pd(PPh3)Cl2, CuI, Et3N, N N N N CH2Cl2, reflux, 3 h Ph 109 Ph Ph Ph 110 R=SiMe3 TBAF, THF rt, 2h30 111 R=H (50%from109)

112 Ph N3 CuI/DIEA/THF CuI/DIEA/THF 100% 82%

Ph N N N N N N

O O O O N N N N N N Ph Ph Ph Ph Click-pybox resin 113a Monomeric ligand 113b 0.8 mmol/g

Schem e 57: Synthesis of supported ligand 113a and of monomeric ligand 113b.

Anchoring of the pybox by this method occurred in quantitative yield as shown by elemental analysis (N loading: 0.8 mmol.g-1 found analytically and consistent with the theoretical content) and by IR spectroscopy (complete disappearance of the azide stretch vibration at 2090 cm-1). For comparison with the homogeneous conditions and to make sure that the triazole functionality in the 4-position of the pybox did not influence the catalyst activity, we also synthesized the analogous ligand 113b under the same conditions but using benzyl azide in place of the modified Merrifield resin. This procedure afforded the desired ligand 113b in 82% yield (scheme 57).

c. Catalysis i. TMSCN epoxide opening

We first decided to evaluate our supported ligand in the ring opening of cyclohexene oxide using TMSCN as nucleophile. The asymmetric ring opening of m eso-epoxides by a cyanide nucleophile is an important method for the synthesis of optically active cyanohydrins as they are valuable building blocks. 50d,67

It is known that the asymmetric ring opening of epoxides is effected by pybox- lanthanide catalysts in good yield and enantioselectivity.150 It was shown that the

best results were obtained in CH2Cl2 using pybox 60-YbCl3 or pybox 60-LuCl3 complexes. We therefore started by studying the effect of complexes of our supported pybox 113a with those two metal salts.

The resin 113a was first incubated with the LnCl3 salt in THF for 1.5 hours at room temperature. THF was then filtered off, the resin was rinsed twice with THF and

dried. This enabled to prepare the active catalyst: LnCl3 salts are scarcely soluble in CH2Cl2 which makes complex formation very difficult and very slow in this solvent. However the solubility in THF is good and permits the formation of the complex in a short time and in an efficient way. As the reaction was reported to give best results in

terms of yield and enantioselectivity in CH2Cl2, we filtered off the THF used for complex formation and then replaced it by CH2Cl2. The ring opening of cyclohexene oxide was thus accomplished at room temperature in CH2Cl2 using 10 mol % of the supported catalyst and 1.2 equivalents of TMSCN (table 7). Conversion of the starting material into the expected -trimethylsilyloxy nitrile 114 reached 98% and

64% ee, after 1 hour, when YbCl3 was used (entry 1). Carrying out the reaction under the same conditions but with LuCl3 gave 97% of the desired product in 57% ee (entry 2). For comparison the reaction was performed with ligand 113b (entries 3 and 4). The results obtained with the homogeneous analog were comparable to those obtained using the heterogeneous pybox catalyst. Both results are very similar to those reported in the literature indicating that neither the presence of the triazole ring nor the polymeric support seem to affect the reaction outcome.

However, when recycling the resin-bound catalyst by filtration and washing with

CH2Cl2, we could observe an important drop of the enantioselectivity whereas the activity of the catalyst remained unchanged (entries 5-8). An explanation might be a

partial decomplexation of the Ln salt in CH2Cl2. The salt remains imprisoned onto the polymer matrix which would explain that the conversion did not decrease. As it is not anymore in a chiral environment, the Ln salt promotes the epoxide opening

without any enantioselectivity. In a control experiment run with YbCl3 in CH2Cl2, we could see that cyclohexene oxide is completely converted into the - trimethylsilyloxy nitrile in a racemic form after 16 hours.

T able 7: Asymmetric ring opening of cyclohexene oxide catalyzed by “click-pybox” ligands 113a and 113b.[a]

OTMS catalyst O TMSCN CN

114 R= TMS Ref. [153] 115 R= Ac

Entry Catalyst Run Conv (%)[b] Ee (%)[c]

1 113a-YbCl3 1 98 64

2 113a-LuCl3 1 97 57

3 113b-YbCl3 1 98 65

4 113b-LuCl3 1 98 55

5 113a-YbCl3 2 97 21

6 113a-YbCl3 3 95 7

7 113a-YbCl3 4 98 4

8 113a-YbCl3 5 97 4

[a] All reactions were carried out in CH2Cl2 at rt for 1 h using 10 mol % of catalyst, 1.2 equiv. TMSCN. [b] Conversion determined by GC-MS analysis. [c] Enantiomeric excess determined by GC-MS after derivatization according to ref. [151]

ii. Silylcyanation of benzaldehyde

We then investigated the silylcyanation of benzaldehyde which is another common method to obtain chiral cyanohydrins.50d,67 The silylcyanation of benzaldehyde with TMSCN is well documented70,152 and has been studied before in our group with TentaGel-bound pybox catalysts.143

The reaction is known to be best performed in acetonitrile. In our case however, this solvent led to very poor results (table 8, entry 1), probably due to insufficient swelling in acetonitrile of the polystyrene resin that we used as a matrix. On the other hand,

CH2Cl2 is a poorer solvent when carrying out silylcyanation reactions with TMSCN but is very efficient to swell the Merrifield resin. As a consequence, the use of

mixtures of CH2Cl2 and acetonitrile was examined. The optimized ratio to obtain a good swelling without loss of activity of the polymer-bound catalyst proved to be 2:3

MeCN/CH2Cl2. U sing this solvent mixture, 10 mol % of the supported pybox, 5 mol % of LnCl3 salt and 1.2 equivalents of TMSCN, 87% of the benzaldehyde was converted into the expected cyanohydrin 116 in 67% ee using YbCl3 (entry 2). When LuCl3 was employed, 78% conversion of benzaldehyde to the cyanohydrin 116 was observed and the ee was 69% (entry 6). These results are comparable to those afforded by the TentaGel-bound catalysts 103a and 103b, previously reported in our group,143 in terms of conversion, but the enantioselectivity is somewhat lower.

