Document [original]

Separation and Recycling of Phosphane Ligands from

Homogeneously Catalyzed Processes

Von der Fakultät für Naturwissenschaften

Department Chemie

der Universität Paderborn

zur Erlangung des Grades eines

Doktors der Naturwissenschaften

Dr. rer. nat.

genehmigte Dissertation

von

László Majoros

aus Sátoraljaújhely (Ungarn)

Paderborn 2006

______________________________________________________________________________

Die vorliegende Arbeit wurde in der Zeit von Januar 2004 bis Juni 2006 im Fachgebiet

für Technische und Organische Chemie der Fakultät für Naturwissenschaften der

Universität Paderborn unter Anleitung von Prof. Dr. Birgit Drießen-Hölscher† und Herrn

Prof. Dr. Nikolaus Risch angefertigt.

Referent: Prof. Dr. Nikolaus Risch

Korreferent: Prof. Dr.-Ing. Hans-Joachim Warnecke

Eingereicht am: 16.06.2006

Mündliche Prüfung am: 11.07.2006

______________________________________________________________________________

Veröffentlichungen:

L. Majoros, J. Hasenjäger, F. Agel, B. Drießen-Hölscher

Poster: 14th International Symposium on Homogeneous Catalysis, ISHC 14, Munich,

July 5 - 9, 2004

Sythesis of Novel Ligands with Axial Chirality for Asymmetric Hydrogenation

Teil dieser Arbeit wurde beim Deutschen Patentamt zum Patent mit der Bayer AG

(Lanxess FC) 2005 angemeldet.

______________________________________________________________________________

Mein besonderer Dank gilt Frau Prof. Dr. Birgit Drießen-Hölscher† für ihre stetige

Diskussionsbereitschaft und die immer freundliche Unterstützung, die sehr zum Gelingen dieser

Arbeit beigetragen haben. Sie war eine sehr liebenswerte und warmherzige Frau, die mich durch

ihre offene und aufrichtige Art von Anfang an zu meiner Promotion verholfen hat.

Frau Prof. Dr. Birgit Drießen-Hölscher verstarb unerwartet im November 2004.

Ich danke herzlich Herrn Prof. Dr. Nikolaus Risch für die Übernahme der Betreuung meiner

Doktorarbeit, die Möglichkeit in seinem Arbeitskreis geforscht haben zu können, sowie für seine

freundschaftliche und fachliche Unterstützung.

Herrn Prof. Dr.-Ing. Hans-Joachim Warnecke möchte ich für die Übernahme des Korreferats und

für die Bereitstellung ausgezeichneter Arbeitsbedingungen danken.

Ich bin der Bayer AG sehr dankbar für die vollständige finanzielle Unterstützung und für die gute

Kooperation. Ich möchte mich bei Prof. Dr. Herbert Hugl und Dr. Björn Schlummer für die

wissenschaftlichen und behilflichen Diskussionen bedanken.

Herrn Dr. Markus Nobis möchte ich mich sehr für seine hilfsreiche fachliche Zusammenarbeit

bedanken.

Weiterhin gilt mein Dank:

Herrn Prof. i.R. Dr. Heinrich C. Marsmann für die fachlichen Diskussionen und Messungen von

NMR-Spektren.

Herrn P.D. Dr. Hans Egold für die Messungen von NMR-Spektren und die anregenden

fachlichen Diskussionen.

Herrn Prof. Dr. Ferenc Joó für die persönliche Unterstützung.

Herrn Prof. Dr. Manfred Grote und Herrn Dr. Ulrich Flörke für die fachlichen Diskussionen.

Meinen Freunden und Kollegen aus dem Arbeitskreis Abdulselam Aslan, Dr. Jens Häsenjäger,

Dr. Ellen Hermanns, Raymond Hodiamont, Johanna Hummel, Annette Lefarth-Risse, Fadime

Mert, Dr. Lars Müller, Sebastian Schmeding und Dr. Andreas Winter für die angenehme

Arbeitsatmosphäre, die zahlreichen anregenden Diskussionen, die freundliche Unterstützung

und auch die vielen privaten Unternehmungen.

______________________________________________________________________________

Besonders meinen Freunden Dr. Brigitta Elsässer und Richárd Szopkó für die persönlichen und

fachlichen Ratschläge und dafür, dass ich mich auf sie immer verlassen konnte.

Herrn Dr. Heinz Weber, Frau Karin Stolte, Frau Mariola Zukowski für die Messungen der

Massenspektren.

Frau Ulrike Sakowski für die ICP Untersuchungen und Frau Ulrike Schnittker für die Messung

der GC Kromatographie.

Ferner Herrn Manuel Traut für seine tatkräftige Arbeit im Labor.

Den anderen Mitarbeiterinnen und Mitarbeitern der Technischen und Organischen Chemie für

das kollegiale und freundliche Arbeitsklima.

Meinen Eltern, Großeltern, Pateneltern und meinem Bruder für die Ermöglichung meines

Studiums und die persönliche Unterstützung mit Rat und Tat.

Mein ganz persönlicher Dank gilt meiner Frau Edina, deren aufrichtige Liebe und großartige Hilfe

mich meine ganze Promotion hindurch begleitet haben.

______________________________________________________________________________

Abbreviations

abs. absolute

acac acethylacetonate

Ar aryl

arom. aromatic

BINAP 2.2´-bis(diphenylphosphino)-1,1´-binaphthyl

Biphemp 2,2´-bis(diphenylphosphino)-6,6´-dimethylbiphenyl

BMIM+BTA- butyl-methyl-imidazolium-bis-triflylamide

BPPFA N,N-dimethyl-1-[(R)-1´,2-bis(diphenylphosphino)ferrocenyl]-amine

BPPM bis(para-phosphophenyl)methane

cat. catalyst

Chiraphos 2,3-bis(diphenylphosphino)-butan

Cl-MeO-Biphep 5,5`-dichloro-6,6`-dimethoxy-2,2`-bis(diphenylphosphino)-1,1`-

biphenyl

COD 1,5-cyclooctadien

cont. content

Conv. conversion

Cy cyclohexyl

d doublett

Dave-Phos 2-dicyclohexylphosphino-2´-(N,N-dimethylamino)-biphenyl

dba dibenzylidenacetone

DEE diethylether

DBE dubutylether

DIOP 4,5-bis(diphenylphosphinomethyl)-2,2-dimethyl-1,3-dioxan

DIPAMP 1,2-bis[(2-methoxyphenyl)-phenylphosphino]-ethan

DMF N,N-dimethylformamid

DMSO dimethyl sulfoxide

DPEPhos bis(2-diphenylphosphinophenyl)ether

DPPF 1,1´-bis(dipehylphosphanyl)ferrocene

DtBPF 1,1´-bis(di-tert-buthylphosphanyl)ferrocene

______________________________________________________________________________

ee enantiomeric excess

Et ethyl

EtOAc ethyl acetate

EtOH ethanol

GC gas chromatography

h. hour(s)

Hz herz

IL ionic liquid

IR infrared

J coupling constant

L. ligand

L-DOPA L-dihydroxyphenylalanin

Lig. ligand

m. multiplet

[M]* metallic catalyst

Me methyl

MeO-Biphep 6,6´-dimethoxy-2,2´-bis(diphenylphosphino)-1,1´-biphenyl

MeOH methanol

min. minute

mL milliliter

mp. melting point

MS mass spectrometry

MTBE methyl-tert-butylether

Naproxen 2-(6-methoxynaphtalen-2-yl)propanoic acid

NMP N-methylpyrrolidon

NMR nuclear magnetic resonance spectroscopy

Norphos [(2R,3R)-8-9-10-trinorbon-5-ene-2,3-diyl]bis(diphenylphosphine)

PE petrolether

PEG polyethylenglycol-monomethylether

Ph phenyl

p[H2] hydrogen pressure

PPh3 triphenylphosphine

______________________________________________________________________________

ppm parts per million

Prod. product

Prophos 1,2-bis-(diphenylphosphino)propane

R substituents

Rt retention time

q quartet

s singlet

S solvent

Segphos (4,4´-bi-1,3-benzodioxole)-5,5´-diylbis(diphenylphosphine)

S/C Substrate/Catalyst

Sub. substrate

Synphos 2,3,2´,3´-tetrahydro-5,5´-bi(1,4-benzodioxin)-6,6´-diyl)bis-

(diphenylphosphane)

t triplet

t time

THF tetrahydrofurane

TsDPEN (1R,2R)-N-(p-tolylsulfonyl)-1,2-diphenylethylenediamine

vs. versus

X-Phos 2-dicyclohexylphosphino-2´,4´,6´-triisopropyl-biphenyl

XantPhos 9,9-dimethyl-4,5-bis(diphenylphosphino)xanthene

______________________________________________________________________________

Contents

1 Introduction.....................................................................................1

2 General Part ....................................................................................4

2.1 Influence of the chirality on the behavior of the compounds ......................4

2.2 Enantiomerically pure compounds ................................................................7

2.3 Catalysis ...........................................................................................................7

2.3.1 Homogeneous vs. heterogenenous catalysis..............................................................8

2.4 Asymmetric reduction ...................................................................................11

2.4.1 Enantioselective hydrogenation.................................................................................12

2.4.2 Mechanism of the asymmertric hydrogenation..........................................................15

2.4.3 Asymmetric homogeneous hydrogenation using metal-catalyst in industrial

application..................................................................................................................18

2.4.4 Chiral Cl-MeO-Biphep ligand.....................................................................................21

2.5 Palladium catalyzed C-N bond-forming process.........................................23

2.5.1 General Buchwald-Hartwig amination reaction [61].....................................................23

2.5.2 Proposed Mechanism of the amination reaction........................................................25

2.5.3 Dave-Phos and X-Phos ligands applied in C-N formation.........................................27

2.6 Biphasic systems for reuse and recycling of the catalyst complexes......29

2.6.1 Immobilization by aqueous catalysts .........................................................................29

2.6.2 Immobilization by nonaqueous biphasic systems......................................................33

2.6.3 Immobilization and fixation to supported organic and inorganic polymers or

matrices .....................................................................................................................35

3 Results and Discussion ...............................................................39

3.1 Aims and Scopes...........................................................................................39

3.2 Asymmetric hydrogenation with different conditions and solvents using

Cl-MeO-Biphep and BINAP ligands ..............................................................40

3.2.1 Comparison of the two biaryl type phosphine ligands 3 and 11 ................................40

3.2.2 Use of different solvents for the reduction of 1..........................................................42

3.2.3 Applying IL as a medium for the enantioselective hydrogenation of 1.......................44

______________________________________________________________________________

3.2.4 Investigation of σ-ability of Cl-MeO-Biphep (3)..........................................................46

3.2.5 Scale up reaction for asymmetric hydrogenation in the research laboratory of

Lanxess FC................................................................................................................47

3.2.6 Further improvement of asymmetric hydrogenation for the industrial applications

with the view of costs.................................................................................................48

3.3 Derivatization of Cl-MeO-Biphep ligand (3)..................................................49

3.4 Optimization of the recycling procedure of Cl-MeO-Biphep ligand via

oxide derivative 3a and its scale up .............................................................51

3.4.1 Designing a separation and recycling cycle to demonstrate the steps of the

complete procedure...................................................................................................51

3.4.2 Optimization of the reduction step using the standard oxide 3a................................54

3.4.3 Optimization of the recovery cycle.............................................................................56

3.4.4 Modeling of the recycling procedure as an industrial process...................................58

3.5 Results of Buchwald-Hartwig amination and the recycling process

applying Dave-Phos and X-Phos ligands.....................................................60

4 Summary and Outlook..................................................................66

4.1 Summary.........................................................................................................66

4.2 Outlook............................................................................................................70

5 Experimental Part.........................................................................72

5.1 General Technique.........................................................................................72

5.2 Characterisation and use of ligand 3 in asymmetric hydrogenation.........74

5.3 Derivatization of ligand 3...............................................................................81

5.4 Optimization of the recycling cycle for ligand 3..........................................84

5.5 Amination reaction using Dave-Phos (7) and X-Phos (8) ligand................98

6 Spectra.........................................................................................111

7 Literature.....................................................................................116

Introduction

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1 Introduction

The appellation “Fine chemicals” can be heard very often in the language of modern

chemistry. During the 1980s lots of leader chemical companies in the world place

increased emphasis on small volume but high value products. These special chemicals

contain specialized polymers, intermediates for high performance structural materials,

and many biologically active compounds.

The bioactive substances usually involve complex organic structures, and often one or

more chiral centers. This class of the compounds, which contains pharmaceuticals,

flavors, food additives, crop protection chemicals has indicated a very significant

development of the homogeneous catalysis [1].

A very fast development has continued in the use of homogeneous catalysis to produce

large volume chemical intermediates and polymers. This growth has occurred despite of

the fact that relatively few new large-scale processes have been brought into

commercial production. For example: Monsanto acetic acid process [2], and

Ruhrchemie/Rôhne-Poulenc process, or Kuraray´s hydroformylation technology for

making 1,4-butanediol. For these processes homogeneous catalysts have been

developed, which are extremely effective [1].

In some cases, big fine chemical companies cooperate together to achieve a common

technical goal by the working in parallel. Several times these companies are stiff

competitors and possess the same license from the inventor [3].

In this work two very effective reaction will be presented named as asymmetric

hydrogenation [4, 5] and Buchwald-Hartwig amination [6-12], both produce pure compounds

with high conversion. These processes have been described in a broad spectrum of the

literature and used as standard reactions for the testing of new catalyst complexes,

which are coordinated to transition metals (Ru, Rh, Pd). In this thesis, the main

emphasis was placed on the asymmetric hydrogenation (Scheme 1.1), which was the

ruthenium catalyzed reduction of ethyl acetoaceate (1) to convert to ethyl-3-

hydroxybutyrate (2) with using Cl-MeO-Biphep ligand (3) [13-15].

Introduction

______________________________________________________________________________

Scheme 1.1 Asymmetric hydrogenation of β-ketoester

Figure 1.1 The applied Cl-MeO-Biphep phosphine ligand, (R/S)-5,5`-dichloro-6,6`-dimethoxy-

2,2`-bis(diphenylphosphino)-1,1`-biphenyl) (3)

3D illustration of molecular structure of 3

OEt

O O

OEt

OH O

[Ru], H

(50 bar)

110

C, 4 h

methylcyclohexane

MeO

PPh

MeO

PPh

(R)-Cl-MeO-Biphep (S)-Cl-MeO-Biphep

S-3

R-3

Introduction

______________________________________________________________________________

The second investigated catalytic process is the well known Buchwald-Hartwig

amination reaction (Scheme 1.2) between bromobenzene (4) and aniline (5) to produce

diphenylamine (6) with the help of Dave-Phos (7) [16-18] and X-Phos ligands (8) [18, 19].

Scheme 1.2 Buchwald-Hartwig amination reaction

Figure 1.2 The applied ligands Dave-Phos (7) (2-dicyclohexylphosphino-2´-(N,N-

dimethylamino)- biphenyl) and X-Phos (8) (2-dicyclohexylphosphino-2´,4´,6´-triisopropyl-

biphenyl) for the Buchwald-Hartwig amination

Lots of aims have been given for the recycling of these supported ligand tags in the past

few years because it is often the price of a more or less sophisticated ligand that

influences the economics of a new process [20].This work has been merely financed by

the Lanxess Fine Chemicals [21] in order to develop a new process for the recycling of

the applied ligand after the asymmetric hydrogenation just like after the Buchwald-

Hartwig amination. Aim of this work is to develop a route to recycle the catalyst.

PCy

NMe

Dave-Phos

PCy

X-Phos

[Pd], base

100

C, 12h

toulene

456

Br NH

General Part

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2 General Part

2.1 Influence of the chirality on the behavior of the compounds

“I call any geometrical figure, or group of points, chiral, and say it has chirality, if its

image in a plane mirror, ideally realized, cannot be brought to coincide with itself” stated

Lord Kelvin in 1904 in his Baltimore Lectures on Molecular Dynamics and the Wave

Theory of Light. The term “chiral” is stemmed from the word “kheir” (greek word)

meaning “hand”.

Kekule [22] determined, the carbon atom has a valence of 4 in 1848. Independently J.H.

van´t Hoff [23] and J. A. Le Bel [24] developed the idea of “asymmetry” in 1874. They have

also recognized: if four different groups are attached to the carbon atom it will result a

tetrahedral structure in which two different arrangements could appear. Louis Pasteur

collected the two different forms of the tartaric acid crystal and found that the two groups

of the crystals polarized the light differently, one to the left and the other to the right.

The mirror image isomers, which have similar properties (e.g. melting point, boiling

point, solubility) but dissimilar optical rotations, are called “enantiomers” [25], for example

the two common amino acid (R)- and (S)-alanine (Figure 2.1).

Figure 2.1 Chirality of the amino acid alanine

If alanine is produced under normal laboratory conditions, both the R and S enantiomers

will be obtained as a racemic mixture. The asymmetric synthesis allows the production

of an excess of one of the forms [26], therefore it is a very significant “tool” in modern

COOH

CNH

COOH

(S)-alanine (R)-alanine

General Part

______________________________________________________________________________

chemistry with which we are able to manufacture a chiral product from a prochiral

substrate. Nature is chiral, and mainly one of the two enantiomers is used, because very

often only one of the forms is of interest. Most of the drugs are chiral, but they differ from

each other significantly in the properties, e.g. the (R)-limonene smells of oranges, while

the (S)-limonene smells of lemons (Figure 2.2).

Figure 2.2 (R)-limonene and (S)-limonene

This example is less dramatic than the difference between the two enantiomers of

thalidomide drugs, which came on the market and was preserved against nausea. The

S-(-)-thalidomide could cause foetal damage while the other enantiomer in principle is

therapeutic agent (Figure 2.3).

Figure 2.3 Optical isomers of Contergan®

Contergan® was distributed in 1950s, but later on it was investigated in detail in 1961,

because there were many birth deformities after admission to trading. Animal

experiments confirmed that the (S)-enantiomer of the thalidomide had a fatal side effect.

To avoid similar cases, one aim of pharmaceutical industry is producing numbers of

products in enantiomerically pure form.

(S)-(-)-thalidomide (R)-(+)-thalidomide

(R)-limonene (S)-limonene

General Part

______________________________________________________________________________

The next example is the Naproxen®, which is widely used as anti-inflammatory, but only

the (S)-enantiomer (Figure 2.4) of it is desired while the (R)-enantiomer is a liver toxin.

The S-Naproxen was produced by a conventional optical resolution of the racemate, but

enantioselective hydrogenation seems to be a better solution to produce it, especially

since the original patent on the drug expired in 1993. Nowadays, this drug is produced in

high yield and high enatiomeric excess using Noyori´s (S)-BINAP-Ru(OCOCH3)2

catalyst [27].

Figure 2.4 The anti-inflammatory enantiomer of the Naproxen®

The development of new active pharmaceutical ingredients (api) with several chiral

centres requires creativity and innovation.

MeO

HCH3

CO2H

(S)-Naproxen

General Part

______________________________________________________________________________

2.2 Enantiomerically pure compounds

As described and shown above, the production of enantiomerically pure drugs is a

significant claim for the industrial application and for the economics, too. There are four

general methods to prepare the desired drugs with one defined enantiomeric form.

The oldest process is the chemical or physical resolution of the obtained racemate in

which the mixture of the enantiomers is reacted with enantiomerically pure auxiliaries

and separated by crystallization or chromatography.

The fermentation processes are known in the field of the biocatalysis, by the utilization of

the chiral synthesis potential of the microorganism. With this method, raw materials are

added to microorganism culture media, and the proliferating microorganisms are allowed

to produce the compound. Generally, microorganisms produce 20 kinds of amino acids

and they have a mechanism to regulate the quantities and qualities of enzymes to yield

amino acids only in the needed amounts.

The most effective route preparing the desired optical isomer is the asymmetric

synthesis in which a chiral organic tag is usually attached to the prochiral substrate

before the enantioselective step of the synhesis and than it is cleaved. By this way,

almost 100 % enantiomeric excess can be reached and the desired optical isomer is

variable with the chirality of the applied auxiliaries. During the last decades there were

intensive researches for developing this method. Academic and industrial research

groups have forced constructing chiral catalysts for two important classes of reactions in

organic chemistry: hydrogenations and oxidations.

2.3 Catalysis

A catalyst is a substance that increases the rate of the reaction without being consumed

itself [26]. For an industrial application, a profitable and useful catalyst must possess a

high turnover number (TON = mol of product per mol of catalyst) and also high turnover

frequency (TOF = TON per hour) [28]. As the production capacity depends on the activity

of the catalyst, the TOF has to be at least 500 h-1 for the experimental scale, and more

General Part

______________________________________________________________________________

than 10.000 h-1 for the large scale process [20]. Naturally, a reaction and the catalyst itself

must be simple, safe and environmentally friendly. Designing suitable molecular

catalysts and reactions according to these above mentioned criteria are feasible through

the deep understanding of the catalytic cycle.

The cost of this auxiliaries for catalytic reaction is usually very high, for example the

typical price of a diphosphanes ligands lies between 5.000 and 20.000 $/kg [29].

Therefore catalyst productivity given as substrate/catalyst ratio (S/C) or the TON value

ought to be >1000 in case of the production of small-scale or high-value chemicals and

>50.000 for large scale product in the industrial application. In many cases the catalyst

reuse increases the productivity.

The enantiomeric excess (% ee) value expresses the enantioselectivity of the catalyst

complex. The ee of the catalyst must be >99 % for the pharmaceuticals and >80 % for

the agrochemicals, if no further purification is possible [20].

ee = % desired enantiomer – % undesired enantiomer

2.3.1 Homogeneous vs. heterogenenous catalysis

The two types of catalytic reactions are named as homogeneous- and heterogeneous

catalysis. The main difference between them: in the homogeneous reaction the catalyst

is in the same phase as the reactants, unlike in the heterogeneous reaction where these

two components are in different phases.

Some examples for the heterogeneous catalysis

• Contact process for manufacturing sulphuric acid

The sulphuric dioxide is converted into sulphuric trioxide by passing the SO2 and

oxygen over a solid vanadium(V) oxide catalyst.

General Part

______________________________________________________________________________

• Hydrogenation of carbon-carbon double bond

This is an example for hydrogenation reaction of the carbon-carbon double

bond in the presence of Ni on heterogeneous fixed bed catalyst, which has an

industrial application to produce margarine from vegetable oil.