T able 8: Asymmetric silylcyanation of benzaldehyde catalyzed by “click-pybox” ligands 113a and 113b.[a]

O H OTMS H catalyst CN TMSCN 116

Entry Catalyst Run Conv (%)[b] Ee (%)[c] [d] 1 113a-YbCl3 1 55 32

2 113a-YbCl3 1 87 67

3 113a-YbCl3 2 76 73

4 113a-YbCl3 3 70 75

5 113a-YbCl3 4 70 78

6 113a-LuCl3 1 78 69

7 113a-LuCl3 2 73 75

8 113a-LuCl3 3 70 77

9 113a-LuCl3 4 68 78

[a] All reactions were carried out in acetonitrile/CH2Cl2 3:2 at rt for 1.5 h using 1.2 equiv. TMSCN, 10

mol % polymer-bound ligand 113a and 5 mol % LnCl3. [b] Conversion determined by GC-MS analysis. [c] Enantiomeric excess determined by chiral GC. [d] Only acetonitrile used as solvent.

We were pleased to note that the ee increased after recycling our PS-bound catalyst. Although the activity decreased slightly, after the fourth run the ee reached 78% which is similar to the best results obtained with the TentaGel-immobilized catalysts (entries 3-5 and 7-9). This result can be explained by a partial complexation of the metal salt on the triazole nitrogen in the first run. As the resin is rinsed once after the first run, this metal salt, complexed on the triazole, would be washed off and only that bound to the pybox would remain. This would account for a slightly lower

reactivity but an improved enantioselectivity. A similar situation has been reported with copper(II) complexes of bis(oxazoline) ligands having a triazole side arm.153 This phenomenon is not rare in the case of supported catalysts. It was also observed with other types of linkers.140,141 For some other reactions, it was shown that the support, for example silica, was detrimental.4e

iii. Alkynylation of imines

Finally we wanted to assess our supported pybox in the alkynylation of imines. This reaction provides direct access to chiral propargylamines.154 These compounds are interesting intermediates for the synthesis of various nitrogen-containing compounds,155 natural products,156 pharmaceuticals,157 herbicides and fungicides158. Methods developed to synthesize optically active propargylamines are quite limited154 and often involve the addition of organometallic reagents to a chiral imine derivative.159

Copper-catalyzed alkyne-imine addition has been reported before.154d-f Recently Portnoy et al. immobilized a pybox onto a Wang resin (scheme 55, compound 105) and used it in the first heterogeneously catalytized asymmetric addition of alkynes to imines.145 They obtained the product with up to 83% ee for the reaction of phenylacetylene with N-benzylideneaniline but they could not efficiently recycle their catalyst. O’Leary used his pybox-copper complexes immobilized by electrostatic interactions on silica in this reaction as well. Even though conversions were generally good, ee:s remained moderate.147

In our case, alkynylation of N-benzylideneaniline 117a took place at room temperature in dichloroethane in the presence of 10 mol % of the “click-pybox”-CuOTf complex (Table 9). All of the starting material was converted into the aminoalkyne 118a which was obtained in 88% ee (entry 1). The homogeneous click-pybox afforded the product in 96% ee (entry 2). Moreover, our polymer-bound catalyst could be recycled by filtration in three consecutive runs without loss of activity, but only a small decrease of enantioselectivity down to 80% ee (entries 3-6). These results remain however superior to those obtained with Portnoy’s Wang resin or with O’Leary’s silica supported catalysts. After four runs, we could observe a significant drop of both conversion and ee, possibly because some air got into the system causing oxidation of copper (I) to copper (II).

We also examined the possibility of reusing the metal-free resin (entry 7). For this purpose, after one run, the resin was washed successively with pyridine, methanol and dicholoromethane and then dried. It was then recharged with CuOTf and assessed in the alkynylation reaction. We were pleased to observe that the activity and selectivity of the resin were completely restored. The so-recycled resin could be used many times without change in its performances.

T able 9: Enantioselective addition of phenylacetylene to benzylideneaniline catalyzed by “click- pybox” ligands 113a and 113b.[a]

Ph Ph N H Ph H catalyst N H Ph C CH 117a 118a

Entry Catalyst Run Conv (%)[b] Ee (%)[c] 1 113a-Cu(I) 1 100 88 2 113b-Cu(I) 1 100 96 3 113a-Cu(I) 2 98 83 4 113a-Cu(I) 3 99 81 5 113a-Cu(I) 4 95 80 6 113a-Cu(I) 5 49 9 7[d] 113a-Cu(I) 1 100 89

[a] All reactions were carried out in dichloroethane at rt for 48 h using 1.5 equiv. of phenylacetylene, 10 mol % polymer-bound ligand 113a and 10 mol % CuOTf. [b] Conversion determined by 1H NMR of the crude product. [c] Enantiomeric excess determined by chiral HPLC.

[d] Polymer-supported catalyst from entry 6 after washings with pyridine/methanol/CH2Cl2 and reloading with copper triflate.

We next investigated the scope of the polymer-bound pybox catalyst with a range of N-arylimines under the optimal conditions used above (table 10). In all cases the corresponding propargylamines were formed in good yields and ee:s.

T able 10: Enantioselective alkynylation of imines catalyzed by “click-pybox” ligand 113a.[a]

Ph R Ar 2 2 R2 N H Ar2 H 113a-Cu(I) N Ar1 Ar1 H Ph C CH R R1 1 117 118

Entry Substrate R1 R2 Conv (%)[b] Ee (%)[c] 1 117a H H 118a: 100 88 2 117b 4-Cl H 118b: 85 90 4 117c 4-Et H 118c: 84 90 5 117d 4-F H 118d:78 84

7 117e Ar1=-Naphthyl H 118e:100 81 9 117f H 4-t-Bu 118f: 73 88 10 117g H 4-Et 118g: 93 88 11 117h H 4-OMe 118h: 73 80

d. Conclusion and perspectives

We have developed a new polymer-supported pybox ligand which presents several advantages in comparison to the ones reported previously: 1) direct grafting on a preformed resin enables to control the cross linking of the resin and its functionalization, thus providing better accessibility to the active sites and thereby improved reactivity. 2) The use of the triazole linker leads a particularly easy way to connect the ligand to the resin under mild conditions and makes the linker resistant to most reaction conditions, therefore preventing decomposition of the immobilized catalyst. 3) The metal-free polymer-bound pybox can be recycled a large number of times without alteration of its performances. In some cases the catalyst itself could as well be reused several times.

In the future it would be interesting to investigate the full potential of our click- resin-pybox. As pybox ligands are useful for a wide range of transformations, many other asymmetric catalytic reactions, such as cyclopropanations140 or D iels Alder reactions, could be tested.

The “click chemistry” proved to be an easy and efficient way of connecting a ligand onto a PS-matrix. This strategy could allow for the attachment on solid supports of other types of ligands for which immobilization remains problematic.

5) Hydroxy-containing phosphinooxazoline ligand a. Phosphinooxazoline ligands

The first phosphinooxazolines (PHOX ) appeared in 1993 and were independently synthesized by Helmchen,160 Pfaltz161 and Williams.162 Since then there has been a growing interest for these ligands4c which have proven to be very effective in various reactions such as allylic substitutions,160-163 Heck reactions,163q,164 hydrogenations,163q,165 hydrosilylations,166 conjugate additions,167 or as pro-catalysts for enantioselective Grignard cross-couplings.168

119a R= iPr Ar =phenyl 119b R= iPr Ar =1-naphthyl O 119c R= t-Bu Ar =phenyl 119d R= Ph Ar =phenyl N PAr2 119e R= CH2Ph Ar = phenyl R 119f R= Me Ar =phenyl

Schem e 58: Some representative examples of PHOX ligands.

These ligands (see examples in scheme 58) contain a (rather) hard and a soft donor atoms to which a metal can coordinate. They are easily synthesized and their structure can be easily tailored for a specific application. A large variety of amino alcohols and carboxylic acid derivatives, readily available with different substitution patterns, can be used as precursors. Two main strategies can be envisioned when dealing with the synthesis of PHOX ligands: 1) introduction of the phosphine moiety before the oxazoline ring formation,163,169 or, 2) formation of the oxazoline ring followed by introduction of the phosphine moiety.162a-b,168,170

a) Bipyridine, 1) BuLi, Et2O CHCl 2) Ph2PCl 1) ZnCl2, PhCl O 3 O NC NC N PPh NH2 2 N PPh2 Br PPh2 HO R Zn R R Cl Cl b) 1) TMEDA, s-BuLi O O 2) Ph2PCl

N N PPh2 R R c)

1) CCl4, Pyridine, CH3CN O LiPPh , THF O 2) PPh3, Pyridine, CH3CN 2 HOOC N F N PPh2 NH F 2 R HO R R

Schem e 59: Some examples of phosphinooxazoline syntheses.

An example of the first strategy is shown in scheme 59, a. The synthesis starts from 2- bromobenzonitrile which is subjected to aromatic nucleophilic substitution before formation of the oxazoline using the appropriate amino alcohol.162a This synthesis can be conducted on a multigram scale. The second route involves, after oxazoline ring formation, either orthometallation (scheme 59, b),169 or nucleophilic aromatic substitution160a,162b,168,170 (scheme 59, c).

Phosphinooxazoline 120, bearing a hydroxy group, was first synthesized by Helmchen and co-workers.170 This ligand was also prepared by our group, using a modification of Helmchen’s procedure.163o It was used in palladium- and iridium- catalyzed allylic substitutions,163o and iridium- or rhodium-catalyzed hydrosilylations of ketones.166e It was shown that the hydroxy group played an important role in determining the outcome of these reactions due to its interaction with the metal center (scheme 60).

O a O b O N N PPh N PPh2 PPh2 2 Ph Ph Ph M M 120 O H OH O H M= Pd(0) or Ir(I) c M= Ir(I) or Rh(I)

N PPh2 HO M Ph M= Pd(II)

Schem e 60: Interaction of the hydroxy group of ligand 120 with different metal centers.

As can be seen in scheme 60, a hydroxy-metal hydrogen bond can be formed when using low valent metal ions such as palladium(0) or iridium(I),163o whereas oxygen coordination occurs with charged or high valent metal centers such as rhodium (III) or iridium (III).166e Both types of interactions can influence the stereochemistry of the reaction.