Some examples for the homogeneous catalysis

The most common examples of the homogeneous catalysis are the acid (eq. a) and the

basic (eq. b) catalyzed reactions following the next general schemes:

In reaction a), one of the reactant gets a proton and it reacts further. Such reactions are

e.g. the transformation of keto-enol tautomers or the inversion of the saccharin.

In reaction b), one of the reactants gives proton to the catalyst and it reacts further. Such

reactions are for example the isomerisation of some organic compounds or the Claisen-

condensation [30].

Remarkable industrial homogeneous catalysis is the Monsanto acetic acid process [2],

which is the major commercial production method for acetic acid. From “syn gas” (CO/H2

=CH

Ni CH

SO21/2 O2V2O5SO3

XHA HX

XH BX

General Part

______________________________________________________________________________

mixture) prepared methanol is reacted with carbon monoxide in the presence of Rh

catalyst to afford acetic acid.

Scheme 2.1 Monsanto acetic acid process

Over 1.000.000 tons of acetic acid are produced every year using this process with high

selectivity and yield.

Return back to our view, the enantioselectivity is one of the main parameters to decide,

which process would be more adequate from the two above mentioned reaction types.

On the surface of a heterogeneous catalyst there are many different catalytically active

centers, therefore the success of these catalysts is limited in enantioselective reactions.

Much of selectivity observed with soluble catalysts in the homogeneous systems, which

come from the process control that is attainable in the liquid phase. Some main

properties of the homogeneous and heterogeneous catalysts are listed in Table 2.1.

Table 2.1 Homogeneous vs. heterogeneous catalysts

Homogeneous catalysts Heterogeneous catalysts

high activity

high selectivity

difficult separation

low reaction temperature

easy control of mixing and concentration

high adaptability

high reproducibility

lower thermic and pressure stability

high activity

low selectivity

simple separation

high reaction temperature

difficult control of mixing and concentration

lower adaptability

lower reproducibility

robust at high P, T

CO/H

Cu/ZnO MeOH

MeOH CO Rh, I

180

C, 30-40 atm

OHH

99 %

General Part

______________________________________________________________________________

As a consequence, the homogeneous catalysis is able to produce high enantiomerically

pure and value drugs with the utilization of the organometallic complexes. Some of the

commercial applications of the homogeneous catalysis are at only the very early stage

of their career. The development, the state of the art, industrial realization and most

recent work will be described in the next chapters.

2.4 Asymmetric reduction

Asymmetric catalytic reduction is one of the most efficient and suitable methods to

produce a wide range of enantiomerically pure compounds. For example, α-amino acids

can be prepared from α-enamides, alcohols from ketones and amines from oximes or

imines (Scheme 2.2).

Scheme 2.2 General scheme for asymmetric hydrogenation of ketone, imine and C-C double

bond

The enantioselectivity and conversion are the most important and exciting trends of the

homogeneous catalysis. The demand for the production of enantiomerically pure

compounds is very high and the chiral metal complexes, which are combined with

organic ligands or auxiliaries, provide the best solution. A well-designed chiral metal

complex can discriminate precisely between enantiotopic groups and catalyze the

formation of a wide range of natural or unnatural substances with high enantiomerical

purity. Molecular hydrogen (hydrogen gas) as the source of hydrogen with transition

metal can be applied as a donor of hydrogen in the asymmetric reduction [31]. By the

utilization of hydrogen gas there is always a danger of an explosion of hydrogen/air

mixture, therefore procedures have been developed, which use manifold hydrogen

sources but avoid using of the gaseous hydrogen. For example, the well-known primary

[M]* H

HX= O, NR, CR

General Part

______________________________________________________________________________

or secondary alcohols (isopropanol, benzyl alcohol) are converted to the corresponding

aldehydes and ketones, whilst hydrogen gas is formed. This process is named as

transfer hydrogenation reaction.

The non transition-metallic complexes are also efficient for the catalytic reduction and

comparable to the metallic processes, for example the lithium aluminium hydride,

sodium borohydride or borane-terahydrofurane [32] as catalysts. Among those catalysts,

the chirally modified boron complexes have received great interest to be selective

reducing agents for amino and phosphino alcohols [33-35].

The enzyme catalyzed reduction of carbonyl groups has also an important role in the

synthesis of chiral compounds. For example, the dehydrogenases enzyme can catalyze

the reduction of carbonyl groups on a practical scale with purified enzymes or with whole

cells, like the more often used Bakers´ yeast system [36].

2.4.1 Enantioselective hydrogenation

The first enantioselective hydrogenation of unsaturated compounds with the help of

metallic catalysts deposited on chiral supports was reported in the 1930s [37]. Osborn

and Wilkinson [38] published their pioneering synthesis of a soluble transition metal

catalyst (Ph3P)3RhCl) to make the catalyzed hydrogenation possible in solution.

Knowles [39] and Horner [40] presented homogeneous asymmetric hydrogenation using

Rh-chiral tertiary phosphine complexes. Knowles has developed the synthesis of the L-

DOPA (Scheme 2.3) from enamide employing a catalytic amount of the

[Rh(R,R)DiPAMP)COD]+BF4- complex. That was the Monsanto Process, which was the

first commercialized catalytic asymmetric synthesis in 1974. The product of this process

had proven to be useful in the treatment of Parkinson´s disease.

General Part

______________________________________________________________________________

Scheme 2.3 The Monsanto synthesis of L-DOPA using [Rh(R,R)DiPAMP)COD]+BF4- catalyst

complex

In the 1970s and early 1980s new catalysts were designed mainly with new optically

pure chelating phosphines using Wilkinson type catalysts. For example, one of the first

Kagan´s tartaric acid derived ligand DIOP [41] in 1971. This development was followed by

new successful ligands, namely DIPAMP [42], prophos [43], chiraphos [44], BPPM [45],

BPPFA [46], norphos [47], and BINAP [48] (Figure 2.5).

MeO

OAc NHAc

CO2HMeO

OAc

CO2H

NHAcH

95 % ee

H3O+

CO2H

NHAcH

L-DOPA

cat.

100%

General Part

______________________________________________________________________________

Figure 2.5 Chiral ligands for asymmetric catalysis

To the middle of 1980s the Rh-based Wilkinson type catalysts were the most used

catalyst systems. Afterwards, Noyori et al. have introduced a new family of Ru-based

complexes, e.g. [Ru(BINAP)(OAc)2], [Ru(BINAP)2Cl4NEt3], or [(arene)Ru(BINAP)I],

which had wider and better applicability in the enantioselective hydrogenation of β-keto

esters than the Rh catalysts. For example, in the hydrogenation of acetophenone using

[Rh(nbd)Cl]2/DIOP have reached only occasionally more than 80 % ee, while the Ru-

based BINAP have allowed the hydrogenation of a variety of functionalized ketones in

enantioselectivities close to 100 % ee [49, 50].

P(C

)

P(C

)

DIOP

OMe

DIPAMP

)

PP(C

)

chiraphos

)

PP(C

)

prophos

COO C(CH

)

P(C

)

BPPM

P(C

)

P(C

)

norphos

Fe C

P(C

)

P(C

)

N(CH

)

BPPFA

P(C

)

P(C

)

BINAP

General Part

______________________________________________________________________________

2.4.2 Mechanism of the asymmertric hydrogenation

In general, the ligand modifies the properties of the metal dramatically, e.g. by stabilizing

different oxidation states or by fine-tuning the electrophilic or nucleophilic properties of

the metal. Probably, no element shows better this effect than ruthenium, which has the

next distinctive properties that are manifested by a wide range of its complexes

containing of ligands: propensity for π-back-bonding, tendency to undergo intra and

intermolecular metallation and ability to form polyhydride complexes. The wide range of

complexes is also a characteristic property of ruthenium, which has been studied very

extensively [51]. Using [RuHCl(PPh3)3] as catalyst, very high rates of hydrogenation of

terminal alkenes, alkynes or polynuclear heteroaromatic compounds was achieved. This

complex catalyzes the reduction of aldehydes and ketones, however the carbonyl

derivative [RuHCl(CO)(PPh3)3] is more efficient for these processes [52], which were

studied by Sanchez-Delgado et al. [53, 54]. The results show the rate is first order with

respect to the concentration of catalyst and substrate and second order with respect to

the hydrogen pressure. A general schematic mechanism for hydrogenation of the C=O

bond is shown in Scheme 2.4. The dependence of the rate on the concentration of

catalyst and substrate, and on the hydrogen pressure is consistent with the mechanism.

General Part

______________________________________________________________________________

Scheme 2.4 Mechanism of hydrogenation of the C=O bond applying [RuHCl(CO)(PPh3)3]

catalyst complex

The above mentioned mechanism operating in hydrogenation is well-known since 30

years. The famous mechanism of enantioselective hydrogenation is the hydrogenation

of methyl (Z)-α-acetamidocinnamate (Scheme 2.4). The ligand is a square planar RhI

complex containing a chelating phosphine ligand P*P, such as e.g. chiraphos (Figure

2.5) and two solvent molecules S, for example methanol or acetone. This

species/complex reacts with the substrate, which acts as a bidentate ligand displacing

the two solvent molecules, giving two diastereomeric square planar species in line 2.

They contain the same optically active chelating ligand, but the metal atom is

coordinated to different sides of the prochiral olefin (re/si sides).

The next step is the oxidative addition of hydrogen forming the two octahedral

dihydrides, which is shown in line 3. This reaction is the rate-determining step.

Cl PPh3

Ph3P

Cl PPh3

Ph3P

R´

PPh3

Ph3P

HHH

CR´

PPh3

Ph3P

HHPPh3

OCHRR´

COH

RR´

Cl PPh3

PPh3

Ph3P

+PPh3

-PPh3

´R

General Part

______________________________________________________________________________

Scheme 2.5 Mechanism of the hydrogenation of methyl (Z)-α-acetamidocinnamate with

Wilkinson-type catalyst

The insertion of the coordinated olefin into one of the Rh-H bonds is followed, giving rise

to the two diastereomeric σ-alkyl complexes of line 4. By reductive elimination the

enantiomeric species of the product are generated (Scheme 2.5).

Experiments verify that the (R) product predominates by more than 95 % ee. Thus, the

final product is not formed from the major diastereomer dominating in line 2, but from the

P S

*CC

NHCOMe

P O

MeO

CNH

CMe Rh

CMe

P O

MeO

HN CO

MeO

-[Rh(P P)S

]

*-[Rh(P P)S

]

Me H

MeO

NMe

R Product S Product

General Part

______________________________________________________________________________

minor diastereomer, which presents in the equilibrium mixture to the extent of less than 5

% according to the NMR measurements [44].

2.4.3 Asymmetric homogeneous hydrogenation using metal-catalyst in industrial

application

Asymmetric hydrogenation played a key role in the fundamental understanding of the

catalytic reaction and offered the route from the simple to the very complex, allowing

accumulation of the necessary knowledge before the next leap go to forward. Actually,

the term “hydrogenation” refers to the step of the H2-activation, because under ambient

conditions H2 is a rather unreactive molecule. The homogeneous hydrogenation allows

the H2-activation under mild conditions where powerful spectroscopic techniques can be

easily used for the investigation of the reaction kinetics and the structures. Abundance of

hydrogenation reaction can be examined almost step by step along the reaction

coordinate and cleared the composition and structure of the reaction intermediates. The

homogeneous hydrogenation, catalyzed by metal complexes offers powerful catalytic

systems by the partially filled d or f electron shells of the transition metal. Due to this fact

they have several interesting features, e.g. the ability to form strong bonds in a variety of

oxidation states and to coordinate with several different ligands in their coordination

sphere. Finally, the possibility of modifying the electronic and steric environment at the

active site by the utilization of tertiary phosphine ligands is a remarkable opportunity to

increase the selectivity and reactivity. Other important conditions, such as temperature,

solvent, pressure, time can be modified in order to regulate the selectivity.

Few catalysts have been developed to produce alcohols from a range of ketones with

absolute stereocontrol and high catalytic efficiencies. One of the best catalyst complexes

for such a reaction (Scheme 2.6 b,) is built from 2,2´-bis(phosphino)-1,1´-biaryl (BINAP)

ligand with ruthenium transition metal precursor developed by Noyori et al. This

discovery was awarded by Nobel Prize. This system requires high temperature and 100

atm hydrogen pressure [55]. Genệt et al. have achieved the same result for the

hydrogenation of β-keto-esters (Scheme 2.6) with [Ru(BINAP)Br2](acetone) catalyst

complex at atmospheric hydrogen pressure [56, 57].

General Part

______________________________________________________________________________

Scheme 2.6 a) Formation of the catalyst complex; b) Hydrogenation of the β-keto-esters

The hydrogenation of (R)-(-)-methyl-3-hydroxypentanoate using BisP*-Ru complex

(Scheme 2.7) is another example developed by Imamoto et al. [58], which can be applied

to a wide range of β-keto-esters, β-keto-phosphonates and β-ketoamides.

Scheme 2.7 a) Formation of the catalyst complex; b) Hydrogenation of the β-keto-esters

= BINAP ligand

Ru acetone

HBr, MeOH

PRu Br

Br Me2CO

OMe

O O

H2, MeOH

RuBr2[(S)-BINAP]

OMe

RuBr2[(S)-BINAP]

t-Bu

Me t-Bu

1, Ru(2-methallyl)

(COD)

2, HBr-MeOH PH PH

t-Bu

Me t-Bu

RuBr

(BisP*)

RuBr

(BisP*), H

MeOH

HOH

Br Br

General Part

______________________________________________________________________________

In the last few years, the industrial application of the epoxidation, dehydroxylation and

especially the hydrogenation have increased rapidly. Among these reactions, the

enantioselective hydrogenation is the best investigated and most applied industrial

reaction. Some of the most popular ligands with the preferred catalyst types and the

state-of-the-art for the hydrogenation of olefins are summarized in Table 2.2 and in

Table 2.3.

Table 2.2 State-of-the-art for the hydrogenation of olefins

Substrate ee [%] TON TOF[h-1] Preferred catalyst types

enamides, enol,

acetates, itaconates

90-98

1000-20000

200-5000

Rh/PCYCL, Rh/FERRO,

Ru/BIAR, Rh/PPM

(C=C-C-OH) type of

olefin

80-95

10000-50000

1000-5000

Ru/BIAR

C=C-COOH type of

olefin

85-95

2000-10000

500-3000

Ru/BIAR, (Rh/PCYCL)

tetrasubstituted (C=C)

85-95

500-2000

200-500

Ru/BIAR, Rh/PCYCL,

Rh/FERRO

C=C without privileged

function

80-95

20-100

2-5

Ru/BIAR, Ir/P^OXAZ,

Rh/PCYCL

Table 2.3 Explanation for the abbreviations of the preferred ligand types

Ligand type

Family of the ligand

PCYCL Ligands with cyclic phosphine, e.g. DuPHOS, ROPHOS

FERRO Ferrocenyl-based ligands, e.g. JOSIPHOS, BPPFA

BIAR Biaryl and heterobiaryl diphosphines, e.g. BINAP, Biphep

PPM Binol-based ligands, e.g. BINOL, BINOP

P^OXAZ Oxazoline-derivatived ligands, e.g. BISOXAZOLINE

As a consequence, there are no universal ligands for the asymmetric transformations

but modifying of the properties of the new ligand by fine tuning is a versatile “tool” to

create proper catalysts for specific reaction types.

General Part

______________________________________________________________________________

The number of commercial applications will increase in the future because more and

more specialized technological companies are developing the know-how and experience

to produce technical quantities of the chiral ligands, which give rise to conduct of

enantioselective catalytic processes with even better activity, productivity and

robustness.

2.4.4 Chiral Cl-MeO-Biphep ligand

Cl-MeO-Biphep has been derived from the family of biaryl diphosphines ligands. It has

been developed and patented by C. Laue at al. (Bayer AG) in 1996 [13], and

commercialized for a new chiral hydrogenation technology with Ru and Rh metal

complexes because of the high demand for active pharmaceutical ingredients. This

ligand delivers greater more than 98.7 % enantioselectivity in asymmetric hydrogenation

of carbonyl groups and carbon-carbon double bonds. Bayer AG (Lanxess FC) has

contracted with the leader R&D chemicals manufacturer Strem Chemicals, Inc. to

produce the ligand in research scale for promoting the development. The general

synthesis of the Cl-MeO-Biphep ligand is depicted in Scheme 2.8.

General Part

______________________________________________________________________________

Scheme 2.8 Synthesis of the Cl-MeO-Biphep biaryl based ligand 3

First of all, bromo-aryl derivative A and chlorodiphenyl-phosphine were mixed in the

presence of Mg and afterwards oxidized to obtain of the arylphosphine-oxide B. This

product was iodized to C, which can be used as a starting material in an Ullmann

coupling reaction to generate biphenyldiphosphine-oxide D. The racemate of the

diphosphine derivative D was treated with (+)-dibenzoyl tartaric acid to separate the two

MeO Br

1, Mg/ClPPh2

2, H2O2

MeO P(O)Ph2

LDA/I2

MeO P(O)Ph2

Cu/DMF

MeO

P(O)Ph2

resolution of

the racemate with

(+)-dibenzoyl tartaric acid

MeO

P(O)Ph2MeO

MeO

P(O)Ph2

HSiCl3/NBu3

MeO

PPh2

MeO

PPh2

P(O)Ph2

General Part

______________________________________________________________________________

isomers E and F and after that it was reduced with HSiCl3 in order to get the (R) and (S)

isomers of biarylphosphine ligands as a pale yellow powder.

B. Drießen-Hölscher et al. [59] have developed a new synthesis route producing Cl-MeO-

Biphep ligand (3) via the corresponding biphenol, which allows introducing several

substituents without the necessity to separate the enantiomers of each derivative.

Bayer´s new synthesis [60] allows the introduction of a wide range of substituents (R-

groups) in place of the phenyl group on the phosphorus because the racemic separation

takes place before the R group is attached.

The typical price of such general ligands as the Cl-MeO-Biphep is between € 10.000-

15.000 / kg and they are usually applied in ton scales per year. Due to the price, in the

last few years the reuse and recycling of these ligands have become a main goal for the

companies, which are interested in the catalytic and chiral technology.

2.5 Palladium catalyzed C-N bond-forming process

2.5.1 General Buchwald-Hartwig amination reaction [61]

Almost 10 years ago Buchwald [62] and Hartwig [63] have presented a new field of

transition metal catalyzed cross coupling chemistry to prepare derivatized anilines and

aryl ethers. These two publications have caused vast activities in academic and

industrial research groups. These palladium catalyzed C-N and C-O bond-forming

reactions are versatile, applicable and reliable both in academic and industrial use i.e.

on small and larger scale, too. Nowadays these techniques have reached the multi-

hundred kg production level in many companies, in spite of their rather rapid

development and application.

Such a system as the Buchwald-Hartwig amination requires four components to prepare

C-N bond. Two of them are the organic ligand and the Pd-precursor: they generate the

efficient catalyst complex. This complex facilitates oxidative addition and provides

sufficient bulkiness to accelerate reductive elimination. The adequate base can promote

General Part

______________________________________________________________________________

the deprotonation of the substrate (amine) before or after the coordination to the

palladium atom. Whilst these systems often possess heterogeneous characteristics, the

selection of the solvent and the solubility of the base or the substrates play a more

significant role than in other transition metal-catalyzed processes.

The C-N coupling reactions usually require ligands for their transformations, which show

high reactivity and selectivity. Tremendous activities have been focused on this field

over the last years [7, 64, 65]. Among the most frequently used ligands, the first to be

mentioned are P(o-Tol)3 and P(t-Bu)3 [62, 66]. The chelating biphosphines BINAP, DPPF,

DtBPF were used solely until Buchwald has presented the synthesis of the monodentate

phosphine ligands with a biphenyl backbone. They allowed the amination of aryl

chlorides and aryl halides even under mild conditions. The development of the new

2,4,6-triisopropyl-substituted ligand X-Phos [18, 67] resulted the more stable and active

derivatives among the biphenyl based ligands. There were used for arenesulfonates and

aqueous amination protocols, too.

In parallel, van Leeuwen [68] has developed XantPhos and DPEPhos ligands, which have

specific activity for coupling reactions of amides, ureas, hydrazines and aryl halides.

Verkade [69] has presented the application of triaminophosphines as electron-rich ligands

with rigid framework. Pyrrole- and pyrazole-based biphenyl ligands were characterized

by Singer et al. [70] in 1998. Such systems require strong base. Beller has described N-

arylindole-substituted ligands [71] and adamantyl-based alkyl-phosphines ligands [72] for

transformation of arly chlorides with high efficiency.

From the view of recycling, a solid-phase bounded derivative of biphenyl-based ligands

was reported by Buchwald et al. [73] which was recyclable at least in three runs.

The possibility of the selection of a Pd-precursor is much more restricted than the choice

of the ligand, which has a broad scope, as mentioned before. The most versatile Pd(0)

precursors are the Pd(dba)2, Pd2(dba)3, but the influence of the dba tag on the reaction

could be remarkable. Among the Pd(II) precursors, Pd(OAc)2, Pd(Cl)2, Pd(acac)2 should

be mentioned. Reduction of Pd(II) species to Pd(0) can happen in situ in the presence of

the ligand and base. The range of the loading of the Pd-precursors is wider than in other

catalytic cross-coupling systems, thus some special reactions turned out to be

successful with palladium loading down to 0.01 mol %, while a typical amount of

palladium in amination reactions usually is 1-2 mol %. The impurities, whatever inorganic

General Part

______________________________________________________________________________

or organic of the applied precursors and components have a great impact on the

efficiency and reliability of these types of cross-couplings.

The subsequent major component of the Buchwald-Hartwig amination is the base e.g.

Cs2CO3, K2CO3, K3PO4, KOH, NaOH, t-BuONa, which has a significant effect on the

nature of the reaction by the solubility of the bases in polar (homogeneous system) or

apolar (heterogeneous system) organic solvents. These are caused by the counterion

and the particle size of the base. Notable side-reactions can also be remarkable by

utilization of different strong bases (low functional group tolerance). Different ligands are

adequate to diverse types of bases thus the base K3PO4 is frequently used with

biphenyl-based ligands while for example the Cs2CO3 mostly promotes the cross-

coupling reactions with the chelating biphosphine ligands.

Solvent / temperature are the last factors described in the Buchwald-Hartwig amination.