We therefore decided to investigate further the influence of these interactions between the hydroxy group and the metal ion coordinated to the PHOX ligand 120. We chose to study the behavior of ligand 120 in the hydrosilylation of imines and in the asymmetric intermolecular Heck reaction.

b. Catalysis i. Asymmetric hydrosilylation of imines

The first hydrosilylation of imines was reported in 1973 by Kagan and co-workers, who used a rhodium complex of D IOP for the chiral induction (scheme 61).171

H O PPh R'' 2 Ph HSi R'' N 2 N PPh NHR'' O 2 ∗ HCl ∗ H R R' R R' R R' [RhCl(C2H4)2]2

Schem e 61: Hydrosilylation of imines using a D IOP-rhodium catalyst.

After deprotection of the amine group, hydrosilylation reactions leads to chiral primary or secondary amines, which are important building blocks and are found in many natural products and pharmaceuticals.50,172 The hydrosilylation of imines is an attractive alternative to hydrogenation as it is conducted under extremely mild conditions and does not require high pressures or temperatures. Most of the catalysts for hydrosilylation of imines are metal complexes of Rh,166d-e,171,173 Ru,166c-d,174 Ti,173c,175 Cu,173c,176 Ni,177 Z n,173c,178 Sn178, Re179 or Ir.166d-e,173b,180 Some organocatalysts have also been developed.181

Hydrosilylation of ketones using PHOX ligand 120 was recently reported by our group.166e It was shown that the enantioselectivities were higher when cationic complexes where used as compared to neutral species. This result was explained by an oxygen-metal coordination in the cationic complex (see scheme 60, b).

We thus wanted to investigate whether this oxygen-metal coordination influenced the outcome of the hydrosilylation of imines. The results of the reaction are reported in table 11.

We first decided to run the reaction in THF, in sealed vials, at 50 °C (entry 1 and 2). In the case of the rhodium catalyst (entry 1), good conversion was obtained (96%) but the ee was low (19%). When using iridium instead of rhodium (entry 2), the conversion decreased (52%) and the ee was even lower (8% ee). As the enantioselectivity seemed low, we decided to run the reactions at room temperature albeit at the cost of the reaction time. As predicted, the reactions in THF were slower for both rhodium and iridium catalysts (entries 3 and 6) giving the desired product in 51% and 30% yield, respectively, after one week. U nfortunately, the enantioselectivity remained similar to what had been observed at higher temperature (18% and 6% ee, respectively).

T able 11: Hydrosilylation of imines using ligand 120.[a]

SiHPh 1. MeOH N Ph2SiH2, [M(COD)Cl]2 N 2 N rt, 1 week 2. HCl

N PPh2

Ph 120 OH

Entry Metal Solvent Conv (%)[b] Ee (%)[c] 1[d] Rh THF 96 19 2[d] Ir THF 52 8 3 Rh THF 51 18

4 Rh CH2Cl2 74 8 5 Rh Toluene 74 30 6 Ir THF 30 6

7 Ir CH2Cl2 61 <5 8 Ir Toluene 17 <5 9[e], [f], Rh THF 94 11 10[e], [g] Ir THF 80 9 11[h] Rh THF 87 5 12[h] Ir THF 75 8 13[i] Rh THF 62 25 14[i] Ir THF 37 8 15[j] Rh THF 69 8 16[j] Ir THF 25 18

[a] All reactions were carried out in 1 mL of the indicated solvent, at rt, for 7 days, using 1.2 equiv. of diphenylsilane, 20 mol % of ligand 120, 5 mol % of [M(COD )Cl]2 and 20 mol % AgBF4. [b] Conversion determined by 1H NMR of the crude product. [c] Enantiomeric excess determined by chiral GC. [d] Reaction run at 50 °C for 3 days.

[e] AgOTf used instead of AgBF4. [f] 5 days reaction time. [g] 1 day reaction time.

[h] AgPF6 used instead of AgBF4. [i] The silver precipitate formed upon addition of AgBF4 was filtered off before adding the other reagents. [j] No silver salt used.

We then screened different solvents (entries 4-5, 7-8). The reactions catalyzed by the rhodium complex gave the best results in toluene but the enantioselectivity remained low (74% conversion, 30% ee). When using the iridium catalyst the best solvent in 74

terms of conversion proved to be dichloromethane (61% conversion) but almost no enantioselectivity was observed.

We also tested the effect of the counter ion by employing different silver sources (entries 11-14). In all cases the reactions were faster, affording the product with increased conversions, but at the cost of a loss of enantioselectivity.

We also tried to remove the silver precipitate that formed upon mixing the ligand,

the rhodium or iridium salt and AgBF4 (entries 9 and 10). Interestingly, the rhodium and iridium complexes exhibited different behaviors. Whereas for the rhodium complex we observed a slight increase in conversion (94%) with a quite important decrease of ee (11%), for the iridium complex both the conversion (80%) and the enantiomeric excess (9%) were not affected.

Finally, we carried out the reactions with the rhodium and iridium catalysts formed without any addition of silver salt to see if the cationic nature of the complex had any influence (entries 15-16). In the case of rhodium, the conversion increased (69%) in comparison to the reaction run under the same conditions apart from the use of the cationic complex (compare entries 3 and 15) but the ee was lower (8% ee instead of 18% ee with the cationic complex). For iridium, on the contrary, lower conversion was afforded (25% with the neutral complex compared to 30% with the cationic complex) but an increased in enantioselectivity was observed (18% ee as compared to 6% with the neutral complex).

As can be seen from these results the complexes formed from ligand 120 and

[Rh(COD )Cl]2 or [Ir(COD )Cl]2 are not effective catalysts for the asymmetric hydrosilylation of imines. The effect of oxygen-metal coordination observed in the hydrosilylation of ketones does not seem to be important for this reaction.

ii. Asymmetric intermolecular Heck reaction

The Heck reaction, i.e. the palladium mediated coupling of an aryl or alkenyl halide or triflate with an alkene in the presence of a base, was first independently discovered in the 1970s by Mizoroki and co-workers182 and by Heck and co-workers.183 It is one of the most versatile catalytic methods for C-C bond formation and it has been applied to a variety of complex natural product syntheses.184 D eep understanding of the reaction mechanism has been gained.164a,b,h,185 An important improvement was realized in the late 1980s by the groups of Shibasaki186 and Overman187 who reported independently the first asymmetric intramolecular Heck reaction. Many examples of asymmetric intramolecular Heck reactions have since then been reported.164f-h,188 As both tertiary and quaternary centers can be generated, this reaction has been widely applied in organic synthesis.184

The asymmetric intermolecular Heck reaction is somewhat more recent: it was first reported in 1991 by Hayashi and co-workers, who used a Pd(BINAP) catalyst.189 Several chiral ligands have then been developed and successfully employed.188 The majority of the reactions involve a reactive O- or N-heterocycle and only tertiary carbon centers can be formed. One important fact is the major difference in regioselectivity when using diphosphine ligands and P,N-type ligands. 164c,d,f,h,188,190 For example, as shown in scheme 61, in the reaction of 2,3-dihydrofuran 121 with phenyl triflate 122, the major product obtained when the reaction is catalyzed by diphosphine complexes results from migration of the double bond (compound 123a). Often, a small amount of the 2,5-dihydrofuran adduct 123b is also produced.189,191 On the contrary, P,N-ligands, such as PHOX , lead exclusively to the formation of compound 123b.5d,e,163q,164a,b,e,192

OTf Pd, Ligand, Base, Solvent O O O 121 122 123a 123b

Schem e 61: Asymmetric intermolecular Heck reaction of 2,3-dihydrofuran and phenyl triflate.

It was shown by our group that, using PHOX ligand 120, an OH-Pd hydrogen bond (scheme 60, a) affected the stereochemistry of palladium-catalyzed allylic alkylations.163o We therefore thought that it would be of interest to study the activity of ligand 120 in the asymmetric intermolecular Heck reaction. By comparison with the activity of the previously reported PHOX ligands,164 we could see if the metal- hydrogen interaction could play a beneficial role in this reaction. The results are summarized in table 12.

In analogy to results by Pfaltz and others,168,188,192 when using PHOX ligands in this reaction, only the 2,5-dihydrofuran derivative 123b was formed. The corresponding 2,3-dihydrofuran derivative 123a, which is formed as a major product when the reaction is catalyzed by BINAP189,191 for example, was not detected.

The reaction was first run in THF at 70 °C using iPrNEt2 as a base (entry 1). U nder these conditions the reaction was extremely slow. Only 6% of the starting materials were converted to the desired product after 10 days. However, the enantioselectivity was excellent (97%). When changing the solvent to benzene (entry 2), the reaction was somewhat faster (14% conversion) but the ee decreased (82%). We then studied the effect of a different base. Thus, the reaction was carried out using proton sponge 164g instead of iPrNEt2, under microwave irradiation, using THF (entry 3), benzene (entry 4) or toluene (entry 5) as solvents. In all cases we could note an important increase in the reaction rate (conversion ≥ 30% within 4 hours) but at the expense of the enantioselectivity (ee:s between 79 and 89%).

T able 12: Asymmetric intermolecular Heck reaction of 2,3-dihydrofuran 121 and phenyl triflate 122 catalyzed by ligand 120.[a]

N PPh2 OTf Ph 120 OH O O Pd(dba)2, Base, 121 122 Solvent 123b

Entry Base Solvent Time Conv (%)[b] Ee (%)[c] [d] 1 iPrNEt2 THF 10 days 6 97 [d] 2 iPrNEt2 Benzene 10 days 14 82 3[e] Proton sponge THF 4 hours 34 89 4[e] Proton sponge Benzene 4 hours 30 85 5[e] Proton sponge Toluene 4 hours 35 79

[a] All reactions were carried out in 1 mL of the indicated solvent, at the indicated temperature, using 5

equiv. of 2,3-dihydrofuran, 6 mol % of ligand 120, 3 mol % of Pd(dba)2 (based on Pd) and 3 equiv. of base. [b] Conversion determined by 1H NMR of the crude product. [c] Enantiomeric excess determined by chiral GC. [d] Reaction run at 70 °C, under thermal heating. [e] Reaction run at 120 °C, under microwave irradiation.

Low conversions have been observed before with PHOX ligands bearing other substituents than t-Bu.164 Therefore it seems that our ligand does not have a suitable substituent on the oxazoline ring for this reaction since only low conversions were obtained even though with good ee:s. D ue to the poor reactivity of our system we could not study the effect of an OH-Pd hydrogen bond.

c. NMR studies

As previously mentioned, it was observed by our group that cationic Ir and Rh complexes of PHOX ligand 120 exhibited higher enantioselectivities in the hydrosilylation of ketones than the corresponding cationic complexes of ligand 119a, whereas the contrary was true for neutral complexes.166e This phenomenon was explained by coordination of the hydroxy oxygen atom to the metal center. A cationic

complex of ligand 120 and iridium was also prepared by stirring [Ir(COD )Cl]2 and 120 in CH2Cl2 followed by ion exchange using AgBF4 (scheme 62).

1 13 The H and C NMR spectra of this complex showed large downfield shifts for Ha (from 4.11 to 5.91 ppm) and Ca (from 77.4 to 84.0 ppm) in the cationic complex compared to the free ligand. This is in accordance with the proposed coordination of

the hydroxy oxygen atom to the iridium cation. At -40 °C a signal for the hydroxy group proton could be seen at 3.66 ppm indicating that the ligand was not deprotonated. Moreover, the olefinic protons from 1,5-cyclooctadiene gave broad signals at room temperature, which is characteristic of an exchange process between certain of these protons.