The solvent plays a main role in stabilizing the intermediates and in dissolving of the

reaction partners, as well. The most frequently applied solvent is toluene, but for

solubility reasons some polar solvents are also commonly used, e.g. DMSO, NMP, DMF.

Because many catalysts are air-sensible the solvent has to be dry and the air contact

has to be avoided during the reaction. In special cases using less air-sensitive ligand,

the air has no influence on the yield.

These reactions are usually conducted inside a range of 70 – 140 ºC by using Pd-

precursor with biphenyl-based ligands. The preparation of the catalyst is worked out

sometimes in situ before the catalytic run allowing sufficient time for the formation of the

active species. In many cases, other additives e.g. water or alcohols can be added to

the mixture to facilitate the reaction and increase the conversion.

2.5.2 Proposed Mechanism of the amination reaction

Two mechanisms were discussed in details by different workgroups. The three main

parts of the mechanism cycle are the oxidative addition of substrate, formation of amido

complexes and the reductive elimination [64] (Scheme 2.9). In the early stage of these

reaction types the whole cycle was not fully characterized but several calculated models

were published giving an impression on the role of the additional phenyl group as a co-

General Part

______________________________________________________________________________

ligand. The rate-determining step is the complexation of the amine to the catalyst.

During the catalytic cycle the concentration of the active catalyst species is increasing to

its steady-state concentration. According to the recent research the σ-substituted

biphenyl based Buchwald ligands own notable role in the sequential coupling reaction of

aryl chlorides [67]. The catalysts with less bulky substituents are required longer exposure

to the amine to become fully activated than those bulkier based derivatives.

Start of catalytic cycle

L-Pd-L

(0)

(II)

M-O-t-Bu

M-X

O-t-Bu

(II)

M-O-t-Bu

OH-t-Bu

(II)

oxidative addition

reductive elimination

Generation of

electron-rich

P(0) species

(II)

OH-t-Bu

M-X

Product

Substrate

Scheme 2.9 Proposed mechanism for the catalytic cycle of the amination [61]

General Part

______________________________________________________________________________

In case of less bulky or smaller ligands, the L:Pd ratio has also significant influence on

the rate of catalyst activation via the phosphine dissociation from bisphosphine complex,

while the rate dependence was influenced by the larger ligands.

2.5.3 Dave-Phos and X-Phos ligands applied in C-N formation

The Buchwald-Hartwig C-O and C-N coupling transformations has been proven to be

robust, reliable and useful to produce nitrogen-containing ligands as well as natural

products and their analogues for the synthesis of heterocycles even on an industrial

scale. Therefore the scope of this technique is enormous. The biphospine BINAP

dominate this field of reactions because this ligand is easily available and widely

examined. The utilization of this ligand does not require any extensive and lengthy

optimization. Naturally, the development of new ligands also continues with high activity,

e.g. the use of Buchwald´s biaryl ligands by Lakshmann [74]. This subsection focuses on

two newly evolved ligands named as Dave-Phos (Scheme 2.10, 7) and X-Phos (Scheme

2.11, 8). The synthesis of their can be seen from Scheme 2.10. and Scheme 2.11.

Scheme 2.10 Synthesis of Dave-Phos ligand (7)

NMe

MgBr

THF, 60

2 h

MgBr

1, CuCl

2, ClPCy

RT or 60

CMe

PCy

General Part

______________________________________________________________________________

Scheme 2.11 Synthesis of X-Phos ligand (8)

Their synthesis has been reported on a lab scale using a Grignard strategy. The first

amount of magnesium was added together with 2-bromo-N,N-dimethylaniline (A) (at

synthesis of Dave-Phos Scheme 2.10) or 1-bromo-2,4,6-triisopropylbenzene (D) (at

synthesis of X-Phos Scheme 2.11) until formation of Grignard reagent was complete.

The second crop of Mg and 2-bromochlorobenzene (B) were also added to the mixture

[75, 76]. In the last step CuCl and ClPCy2 were reacted with the mixture to get the ligands

(7, 8).

Using the Buchwald´s ligand Dave-Phos, two patents were reported by Pfizer on a 3-kg

scale for the synthesis of CP 529,414 [77, 78]. Efficient scale-up procedure was also

completed with X-Phos ligand for the large scale Pd-catalyzed hydrazonation of

aromatic chlorides by Mignani et al. [76]. Because of the competition among the industrial

groups the number of examples not published openly may be much larger in this field of

research.

MgBr

MgBr PCy

THF, 60

2 h

1, CuCl

2, ClPCy

RT or 60

General Part

______________________________________________________________________________

2.6 Biphasic systems for reuse and recycling of the catalyst

complexes

As described before, the price is a very determining parameter in the catalysis and chiral

business. After the asymmetric hydrogenation, used catalysts are usually difficult to

recycle because of accumulated contaminations. Immobilization methods e.g. with ionic

liquid, silica, alumina or clay could solve these problems and in this manner reused

catalysts are also at least as selective and active for up to 15 times without leaching like

the brand new synthesized complexes. The homogeneous catalysis, in this sense could

be attainable with aqueous “heterogenized”, “immobilized” or “anchored” catalyst

complexes.

2.6.1 Immobilization by aqueous catalysts

One of the most employed and important method in this field is the immobilization

technique of the aqueous catalyst. That mode uses a homogeneous catalyst, dissolved

in water as a “mobile” phase (mobile support). In this manner, the catalyst and the

reactants are easily separable just after the reaction, at approximately the same

temperature and without any chemical stress. In this relation the catalyst is not

“anchored” but “immobilized” as well as “heterogenized” on “liquid supports”. Those

systems belong to type of the immobilization by aqueous catalysts in which the

procedure does not contain any additional steps (except for temperature control) to

promote the phase separation. It makes possible a new start of the catalytic runs

immediately in the same phase without any additional reaction. Many papers review the

fundamentals and limitations of the aqueous-phase homogeneous catalysis and the

special role of the water [79, 80, 81]. The solubility of the ligand in water is increased by

introduction of highly polar substituents, for example -SO3Na, -NH2, -OH, or -COOH and

by variation of the nature and the number of them and/or by the condition (e.g. pH) of

the aqueous phase. By that way, almost any desired ratio of hydrophobic and

hydrophilic properties can be obtained. For example, the solubility of hydroxyl

phosphines depends on the nature of the parent phosphine and on the number of

General Part

______________________________________________________________________________

hydroxy substituents. A special case is the triphenylphosphine ligand with one (mono-,

M) two (di-, D) or three (tri-, T) meta-positioned sulfonic acid groups. These derivatives

differ in their hydrophilicity and their hydrophobicity following the next series with

increasing in hydrophilic characteristic: TPPMS<TPPDS<TPPTS. The last ligand

contains three meta-positioned sulfonic acid groups. A review about the synthesis of

water-soluble ligands has been published in detail by Herrmann and Kohlpainter [82].

Some of such water-soluble ligands are listed in Figure 2.9.

Figure 2.9 Water-soluble ligands used for oxo homogeneous catalysts

The great advantages of the ligands listed in the previous table are, that they are able to

overcome the basic problem of homogeneously catalyzed processes: the separation of

the product phase from the catalyst itself. Several times, the separation processes

COOH

1945 Gilmann, Brown

TPPMS

1958 Ahland, Chatt

1975 Joó, Beck

1978 Wilkinson

TPPDS 2

1975 Kuntz / Rhône Poulenc

1987 Kuraray Corp.

TPPTS

1975 Kuntz / Rhône Poulenc

1982 Cornils / Ruhrchemie

HOCH

1973 Chatt et al.

1989 Harrison et al.

General Part

______________________________________________________________________________

include thermal operations such as distillation or rectification, which may lead to

decomposition of the catalyst complex and/or can decrease the lifetime and productivity

of the catalyst, due to the thermal stress on the catalyst. The separation processes are

easier in biphasic systems in which the water-soluble catalysts and the aqueous

biphasic system are incorporated. The next figure shows a general example for the

biphasic catalyst system in water (Scheme 2.11).

Scheme 2.11 General biphasic catalytic system for hydroformulation reaction

The hydrophilic ligand containing the water-soluble catalyst converts the substrates (A-B

= syngas, S = propene) to the products in which the catalyst (polar phases) can be

separated from the product (nonpolar phases) by simple phase separation after the

reaction. The leaching and loss rate of the catalysts are often below the limits of the

detection, because of the insolubility and polarity of the ligand in the organic phase.

Naturally, the aqueous biphasic systems require a minimum solubility of the reactant (S

and A-B) in the organic phase. The incorporation of the biphasic system with the

hydrogenation of C=O and C=C bonds have been published by Sinou [83], Southern [80]

and by Herrmann and Kohlpainter [82], especially with chemical aspects up to 1993. The

Cat.

A-B

Cat.

A-B

AB=P

nonpolar ph.

polar ph.

nonpolar ph.

General Part

______________________________________________________________________________

nowadays investigated biphasic hydrogenation, using plenty of substrates mainly with

the water-soluble TPPMS ligand coordinated to Rh or Ru complexes [84-86] could be a

versatile key for the selective reductive operation in industry. Scheme 2.12 shows some

very widely examined reactions.

Scheme 2.12 Two examples for deeply investigated reactions

Existing evidence for the extension of two-phase catalysis into the new area of a C1-

chemistry, for example Leitner et al. [87] described biphasic hydrogenation of CO2 to

formic acid. The biphasic hydrogenation of aromatic nitro compounds with Pd or Rh

catalysts are investigated by Tafesh [88].

Activities on this field are the development of new solvent system such as N-

methylpyrrolidon (NMP) or polyalkylene glycols. Alkali salts of mono-sulfonated

triphenylphosphane (TPPMS) ligands combined with Rh are soluble in such a medium.

The combination of the homogeneous catalysis with a catalyst recycling by a phase

separation is the key advantage in this technique.

CH CHO H

CH CH

3-methyl-2-buten-1-al 3-methyl-2-buten-1-ol

"prenol"

TPPMS

TPPTS

fumaric/maleic acid

COOHH

succinic acid

HHOOC

HCOOH

COOHH

HCOOH

General Part

______________________________________________________________________________

2.6.2 Immobilization by nonaqueous biphasic systems

The low water solubility and the moisture sensibility of many organic compounds limit the

application of aqueous catalysts. The nonaqueous biphasic system provides the catalyst

only in the catalyst phase under the reaction conditions. Such kind of phases could be

for example fluorous phases or ionic liquid phases. The choice of a nonaqueous phase

for a defined reaction depends on the solvent properties of the product, if it is e.g.

apolar, the catalyst phase should be polar and vice versa.

The fluorous phase is defined as the fluorocarbon-rich phase of a biphasic system

consisting mostly perfluorinated alkanes, ethers or tertiary amines. Perfluorinated alkyl

ethers or perfluorinated alkanes are also used as solvent. The mostly applied ligand for

such an application is the normal homogeneous catalyst by modified with attached

flourous ponytail to the core of the ligand. The most effective fluorocarbon ligands are

linear or branched perfluoroalkyl chains with high carbon number. These ligands have

been applied with success for cross-coupling, Diels-Alder, hydrosilylation and of course

for hydrogenation reactions [89, 90]. In this case, again the phase separation is the key

step of the recovery of the ligands paying attention on the solubility properties of these

systems.

The other more detailed nonaqueous biphasic system uses ionic liquids (IL) as a second

phase in addition to the product phase. These liquids are solvents that are entirely

composed of ions. They have no vapor pressure and can be used as liquids over a wide

range of temperature. They possess high ionic conductivity and a broad electrochemical

window. Ionic liquids are currently under intensive investigation as alternative solvents

for the biphasic catalysis. The term ionic liquid refers to 1-alkyl-3-methylimidazolium

salts and pyridinium salts. The alkyl chain (R) corresponds to the structure CnH2n+1, while

the counter anion (X-) could be AlCl4, SnCl3, BF4, PF6, CF3SO3, SbF6 or other molted

salts e.g. ammonium or phosphonium. Examples for the structure of these liquids are

shown in the Figure 2.7.

General Part

______________________________________________________________________________

Figure 2.7 General structures of ionic liquids

In general, IL contains a bulky anion and a large cation with low symmetry. Therefore

the lattice energy and the melting point of this solvent are low. The individual properties

(polarities, melting points etc.) of the easily prepared IL are fine tunable by selection of

the anion as well as the cation´s. The first research in the homogeneously catalyzed

processes with IL was described in case of chloroaluminate melts for the Ni-catalyzed

dimerization of propene by Guibard et al. in 1990 [91]. Because of the advantages of the

excellent solubility of the organometallic compounds (numbers of traditional catalysts

complexes) in IL, in some cases this liquid is used as a replacing media of the

conventional organic solvent and as a supporting phase for the catalyst. In such cases

the reuse or the recovery of the complexes are usually easy by simple phase separation

or by extraction immediately after the reaction. These media also have an important

influence on the reaction rate and selectivity, which depend on the anion that can be

coordinating or noncoordinating as well as Lewis-acid, Lewis-basic or neutral. In this

case, the cation does not play a significant role.

High selectivity and enhanced activity are reachable with IL in the hydrogenation

reaction of alkenes in which the catalysts are equipped with the customary Ru, Rh, Pd or

Pt metals. Examples are reported e.g. for enamide preparation with successfully

immobilization and reuse of the catalyst several times without loss of catalytic activity [92],

for Sonogashira coupling reactions performed in IL without copper salts and bulky

phosphine ligands. The hydrogenation of β-aryl ketoesters using Ru/BINAP complex at

room temperature IL has been published by Ngo at al. [93, 94] without metal contamination

of the product and without leaching of the catalyst. In case of the hydrogenation of

cyclohexadiene [95] and sorbic acid [96] the reactions show an extraordinary high product

selectivity (Scheme 2.13).

imidazolium ionic liquid pyridinium ionic liquid

General Part

______________________________________________________________________________

Scheme 2.13 Hydrogenation of sorbic acid in IL

In conclusion, the ionic liquid as new class of a polar solvent provides a fine tunable

medium for many biphasic homogeneous reactions by the appropriate selection of the

anion, cation and the co-solvent. Consumption of the amount of the catalyst and the

organic solvent can be reduced by utilization of the IL because of its nonvolatility

property and the easy phase separation.

2.6.3 Immobilization and fixation to supported organic and inorganic polymers or

matrices

An intensive research in this field started in the late 1960s when ligands named as

”supported” or “anchored” metal catalyst complexes were applied. These types of

processes combine the advantages of the homogeneous catalysis (high selectivity and

activity, good reproducibility) and the heterogeneous catalysis (easy separation and long

lifetime of the catalysts). The first publications came from Acres et al. [97]. The anchoring

of the complexes could be done by different methods: the first to be mentioned is the

fixation or immobilization via covalent bonding to the organic and to the inorganic

supports.

The most frequently used organic support is the polystyrene and styrene-divinylbenzene

copolymers with several functional groups. The phosphinated polystyrene (eq. 1) seems

to be the best auxiliary to design the structure of the anchored ligand [98] (Scheme 2.14).

The often used routes to prepare polymer-anchored ligands (eq. 2) are the displacement

of a ligand by coordinating to a soluble metal catalyst. The suitable complexing groups

and polymers can be designed by simple organic synthesis. Instead of polystyrene

COOH

[Cp*Ru(diene)]CF

/ MTBE

COOH

General Part

______________________________________________________________________________

derivatives as a polymer, cellulose, polyacrylates, polyvinyls are also often applied in

this technique for hydrogenation, hydrosilylation, oligomerization, dimerization reactions.

For example, in the case of hydrogenation of olefins, the recycling of the catalyst is

easily practicable because the complexes bounded to organic matrices have different

affinity between the nonpolar olefins (product) and the polar organic matrixes. In

principle, the chemoselectivity of immobilized metal (Rh, Ru, Pd) complexes is similar,

whilst the activities are lower in comparison to the homogeneous systems. The steric

properties (crosslinking, degree of flexibility) of the organic supports have a great

importance in these systems because the catalytic reactions particularly take place on

the surface of the polymers.

Scheme 2.14 Universal route for preparing and coordinating the functionalized ligand to the

catalyst complex

The latest works and activities using soluble polymers to recover the catalyst have been

published by Bergbreiter [99]. Xiao et al. [100] have published the hydrogenation of ketones

with supported organic complexes applying a poly(ethylene glycol)-supported (PEG-2)

chiral diamine as ligand, which is attached to the phenyl rings. Chen at al. [101] have

prepared soluble bifunctional polymeric BINOL-BINAP and BINOL-BINAPO copolymers

by condensation for enantioselective reactions and in the same year recyclable PEG

and diguanidinium tethered BINAP have been described by Dellis et al. [102].

PPh

RhCl(PPh

)

PPh

RhCl(PPh

)

-PPh

p = polymer or polymeric network

PPh

LiPPh

General Part

______________________________________________________________________________

The use of inorganic support is less common than the previously mentioned organic

polymers, although the better physical properties of the former can be more

compensating for the better chemical properties of the latter [103]. These usually provide

higher temperature, solvent and aging stability and rigid structure, which prevents the

deactivation of the bounded catalysts. Disadvantages of these systems are the limited

number of reactive surface groups (possibility of the further functionalization) and a

lower limit of functional groups than in the organic supports. The commonly applied

inorganic supports are silica, clay, glass, alumina, magnesia, ceramic. Among these

auxiliaries, the silanol group modified silica is the most preferred support because of its

pore size, pore volume, form and size of particles, surface area and number and nature

of the surface groups. The mechanism of the catalytic system and the nature of such

catalyst complexes remain unclear. Two alternative approaches have been applied to

describe the attachment of the ligand to the supports (eqs. 3 and 4) (Scheme 2.15).

Scheme 2.15 eq. 3, ligand group is attached to the support, eq. 4, reaction between the phosphine-

functionalized silica and the monomeric metal complex

Recent publications were presented in the hydrogenation of ketones using mainly silica-

immobilized catalysts, e.g. Tu et al. [104, 105] have developed the chiral Ru-TsDPEN

catalyst, which was successfully immobilized on amorphous silica gel and mesoporous

p = polymer or polymeric network

Si (H

Si-(CH

)

-PPh

- C

OH Si

Si CH

)

(CH

)

Rh(CO)

acac Si

(CH

)

Rh(CO)acac

-CO

OOH

PPH

PPh

General Part

______________________________________________________________________________

silicas of MCM-41 and SBA-15. Pugin et al. [106] published a silica gel supported chiral

biaryl-diphosphine ligands (MeO-Biphep, Biphemp) for testing and recycling in

asymmetric hydrogenation of methyl-acetamidocinnamate.

Other methods for the fixation of the ligand to the support are also accomplished, for

example by ionic bond and by chemisorption or physisorption. Finally, the immobilization

can take place by impregnation of the solid support with a liquid medium, which contains

the dissolved homogeneous catalyst. The medium can be either of organic nature

(SLPC = supported liquid-phase catalyst) or water nature (SAPC = supported aqueous-

phase catalyst).

Results and Discussion

______________________________________________________________________________

3 Results and Discussion

3.1 Aims and Scopes

The modern “green” chemistry requires minimizing of energy consumption and waste

production. These two parameters have become a major concern for the chemical

industry. The use of catalytic systems could be the answer, because they render rapid

and selective chemical reactions.

As described in the last chapters, the ligand has a significant practical role in the

catalytic transformations of different compounds. The appropriately selected ligand

allows the reaction to perform with high conversion and selectivity giving a notable

chance of profit for the manufacturer.

Our primary aim in the project was the recovery of the used ligand with at least 70 %

after the reaction and the reuse of it in the next two runs. The Cl-MeO-Biphep ligand (3)

is patented by Bayer AG (Lanxess FC) and applied for asymmetric transformations on

an industrial scale. The standard reaction of the project was the reduction of β-ketoester

to the corresponding alcohols (Scheme 1.1). In addition this ligand could be powerful in

many other reactions to yield natural products, pharmaceuticals or special intermediates.

The manufacturing costs of the product are determined by the used catalyst, solvent,

and mainly by the applied ligand. That is why it will be useful to recycle the catalyst.

The initial work on this field was the control of the reaction conditions (temperature, H2

pressure, reaction time, precursor and S/C ratio) with which appropriate conversion and

highest ee could be reached. The following step was the test of different solvents to

accomplish an advantageous reaction medium for the complete recovery of the

complexes with e.g. SLPC systems or IL. Latest concept was the derivatization of the Cl-

MeO-Biphep ligand in order to get an opportunity to obtain the derivative of the organic

ligand in its pure solid form after the catalytic reaction. In this manner, the recycled

ligand was reused in a new catalytic cycle to investigate the activity and selectivity in the

hydrogenation reaction.

Another part of the project was the amination reaction (Scheme 1.2) using two

Buchwald´s ligands mentioned earlier (section 2, compound 7 and 8). Due to the similar

Results and Discussion

______________________________________________________________________________

chemical properties compared to Cl-MeO-Biphep (3), the Dave-Phos (7) or X-Phos (8)

can be recovered via derivatization of the ligand.

3.2 Asymmetric hydrogenation with different conditions and solvents

using Cl-MeO-Biphep and BINAP ligands

Scheme 3.1 Asymmetric hydrogenation of β-ketoester

To reach our aims, firstly the conditions of the hydrogenation reaction and the applied

ligand itself were investigated in order to determine and to increase the activity of the

system. In the following work, several types of recycling methods were tested to recover

and/or reuse the organic ligand by building the catalyst complexes 10 and 12 with the

corresponding precursor 9 before the standard hydrogenation reaction.

3.2.1 Comparison of the two biaryl type phosphine ligands 3 and 11

Firstly, asymmetric hydrogenation of 1 was carried out using Cl-MeO-Biphep (3) and

BINAP ligand (11) with [bis-(2-methylallyl-cycloocta-1,5-diene) ruthenium(II)] complex (9)

as precursor to gain experiences about the activity of the systems and to draw a

comparison between ligand 3 and ligand 11. In Scheme 3.2 a, and 3.2 b, the synthesis

of complex 10 and 12 is depicted.

OEt

O O

OEt

OH O

[Ru], H

(50 bar)

110

C, 4 h

methylcyclohexane

Results and Discussion

______________________________________________________________________________

Scheme 3.2a Synthesis of the new [RuBr2(Cl-MeO-Biphep)] catalyst 10

Scheme 3.2b Synthesis of the known [RuBr2(BINAP)] catalyst 12

The hydrogen pressure and the reaction time were changed to obtain the highest

conversion, which will be adopted as a standard condition for further investigations.