O N Ph PPh2 BF 4 Ha Ir O H

Schem e 62: Formation of a cationic complex of ligand 120 and iridium.

Pentacoordinated d8 transition metal complexes are known to preferentially adopt a trigonal bipyramidal structure.193 Intramolecular rearragement mechanisms in these structures have been observed before.194 The first report of this intramolecular rearrangement was accounted for by U dovich and Clark in 1969.195

More insight into the mechanism of the rearrangement was gained later thanks to studies by Osborn and Shapley.194b-d In particular, they investigated the exchange process in diene complexes of pentacoordinated Ir(I) and Rh(I) of the type

[RM(diene)L2] (R = H or Me, M = Ir or Rh, L = tertiary phosphine, diene = COD or NBD ). IR and NMR spectroscopies unambiguously established a trigonal bipyramidal ground state for these complexes, with the R group occupying one axial position, the phosphine ligands placed in two equatorial positions, and the diene bridging the remaining equatorial and axial positions (scheme 63).

R R=H or Me L M L =tertiary phosphine L =diene

Schem e 63: General structure of the diene complex of pentacoordinated Ir(I) or Rh(I).

It was also seen by variable-temperature NMR studies that two independent dynamic processes occurred. At high temperatures (117 °C), the authors found evidence for an intermolecular dissociative process. At lower temperatures, this process was not observed, but a second process took place: an intramolecular rearrangement of the axial and equatorial double bonds. The authors could show that this intramolecular rearrangement only interchanges the non-equivalent olefinic

double bonds and not the two phosphine ligands. They proposed four mechanisms to explain this intramolecular exchange process, two of which could be discarded using the NMR observations. However, they could not distinguish between the last two processes: the pseudorotation process (also called Berry pseudorotation196) and a twist process (scheme 64).

a) pseudorotation process

1 R L1 L2 R L1 2 L1 L1 1 M L as M R R as M R L1 as M 2 2 L2 L2 L2 pivot 2 pivot 1 pivot 1 2

b) twist process

R R R 2 1 L1 L1 2 L1 M M M L2 L2 L2 1 1 2

Schem e 64: Pseudorotation and twist processes that can be involved in the intramolecular rearrangement of the diene.

The first process that can be envisioned to explain olefin site interchange (scheme 64, a) involves three successive and reversible permutations of four ligands. The first step

is a pseudorotation using L2 as pivot. It is followed by a pseudorotation using R as a pivot, and finally, the last permutation is a pseudorotation with L1 as pivot.

The second process proposed leads to interchange of the axial and equatorial olefin sites without affecting the other ligands. It proceeds through a twist of the diene about an axis perpendicular to the plane of the double bonds. The intermediate structure has a somewhat contracted olefin-M-olefin angle and is close to having a square pyramidal geometry.

We wished to gain more understanding into the structure and the process at work in our cationic Ir complexes of PHOX ligand 120. The observation of such a rearrangement process in which the two olefin sites are interchanged would indeed be an indication that our cationic iridium COD complex of PHOX ligand 120 has a pentacoordinated structure with the hydroxy group oxygen occupying the fifth coordination site on the metal center (no such rearrangement process proceeds in complexes having a square planar structure). We therefore decided to further study and compare the dynamic behavior of the cationic iridium complexes of ligands 120 and 119a by NMR spectroscopy.

As described previously by our group,166e we prepared the cationic iridium complex 124 of ligand 120 by strirring the latter overnight with one equivalent of

[Ir(COD )Cl]2 in dichloromethane. Water and AgBF4 were then added in order to - exchange the chloride couter-ion to the BF4 anion. The same was done using 119a, yielding the cationic complex 125 (scheme 65).

O O

N PPh2 N PPh2 Ph BF4 BF4 H Ir(I) Ir(I) O H 124 125

Schem e 65: Representation of the cationic complexes 124 of ligand 120 and 125 of ligand 119a (COD has been omitted for clarity).

We then undertook a study of the dynamic behavior of these complexes by NMR spectroscopy. The one-dimensional 1H NMR spectra of 124 and 125 were in accordance with those observed before. Interestingly, the 1H-1H NOESY spectra of complexes 124 (scheme 66, a) and 125 (scheme 66, b) showed that cross peaks with a different phase (different from cross peaks reflecting spacial proximity) could only be seen in the case of 124. Those cross peaks are indicative of site exchange between the COD protons. To investigate whether this situation was the result of the interaction of the hydroxy oxygen with the iridium cation, one equivalent of water was added to 1 1 a CD Cl3 solution of 125 and the H- H NOESY spectrum was recorded (scheme 66, c). It can be seen in this spectrum that the addition of water led to the appearance of cross peaks with a different phase, similar to what was seen for complex 124, indicative, here as well, of an exchange process.

The observation that an exchange process of the COD protons proceeds at room temperature in complex 124 confirms the proposed pentacoordinated structure with the hydroxy group oxygen coordinated to the iridium center. In complex 125, this rearrangement is only observed when water has been added since ligand 119a does not possess any suitable atom available to occupy one more coordination site on the metal. Once water is added, a pentacoordinated structure is formed with water coordinating the iridium ion.

ppm ppm

1.5 1.5

2.0 2.0

2.5 2.5 3.0 3.0 3.5 3.5 4.0 4.0 4.5 4.5 5.0

5.0 5.5

6.0 a) 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm b) 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm

ppm

1.5

2.0

2.5 3.0 3.5 4.0

4.5

5.0

5.5

c) 5.5 5.0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 ppm

Schem e 66: 1H-1H NOESY spectra of complexes a) 124, b) 125, c) 125 after addition of one equivalent of water.