Table 3.1 Results of the hydrogenation of 1 applying different conditions and ligands

Entry Ligand Substrate pH2

[bar]

T [ºC] t [h] Conv.[a]

[%]

Product

110

97.5

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). S/C=100. solvent: ethanol

In both cases (Table 3.1, Entry 1, 3), when ligand 3 was used, the conversion as well as

the activity of the ligand was higher than with ligand 11. As described in chapter 2, the

BINAP (11) is the mostly applied phosphine ligand in asymmetric industrial processes.

MeO

PPh

[RuBr

(Cl-MeO-Biphep)]

COD Ru HBr

[(RuBr

(BINAP)]

HBr

11 9

PPh

COD Ru

Results and Discussion

______________________________________________________________________________

The tested ligand 3 is also at least as active in case of hydrogenation of β-ketoesters

(Table 3.1) as the extensively used and investigated BINAP 11. Further investigations

were focused exclusively on the ligand 3. The results of the spectroscopic

measurements showed slight modification and/or decomposition of 3 when the reaction

time was reduced (4 hours). This could be monitored by 31P-NMR spectra after the

reactions.

3.2.2 Use of different solvents for the reduction of 1

Similar to the previous examples, the reactions are commonly conducted and deeply

investigated in MeOH or EtOH in most of the cited literatures, due to the good solubility

of the hydrogen in these solvents. Other media than cyclohexane were tested in order to

solve the problem of the crystallization of the solvent in bigger scale industrial

applications. Thus beside cyclohexane, methylcyclohexane was also tested as medium

in the hydrogenation reaction under standard conditions to monitor the activity and

selectivity of the complex 10 after more consecutive runs. Table 3.2 and Table 3.3 show

the results of the hydrogenation in these solvents in consecutive runs.

In both cases (Table 3.2 and 3.3), the separation of the product 2 was performed via

simple vacuum distillation and the residue consisting of complex 10 was used in the

following run. In this manner, the same complex 10 was reused in 4 and 6 consecutive

runs.

Table 3.2 Hydrogenation results using cyclohexane as solvent

Run Ligand Substrate pH2

[bar]

T [ºC] t

[h]

Conv.[a]

[%]

ee[b]

[%]

Product

3(R)

110

2(R)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured by chiral

GC (Lipodex-E column). S/C=100. The same catalyst residue of 10 was used in every run.

Results and Discussion

______________________________________________________________________________

Table 3.3 Hydrogenation results using methylcyclohexane as solvent

Run Ligand Substrate pH2

[bar]

[ºC]

[h]

Conv.[a]

[%]

ee[b]

[%]

Product

3(R)

110

2(R)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured

by chiral GC (Lipodex-E column). S/C=100. The same catalyst residue of 10 was used in every run.

We were pleased to notice that all conversions remained nearly 100 %, which means

that the activity of complex 10 is excellent under these conditions. During the whole

process the catalyst 10 did not decompose. However, after the last run [RuBr2-(Cl-MeO-

Biphep)] complex 10 could be transformed and oxidized as the 31P-NMR spectra

indicate when cyclohexane or methylcyclohexane was used. The ee values (ranging

from 40 % - 53 % and 15 % - 64 %, Table 3.2 and 3.3) show the same tendencies but

slightly higher excesses were reached when methylcyclohexane was employed as a

reaction medium. On the other hand, in all cases the ee drops after each run indicating

impurities in the system.

The properties of methylcyclohexane when employing in bigger scales are also more

eligible than cyclohexane´s due to the more complicated handling.

Propylene carbonate was also tried as a solvent for the transformation of reaction 1

because of the high boiling point (240 ºC) of the medium. It could give rise to accomplish

the reuse of the complex 10 during more runs. In principal, the solvent phase can

preserve the catalyst 10, which can be utilized in several runs. The separation of the

product could occur by distillation. Unfortunately, we did not have success with this

process because the formation of hydride species [107] (δ (ppm) = 43.62, 59.06) and

oxidization of the complex 10 (δ (ppm) = 26.73, 29.01) was observed after one

hydrogenation reaction indicating by the lack of the catalyst peak (δ (ppm) = -14.91) in

the 31P-NMR spectra.

Results and Discussion

______________________________________________________________________________

3.2.3 Applying IL as a medium for the enantioselective hydrogenation of 1

In this subsection the most encouraging recycling concept was the application of IL

(BMIM+BTA- = butyl-methyl-imidazolium-bis-triflylamide) as the solvent creating the

immobilized catalyst of complex 10. This liquid provides special media for recovering the

organic ligand, through the separation in such a biphasic system could be conducted by

simple distillation or extraction immediately after the transformation. The first and the

second recovery test (Table 3.4 and Table 3.5) present the results, which show a great

efficiency of the catalyst under these conditions.

Table 3.4 Hydrogenation using IL (BMIM+BTA-) as media (first recovery test)

Run Ligand Substrate pH2

[bar]

[ºC]

[h]

Conv.[a]

[%]

ee[b]

[%]

Product

3(R)

110

86.5

82.8

60.0

58.5

2(R)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured

by chiral GC (Lipodex-E column). S/C=100. The same catalyst residue of 10 was used in every run.

Table 3.5 Hydrogenation using IL (BMIM+BTA-) as media (second recovery test)

Run Ligand Substrate pH2

[bar]

[ºC]

[h]

Conv.[a]

[%]

ee[b]

[%]

Product

3(R)

110

87.5

93.5

82.7

69.2

52.2

2(R)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured

by chiral GC (Lipodex-E column). S/C=100. The same catalyst residue 10 was used in every run.

In the first case (Table 3.4), the separation of the product 2 was done by extraction with

n-hexane, while in the second recovery test (Table 3.5) vacuum distillation was applied

after each run. No significant differences between two ranges of results (conversion and

Results and Discussion

______________________________________________________________________________

ee) were observed in spite of the thermal stress on the catalyst 12, however the product

2 is obtained in higher purity when distillation was used (verified by 1H-NMR).

The conversions in both cases reveal that in such a biphasic system the potential of the

complex 10 shows high-level consistency without loss of catalytic activity during at least

three subsequent runs. In both cases (Table 3.4, Table 3.5), the value of ee decreased

slower after each run presenting less impurities in the system. The leaching of the

catalyst may be avoided when distillation was used for the separation of product 2.

In the last part, a mixture of IL (BMIM+BTA-) and the commonly applied EtOH was

investigated to combine both advantages of them (good hydrogen solubility and

excellent immobilization of the catalyst) in order to improve the performance of

asymmetric reduction. Both, extraction and distillation are applicable for the separation

of the product 2 from IL phase, but the latter mentioned process was more convenient.

In case of extraction, slightly leaching (verified by 1H-NMR) of the catalyst 10 from the IL

phase may occur.

Table 3.6 Hydrogenation using IL (BMIM+BTA-)/EtOH (1:1) as reaction media

Run Ligand Substrate pH2

[bar]

[ºC]

t [h] Conv.[a]

[%]

ee[b]

[%]

Product

3(R)

110

98.5

96.5

96.2

28.8

59.9

58.6

2(R)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured

by chiral GC (Lipodex-E column). S/C=100. The same catalyst residue 10 was used in every run.

Finally, the highest ee (Table 3.6, Run 1) compared to the investigated systems was

achieved using IL/EtOH (1:1). Less impurity appeared due to the addition of IL when the

reduction was carried out in common organic solvents. This fact was indicated also in

the ee values.

Results and Discussion

______________________________________________________________________________

As a consequence, IL has a great advantage of recyclability and provides an excellent

medium in which the compound 1 was hydrogenated both with high conversion and high

ee (Tables 3.4, 3.5, 3.6). A disadvantageous property of IL system is, that the loaded

catalyst especially the ligand is no more separable from this liquid. In some cases, the

deactivated ruthenium may be separated from the ligand. This ligand in IL solution can

be reused in catalytic transformation by adding fresh Ru-precursor.

Our aspect during the project was to accomplish an industrially-suited process in which

the recycling of the ligand is profitable. The reduction in IL provides encouraging results

and facilitates the recovery of the ligand. As a disadvantage, these liquids are usually

purchased at a too high price (> 600 €/kg) for an industrial application.

To summarize, further asymmetric hydrogenations will be commonly conducted in

methylcyclohexane at 50 bar hydrogen pressure and at 110 ºC for 4 hours.

3.2.4 Investigation of σ-ability of Cl-MeO-Biphep (3)

To estimate the σ-donor ability of the phosphorous center of the Cl-MeO-Biphep (3),

phosphane-selenide (14) was prepared in situ from the corresponding diphosphanes

with elemental selenium in chloroform under reflux [108] (Scheme 3.3). An increase in this

coupling constant indicates a less basic phosphane. The σ-donor ability of a phosphane

group can be calculated by measuring of the magnitude of 1JP,Se in the 77Se isotopomer.

Scheme 3.3 Synthesis of diphosphane selenides

Se (powder)

CHCl

reflux, 5h

13 14

Results and Discussion

______________________________________________________________________________

Table 3.7 31P-77Se coupling constants of different ligands in compound 14 [108]

Entry Diphosphane Ligand 1JP,Se in 14 [Hz][a]

BINAP

Cl-MeO-Biphep

MeO-Biphep

Synphos

Segphos

PPh3

738

764

742

740

738

732

[a] recorded in CDCl3

The 31P-77Se coupling constant of Cl-MeO-Biphep (Table 3.7, Entry 2) is in good

agreement with the literature [108], which means that this ligand has lower σ-donor ability

than other chiral ligands e.g. MeO-Biphep, synphos or segphos. Due to this, ligand 3 is a

poor σ-donor but a very good π-acceptor. This electrodeficiency on the phosphorous

center is crucial in obtaining high levels of enantioselectivity. The measured 1JP,Se value

could explaine the observed low affinity to oxygen of ligand 3 under mild conditions,

which also verifies the low σ-donor ability of ligand 3.

3.2.5 Scale up reaction for asymmetric hydrogenation in the research laboratory of

Lanxess FC

The scale up of a well-working laboratory scale reaction can always cause problems.

The chemical reaction is fixed at any given temperature, but this parameter may be

influenced by mass and heat transfer. In addition, impurities of bulk materials,

separation, unit operation problems or material handling problems may also cause side

reactions, inhibition effects or decreasing of the yield.

During the cooperation with Lanxess FC, we had an opportunity to perform and verify

the documented reaction conditions (Subsection 3.2) in 2 liter scale in Leverkusen. As

we could observe the catalyst 10 remains active in two consecutive runs, while the ee

decreases significantly after the first catalytic cycle.

Results and Discussion

______________________________________________________________________________

Table 3.8 Hydrogenation results using methylcyclohexane as the solvent in 2 liter scale

Run Ligand Substrate pH2

[bar]

[ºC]

t [h] Conv.[a]

[%]

ee[b]

[%]

Product

3(R)

110

98.5

2(R)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured

by chiral GC (Lipodex-E column). S/C=100. The same catalyst residue of 10 was used in both runs.

Herein, we show that our reaction conditions are appropriate for the enantioselective

reactions (Table 3.8, Run 1) even in hundredfold scale. However, we observed a notable

drop in the ee (Table 3.8, Run 2) due to system impurities in the case of the more

difficult handling of complex 10 in larger scale and the possible lack of heat exchange.

3.2.6 Further improvement of asymmetric hydrogenation for the industrial applications

with the view of costs

Some parameters can considerably influence the costs of an industrial reaction. The

main cost-determining compounds are the precursor 9 and the ligand 3. This work

focuses on reducing the cost of the ligand via recycling, but the second main factor of

such a transformation is the consumed amount of the valuable precursor (~200 € / g). To

increase the profitability of the catalytic system in industrial application based on ligand 3

the ratio of substrate to catalyst, as well as the type of precursor 9 are varied. In this

subsection two possibilities will be presented to increase the efficiency of the catalyst 10

via the precursor system. On the one hand, the S/C ratio could be adjusted to 1000

(Table 3.9 Entry 1, 2) with the preservation of the activity and selectivity of the catalyst.

In this manner, the initial amount of precursor 9 will be decreased by achieving similar

results. The recycling of the ligand 3 will be simpler if the system contains less amount of

ruthenium. On the other hand, precursor 9 could be changed to the commonly used and

cheaper ruthenium (III) chloride hydrate (Table 3.9, Entry 3a, 3b).

Results and Discussion

______________________________________________________________________________

Table 3.9 Results of further investigations to reduce the cost of the industrial application

Entry Ligand Subst. Precursor S/C pH2

[bar]

[ºC]

[h]

Conv.[a]

[%]

ee[b]

[%]

Prod.

1[c]

2[c]

3a[c]

3b[c]

)

3(S)

RuCl3xH2O

1000

100

110

94.5

54.3

57.9

)

2(S)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured by chiral GC (Lipodex-E

column). [c] These are single reactions without attempt for recycling.

As a conclusion, the adjustment of the S/C ratio to 1000 (Table 3.9, Entry 1, 2) and the

use of a new precursor (Table 3.9, Entry 3a, 3b) did not have notable influence on the

conversion. It remains on a high level. The ee drops significantly in the first reaction

using less amount of precursor (Table 3.9, Entry 1, 2), indicating that RuCl3xH2O

auxiliary is at least as appropriate to create efficient and selective catalyst complex with

ligand 3 than precursor 9. The ee values are in good agreement with the hydrogenation

results in methylcyclohexane (Table 3.3, Run 1). However, these two reactions do not

show an authentic picture about the properties of the RuCl3xH2O precursor. Beside the

excellent conversions, better enanioselectivities may be achieved by more properly

selected conditions (p(H2), T, t).

3.3 Derivatization of Cl-MeO-Biphep ligand (3)

In respect to recycling, the using of IL was not convenient for an industrial process. The

further aim was to find a new concept for recovery of the ligand. The new scope of our

development was the derivatization of the applied ligand, which was known for other

chiral ligands years ago in the literature but was not used as a key step for the recycling

of metal-suited catalyst complexes.

Results and Discussion

______________________________________________________________________________

The derivatizations of ligand 3 to intermediates 3a - 3d (Figure 3.1) were performed in

order to yield beneficial intermediates to recycle the ligand 3 after the enantioselective

hydrogenation of ethyl acetoacetate (1).

The idea of oxide 3a was hit upon by examining the synthesis of the Cl-MeO-Biphep

ligand (3), because the last step is the reduction of the oxide of 3 (Scheme 2.8 E, F).

The sulfide 3b and the borane complex 3c of diphosphine ligand are mentioned in the

literature [109-111]. Our purpose with the last derivative 3d was to turn it into a water-

soluble compound and to recycle it by phase separation. From the view of recycling, the

complete transformation of Cl-MeO-Biphep ligand (3) into the corresponding derivatives

3a - 3d without formation of byproducts is a major requirement.

Here, we report promising derivatization procedures for 3a and 3b in quantitative yields

(Table 3.10). 3c was prepared with maximum 79 % of conversion. Unfortunately, we did

not have success to obtain the pure protonated form of 3d. 31P-NMR spectrum of 3d

shows mainly the significant peak of the Cl-MeO-Biphep ligand (3), thus the formation of

3d did not take place even by changing the conditions of the preparation.

Structure of derivatives 3a and 3b were also confirmed by mass spectrometry (EI).

Figure 3.1 Derivatives of ligand 3

MeO

PPh

MeO

3a 3b

xTHF

HCl

MeO

P(R)Ph2

P(R)Ph23a, R = O

3b, R = S

3c, R = BH3

3d, R = H+Cl-

Results and Discussion

______________________________________________________________________________

Table 3.10 31P-NMR data for diphosphine derivatives of 3

Entry Ligand

(reactant)

Diphosphane

derivative

31P-NMR[a]

δ / ppm

1JP-C

[Hz]

29.12

43.81

22.76

[a] recorded in CDCl3

To summarize, oxide 3a and sulfide 3b formed (Table 3.10, Entry 1, 2) from 3 have been

synthesized with excellent reliability and without formation of byproducts verified by two

satellite peaks (derived from P-C couplings) near the main peak in the 31P-NMR spectra

of 3a and 3b and by 2D-NMR spectra. Thus, the possibility of their use in the recycling

procedure was obvious.

Recycling reactions were also conducted with the sulfide derivative 3b, but the isolation

of this ligand derivative and the purification procedure were too difficult to apply routinely

in the recycling. Moreover during the reduction of 3b using LiAlH4 as reducing agent,

unfavorable H2S gas is formed. Most encouraging results have been achieved with

derivative 3a, therefore the attempt for recycling will be performed and optimized solely

via Cl-MeO-Biphep oxide derivative (3a) in the further investigations.

3.4 Optimization of the recycling procedure of Cl-MeO-Biphep ligand

via oxide derivative 3a and its scale up

3.4.1 Designing a separation and recycling cycle to demonstrate the steps of the

complete procedure

Results and Discussion

______________________________________________________________________________

Scheme 3.4 Separation and recycling cycle for phosphine ligands from the catalytic process

Results and Discussion

______________________________________________________________________________

This process cycle has been found to depict the complete recycling procedure. The

consecutive steps of the Scheme 3.4 are performed first with standard (not reacted

before) compound (e.g. ligand 3, complex 10) and afterwards with end-product 10 of the

enantioselective hydrogenation to reveal the validity and the limitation of the proposed

cycle (Scheme 3.4).

Firstly, oxidation and purification of the in situ formed complex 10 (Scheme 3.4, Step III-

IV) were executed to monitor the proposed recycling cycle and to estimate the quality

and yield of the recovered oxide 3a. When steps III-IV (Table 3.11, Entry 1) were

performed, 31P-NMR indicated that the P-O bond of Cl-MeO-Biphep ligand oxide (3a)

gave one single peak in the spectra (δ = 29.24 ppm). In this case, the conversion of

oxidation of the complex 10 is nearly 100 %.

Next results were achieved by conducting steps I-IV in the Lanxess FC laboratory

yielding 36.5 % of 3a (Table 3.11, Entry 2). The recorded 31P-NMR spectrum shows the

significant peak of derivative 3a at 29.27 ppm (Table 3.11, Entry 2) but this oxide

contains a notable amount of product 2 according to 1H-NMR spectrum because of the

uncomplete distillation of 2 in vacuo.

Additional reactions were carried out in which the first half of the recycling procedure

(Table 3.11, Entry 3, 4) has been tested resulting in 50.5 % of 3a (31P-NMR, δ = 29.04

ppm) after the step IV (Scheme 3.4). The same reaction was repeated by carrying out

one enantioselective hydrogenation resulting in 59 % oxide 3a. Outcomes and

conditions of reactions are collected in the next table (Table 3.11).

In the last run (Table 3.11, Run 6) less substrate was applied (S/C=10) decreasing the

significant contamination of the recovered ligand 3 by product 2. We could verify very

pure ligand oxide indicated by P-C coupling in the 31P-NMR spectra at δ = 28.85 ppm

(yield 63 %).

Results and Discussion

______________________________________________________________________________

Table 3.11 First results of recycling procedure

Entry

Steps

(Scheme 3.4)

Reactant

Sub.

Conv.[a]

[%]

ee[b]

[%]

Prod.

Recycled

derivative

[yield]

31P-

NMR[c]

δ / ppm

2[d]

3[e]

4[f]

5[g]

6[h]

III-IV

I-IV

10[h]

3(R)[i]+10[j]

3(S)[i]+10[j]

98.5

82.7

67.1

77.9

51.2

2(R)

2(S)

3a (- %)

3a (36.5 %)

3a (50.5 %)

3a (59 %)

3a (63 %)

29.24

29.27

29.04

29.79

28.85

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured by chiral GC (Lipodex-E

column). [c] recorded in CDCl3, significant peak of the oxide derivative 3a, [d] Reactions were conducted in the Lanxess FC

laboratory. [e] first run of asymmetric hydrogenation, [f] second run of asymmetric hydrogenation, S/C=100. The same catalyst

residue of 10 was used in both consecutive runs. Reaction conditions: p[H2] = 50 bar, T = 110 ºC, t = 4 hours, methylcyclohexane [g]

Typical hydrogenation was taken place. S/C=100. [h] Typical hydrogenation reaction was carried out. S/C=10. [i] reactant for the step

I (Scheme 3.4) [j] reactant for the step III (Scheme 3.4)

In summary, the oxide 3a has been isolated in its pure form (Table 3.11, 31P-NMR data)

in the recycling steps and more than half of its initial amount could be recovered via this

method. In all cases, there were no paramagnetic effects in the 31P-NMR spectra

because of the lack of Ru-derivative (RuO2). However, the purity of the recovered 3a is

still not sufficient because product 2 contaminates significantly the oxide derivative 3a.

Further work was accomplished in order to optimize steps I-IV of the cycle (Scheme 3.4).

3.4.2 Optimization of the reduction step using the standard oxide 3a

A well-known reduction procedure [112] of Cl-MeO-Biphep ligand (3) (Scheme 3.4, Step

V) exists already in the patented synthesis route of 3 applying HSiCl3 as reducing agent

(Scheme 2.8). This reduction was improved step by step to implement it with high

reliability using standard, purchased ligand 3 working out the last reaction step in our

proposed catalytic cycle (Scheme 3.4).

Results and Discussion

______________________________________________________________________________

The complete step V. (Scheme 3.4) took place in three consecutive reactions using the

same ligand 3 increasing the amount of reducing agent (0.3 ml, 1.3 ml, 2 ml) stepwise in

each run. As a result, we could work out the condition of the complete reduction

(followed by 1H-NMR and 31P-NMR) of purchased ligand 3 for the last synthesis step in

the recycling procedure. These optimized conditions were employed in the further work.

The most convenient way to follow the increase of the rate of the reduced ligand oxide

3a is to compare the 31P-NMR spectra after each step. Moreover, the 1H-NMR spectra

may give additional information.

Table 3.12 Results of the reduction process with standard ligand 3

Entry

Reactant[a]

Volume

of the added

reducer [mL]

Product(s)

31P-NMR[b]

δ / ppm

(oxidized)

31P-NMR[b]

δ / ppm

(reduced)

Conv. of

the reduction

[%]

0.3

1.3

3a+3

28.63

27.9

-15.53

-15.17

-15.07

[a] Always the very same reactant was used. [b] recorded in CDCl3

In the 31P-NMR spectra the peak of the reduced ligand is not always well-defined.

Probably, beside the completely reduced ligand side products (showing AB system in

the NMR spectra) can also be formed. Close to the significant peak of the ligand we can

observe coupled peaks (P-C and P-P), respectively. We assume that at the beginning

stage of the reaction the mono-oxide form of 3a can also be generated.

Reduction of newly synthesized Cl-MeO-Biphep oxide (3a) was carried out under these

conditions with complete transformation (99 %) and in a yield of 95 %. The next steps

VI-I (Scheme 3.4) were performed by application of auxiliary 3 to control the activity and

the selectivity of the reduced Cl-MeO-Biphep (3a) in the enantioselective hydrogenation

of ethyl acetocetate (1). However, the reduced ligand 3 contains little amounts of other

species (e.g. dimer or mono-oxide form of 3), but they did not have appreciable impact

on the activity of the catalyst 10, as summarized in Table 3.13. The ee decreased

slightly compared to the former results indicating impurities of ligand 3 in the system.

Results and Discussion

______________________________________________________________________________

Table 3.13 Result of hydrogenation using reduced ligand 3

Entry

Reaction steps

(Scheme 3.4)

Ligand

Substrate

pH2

[bar]

[ºC]

t [h] Conv.[a]

[%]

ee[b]

[%]

Product

1 V-VI-I 3(S) 1 50 110 4 99 71.1 2(S)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured by chiral GC (Lipodex-E

column). S/C=100.

3.4.3 Optimization of the recovery cycle

Thus, we have worked out a total reduction procedure of ligand 3a. Therefore our next

goal was to conduct the whole catalytic cycle using all steps of Scheme 3.4 and to

perform the hydrogenation reaction again with the recycled ligand 3.

The first aim was to determine the yield of the recovered ligand 3 and then a new

hydrogenation was performed using it to check the activity of the recycled Cl-MeO-

Biphep ligand (3) (Table 3.14). In this case, we could achieve excellent conversion

(99%). Afterwards, a more detailed description [13] combined with our former experiences

was employed to carry out the reduction step, which was routinely applicable and

resulted in a more pure ligand of 3 after the recycling.

Table 3.14 Recycling results using steps of Scheme 3.4 and conducting a new hydrogenation

with the recycled ligand 3

Entry

Reaction steps

(Scheme 3.4)

Reactant

31P-NMR[a]

δ / ppm of

recovered 3

Yield of

recovered 3

[%]

Conversion[b]

of the

hydrogenation

[%]

1[c] II-I 3(S) -15.17 49 99

[a] recorded in CDCl3 [b] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [c] Recycled ligand 3 was used for the

reaction. S/C=100.

As a result of all experiences, three complete recycling procedures were conducted to

determine the quality and to improve the yield of the recovered ligand 3. Initial amount of

Results and Discussion

______________________________________________________________________________

the ligand 3 was adjusted to 0.5 g with which the cycle was investigated on a larger

scale. The first problem of the scale-up reaction was caused by the non appropriate

solvent, dibutylether, in step IV (Scheme 3.4), which has a high boiling point (142 ºC).

Therefore, more than 40 % of pure oxide 3a was lost by the evaporation of this solvent

after the precipitation of RuO2. The other problems were the handling of the bigger

volumes and amounts of compounds and the avoiding the air-contact during each step

of the cycle, except for step III and IV (Scheme 3.4).

To investigate the quality and quantity of the recovered ligand 3 after the complete

recycling cycle, NMR, ICP-AES in order to determine the Ru conent and MS techniques

were applied.

All 31P-NMR spectra indicated mainly the peak of Cl-MeO-Biphep (3) (Table 3.15), as

well as complete reduction of the oxide derivative 3a without formation of byproducts.

These results were also easy to assign with the help of 1H-NMR spectra in which the

oxidation of ligand 3 could be well demonstrated.

After all recycling procedures, the ruthenium content remained in the same order of

magnitude verifying our good precipitation strategy for RuO2. Nevertheless, in the last

procedure (Table 3.15, Entry 3) the initial amount of Ru-precursor (RuCl3xH2O) was

tenfold more than in procedure 1 or 2 (Table 3.15). Percent of remainder ruthenium

amounts ranged from 0.8 % to 1.6 %.

In reaction 3 (Table 3.15, Entry 3), the S/C ratio was adjusted to 10 using ~ 5 g of ligand

3. Therefore the contamination of the product had less influence than in the previous

procedures, what is in good agreement with the NMR measurements. This fact indicates

that the main problem of the full recycling cycle is the uncomplete separation of the

product 2 by vacuum distillation (Scheme 3.4, step II). The highest yield (49 %) was

achieved in reaction 2 (Table 3.15, Entry 2), when almost the half of the initial amount of

ligand 3 was recovered in its pure solid form (31P-NMR, δ = -15.16 ppm). In all cases, the

structure of the recovered ligand 3 was confirmed by mass spectrometry (EI).

One of our initial goals was to recover more than 70 % of the applied ligand after the

reaction. This should be accomplishable by further optimizations, which will be described

in the next chapter.

Results and Discussion

______________________________________________________________________________

Table 3.15 Results conducting the complete recycling cycle

Entry

Reaction

steps

(Scheme 3.4)

Lig.

Subst.

Prod.

Conv.[a]

[%]

ee[b]

[%]

Total

Yield[c]

[%]

[Ru][d]

cont.

[mg/kg]

31P-

NMR[e]

δ / ppm

1[f]

2[g]

3[h]

I-V

3(S)

2(S)

87.1

73.4

92.6

28.3

1000

808

1865

-15.15

-15.16

-15.08

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured by chiral GC (Lipodex-E

column). [c] yield of the recycled ligand (3), [d] Ru content of the recycled ligands 3 were measured by ICP-AES. [e] 31P-NMR peak of

the recovered ligand 3, recorded in CDCl3, [f] ~0.5 g ligand was used. S/C=100. [g] ~0.5 g ligand was used. S/C=100. [h] ~5 g ligand

and RuCl3xH2O as precursor were used. S/C=10.

To summarize, we have found a recycling cycle (Scheme 3.4) with good performance to

recover the ligand in its solid form. The high quality of 3 was revealed using several

techniques to test the validity of our proposed cycle. However, further work is necessary

to increase the yield of the recycled ligand 3 giving rise to optimize this method as

industrially-suited process.

3.4.4 Modeling of the recycling procedure as an industrial process

Our last investigation focused on the imitation of a real industrial process in which one

recovery process of ligand 3 was taken place after 10 production steps (Scheme 1.1).

We collected all residues of 10 from the hydrogenation reactions. By this way, we could

assemble more detailed information about each consecutively conducted

enantioselective hydrogenation. Data are summarized in Table 3.16.

Results and Discussion

______________________________________________________________________________

Table 3.16 Results of 10 consecutive enantioselective hydrogenations

Run[a]

Reaction steps

(Scheme 3.4)

minit. compl.

[g]

Vsub

[ml]

mresidue after the

distillation step

(Scheme 3.4, II)

[g]

Vprod.

[ml]

Conv.[b]

[%]

ee[c]

[%]

Total

I-II

0.076

0.072

0.073

0.075

0.074

0.077

0.743

0.068

0.077

0.094

0.079

0.081

0.068

0.053

0.096

0.117

0.106

0.839

0.7

0.69

0.6

0.76

0.91

0.74

0.63

0.53

0.73

0.85

7.14

89.5

97.5

97.8

63.7

59.1

56.6

58.3

58.9

57.7

57.2

59.2

[a] Typical hydrogenation was conducted. S/C=100. [b] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [c]

Enantiomeric excesses were measured by chiral GC (Lipodex-E column).

In conclusion, 10 consecutive hydrogenations were carried out in which 71.4 vol. % of

the total products 2 could be distilled. The average conversion was 97.8 % (very high

level) and the total ee was 59.2 % (Table 3.16, last row, and Table 3.17, Entry 1).

As it can reveal, the combined residues of 10 were slightly contaminated by product 2 in

spite of the precise vacuum distillation.

The complete recycling procedure (Scheme 3.4) was performed with the collected

residues of 10, which yielded 38 % recovered ligand 3 in its pure form (verified by 31P-

NMR). Furthermore, the recovered Cl-MeO-Biphep ligand (3) occurred as active catalyst

(Table 3.17, Entry 2) compared to the purchased 3 (Table 3.17, Entry 1). 1H-NMR

spectrum shows little amount of impurities from the product 2, but it has no influence in

Results and Discussion

______________________________________________________________________________

respect to the further application of the ligand (Table 3.17, Entry 2). The ee value

indicates a similar tendency in concern to the enantioselectivity.

Table 3.17 Result of recovery process using the collected residue from the 10 hydrogenation

reactions

Entry[a]

Reaction

steps

(Scheme 3.4)

Lig.

Subst.

Conv.[b]

[%]

ee[c]

[%]

Prod.

Total

Yield[d]

[%]

[Ru][e]

cont.

[mg/kg]

31P-

NMR[f]

δ / ppm

2[g]

I-V

3(S)

97.8

59.2

56.9

2(S)

446

-15.15

[a] Conducting typical hydrogenation with S/C=100. [b] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [c]

Enantiomeric excesses were measured by chiral GC (Lipodex-E column). [d] yield of the recycled ligand 3, [e] Ru content of recycled

ligands 3 were measured by ICP-AES. [f] 31P-NMR peak of the recovered ligand 3, recorded in CDCl3, [g] Hydrogenation reaction

was carried out with the recycled ligand 3.

Although, in this case the value of the ruthenium content was the lowest (446 mg/kg,

remaining 0.4 % of the initial Ru content in the ligand) applying the complete recycling

cycle. The yield of the ligand 3 was on an average level compared to the outcomes of

Table 3.15 after the asymmetric hydrogenations.

3.5 Results of Buchwald-Hartwig amination and the recycling process

applying Dave-Phos and X-Phos ligands

Scheme 1.2 General Buchwald-Hartwig amination reaction

[Pd], base

100

C, 12h

toulene

456

Br NH

Results and Discussion

______________________________________________________________________________

At the beginning of this part of the project, we have already collected a lot of

experiences about the recycling of Cl-MeO-Biphep ligand (3), for this reason the major

attempt was to use the same recycling cycle (Scheme 3.4) for the two Buchwald ligands,

too.

Our standard amination reaction is depicted in the Scheme 1.2. The nature and

conditions of C-C coupling reactions differ from the enantioselective hydrogenation, but

the applied ligands, named as Dave-Phos (7) and X-Phos (8) denote a number of

similarities. These reactions work under mild conditions and do not require gas pressure.

Therefore, formation of stable intermediates, which can hamper the recycling, is more

seldom than in the asymmetric hydrogenation (confirmed by 31P-NMR spectra). These

transformations need special Pd-precursor and appropriately selected base as well as

inert atmosphere to achieve complete transformation. Directly after the reaction, the

separation of the product 6 causes the main problem to obtain pure ligand. Afterwards,

the separation of the ligand 7 and 8 from Pd-precursor occurs by precipitation and

continues via their derivatization. The Scheme 3.4 describes the general route for

recycling, which was employed for the recovery of the Buchwald´s ligands either. Degree

work has been presented from this part of the dissertation [113].

First of all, the C-C transformations were carried out with both ligands 7 and 8 to gain

the first outcomes about the ligand activity. The factor enantioselectivity has no role in

the Buchwald-Hartwig amination because of the lack of the chirality in the product 6 and

the ligands as well. Thus, the efficiency of the reaction is demonstrated by measuring

the conversion of the product 6. The first reactions were conducted by properly adjusted

conditions in a 250 mL scale, which were performed in the Lanxess FC laboratory (Table

3.18, Entry 1, 2). The same reactions were conducted in our laboratory in a 30 mL scale

(Table 3.18, Entry 3). Other base NaOtBu was selected in order to avoid the increase of

accessory phosphorous content, which could have disturbed the especially versatile 31P-

NMR measurements after the amination. Under these conditions, complete conversions

were achieved with Dave-Phos ligand (7) after 2 hours as detected by GC (Sil-Pona

column).

As it can be seen in Table 3.18, the coupling reactions gave acceptable results, thus the

additional investigations were to characterize the derivatives of ligands 7 and 8,

Results and Discussion

______________________________________________________________________________

particularly their oxide and sulfide forms. Afterwards, steps of the cycle (Scheme 3.4)

were performed to bring the oxidation and reduction of ligands 7, 8 to perfection.

Table 3.18 Results of Buchwald-Hartwig aminations

Entry

Ligand

Substrate

Precursor

Base

[ºC]

[h]

Conv.

[%]

Product

Scale

(mL)

4+5

Pd2dba3

K3PO4

NaOtBu

100

72[a]

78.5[a]

99[b]

250

[a] Conversions were determined by GC-MS in the Lanxess FC laboratory (Method: GC2_0341_01). [b] Conversions were measured

by GC (Sil-Pona column, 50 m).

The methods mentioned in chapter 3.3 were applied to prepare and to characterize the

derivatives of ligands Dave-Phos (7) and X-Phos (8). Because of the encouraging

results of Cl-MeO-Biphep oxide (3a) and sulfide (3b) derivatives, we have synthesized

solely these two forms of Dave-Phos (7) and X-Phos (8) ligands. Preparation of 7a, 7b,

8a, 8b (Figure 3.2) were taken place by the same procedures, which were used for the

formation of Cl-MeO-Biphep derivatives 3a and 3b.

Figure 3.2 Derivatives of ligand 7 and 8

P(R)Cy

N7a, R = O

7b, R = S

P(R)Cy

8a, R = O

8b, R = S

Results and Discussion

______________________________________________________________________________

Table 3.19 31P-NMR data for phosphane derivatives of 7 and 8

Entry

Ligand

(reactant)

31P-NMR[a]

δ / ppm

(standard)

Phosphane

Derivative

31P-NMR[a]

δ / ppm

(reacted)

1JP-C

[Hz]

-9.47

-11.96

49.82

69.68

44.24

59.58

65.2

49.5

64.8

[a] recorded in CDCl3

The derivatization of ligands 7 and 8 were carried out with complete conversions and in

quantitative yields for all four cases. The recorded 31P-NMR spectra showed the P-C

coupling for three of the derivatives (7a, 7b, 8a) indicating very pure forms.

In addition, 7a, 7b, 8a, 8b were isolated in high yield, but our further studies focused

especially on the oxides of Dave-Phos (7a) and X-Phos ligands (8a).

The complete reduction of two substances 7a, 8a was obvious requirement using as key

step in the recycling process. Unfortunately, the complete reduction of standard 7a and

8a could not be realized in good conversion, because more than 15 % of X-Phos oxide

(8a) and 17 % of Dave-Phos oxide (7a) were not reduced under the same conditions,

which were applied for the complete transformation of Cl-MeO-Bihep oxide (3a).

However, the purification of the completely reduced forms of 7a and 8a could be carried

out by column chromatography, but this method is not very attractive for an industrially-

suited application because of the relative high costs.

The following step was the work-up of the reaction mixture in which after the separation

of the base (NaOtBu) with water. a new problem arose, namely the isolation and

purification of 7 and 8.

The product 6 is solid (mp = 53 – 55 ºC), therefore the vacuum distillation (200 ºC, 14

mbar) was proven to be the best solution to separate diphenylamine (6) from the ligand

7 and 8. By this method 71 - 77 % of 6 could be separated. A remarkable tendency

observed when the scale up of amination reaction (Scheme 1.2) was performed. Even

more 6 could be distilled from the reaction mixture up to 84 %, although complete

Results and Discussion

______________________________________________________________________________

separation of 6 could not be achieved. Unfortunately, Dave-Phos ligand (7) has less

thermal stability (lower melting point) under vacuum distillation (verified by NMR

measurements), that is why the separation of that ligand (7) is not possible by this way.

The column chromatography can also overcome the separation problem of the product

6, but it is not very profitable.

For the separation of ligand 7 and 8 another idea emerged, namely the protonation of

the ligand after the C-C coupling. These ligands (7, 8) should become water-soluble and

easily separable by phase separation. This method was also tested, but we did not have

notable results for application in the recycling, because of the formation of byproducts.

In summary, the vacuum distillation of 6 was applied exclusively and successfully for the

amination with ligand 8 before the recycling method. The results of reduction of 8

provided also more encouraging outcomes than using the same method for ligand 7.

As a last step, the recycling steps I-IV (Scheme 3.4) were implemented using X-Phos

ligand (8) in order to evaluate the yields and the reliability of the proposed cycle after the

Buchwald-Hartwig amination. In the next table (Table 3.20) some outcomes of the

recycling procedure are collected.

Table 3.20 Results of the recycling procedure applying X-Phos ligand (8)

Entry

Reaction

steps

(Scheme 3.4)

Lig.

Subst.

Distilled

Product

[%]

Conv.[a]

[%]

Yield of

recovered

ligand

[%]

31P-

NMR[a]

δ / ppm

(8a)

1[c]

2[d]

I-IV

4+5

6 (70 %)

6 (84 %)

8a (70 %)

8a (72 %)

44.52

45.19

[a] Conversions of the aminations were determined by GC (Sil-Pona column), [b] recorded in CDCl3, [c] Amination was conducted in

threefold scale with X-Phos ligand (8). [d] Amination was carried out in fivefold scale with X-Phos ligand (8) and purified by column

chromatography.

To conclude, on the one hand the amination reaction with X-Phos ligand (8) resulted in a

high yield (72 %) pure oxide of 8a without formation of byproducts after the recycling

steps I-IV (Scheme 3.4). Our proposed aim was achieved, i.e. the pure oxide (8) was

Results and Discussion

______________________________________________________________________________

isolated what was confirmed by NMR techniques. Actually, further steps are needed to

obtain the pure ligand 8 after the reduction. On the other hand, the recycling procedure

did not succeed using Dave-Phos (7) because of its lower thermal stability and

cumbersome reduction.

We suppose that the reduction procedure with X-Phos ligand (8) can be conducted in an

effective way, however additional experiments i.e. improvement of all steps of Scheme

3.4 are required.

Summary and Outlooks

______________________________________________________________________________

4 Summary and Outlook

4.1 Summary

In this work, the main emphasis was placed on the reuse and recovery of the applied

organic ligands 3, 7, 8 from homogeneously catalyzed processes.

As a standard test reaction, the enantioselective hydrogenation of ethyl acetoacetate (1)

was applied to investigate Cl-MeO-Biphep ligand (3).

Scheme 4.1 Asymmetric hydrogenation of β-ketoester

The first concept was the reuse of the same catalyst residue in consecutive runs. This

idea can be implemented simply in ionic liquid, which gives rise to apply the same

complex in more consecutive cycles preserving the catalyst on high activity even after

four or six runs in the enantioselective hydrogenation. Using IL as a medium for the

enantioselective hydrogenation with the same catalyst (10) provides a very simple and

OEt

O O

OEt

OH O

[Ru], H

(50 bar)

110

C, 4 h

methylcyclohexane

PCy2

NMe2

PCy2

MeO

PPh2

Summary and Outlooks

______________________________________________________________________________

effective manner to reduce the costs of the processes via reusing the same complex

(Table 4.1, Entry 3). Unfortunately, nowadays this reaction medium is purchased at a

high price. Mixtures of IL and EtOH (1:1) (Table 4.1, Entry 4), cyclohexane and

methylcyclohexane (Table 4.1, Entry 1, 2) were also tested as media for the standard

reduction of β-ketoester applying the same catalyst residue [RuBr2(Cl-MeO-Biphep)] (10)

at least in four runs with high conversions, i.e. without loss of catalytic activity. In the

Table 4.1 some outcomes of the first run are collected applying different solvents for the

reuse of the complex 10 and presenting the improvement of the enantioselectivity.

As shown, the enantiomeric excesses increased significantly up to 96.2 % indicating

less impurities in the system when IL or a mixture of IL/EtOH was provided the medium

for the reaction. The formation of byproducts was also diminished applying this medium.

These observations were verified by NMR measurements.

As a conclusion, the same catalyst 10 could be applied in more consecutive cycles

presenting similar tendency in concern to the conversions and to the ee values. The

application of the reaction in a bigger scale was also successful with constant

conversion and ee, which indicates that this catalytic system could be useful in process

development, too.

Table 4.1 Hydrogenation results in different media after the first run and changing main

parameters

Entry Ligand solvent Substrate pH2

[bar]

[ºC]

t [h] Conv.[a]

[%]

ee[b]

[%]

Product

1[c]

2[c]

3[c]

4[c]

5[d]

6[e]

7[f]

3(R)

cyclohexane

methylcyclohexane

IL/EtOH

methylcyclohexane

110

98.5

94.5

93.5

96.2

54.3

2(R)

[a] Conversions were determined by 1H-NMR (200 MHz, CDCl3). [b] Enantiomeric excesses were measured by chiral GC (Lipodex-E

column). [c] Hydrogenation was carried out in a 20 mL scale. S/C=100. [d] Hydrogenation was carried out in a 2000 mL scale.

S/C=100. [e] Hydrogenation was carried out with S/C=1000 in a 20 mL scale. [f] Hydrogenation was conducted with precursor

RuCl3xH2O in a 20 mL scale.

Summary and Outlooks

______________________________________________________________________________

Other supplementary investigations have also been performed in order to reduce the

cost of the complete process, namely the changing of the S/C ratio to 1000 using less

amount of precursor (Table 4.1, Entry 6) or the use of simple RuCl3xH2O auxiliary

instead of [bis-(2-methylallyl-cycloocta-1,5-diene) ruthenium(II)] complex (9) (Table 4.1,

Entry 7). The results were in good agreement and comparable with the outcomes of the

first hydrogenation runs when the appropriate selected conditions were used.

Apart from these results, our major challenge was to figure out a recovery route

consisting of easy, fast and reliable steps in a bigger scale with which the applied

organic ligand can be recycled in pure solid form after the catalytic transformation.

Derivatization to the oxide 3a and sulfide 3b of Cl-MeO-Biphep ligand (3) was

investigated and synthesized in quantitative yield in order to prepare pure intermediates

without formation of byproducts.

Scheme 4.2 Preparation of ligand oxide 3a (key step in the recycling cycle)

Among the characterized derivatives, oxide form 3a of ligand 3 proven to be the best

intermediate. Later on, 3a was applied in the recycling procedure (Scheme 3.4)

successfully. It was possible to recover up to 78.1 % of ligand oxide 3a (Table 3.15,

Entry 3) and up to 49 % of ligand 3 (Table 3.15, Entry 2) after the reduction step

(Scheme 3.4, Step V). Naturally, further optimizations are needed to achieve nearly 70

% yield for the recovered pure ligand 3 and to develop this process as a profitable

industrial application. The appropriate quality of the recycled Cl-MeO-Biphep (3) was

confirmed by NMR, MS and ICP-AES teqhniques. The activity and selectivity of the

recovered ligand 3 is in good agreement with the purchased Cl-MeO-Biphep ligand (3)

(Table 3.17).