More detailed NMR measurements were then carried out in order to determine the exchange rates for the COD protons in complex 124 and in complex 125 after addition of water.

The exchange rates of these two systems are low and do not affect the line shape of the signals involved in the exchange process. Moreover, the signals present a large chemical shift difference. The exchange rate could therefore be measured using one- and two-dimensional EX SY magnetization transfer.

U sing this method, it was observed that, at room temperature, the exchange was much faster in complex 124 (0.630 ± 0.008 s-1) than in complex 125 to which one equivalent of water had been added (0.092 ± 0.003 s-1).

It can therefore be concluded from these NMR experiments that the hydroxy group oxygen coordinates to the iridium center in the cationic Ir(I) complex of 120, which is necessary to allow for the exchange process of the olefin sites in the COD ligand as

such a rearrangement only proceeds in pentacoordinated structures. At 25 °C, this rearrangement is absent in the case of the cationic complex of 119a, confirming that its structure is not pentacoordinated. When one equivalent of water is added to the cationic complex 125, an exchange process similar to that observed in 124 can be seen, as a result of coordination of one molecule of water. However in that case, the rearrangement proceeds at a much slower rate.

d. Conclusion and perspectives

The hydroxy-containing phosphinooxazoline ligand 120 has been evaluated in the asymmetric hydrosilylation of imines and in the asymmetric intermolecular Heck reaction. NMR studies of cationic complexes of this ligand have also been performed.

This ligand gave poor results in terms of conversion and enantioselectivity in the hydrosylilation of imines and the beneficial effect of the hydroxy group oxygen coordination to the metal center, which had been observed in hydrosilylations of ketones, could not be demonstrated here.

Ligand 120 furnished excellent levels of enantioselectivty in the asymmetric intermolecular Heck reaction but unfortunately conversions were quite low. Therefore a hydrogen bond between the hydrogen atom of hydroxy function and the palladium center could not be evidenced.

The dynamic behavior of a cationic iridium COD complex of ligand 120 was studied by NMR spectroscopy. Rearrangement of the olefinic groups was shown to occur as a result of the presence of the hydroxy function allowing a pentacoordinated structure to be formed through coordination of the oxygen atom to the metal center.

6) Concluding remarks and outlook

This thesis deals with the study of pyridine-bis(oxazoline) and phosphinooxazoline ligands.

Six new bifunctional pyridine-bis(oxazoline) ligands, bearing in the 4-position of the oxazoline rings various basic functions which differ in terms of their steric and basic properties, have been conveniently synthezised from the same readily available precursor. These ligands were assessed in the metal-catalyzed asymmetric addition of cyanides to benzaldehyde. U nfortunately they did not afford as good results as expected in this reaction as no dual activation could be demonstrated with certainty. However, our ligands could be evaluated in other kinds of reactions, employing for example another type of metal. Some minor changes in their structure, in order to tune their properties to one specific reaction, can also be envisioned.

Two pyridine-bis(oxazoline) ligands bearing bulky substituents in the 4-position of the oxazoline rings and a macrocycle containing a pyridine-bis(oxazoline) and a diaza-crown ether moieties have been synthesized using the “click chemistry”. These compounds have been tested in metal-catalyzed asymmetric reactions. Moreover, NMR studies of complexes of the macrocycle with various bifunctional molecules proved the ability of the macrocyclic ligand to encapsulate a bifunctional molecule bound at one end to the crown ether and at the other end to the pybox moiety. A further development could be the use of this macrocycle for substrate-selective reactions.

A pyridine-bis(oxazoline) ligand has been efficiently and easily attached to a polymeric resin by means of the “click chemistry”. This supported ligand was combined with different metal salts. The catalysts thus obtained were used in several catalytic asymmetric reactions and generally afforded good results. Moreover, the polymer-bound ligand could be recycled a large number of times without deterioration of its performances.

A phosphinooxazoline ligand equipped with a hydroxy function on the oxazoline ring was used in catalysis in order to investigate whether interaction between the hydroxy group and the metal center had an influence. Poor results were afforded in the hydrosilylation of imines in terms of conversions and ee:s. This ligand was also evaluated in the asymmetric intermolecular Heck reaction. In this reaction high ee:s were achieved but unfortunately conversions were low. A cationic iridium complex of this ligand has been studied by NMR spectrocopy. Oxygen complexation between the hydroxy function of the ligand and the metal center was evidenced. Rearrangement of the olefin bound to the metal was also shown to proceed thanks to the interaction of the hydroxy oxygen atom and the metal cation. Benefit could be taken from the understanding of this interaction for the development of new catalytic asymmetric methods.

7) Acknowledgements

First, I would like to thank my supervisors Prof. Christina Moberg and D r. V incent Levacher.

Secondly, I am grateful for the financial support provided CNRS-Haute Normandie and EGID E. The Aulin-Erdtman Foundation, the Ragnar och Astrid Signeuls Foundation and the Knut and Alice Wallenberg Foudation are also acknowledged for making it possible for me to present my work at several conferences.

I also want to warmly thank Torbjörn Norin for valuable discussions and comments about this thesis.

Finally, I would like to acknowledge all my present and former colleagues at IRCOF (Rouen) and at the Chemistry D epartment at KTH (Stockholm) for their help with chemistry or administration matters.

8) Experimental section

Form ation of a 1:1 com plex of pybox 60 and benzyl am m onium chloride (section 3c): Pybox 60 (3.69 mg, 0.01 mmol) and benzylammonium chloride (1.44 mg, 0.01

mmol) were mixed in CD 3OD (0.5 mL) and stirred at rt under N2 for 2 h. The mixture was transferred to an NMR tube and analyzed directly.