MeO

PPh

C, 6h

MeO

P(O)Ph

33a

Summary and Outlooks

______________________________________________________________________________

The model reactions of 10 consecutive hydrogenations were also carried out to collect

outcomes about the total conversion (97.8 %) and enantiomeric excess (59.2 %).

The other investigated reaction is the Buchwald-Hartwig amination between

bromobenzene (4) and aniline (5) was also tested using Dave-Phos (7) and X-Phos (8)

ligands.

Scheme 4.3 General Buchwald-Hartwig amination reaction

Optimization of the reaction was also carried out by changing the applied base by which

99 % conversion was reached in a 30 mL scale.

Table 4.2 Base vs. conversion in the amination reaction

Entry

Ligand

Base

Conv. of 6

[%]

K3PO4

NaOtBu

72[a]

78.5[a]

99[b]

[a] Conversions were determined by GC-MS in the Lanxess FC laboratory (Method: GC2_0341_01).

[b] Conversions were measured by GC (Sil-Pona column, 50 m).

The developed recycling routes were extended and optimized for the two biaryl

phosphine Buchwald-Hartwig ligands. The preparation of oxide forms 7a, 8a and sulfide

forms 7b, 8b was completed in quantitative yields. All these derivatives were also

completely characterized.

[Pd], base

100

C, 12h

toulene

456

Br NH

Summary and Outlooks

______________________________________________________________________________

Scheme 4.4 Preparation of ligand oxide 8a (key step in the recycling cycle)

Unfortunately, Dave-Phos ligand (7) has lower thermal stability. Therefore, the

separation of product 6 did not succeed by vacuum distillation without decomposition of

the ligand 7.

Up to 72 % of X-Phos oxide derivative (8a) was recovered in the recycling procedure,

although further steps are required to estimate the quality and quantity of the recycled

ligand 8.

To conclude, the recovery procedure is applicable for the X-Phos ligand (8), too.

Completing all steps of the recovery cycle (Scheme 3.4), same results may be achieved

using ligand 8, compared to Cl-MeO-Biphep (3).

Separation of both product 2 and 6 is a key step to recycle pure and even more active

ligand for new catalytic reactions.

4.2 Outlook

The scaling up in various size plants can lead to variations in yielded products. The first

authentic process optimization can be performed in a 500 kg scale, therefore the

developed recycling procedure should be tested in 1 kg, 5 kg and 100 kg scale before.

The yields of recycled ligand oxides (3a, 8a) increased significantly ranging from 50.5 %

to 78.1 %. These results can indicate that the performance of the developed process

may be more efficient in larger scale.

H2O2

OoC, 6h

PCy2P(O)Cy2

88a

Summary and Outlooks

______________________________________________________________________________

The results of the hydrogenation reactions in cyclohexane and methylcyclohexane give

rise to consider maybe there is only the need of a little part of the used catalyst complex

10. In this case, there is a possibility to decrease the precursor/ligand mol ratio.

Replacement of [bis-(2-methylallyl-cycloocta-1,5-diene) ruthenium(II)] (9) by RuCl3xH2O

precursor could also be profitable in production scale.

Because of the formation of hydride complexes in the hydrogenation reaction, the

influence of the hydrogen gas pressure should be optimized further.

The last step in the recycling cycle, namely the reduction should also be carried out and

optimized for X-Phos ligand (8).

Experimental Part

______________________________________________________________________________

5 Experimental Part

5.1 General Technique

All reactions were carried out under argon atmosphere and all equipments e.g. flasks,

Schlenk-tubes, polyethylene syringes, V2A-stainless steel needles were evacuated and

flushed three times with inert gas before the utilization. All solvents were dried, distillated

and stored under argon. During the reactions and workup, the addition and the removal

of reactive agents and solvents were taken place under inert gas counter flow.

All chemicals and solvents were purchased from general fine chemicals manufacturers,

(Aldrich, Merck, Fluka or Strem). The argon purity was signed with 4.8, as well as the

hydrogen gas with 5.0. Both of them were employed without any further purification.

All catalytic hydrogenations were carried out in a 125 mL stainless steel autoclave,

which was evacuated and flushed three times with argon gas. The temperature was

regulated by oil bath and the autoclave was equipped with external stirrer and

manometer.

The temperature was always regulated by water or oil bath.

NMR: The spectra were measured using BRUKER ARX 200, AMX 300, ARX 500. All

spectra were recorded at room temperature. The chemical shift values of 1H-NMR and

13C-NMR spectra are given in ppm relative to SiMe4. 31P-NMR spectra were measured

relative to external 85 % H3PO4 standard. The resonance multiplicity is described as s

(singlet), d (doublet), t (triplet), q (quartet), m (multiplet). Broad resonances are indicated

broad (br).

Mass Spectrometry: Fision MD 800. Relative intensity is related to basis peak.

IR Spectra: Nicolet FT-IR 510 p. The spectra were measured as KBr pellets or as thin

films of neat compound. The absorptions are given in wave numbers (cm-1). Origin 6.0

software was used to create the spectra.

Experimental Part

______________________________________________________________________________

ICP-AES: Spektroflame D, Ar plasma, 1150 W, (267.876 nm, 240.272 nm)

GC: The enantiomer excess (ee) of the standard asymmetric hydrogenation reaction

(Scheme 1.1) was determined by Chrompack (Varian) CP9002.

Column: 25 m Lipodex-E

Temperature: Column 100 ºC isotherm

Injection temperature: 260 ºC

Detector temperature: 300 ºC (FID)

Hold Time: 20 min

Mobile phase: Helium (0.6 bar)

t of ((R)-2)-enantiomer: 9.66 min

t of ((S)-2)-enantiomer: 10.51 min

The conversions of the Buchwald-Hartwig amination (Scheme 1.2) were followed after

each 30 min by gas chromatography.

Column: 50 m Sil-Pona

Initial temperature: 80 ºC

End temperature: 250 ºC

Injection temperature: 250 ºC

Detector temperature: 300 ºC (FID)

Heat of rate: 8 ºC /min

Mobile phase: Helium (0.6 bar)

Rt of bromobenzene (4): 17.85 min

t of aniline (5): 18.43 min

t of diphenylamine (6): 13.87 min

Experimental Part

______________________________________________________________________________

5.2 Characterisation and use of ligand 3 in asymmetric hydrogenation

5.2.1 Characterisation of (R/S)-5,5`-dichloro-6,6`-di-methoxy-2,2`-bis (diphenyl-

phosphino)-1,1`-biphenyl) Cl-MeO-Biphep (3)

mp = 177 - 179 ºC

1H-NMR (500 MHz, CDCl3): δ = 3.21 (s, 6H, OCH3), 6.99 (d, J = 8.2 Hz, 2H, ArH), 7.22 –

7.28 (m, 10H, ArH), 7.29 – 7.35 (m, 10H, ArH), 7.37 – 7.39 (d, J = 8.2 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.1 (2C, OCH3), 128.0 – 138.4 (34C, ArC), 154.4 (2C,

ArC-OCH3)

31P-NMR (121 MHz, CDCl3): δ = -14.92 (2P,PPh2)

M/z (calculated) = 651.5

MS (EI / 200 ºC, 70 eV, R=1000): M/z (%) = 651.1 [M+] (1), 573.2, 527.1, 465.2, 433.1,

386.1, 325.1, 264.1, 238.2, 183.0, 174.1, 108.0, 77.1, 31.1

IR (KBr):

[cm-1] = 3048, 2996, 2940, 1953, 1895, 1812, 1772, 1635, 1583, 1560,

1448, 1423, 1359, 1236, 1130, 1056, 1016, 869, 815, 742, 501, 433

5.2.2 Preparation of catalyst 10

(R)-Cl-MeO-Biphep (3) (22.8 mg, 0.033 mmol) and [(1,5-COD)Ru(2-methylallyl)2] (9) (9.6

mg, 0.03 mmol) were placed in a 25-mL flask and degassed. Anhydrous acetone (3 mL)

was added dropwise afterwards HBr (7.2 µL, 48 %) was slowly introduced to the

MeO

PPh

Experimental Part

______________________________________________________________________________

suspension and the mixture was stirred for about 30 min at room temperature whilst

brown solution formed, which was evaporated under vacuum. The brown solid residue

(9.5 mg, 0.01 mmol) was used without any purification as a catalyst for the

hydrogenation reaction of the desired substrate.

1H-NMR (500 MHz, CDCl3): δ = 3.26 (s, 6H, OCH3), 7.03 (d, J = 8.2 Hz, 2H, ArH), 7.22 –

7.28 (m, 10H, ArH), 7.32 – 7.36 (m, 10H, ArH), 7.41 (d, J = 8.2 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.2 (2C, OCH3), 128.4 – 134.7 (34C, ArC), 154.5 (2C,

ArC-OCH3)

31P-NMR (121 MHz, CDCl3): δ = -14.91 (2P,PPh2)

5.2.3 Preparation of catalyst 12

(R)-BINAP (11) (20.5 mg, 0.033 mmol) and [(1,5-COD)Ru(2-methylallyl)2] (9) (9.6 mg,

0.03 mmol) were placed in a 25 mL flask and degassed. Anhydrous acetone (3 mL) was

added dropwise. HBr (7.2 µL, 48 %) was slowly introduced to the suspension and the

mixture was stirred for about 30 min at room temperature whilst a brown solution formed.

The solvent was removed under reduced atmosphere. The brown solid residue (0.01

mmol, 8.8 mg) was used without any purification as a catalyst for the hydrogenation

reaction of the desired substrate.

31P-NMR (121 MHz, CDCl3): δ= -11.32 (2P,PPh2)

5.2.4 General procedure for enantioselective hydrogenation of β-ketoester

The corresponding catalyst complex 10 or 12 was applied for the hydrogenation of 1 in

the selected solvent. The solution was placed in a 125 mL stainless steel autoclave,

which was adjusted at hydrogen pressure and heated to 110 ºC for 24 or 4 hours. The

substrate to catalyst ratio could be adjusted from 10 to 1000.

Experimental Part

______________________________________________________________________________

5.2.5 Recycling of 10 in cyclohexane (Table 3.2)

(R)-[(Cl-MeO-Biphep)-RuBr2] (10) (36.5 mg, 0.04 mmol) was used without any

purification as a catalyst for the hydrogenation reaction of the desired substrate (4 mmol)

in cyclohexane (10 mL). The solution was placed in a 125 mL stainless steel autoclave,

which was adjusted at 50 bar hydrogen pressure and heated to 110 ºC for 4 hours. The

substrate to catalyst ratio was 100. The product 2 was distilled off under reduced

atmosphere at 148 – 150 ºC.

Conversion = 99 %, ee = 53 %

The same catalyst residue 10 was reused in every runs. Fresh substrate 1 was added to

to 10 and the hydrogenation was repeated four times under these conditions. Solvents

were removed under reduced atmosphere after each run.

Spectrum of the used complex 10 after the last run:

31P-NMR (121 MHz, CDCl3): δ = 27.25 (2P,P(O)Ph2), 29.41 (2P,P(O)Ph2), 41.67

(hydride complex of 10)

5.2.6 Recycling of 10 in methylcyclohexane (Table 3.3)

All reactions were performed similarly to the procedure “e” but methylcyclohexane

(10mL) was used as solvent instead. S/C=100. After the hydrogenation the product 2

was distilled off in vacuo.

Conversion = 99 %, ee = 64 %

The same catalyst residue 10 was reused in every runs. Fresh substrate 1 was added to

10 and the hydrogenation was repeated six times under these conditions. Solvents were

removed under reduced atmosphere after each run.

Spectrum of the used complex 10 after the last run:

31P-NMR (121 MHz, CDCl3): δ = 27.78 (2P,P(O)Ph2), 30.01 (2P,P(O)Ph2), 37.4, 58.35

(hydride complex of 10)

Experimental Part

______________________________________________________________________________

5.2.7 Recycling of 10 in propylene carbonate

[(Cl-MeO-Biphep)-RuBr2] (10) (36.5 mg, 0.04 mmol) was used without any purification as

a catalyst for the hydrogenation reaction of the desired substrate 1 (4 mmol) in

propylene carbonate (16 mL). The solution was placed in a 125 mL stainless steel

autoclave, which was adjusted at 50 bar hydrogen pressure and heated to 110 ºC for 4

hours. The substrate to catalyst ratio was 100. The product 2 was separated by vacuum

distillation but it was not confirmed by 1H-NMR.

Spectrum of the used complex 10 after the reaction:

31P-NMR (121 MHz, CDCl3) δ = 26.73 (2P,P(O)Ph2), 29.01 (2P,P(O)Ph2), 43.62, 59.06,

65.96 (hydride complex of 10)

5.2.8 Recycling of 10 in IL (BMIM+BTA-) medium (Table 3.4, 3.5)

(R)-[(Cl-MeO-Biphep)-RuBr2] (10) (36.5 mg, 0.04 mmol) was used without any

purification as a catalyst for the hydrogenation reaction of the desired substrate 1

(4mmol) in butyl-methyl-imidazolium-bis-triflylamide (8 mL). The solution was placed in a

125 mL stainless steel autoclave, which was adjusted at 50 bar hydrogen pressure and

heated to 110 ºC for 4 hours. The substrate to catalyst ratio was 100. The product 2 was

isolated either by extraction with n-hexane (30 mL) (first recovery test) or vacuum

distillation at 145 – 147 ºC (second recovery test) after every run.

Conversion = 99 %, ee = 93.5 %

The same catalyst 10 and IL were reused in every runs. Fresh substrate 1 was added to

the resulting IL and the hydrogenation was repeated five and four times under these

conditions.

Spectrum of the used complex 10 after the last run:

31P-NMR (121 MHz, CDCl3): δ = -15.18 (2P,PPh2), 56.93, 57.63 (hydride complex of 10)

Experimental Part

______________________________________________________________________________

5.2.9 Recycling of 10 in IL (BMIM+BTA-)/EtOH (1:1) medium (Table 3.6)

[(Cl-MeO-Biphep)-RuBr2] (10) (36.5 mg, 0.04 mmol) was used without any purification as

a catalyst for the hydrogenation reaction of the desired substrate 1 (4 mmol) in ionic

liquid (4 mL) and ethanol (4 mL). The solution was placed in a 125 mL stainless steel

autoclave, which was adjusted at 50 bar hydrogen pressure and heated to 110 ºC for 4

hours. S/C=100.

The separation of 2 was performed either by extraction or by distillation.

Conversion = 98.5 %, ee = 96.2 %

a, The IL/EtOH phase was extracted with n-hexane (30 mL) and after the phase

separation the solvents were evaporated.

b, Ethanol and product 2 were separated at 145 – 147 ºC by vacuum distillation and the

solvent was removed afterwards under reduced atmosphere.

Fresh ethanol and substrate 1 were added to the resulting IL, the hydrogenation was

repeated four times under these conditions.

5.2.10 Preparation of diphosphane selenide derivative (14)

The (R)-[(Cl-MeO-Biphep)-RuBr2] (10) ligand (119 mg, 0.12 mmol) was added to an

excess of selenium (239 mg, 3.03 mmol) and suspended in toluene (7 mL), which was

refluxed during 12 hours at 80 ºC. After that, the solution was cooled down and filtered

by syringe filter and ca. 0.4 mL was placed in a NMR tube. It was analysed in 0.1 mL

C6H6 by 31P-NMR.

MeO

P(Se)Ph

Experimental Part

______________________________________________________________________________

31P-NMR (121 MHz, C6H6): δ = 32.25 (2P,P(Se)Ph2), 1JP-Se = 381.5 Hz), 35.39 (2P,

P(Se)Ph2), 38.53 (2P,PPh2, 1JP-Se = 381.5 Hz)

5.2.11 Scale up reaction for enantioselective hydrogenation of 1 (Table 3.8)

[(Cl-MeO-Biphep)-RuBr2] (10) (8.76 g, 9.6 mmol) was used as a catalyst for the

hydrogenation of the desired substrate (1) (125 mL, 0.96 mol) in methylcyclohexane

(1800 mL). The solution was placed in a stainless steel autoclave, which was adjusted to

50 bar hydrogen pressure and heated to 110 ºC for 12 hours. S/C=100. After the

reaction the product 2 was distilled off at 145 – 147 ºC in vacuo.

Conversion = 98.5 %, ee = 86 %

The same catalyst 10 was applied in both consecutive runs. Fresh substrate 1 was

added to the catalyst residue 10 and the hydrogenation was repeated once again under

these conditions.

Spectra of the used complex 10 after the first run:

1H-NMR (400 MHz, CDCl3): δ = 3.18 (s, 6H, OCH3), 6.92 (d, J = 8.2 Hz, 2H, ArH), 7.15 –

7.20 (m, 10H, ArH), 7.22 – 7.31 (m, 10H, ArH), 7.33 (d, J = 8.2 Hz, 2H, ArH)

31P-NMR (121 MHz, CDCl3): δ = - 15.02 (2P,PPh2), 28.86 (2P,P(O)Ph2)

5.2.12 Supplementary hydrogenation reaction adjusting the S/C ratio to 1000

(Table 3.9, Entry 1, 2)

2.2 mg (0.007 mmol) precursor 9 and 5.5 mg (0.008 mmol) Cl-MeO-Biphep (3) were

stirred in 6 mL acetone with one drop HBr (48 %) to prepare 7.3 mg (0.008 mmol) [(Cl-

MeO-Biphep)-RuBr2] catalyst (10).

After the evaporation of solvent, the complex 10 was reacted with 1 mL (8 mmol) ethyl

acetoacetate (1) as substrate using 50 bar hydrogen pressure at 110 ºC for 4 hours in

methycyclohexane in a 125 mL stainless steel autoclave. The product 2 was distilled off

at 145 – 147 ºC in vacuo.

Experimental Part

______________________________________________________________________________

Conversion = 94.5 %, ee = 54.3 %

Spectrum of the used complex 10 after the reaction:

31P-NMR (121 MHz, CDCl3): δ = - 15.46 (2P, PPh2)

5.2.13 Supplementary hydrogenation changing the precursor to RuCl3xH2O (Table

3.9, Entry 3, 4)

7.3 mg (0.08 mmol) [(Cl-MeO-Biphep)-RuBr2] catalyst (10) was prepared from 15 mg

(0.08 mmol) RuCl3xH2O precursor, 50 mg (0.076 mmol) 3 and 14,2 μL HBr (48 %) in

acetone (6 mL). This mixture was stirred for 1 hour and after the solvent was

evaporated.

The prepared 10 was added to 1 mL (8 mmol) ethyl acetoacetate (1) as substrate using

50 bar hydrogen pressure at 110 ºC for 4 hours in methycyclohexane in a 125 mL

stainless steel autoclave. The product 2 was distilled off at 145 – 147 ºC in vacuo.

Conversion = 99 %, ee = 65 %

Spectrum of the used complex 10 after the reaction:

31P-NMR (121 MHz, CDCl3): δ = 29.32 (2P, P(O)Ph2), 30.87 (2P, P(O)Ph2)

Experimental Part

______________________________________________________________________________

5.3 Derivatization of ligand 3

5.3.1 Cl-MeO-Biphep oxide derivative 3a [114] (Table 3.10)

Cl-MeO-Biphep (3) (0.36 g, 0.55 mmol) and 10 mL of CH2Cl2 were placed in a 100 mL

round-bottomed flask. To the cooled solution 4 mL of H2O2 (35 %) was added at 0 ºC.

The mixture was stirred for 2 hours at 0 ºC and then for 4 hours at room temperature.

Afterwards 10 mL water was added. Aqueous phases were extracted with 3x3 mL of

CH2Cl2. The organic phases were washed with 10 mL aqueous sodium hydrogen sulfite

(NaHSO3) dried over MgSO4 and the solvent was distilled off. White solid 3a could be

isolated in its pure solid form as indicated by P-C coupling (quantitative yield, 0.378 g,

99 %).

mp = 220 – 223 ºC

1H-NMR (500 MHz, CDCl3): δ = 3.46 (s, 6H, OCH3), 7.01 (q, J = 8.3 Hz, 2H, ArH), 7.24 –

7.28 (m, 4H, ArH) 7.34 – 7.39 (m, 4H, ArH), 7.41 – 7.44 (m, 4H, ArH), 7.48 – 7.53 (m,

2H, ArH), 7.62 – 7.67 (q, J = 7.9 Hz, 8H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.5 (2C, OCH3), 128.0 – 137.0 (34C, ArC), 154.6 (1C,

ArC-OCH3), 154.7 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = 28.86 (P-C coupling), 29.12 (2P,P(O)Ph2), 29.32 (P-C

coupling)

M/z (calculated) = 683.5

MS (EI / 200 ºC, R=1000): M/z (%) = 683.2 [M+] (3), 651.4, 604.9, 558.9, 480.9, 448.9,

341.0, 310.0, 277.0, 201.0, 154.0, 77.0, 46.9

MeO

P(O)Ph

Experimental Part

______________________________________________________________________________

IR (KBr):

[cm-1] = 3016, 2955, 2345, 1992, 1842, 1756, 1563, 1434, 1365, 1257,

1203, 1114, 1016, 885, 815, 723, 694, 520, 433

5.3.2 Cl-MeO-Biphep sulfide derivative 3b [108] (Table 3.10)

Cl-MeO-Biphep (3) (0.5 g, 0.77 mmol) and elemental sulphur (0.39 g, 1.53 mmol) were

stirred in 10 mL toluene at 80 ºC for 12 hours. The mixture was cooled down and then

filtered and dried over MgSO4. Afterwards it was evaporated to obtain a pale brown solid

3b in quantitative yield (0.55 g, 99 %). 31P-NMR spectrum shows total conversion.

mp = 231 – 233 ºC

1H-NMR (500 MHz, CDCl3): δ = 3.16 (s, 6H, OCH3), 6.93 – 7.11 (m, 4H, ArH), 7.18 –

7.26 (m, 6H, ArH), 7.32 – 7.35 (m, 6H, ArH), 7.62 – 7.72 (m, 4H, ArH), 7.78 – 7.82 (m,

4H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 59.5 (2C, OCH3), 127.8 – 135.7 (34C, ArC), 154.0 (1C,

ArC-OCH3), 154.1 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = 43.60 (P-C coupling), 43.81 (2P,P(S)Ph2), 44.02 (P-C

coupling)

M/z (calculated) = 714.1

MS (EI / 200 ºC, R=1000): M/z (%) = 714.2 [M+] (100), 529.2, 497.1, 465.2, 451.1, 373.1,

357.1, 297.0, 183.1, 139.0, 57.1

MeO

P(S)Ph

Experimental Part

______________________________________________________________________________

5.3.3 Cl-MeO-Biphep borane complex 3c (Table 3.10)

Cl-MeO-Biphep (3) (0.4 g, 0.61 mmol) and 6 mL of BH3xTHF (1 M solution in THF) were

stirred at room temperature for 6 hours. The mixture was hydrolyzed by adding a

solution of 10 mL H2O dropwise and extracted with CH2Cl2 (3x3 mL). The solution was

dried over MgSO4 and evaporated to give a white solid mono borane complex 3c (0.294

g, 71 %) as a simple product.