Form ation of a 1:2 com plex of pybox 60 and 1,4-dibenzylam m onium dichloride (section 3c): Pybox 60 (3.69 mg, 0.01 mmol) and 1,4-dibenzylammonium dichloride

(1.05 mg, 0.005 mmol) were mixed in CD 3OD (0.5 mL) and stirred at rt under N2 for 2 h. The mixture was transferred to an NMR tube and analyzed directly.

Form ation of a 1:1 com plex of m acrocycle 95 and 1,4-dibenzylam m onium dichloride (section 3c): Macrocycle 95 (4.85 mg, 0.005 mmol) and 1,4-

dibenzylammonium dichloride (1.05 mg, 0.005 mmol) were mixed in CD 3OD (0.5 mL) and stirred at rt under N2 for 2 h. The mixture was transferred to an NMR tube and analyzed directly.

Form ation of a 1:2 com plex of pybox 60 and 1,7-heptanediam m onium dichloride (section 3c): Pybox 60 (7.38 mg, 0.02 mmol) and 1,7-heptanediammonium dichloride

(2.01 mg, 0.01 mmol) were mixed in a CD Cl3/CD 3OD 3:1 mixture (0.5 mL) and stirred at rt under N2 for 2 h. The mixture was transferred to an NMR tube and analyzed directly.

Form ation of a 1:1 com plex of m acrocycle 95 and 1,7-heptanediam m onium dichloride (section 3c): Macrocycle 95 (9.69 mg, 0.01 mmol) and 1,7-

heptanediammonium dichloride (2.01 mg, 0.01 mmol) were mixed in a CD Cl3/CD 3OD 3:1 mixture (0.5 mL) and stirred at rt under N2 for 2 h. The mixture was transferred to an NMR tube and analyzed directly.

Form ation of a ruthenium olefin com plex of pybox 60 and 10-undecanoic acid

(section 3c): Pybox 60 (7.38 mg, 0.02 mmol), [(p-cymene)RuCl2]2 (6.12 mg, 0.01 mmol) and 10-undecanoic acid (4.04 µL, 0.02 mmol) were stirred in dry

dichloromethane at rt under N2 for 1 h. The reaction mixture was concentrated under reduced pressure. The residue was washed with ether in hexane (1:1). The complex

thus obtained was dissolved in CD Cl3 and analyzed by NMR spectroscopy.

Form ation of a ruthenium olefin com plex of m acrocycle 95 and 10-undecanoic

acid (section 3c): Macrocycle 95 (8.17 mg, 0.008 mmol), [(p-cymene)RuCl2]2 (2.58 mg, 0.04 mmol) and 10-undecanoic acid (1.7 µL, 0.008 mmol) were stirred in dry THF

at rt under N2 for 1 h. NaH (0.20 mg, 0.008 mmol) was added and the mixture was stirred for an additional 20 min. The reaction mixture was concentrated under

reduced pressure. The residue was washed with ether in hexane (1:1). The complex

thus obtained was dissolved in CD Cl3 and transferred to an NMR tube for analysis.

G eneral procedure for enantioselective hydrosilylation of im ines (section 5c.i):

Ligand 120 (8.74 mg, 0.02 mmol), [M(COD )Cl]2 (0.005 mmol), silver salt (0.02 mmol) and N-(1-phenylethylidene)methaneamine (1.00 mmol) were suspended in dry

solvent (1 mL) under N2. The suspension was stirred at rt for 1 h. D iphenylsilane (1.20 mmol, 223 µL) was added and the reaction mixture was stirred at rt under N2. The reaction was quenched at 0 °C with methanol (1 mL) and the mixture was stirred for 30 min. HCl (5 mL of a 1M solution) was added and the mixture was stirred for 1 h at rt. The phases were separated. NaOH (20 mL of a 3M solution) was added to the

water phase. The water phase was extracted with Et2O (3*50 mL). The resulting combined organic phases were dried and the solvent was removed under vacuum. For GC-MS determination of enantiomeric excess, the amine was converted to the corresponding trifluoroacetamide: Amine (50.7 mg, 0.375 mmol) was dissolved in

CH2Cl2 (5 mL). Trifluoroacetic anhydride was added (5.00 mmol, 1 mL) and the solution was stirred for 2 h at rt. The volatiles were evaporated and the residue was

dissolved in CHCl3 (5 mL) and washed with phosphate buffer pH 6.8-7 (2*5 mL). The organic phase was then dried and concentrated under vacuum.

N-(1-phenylethylidene)m ethaneam ine synthesis: Methylamine (10 mL of 2M THF

solution) and TiCl4 (2 mL of 1M solution in CH2Cl2) were added to acetophenone (0.47 mL, 4 mmol) at 0 °C under N2. This mixture was stirred and slowly warmed up to room temperature overnight. The white precipitate that had formed was filtered

off under N2 on a plug of celite. The solvent was removed to afford the pure imine in quantitative yield.

G eneral procedure for enantioselective H eck reaction (section 5c.ii): Ligand 120

(7.87 mg, 0.018 mmol) and Pd(dba)2 (5.18 mg, 0.009 mmol) were dissolved in the indicated dry solvent (0.5 mL). This mixture was stirred at rt for 1 h under N2. The base (0.90 mmol), phenyl triflate (49 µL, 0.30 mmol) and 2,3-dihydrofuran (113 µL, 1.50 mmol) were dissolved in 0.5 mL of solvent and added to the previous mixture. The resulting reaction mixture was stirred at the indicated temperature for the indicated time. The reaction was monitored by GC-MS.

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