Conversion = 79 %

1H-NMR (500 MHz, CDCl3): δ = 3.01 (s, 6H, OCH3), 7.06 (t, J = 8.4 Hz, 2H, ArH), 7.10 –

7.21 (m, 4H, ArH), 7.22 – 7.31 (m, 8H, ArH), 7.33 – 7.45 (m, 6H, ArH), 7.45 – 7.53 (t, J =

7 Hz, 2H, ArH), 7.60 – 7.68 (t, J = 7 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 59.2 (2C, OCH3), 128.0 – 135.5 (34C, ArC), 154.6 (1C,

ArC-OCH3), 154.7 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = -15.23 (2P,PPh2), -15.05 (2P,PPh2), 22.76

(2P,P(BH3)Ph2)

5.3.4 Cl-MeO-Biphep hydrochloric acid salt adduct 3d (Table 3.10)

MeO

P(HCl)Ph

MeO

PPh2

BH3

Experimental Part

______________________________________________________________________________

Cl-MeO-Biphep (3) (0.3 g, 0.46 mmol) and 2 mL of HCl (37 %) were stirred in 5 mL of

methanol at 0 ºC and then for 4 hours at room temperature. 6 mL mixture of MeOH /

H2O (1:1) were added and then extracted with methanol (3x3 mL). The organic solvent

was dried over MgSO4 and evaporated. The product 3d could be obtained as a pale

yellow solid (0.201 g, 60 %) but not confirmed by NMR measurements.

1H-NMR (500 MHz, CDCl3): δ = 3.22 (s, 6H, OCH3), 7.0 (d, J = 8.7 Hz, 2H, ArH), 7.19 –

7.24 (m, 10H, ArH), 7.27 – 7.28 (m, 10H, ArH), 7.32 – 7.39 (d, J = 7.4 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.1 (2C, OCH3), 128.0 – 138.3 (34C, ArC), 154.6 (1C,

ArC-OCH3), 154.7 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = -15.19 (2P,PPh2)

5.4 Optimization of the recycling cycle for ligand 3

5.4.1 Steps III-IV of the recycling cycle (Table 3.11, Entry 1)

47 mg, (0.072 mmol) Cl-MeO-Biphep ligand (3) and 22 mg (0.07 mmol) were stirred with

dropwise added 14,2 μL HBr (48 %) in acetone (6 mL) to prepare (76 mg, 0.083 mmol)

[(Cl-MeO-Biphep)-RuBr2] catalyst (10) after the evaporation of the solvent. The complex

10 was oxidized by 1 mL of H2O2 (35 %) in 2 mL dichloromethane. The black liquid was

stirred overnight at room temperature. 15 mL water was added and after the phase

separation the organic phase was evaporated.

Afterwards 4 mL of dibutylether was given to the residue to precipitate the Ru-derivative

(RuO2) from the ligand oxide 3a and this mixture was stirred at 140 °C overnight. The

solution was cooled down and filtered. The filtrated solid was washed with 3x3 mL of

dibutylether and the organic phases were dried over MgSO4 and evaporated under

reduced atmosphere resulting the oxide as a white solid 3a (68.9 mg, 0.1 mmol).

Experimental Part

______________________________________________________________________________

1H-NMR (500 MHz, CDCl3): δ = 3.45 (s, 6H, OCH3), 7.01 (q, J = 8.4 Hz, 2H, ArH), 7.23 –

7.26 (m, 4H, ArH), 7.33 – 7.35 (m, 4H, ArH), 7.40 – 7.43 (m, 4H, ArH), 7.48 – 7.51 (m,

2H ArH), 7.53 – 7.56 (m, 2H, ArH), 7.57 – 7.65 (m, 6H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.5 (2C, OCH3), 128.0 – 137.0 (34C, ArC), 154.6 (1C,

ArC-OCH3), 154.7 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = 29.24 (2P,P(O)Ph2)

5.4.2 Steps I-IV of the recycling cycle performed in the Lanxess FC laboratory

(Table 3.11, Entry 2)

[(Cl-MeO-Biphep)-RuBr2] (10) (8.76 g, 9.6 mmol) was used as a catalyst for the

hydrogenation of the desired substrate (1) (125 mL, 0.96 mol) in methylcyclohexane

(1800 mL). The solution was placed in a stainless steel autoclave, which was adjusted to

50 bar hydrogen pressure and warmed to 110 ºC for 12 hours. S/C=100. Conversion of

hydrogenation is 98.5 %.

After the first run 2.0 g (2.19 mmol) [(Cl-MeO-Biphep)-RuBr2] (10) from the reaction

residue was dissolved in 120 mL CH2Cl2 and then 5 mL H2O2 were introduced slowly to

the mixture and stirred overnight. Afterwards 250 mL water was given to perform the

phase separation. The organic layer containing solid (RuO2) was filtered and removed to

obtain brown oily residue, which was extracted with 150 mL n-hexane. The solvent was

dried over MgSO4 and removed under reduced atmosphere. The desired oxide was

obtained as a white solid 3a (0.547 g, 36.5 %).

1H-NMR (500 MHz, CDCl3): δ = 3.43 (s, 6H, OCH3), 6.98 (q, J = 8.3 Hz, 2H, ArH), 7.16 –

7.21 (m, 4H, ArH), 7.23 – 7.32 (m, 4H, ArH), 7.38 – 7.50 (m, 4H, ArH), 7.53 – 7.58 (m,

2H, ArH), 7.61 – 7.67 (m, 2H, ArH), 7.69 – 7.76 (m, 6H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.6 (2C, OCH3), 128.0 – 134.5 (34C, ArC), 154.8 (2C,

ArC-OCH3)

31P-NMR (400 MHz, CDCl3): δ = 29.27 (2P,P(O)Ph2),

Experimental Part

______________________________________________________________________________

5.4.3 Steps I-IV of the recycling cycle (Table 3.11, Entry 3, 4)

58 mg (0.089 mmol) Cl-MeO-Biphep ligand (3) and precursor 29 mg (0.09 mmol)

precursor 9 were stirred with dropwise added 14,2 μL HBr (48 %) in acetone (6 mL) to

prepare [(Cl-MeO-Biphep)-RuBr2] complex (10) after the evaporation of solvent. The

complex 10 was reacted with 1.0 mL (8 mmol) ethyl acetoacetate (1) as substrate in 10

mL of methylcyclohexane in a 125 mL stainless steel autoclave. Two consecutive runs

were carried out by applying same catalyst complex using 50 bar of hydrogen pressure

at 110 °C for 4 hours.

After the second run the reaction residue was treated with 1 mL H2O2 (35 %) in 5 mL of

dichloromethane for 1 hour at room temperature resulting dark brown solution. Then 25

mL water and additional 5 mL CH2Cl2 were added for phase separation. The organic

layer was evaporated and dibutylether (3 mL) was added to precipitate the Ru-derivative

(RuO2) from the ligand oxide 3a. The liquid was stirred and heated for 2 hours at 140 °C

then it was cooled down slowly. After the filtration, the solid was washed with 10 mL of

dibutylether and the filtrate was dried over MgSO4 and evaporated by in vacuo to obtain

(30.8 mg, 50.5 %) oxide form 3a of the ligand.

1H-NMR (500 MHz, CDCl3): δ = 3.46 (s, 6H, OCH3), 7.01 (q, J = 8.4 Hz, 2H, ArH), 7.25 –

7.29 (m, 4H, ArH), 7.34 – 7.38 (m, 4H, ArH), 7.41 – 7.45 (m, 4H, ArH), 7.46 – 7.54 (m,

2H, ArH), 7.61 – 7.66 (m, 8H, ArH)

13C-NMR(125 MHz, CDCl3): δ = 60.5 (2C, OCH3), 128.0 – 132.6 (34C, ArC)

31P-NMR (200 MHz, CDCl3): δ = 29.04 (2P,P(O)Ph2)

5.4.5 Steps I-IV of the recycling cycle (Table 3.11, Entry 5)

50 mg (0.077 mmol) Cl-MeO-Biphep (3) 22 mg (0.068 mmol) precursor 9 were stirred

with dropwise added 14,2 μL HBr (48 %) in acetone (6 mL) to prepare complex 10 after

the evaporation of solvent. The complex 10 was reacted with 1.0 mL (8 mmol) ethyl

acetoacetate (1) as substrate in 15 mL methylcyclohexane in a 125 mL stainless steel

autoclave. One hydrogenation reaction was taken place by applying the catalyst

Experimental Part

______________________________________________________________________________

complex using 50 bar of hydrogen pressure at 110 °C for 4 hours. Conversion of

hydrogenation: 58 %.

The reaction residue was treated with 2 mL H2O2 (35 %) in 9 mL dichloromethane for 1

hour at room temperature resulting dark brown solution. Then 25 mL water and

additional 5 mL CH2Cl2 were added to the phase separation. The organic layer was

evaporated and dibutylether (4 mL) was added to precipitate the Ru-derivative (RuO2)

from the ligand oxide 3a. The liquid was stirred and heated for 2 hours at 140 °C then it

was cooled down slowly. After the filtration, the solid was washed with 10 mL of

dibutylether and the filtrate was dried over MgSO4 and evaporated by vacuum pump to

obtain (31 mg, 59 %) oxide form 3a of the ligand.

1H-NMR (500 MHz, CDCl3): δ = 3.39 (s, 6H, OCH3), 6.99 (q, J = 8.4 Hz, 2H, ArH), 7.26 –

6.32 (m, 4H, ArH), 7.37 – 7.43 (m, 4H, ArH), 7.45 – 7.49 (m, 4H, ArH), 7.51 – 7.55 (m,

2H, ArH), 7.57 – 7.63 (m, 8H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.5 (2C, OCH3), 128.0 – 132.6 (34C, ArC), 169.3 (2C,

ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = 27.68 (2P, P(O)Ph2), 29.79 (2P, P(O)Ph2)

5.4.6 Steps I-IV of the recycling cycle (Table 3.11, Entry 6)

0.542 g (0.83 mmol) Cl-MeO-Biphep (3) 0.223 g (0.7 mmol) precursor 9 were stirred

with dropwise added 0.15 mL HBr (48 %) in acetone (30 mL) to prepare complex 10

after the evaporation of solvent. The complex 10 was reacted with 1.0 mL (8 mmol) ethyl

acetoacetate (1) as substrate in 60 mL of methylcyclohexane in a 125 mL stainless steel

autoclave. One hydrogenation reaction was taken place by applying the catalyst

complex using 50 bar of hydrogen pressure at 110 °C for 4 hours. S/C=10. Conversion

of hydrogenation: 98 %.

The reaction residue was treated with 8 mL H2O2 (35 %) in 15 mL dichloromethane for 1

hour at room temperature resulting dark brown solution. Then 25 mL water and

additional 5 mL CH2Cl2 were added to the phase separation. The organic layer was

evaporated and dibutylether (20 mL) was added to precipitate the Ru-derivative (RuO2)

Experimental Part

______________________________________________________________________________

from the ligand oxide 3a. The liquid was stirred and heated for 2 hours at 140 °C then it

was cooled down slowly. After the filtration, the solid was washed with 10 mL

dibutylether and the filtrate was dried over MgSO4 and evaporated in vacuo to obtain

(0.355 g, 63 %) oxide form 3a of the ligand.

1H-NMR (500 MHz, CDCl3): δ = 3.39 (s, 6H, OCH3), 6.99 (q, J = 8.4 Hz, 2H, ArH), 7.17 –

7.26 (m, 4H, ArH), 7.30 – 7.34 (m, 4H, ArH), 7.37 – 7.42 (m, 4H, ArH), 7.44 – 7.49 (m,

2H, ArH), 7.58 – 7.65 (m, 8H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.4 (2C, OCH3), 128.4 – 137.0 (34C, ArC), 154.6 (1C,

ArC-OCH3), 154.7 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = 28.85 (2P,P(O)Ph2)

5.4.7 Reduction procedure of 3a [112] (Table 3.12)

0.1 g (0.146 mmol) Cl-MeO-Biphep oxide (3a) was solved in 10 ml xylene and 3 ml NEt3.

This mixture was heated to 60 °C under reflux then a mixture of 2 ml trichlorosilane and

5 ml xylene was added slowly to the suspension. It was heated and stirred overnight at

110 °C. Afterwards the reaction mixture was cooled to room temperature and solved in

15 mL CH2Cl2. Then the solution was cooled to 0 °C and NaOH (10 w/w %) was added

dropwise until pH=10 was reached. The suspension was filtered under argon

atmosphere over 5 g Al2O3 (90 active, acidic). The organic phase was collected in a

second flask and the water phase was extracted with 20 mL CH2Cl2. The collected

dichloromethane phases were washed two times with 10 mL water under argon

atmosphere. The organic layer was dried over MgSO4 and reduced to a volume of 5 mL

in vacuo since crystallization of the ligand 3 started. Organic solvent was removed under

reduced atmosphere, thus 3 was obtained as a white powder (68 mg, 71 %).

This reaction was performed in three consecutive runs using total amount of 2 ml

reducing agent and 0.1 g standard Cl-MeO-Biphep oxide derivative (3a).

1H-NMR (500 MHz, CDCl3): δ = 3.22 (s, 6H, OCH3), 6.99 (d, J = 8.2 Hz, 2H, ArH), 7.21 –

7.25 (m, 10H, ArH), 7.25 – 7.33 (m, 10H, ArH), 7.37 (d, J = 8.2 Hz, 2H, ArH)

Experimental Part

______________________________________________________________________________

13C-NMR (125 MHz, CDCl3): δ = 59.6 (2C, OCH3), 128.0 – 133.0 (34C, ArC), 167.7 (2C,

ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = - 15.07 (2P,Ph2)

5.4.8 Hydrogenation with reduced ligand 3 (Table 3.13)

The reduction procedure was performed with 0.118 g, (0.173 mmol) extra pure Cl-MeO-

Biphep oxide derivative 3a, which was dissolved in a mixture of 5 mL xylene and 3 mL

NEt3. This solution was heated to 60 °C under reflux then a mixture of 4 mL (in two

portions) trichlorosilane and 9 ml xylene was added slowly to the suspension. It was

heated and stirred overnight at 110 °C. Afterward the mixture was cooled to room

temperature and solved in 15 mL CH2Cl2. Then the solution was cooled to 0 °C and

NaOH (10 w/w %) was dropped until pH=10 was reached. The suspension was filtered

under argon atmosphere over 5 g Al2O3 (90 active, acidic). The organic phase was

collected in a second flask and the water phase was extracted with 20 mL CH2Cl2. The

collected dichloromethane phases were washed two times with 20 mL water under

argon atmosphere. The organic layer was dried over MgSO4 and reduced for a volume

of 5 mL in vacuo when the crystallization of the ligand 3 started. The solvent was

removed under reduced atmosphere. Ligand 3 was obtained as a white powder (0.11 g,

95 %) and used continually in the next hydrogenation reaction.

Afterwards typical hydrogenation reaction was conducted in which the catalyst complex

(10) was prepared from (51 mg, 0.079 mmol) recovered Cl-MeO-Biphep ligand (3), (23

mg, 0.072 mmol) Ru(II)-bis-(2-methylallyl)cycloocta-1,5-diene-complex (9) and 14,2 μL

HBr (48 %) in 6 mL acetone. The solvent was evaporated. Afterwards ethyl acetoacetate

(1) (1.0 mL, 8 mmol) and the prepared catalyst complex 10 were placed with 15 mL of

methylcyclohexane in a 125 mL stainless steel autoclave using 50 bar of hydrogen

pressure at 110 °C for 4 hours. Conversion = 99 %, ee = 71.1 %

1H-NMR (500 MHz, CDCl3): δ = 3.18 (s, 6H, OCH3), 6.94 (d, J = 8.2 Hz, 2H, ArH), 7.16

– 7.20 (m, 10H, ArH), 7.26 – 7.28 (m, 10H, ArH), 7.32 – 7.37 (d, J = 8.2 Hz, 2H, ArH)

Experimental Part

______________________________________________________________________________

13C-NMR (125 MHz, CDCl3): δ = 59.5 (2C, OCH3), 127.8 – 138.3 (34C, ArC), 154.4 (1C,

ArC-OCH3), 154.4 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = - 15.13 (2P,PPh2)

5.4.9 Optimization of steps of the recycling cycle (Table 3.14)

47 mg, (0.072 mmol) Cl-MeO-Biphep ligand (3) and 22 mg (0.07 mmol) precursor 9 were

stirred in 6 mL acetone and than 0.15 mL HBr (48 %) was added dropwise. The solvent

was evaporated completely. The prepared (76 mg, 0.083 mmol) [(Cl-MeO-Biphep)-

RuBr2] catalyst (10) was oxidized by 1 mL of H2O2 (35 %) in 2 mL dichloromethane at

0ºC. The black liquid was stirred overnight at room temperature. 15 mL water was added

and after the phase separation the organic phase was evaporated.

Afterwards 4 mL dibutylether was given to the residue to precipitate the Ru-derivative

(RuO2) from the ligand oxide 3a and this mixture was stirred at 140 °C overnight. The

solution was cooled down and filtered. The filtrated solid was washed with 3 x 3 mL

dibutylether and the organic phases were evaporated under reduced atmosphere

resulting the oxide as a white solid 3a (68.9 mg, 0.1 mmol).

This phosphine oxide 3a was dissolved without any further purification in a mixture of

8mL xylene and 1.5 mL NEt3. This solution was heated to 60 °C under reflux then a

mixture of 1.5 mL trichlorosilane and 0.8 ml xylene was added slowly (in two portions) to

the suspension. It was heated and stirred overnight at 110 °C. Afterwards the mixture

was cooled to room temperature and solved in 15 mL CH2Cl2. Then the solution was

cooled to 0 °C and 2 ml NaOH (30 w/w %) was added dropwise to a pH of 10 was

reached. The suspension was filtered under argon atmosphere over 5 g Al2O3 (90 active,

acidic). The organic phase was collected in a second flask and the water phase was

extracted with 18 mL CH2Cl2. The collected dichloromethane phases were extracted with

22 mL brine under argon atmosphere. After the phase separation the organic layer was

dried over MgSO4, filtered and the solvent was completely distilled off. The product 3

was crystallized from chloroform at 0 °C and obtained as a white powder (23 mg, 49 %).

Experimental Part

______________________________________________________________________________

1H-NMR (500 MHz, CDCl3): δ = 3.18 (s, 6H, OCH3), 6.94 (d, J = 8.2 Hz, 2H, ArH), 7.16 –

7.23 (m, 10H, ArH), 7.27 – 7.28 (m, 10H, ArH), 7.31 – 7.34 (d, J = 8.2 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.1 (2C, OCH3), 126.0 – 138.4 (34C, ArC), 154.4 (1C,

ArC-OCH3), 154.5 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = -15.17 (2P,PPh2)

The recovered 3 was tested further in a typical hydrogenation reaction. 23 mg (0.035

mmol) Cl-MeO-Biphep (3), 11 mg (0.035 mmol) precursor 9 and 6 mL acetone were

stirred and than 0.75 μL HBr (48 %) was added. The solvent was evaporated

completely. The prepared 10 was reacted with 0.5 mL (4 mmol) ethyl acetoacetate (1) as

substrate in 10 mL methylcyclohexane in a 125 mL stainless steel autoclave.

Hydrogenation reaction was taken place by using 50 bar of hydrogen pressure at 110 °C

for 4 hours. Conversion of hydrogenation: 99 %. After the reaction the product 2 was

distilled off in vacuo at 148 – 150 °C.

Conversion = 99 %

5.4.10 Optimization of each step of the whole recycling (Table 3.15, Entry 1)

The catalyst complex 10 was prepared from 0.531 g (0.82 mmol) Cl-MeO-Biphep (3),

0.251 g (0.79 mmol) precursor 9 and 0.15 mL HBr (48 %) in 20 mL acetone. The solvent

was evaporated and the complex 10 was reacted with 10.4 mL (80 mmol) ethyl

acetoacetate (1) in 40 mL methylcyclohexane in a 125 mL stainless steel autoclave.

Hydrogenation reaction was conducted by using 50 bar of hydrogen pressure at 110 °C

for 4 hours. After the reaction the product 2 was distilled off in vacuo at 148 – 150 °C.

Conversion = 99 %. ee = 87.1 %

The oxidation step was carried out with 8 mL H2O2 (35 %) in 25 mL dichloromethane at

0 ºC overnight. Then 50 mL dichloromethane and 140 mL water were added for the

phase separation. The organic layer was evaporated to obtain 1.638 g solid residue.

Afterwards 30 mL DBE was added to this powder to separate the Ru-derivative (RuO2)

from the ligand oxide 3a and this mixture was stirred at 140 °C overnight. The solution

Experimental Part

______________________________________________________________________________

was cooled down and the solid was filtered off. The residue was washed with 3x10 mL

diethylether and the organic layers were collected and evaporated under reduced

atmosphere resulting in the oxide 3a as a white solid (0.56 g, 0.82 mmol).

This solid was dissolved in 30 mL xylene and 16 mL (0.12 mol) NEt3 and reduced by a

mixture of 19 mL (0.19 mol) HSiCl3 and 10 mL xylene. It was heated and stirred

overnight at 110 °C. Afterwards the mixture was cooled to room temperature and 15 mL

CH2Cl2 was added. Then the solution was cooled to 0 °C and 8 ml NaOH (30 w/w %)

was dropped until pH=10 was reached. The suspension was filtered under argon

atmosphere over 5 g Al2O3 (90 active, acidic) and washed with 80 mL dichloromethane.

The organic phases were collected in a second flask and the phase separation was

carried out with 50 mL water and 10 mL brine. After phase separation, the organic layer

was dried over MgSO4, filtered and the solvent was completely distilled off. The product

3 was crystallized from 8 mL chloroform at 0 °C and obtained as a white powder (0.174

g, 33 %).

1H-NMR (500 MHz, CDCl3): δ = 3.20 (s, 6H, OCH3), 6.97 (d, J = 8.2 Hz, 2H, ArH), 7.18 –

7.22 (m, 10H, ArH), 7.26 – 7.30 (m, 10H, ArH), 7.34 – 7.36 (d, J = 8.2 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.1 (2C, OCH3), 128.0 – 138.4 (34C, ArC), 154.3 (1C,

ArC-OCH3), 154.4 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = - 15.15 (2P,PPh2)

M/z (calculated) = 651.5

MS (CI / 120 ºC, R=1000): M/z (%) = 651.2 [M+] (2), 524.2, 462.2, 417.2, 391.3, 319.3,

263.1, 201.1, 153.1, 57.1, 43.1

Ru content of catalyst complex before the hydrogenation (calculated) = 124.2 g Ru/kg

ICP-AES = 1000 mg/kg (Ru content after the recycling)

Experimental Part

______________________________________________________________________________

5.4.11 Optimization of each step of the whole recycling (Table 3.15, Entry 2)

The catalyst complex 10 was prepared from 0.533 g (0.82 mmol) Cl-MeO-Biphep (3),

0.248 g (0.78 mmol) precursor 9 and 0.15 mL HBr (48 %) in 20 mL acetone. The mixture

was stirred for 1hour after that the solvent was evaporated and the complex 10 was

reacted with 10.4 mL (80 mmol) ethyl acetoacetate (1) as substrate in 40 mL

methylcyclohexane in a 125 mL stainless steel autoclave. Hydrogenation reaction was

conducted by using 50 bar of hydrogen pressure at 110 °C for 4 hours. After the reaction

the product 2 was distilled off in vacuo at 148 – 150 °C.

Conversion = 99 %. ee = 73.4 %

The oxidation step was carried out with 10 mL H2O2 (35 %) in 20 mL dichloromethane at

0 ºC overnight. Then 100 mL dichloromethane and 100 mL water were added to allow

phase separation. The organic layer was evaporated to obtain 0.957 g residue.

Afterwards 40 mL MTBE was added to this solid to separate the Ru-derivative (RuO2)

from the ligand oxide 3a and this mixture was stirred at 140 °C for 4 hours. The solution

was cooled down and the solid was filtered off. The residue was washed with 2x10 mL

MTBE and the organic phases were collected and evaporated under reduced

atmosphere resulting in the oxide 3a as a white solid (0.719 g).

This solid was dissolved in 30 mL xylene and 16 mL (0.12 mol) NEt3 and reduced by a

mixture of 19 mL (0.19 mol) HSiCl3 and 10 mL xylene. It was heated and stirred

overnight at 110 °C. Afterwards the mixture was cooled to room temperature and 15 mL

CH2Cl2 was added. Then the solution was cooled to 0 °C and 15 ml NaOH (30 w/w %)

was dropped until pH=10 was reached. The suspension was filtered under argon

atmosphere over 5 g SiO2 (60, neutral) and washed with 150 mL dichloromethane. The

organic phases were collected in a second flask and the phase separation was carried

out with 100 mL water and 8 mL brine. After phase separation, the organic layer was

dried over MgSO4 and filtered. The sovent was completely distilled off and the product 3

was crystallized from 8 mL chloroform at 0 °C and obtained as a white powder (0.261 g,

49 %).

Experimental Part

______________________________________________________________________________

1H-NMR (500 MHz, CDCl3): δ = 3.19 (s, 6H, OCH3), 6.97 (d, J = 8.2 Hz, 2H, ArH), 7.18 –

7.25 (m, 10H, ArH), 7.26 – 7.33 (m, 10H, ArH), 7.34 – 7.38 (d, J = 8.2 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.1 (2C, OCH3), 128.1 – 138.4 (34C, ArC), 154.4 (1C,

ArC-OCH3), 154.5 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = - 15.16 (2P,PPh2)

M/z (calculated) = 651.5

MS (EI / 200 ºC, 70 eV, R=1000): M/z (%) = 651.3 [M+] (1), 577.3, 541.3, 503.2, 479.2,

429.2, 355.1, 327.1, 279.2, 224.2, 195.2, 149.1, 105.1, 69.1, 43.0

Ru content of catalyst complex before the hydrogenation (calculated) = 122.5 g Ru/kg

ICP-AES = 808 mg/kg (Ru content after the recycling)

5.4.12 Optimization of each step of the whole recycling (Table 3.15, Entry 3)

The catalyst complex 10 was prepared from 5.212 g (8 mmol) Cl-MeO-Biphep (3), 1.66 g

(8 mmol) RuCl3xH2O precursor and 1.5 mL HBr (48 %) in 40 mL acetone. The mixture

was stirred for 1 hour. The solvent was evaporated and the complex 10 was reacted with

10.4 mL (80 mmol) ethyl acetoacetate (1) as substrate in 40 mL methylcyclohexane in a

125 mL stainless steel autoclave. Hydrogenation reaction was taken place by using 50

bar of hydrogen pressure at 110 °C for 4 hours. After the reaction the product 2 was

distilled off in vacuo at 148 – 150 °C.

Conversion = 99 %. ee = 92.6 %

The oxidation step was carried out with 18 mL H2O2 (35 %) in 50 mL dichloromethane at

0 ºC overnight in a 1000 mL round-bottomed flask. Then 300 mL dichloromethane and

100 mL water were added to allow phase separation. The organic layers were

evaporated to obtain dark brown powder residue.

Afterwards 200 mL MTBE was added to this powder to separate the Ru-derivative

(RuO2) from the ligand oxide 3a and this mixture was stirred at 140 °C for 4 hours. The

solution was cooled down and the solid was filtered off. 200 mL MTBE was used for

Experimental Part

______________________________________________________________________________

washing the flask. The residue was washed with 2x10 mL MTBE and the organic layers

were collected and evaporated under reduced atmosphere resulting in the oxide 3a as a

white solid (4.27 g, 78.1 %).

This solid was solved in 110 mL xylene and 100 mL (0.72 mol) NEt3 and reduced by a

mixture of 120 mL (1.2 mol) HSiCl3 and 100 mL xylene in two portions in a 1000 mL

round-bottomed flask. It was heated and stirred overnight at 110 °C. Afterwards the

mixture was cooled to room temperature and 100 mL CH2Cl2 was added. Then the

solution was cooled to 0 °C and 40 ml NaOH (30 w/w %) was added dropwise to pH=10

was reached. The suspension was filtered via Büchner funnel, which was filled with 10 g

SiO2 (60, neutral). The residue was washed with 650 mL dichloromethane. The organic

phases were collected in a second flask and reduced for its half volume. Afterwards

phase separation was carried out with 400 mL water and 60 mL brine. The organic layer

was dried over MgSO4, filtered and the solvent was completely distilled off. The product

3 was crystallized from 15 mL chloroform at 0 °C and obtained as a white powder (1.476

g, 28.3 %).

1H-NMR (500 MHz, CDCl3): δ = 3.25 (s, 6H, OCH3), 7.01 – 7.03 (m, 2H, ArH), 7.23 –

7.30 (m, 10H, ArH), 7.31 – 7.37 (m, 10H, ArH), 7.38 – 7.41 (d, J = 8.3 Hz, 2H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.2 (2C, OCH3), 127.9 – 138.4 (34C, ArC), 154.5 (1C,

ArC-OCH3), 154.6 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = - 15.08 (2P,PPh2)

M/z (calculated) = 651.5

MS (EI / 200 ºC, 70 eV, R=1000): M/z (%) = 651.1 [M+] (1), 636.9, 619.1, 573.2, 527.1,

481.1, 465.1, 431.1, 373.0, 325.1, 294.1, 244.1, 183.0, 149.0, 108.0, 91.1, 57.1, 43.0

Ru content of catalyst complex before the hydrogenation (calculated) = 116.7 g Ru/kg

ICP-AES = 1865 mg/kg (Ru content after the recycling)

Experimental Part

______________________________________________________________________________

5.4.13 Modeling of the recycling procedure as an industrial process (Table 3.16

and Table 3.17, Entry 1)

The catalyst complex for 10 hydrogenation reactions was prepared with 0.527 g (0.8

mmol) Cl-MeO-Biphep (3) and 0.227 g (0.7 mmol) precursor 9 in 20 mL anhydrous

acetone. 0.15 mL HBr (48 %) was added dropwise and stirred for 1 hour afterwards the

solvent was evaporated.

Prepared [(Cl-MeO-Biphep)-RuBr2] (10) (0.08 mmol) was used without any purification

as a catalyst for each hydrogenation reaction with 1 mL (8 mmol) substrate 1 in

methylcyclohexane (15 mL). The solution was placed in a 125 mL stainless steel

autoclave, which was adjusted at 50 bar hydrogen pressure and warmed to 110 ºC for 4

hours. The substrate to catalyst ratio was 100. The solvent was evaporated and the

product 2 was separated by vacuum distillation at 148 - 150 ºC from the residue, which

contains ligand 3 and precursor 9. The same hydrogenation was carried out 10 times

using always new catalyst complex 10. The product 2 was separated by vacuum

distillation at 148 – 150 ºC after each hydrogenation.

Conversion = 97.8 %. ee = 59.2 %

All residue were collected together after 10 hydrogenation reactions and 0.839 g residue

was oxidized by 8 mL H2O2 (35 %) in 20 mL dichloromethane at 0 ºC overnight in a 200

mL round-bottomed flask. Then 45 mL dichloromethane and 120 mL water were added

to allow phase separation. The organic layers were evaporated to obtain dark brown

powder residue.

Afterwards 40 mL DBE was added to this powder to separate the Ru-derivative (RuO2)

from the ligand oxide 3a and this mixture was stirred at 140 °C for 4 hours. The solution

was cooled down and the solid was filtered off. 13 mL DBE was used for washing the

flask. The residue was washed with 2x3 mL DBE and the organic layers were collected

and evaporated under reduced atmosphere resulting the oxide as a white solid 3a

(0.576 g).

This solid was solved in 40 mL xylene and 16 mL (0.12 mol) NEt3 and reduced by a

mixture of 19 mL (0.19 mol) HSiCl3 and 10 mL xylene. It was heated and stirred

overnight at 110 °C. Afterwards the mixture was cooled to room temperature and extra

Experimental Part

______________________________________________________________________________

10 mL CH2Cl2 was added. Then the solution was cooled to 0 °C and 8 ml NaOH (30 w/w

%) was added dropwise until pH=10 was reached. The suspension was filtered under

argon atmosphere over 5 g Al2O3 (90 active, acidic) and washed with 130 mL

dichloromethane. The organic phases were collected in a second flask and the phase

separation was carried out with 50 mL water and 20 mL brine. After the phase

separation the organic layer was dried over MgSO4, filtered and the solvent was

completely distilled off. The product 3 was crystallized from 10 mL chloroform at 0 °C

and obtained as a white powder (0.202 g, 38 %). The average conversion of 10

hydrogenations is 97.8 % and average ee of the hydrogenation is 59.2 %.

1H-NMR (500 MHz, CDCl3): δ = 3.23 (s, 6H, OCH3), 6.97 – 7.03 (d, J = 8.2 Hz, 2H, ArH),

7.21 – 7.28 (m, 10H, ArH), 7.29 – 7.35 (m, 10H, ArH), 7.36 – 7.43 (d, J = 8.2 Hz, 2H,

ArH)

13C-NMR (125 MHz, CDCl3): δ = 60.1 (2C, OCH3), 128.0 – 138.4 (34C, ArC), 154.4 (1C,

ArC-OCH3), 154.5 (1C, ArC-OCH3)

31P-NMR (200 MHz, CDCl3): δ = -15.15 (2P,PPh2)

M/z (calculated) = 651.5

MS (CI / 120 ºC, 70 eV, R=1000): M/z (%) = 651.2 [M+] (2), 623.4, 591.4, 525.2, 467.2,

403.2, 391.3, 263.1, 201.1, 115.1, 57.1, 43.1

Ru content of catalyst complex before the hydrogenation (calculated) = 114.4 g Ru/kg

ICP-AES = 446 mg/kg (Ru content after the recycling)

5.4.14 Hydrogenation reaction using recovered ligand 3 (Table 3.17, Entry 2)

58 mg (0.08 mmol) recovered 3, 29 mg (0.08 mmol) were stirred in 6 mL acetone and

then 14.2 μL HBr (48 %) was added dropwise. The mixture was stirred for 1 hour after

that the solvent was evaporated to obtain catalyst complex 10. Typical hydrogenation

was conducted with this catalyst complex 10 for the hydrogenation of 1mL 1 (8 mmol) in

methylcyclohexane (10 mL). The solution was placed in a 125 mL stainless steel

Experimental Part

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autoclave, which was adjusted at the appropriate bar hydrogen pressure and warmed up

to 110 ºC for 24 or 4 hours. S/C=100. The product 2 was separated by vacum distillation

at 148 – 150 ºC.

Conversion = 99 %. ee = 56.9 %

5.5 Amination reaction using Dave-Phos (7) and X-Phos (8) ligand

5.5.1 General amination reaction with Dave-Phos ligand (7) performed in Lanxess

FC laboratory (Table 3.18, Entry 1)

The amination reaction was conducted under argon in a 250 mL scale (10 wt%). 24.5

mL (0.27 mol) of aniline and 28.2 mL (0.27 mol) bromobenzene were added in a 500 mL

round-bottomed flask to 250 mL toluene. Afterwards 85.4 g (0.4 mol) K3PO4 as a base

and a mixture of 3.7 g (4.02 mmol) Pd2dba3 and 3.1 g (8.05 mmol) Dave-Phos (7) in 50

mL toluene were placed to the solution.

The reaction was conducted at 100 °C overnight and after that 200 mL water was added

to perform phase separation at room temperature.

Conversion = 72 % (determined by GC-MS)

5.5.2 General amination reaction with X-Phos ligand (8) performed in Lanxess FC

laboratory (Table 3.18, Entry 2)

The amination reaction was conducted under argon in a 250 mL scale. 24.5 mL (0.27

mol) of aniline and 28.2 mL (0.27 mol) bromobenzene were added in a 500 mL round-

bottomed flask to 250 mL toluene. Afterwards 85.4 g (0.4 mol) K3PO4 as a base and a

mixture of 3.7 g (4.02 mmol) Pd2dba3 and 3.8 g (8.05 mmol) X-Phos (8) in 50 mL toluene

were placed to the solution.

Experimental Part

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The reaction was conducted at 100 °C overnight and after that 200 mL water was added

to perform phase separation at room temperature.

Conversion = 78.5 % (determined by GC-MS)

5.5.3 Improvement of general amination reaction using Dave-Phos ligand (7)

(Table 3.18, Entry 3)

The amination reaction was conducted under argon in a 25 mL scale. 0.9 mL (9.87

mmol) aniline and 1 mL (9.5 mmol) bromobenzene were added in a 500 mL round-

bottomed flask to 30 mL toluene. Afterwards 2.85 g (29.7 mmol) NaOtBu as a base and

a mixture of 0.15 g (0.16 mmol) Pd2(dba)3 and 0.13 g (0.33 mmol) Dave-Phos (7) in 5

mL toluene were placed to the solution. The reaction was taken place at 100 °C

overnight.

After the reaction 20 mL water was added to perform phase separation at room

temperature.

Conversion = 99 % (determined by GC-MS)

5.5.4 Characterization of (2-dicyclohexylphosphino-2´-(N,N-dimethylamino)-

biphenyl) (Dave-Phos) 7

mp = 117 – 119 ºC

1H-NMR (500 MHz, CDCl3): δ = 0.79 – 0.99 (m, 2H, CH2), 1.01 – 1.21 (m, 4H, CH2), 1.22

– 1.45 (m, 4H, CH2), 1.53 – 1.68 (m, 7H, CH, CH2), 1.74 – 1.76 (m, 2H, CH2), 1.82 –

1.84 (m, 2H, CH2), 2.03 – 2.10 (m, 1H, CH), 2.49 (s, 6H, N(CH3)2), 6.99 – 7.03 (m, 2H,

PCy

Experimental Part

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100

ArH), 7.06 – 7.09 (m, 1H, ArH), 7.31 – 7.36 (t, J = 7.7 Hz, 3H, ArH), 7.42 (t, J = 7.5 Hz,

1H, ArH), 7.58 (d, J = 7.4 Hz, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 26.5 – 30.9 (10C), 33.4 – 36.8 (2C), 43.3 (2C), 117.3

(ArC), 120.7 (ArC), 125.9 (ArC), 128.1 (ArC), 130.5 (ArC), 132.4 (ArC), 132.8 (ArC),

135.3 (ArC), 135.8 (ArC), 135.9 (ArC), 149.6 (ArC), 151.5 (ArC)

31P-NMR (500 MHz, CDCl3): δ = - 9.47 (P,PCy2)

M/z (calculated) = 393.5

MS (EI / 200 ºC, R=1000): M/z (%) = 393.2 [M+] (4), 349.1, 311.0, 310.2, 267.1, 212.3,

194.1, 183.3, 152.0, 55.1

IR (KBr):

[cm-1] = 3049, 2923, 2850, 2769, 2651, 1920, 1592, 1494, 1442, 1317,

1269, 1239, 1195, 1157, 1106, 1051, 1003, 946, 885, 850, 746, 671, 619, 572, 543, 522,

499, 464.

5.5.5 Characterization of (2-dicyclohexylphosphino-2´,4´,6´-triisopropyl-biphenyl)

(X-Phos) 8

mp = 178 – 180 ºC

1H-NMR (500 MHz, CDCl3): δ = 1.00 (d, J = 6.7 Hz, 6H, CH2), 1.07 – 1.30 (m, 16H, CH3),

1.33 – 1.39 (m, 6H, CH2), 1.61 – 1.64 (m, 2H, CH2), 1.69 – 1.71 (m, 4H, CH2), 1.75 –

1.77 (m, 4H, CH2), 1.89 (s, 2H, CH), 2.41 – 2.49 (m, 2H, CH(CH3)2), 2.96 (m, 1H,

PCy

Experimental Part

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101

CH(CH3)2), 7.04 (s, 2H, ArH), 7.17 – 7.23 (m, 1H, ArH), 7.32 – 7.41 (m, 2H, ArH), 7.63

(t, J = 7 Hz, 1H, ArH )

13C-NMR (125 MHz, CDCl3): δ = 22.9 (2C), 24.0 (2C), 25.8 (2C), 26.5 – 27.6 (10C), 30.6

(2C), 34.1 (1C), 34.6 (1C), 34.7 (1C), 120.3 (2C, ArC), 126.1 (ArC), 127.6 (ArC), 131.6

(ArC), 132.3 (ArC), 136.5 (ArC), 136.6 (ArC), 146.0 (ArC), 147.6 (ArC), 147.7 (ArC),

147.9 (ArC)

31P-NMR (500 MHz, CDCl3): δ = - 11.96 (P,PCy2)

M/z (calculated) = 476.7

MS (EI / 200 ºC, R=1000): m/z (%) = 476.5 [M+] (6), 433.2, 419.0, 351.2, 278.9, 269.2,

225.1, 183.0, 178.0, 83.1, 55.1

IR (KBr):

[cm-1] = 3042, 2959, 2940, 2923, 2845, 1606, 1570, 1448, 1359, 1317,

1267, 1168, 1106, 1054, 997, 945, 889, 875, 779, 767, 650, 596, 517, 462

5.5.6 Dave-Phos oxide derivative 7a (Table 3.19, Entry 1)

Dave-Phos ligand (7) (0.35 g, 0.89 mmol) and 10 mL CH2Cl2 were placed in a 100 mL

round-bottomed flask. To the cooled solution 3 mL H2O2 (35 %) was added at 0 ºC. The

mixture was stirred at 0 ºC than room temperature overnight. Afterwards 10 mL water

was added. Aqueous phase was extracted with 3x3 mL CH2Cl2. The organics phases

were dried over MgSO4 and evaporated to gain a pale yellow solid 7a (quantitative

yield).

mp = 141 – 143 ºC

P(O)Cy

Experimental Part

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102

1H-NMR (500 MHz, CDCl3): δ = 0.88 – 1.05 (m, 2H, CH2), 1.09 – 1.27 (m, 5H, CH2), 1.28

– 1.46 (m, 4H, CH2), 1.47 – 1.63 (m, 5H, CH2), 1.69 – 1.79 (m, 4H, CH2), 1.87 – 2.06 (m,

2H, CH), 2.55 (s, 6H, N(CH3)2), 6.97 – 7.07 (m, 3H, ArH), 7.32 – 7.39 (m, 2H, ArH), 7.46

(t, J = 7.6 Hz, 1H, ArH), 7.53 (t, J = 7.4 Hz, 1H, ArH), 7.97 (t, J = 7.3 Hz, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 25.6 – 26.7 (10C), 36.4 – 37.7 (2C), 44.0 (2C), 117.5

(ArC), 121.1 (ArC), 126.6 (ArC) 128.7 (ArC), 130.7 (ArC), 132.0 (ArC), 132.8 (ArC),

133.7 (ArC), 134.6 (ArC), 144.6 (ArC), 144.8 (ArC), 151.3 (ArC)

31P-NMR (500 MHz, CDCl3): δ = 49.65 (P-C coupling), 49.82 (P,P(O)Cy2), 49.97 (P-C

coupling)

M/z (calculated) = 409.5

MS (EI / 200 ºC, R=1000): m/z (%) = 409.2 [M+] (47), 394.2, 365.2, 326.2, 283.1, 244.1,

228.1, 215.1, 194.1, 180.1, 152.1, 83.1, 55.1

IR (KBr):

[cm-1] = 3053, 2925, 2850, 2775, 2661, 2370, 1593, 1494, 1442, 1315,

1277, 1165, 1105, 1055, 1003, 848, 746, 669, 619, 572, 503, 447

5.5.7 Dave-Phos sulfide derivative 7b (Table 3.19, Entry 2)

0.4 g (1 mmol) Dave-Phos ligand (7) and elemental sulphur (0.32 g, 1.23 mmol) were

stirred in 10 mL toluene at 95 ºC for 12 hours. The mixture was cooled down and then

filtered and dried over MgSO4. Afterwards it was evaporated to obtain a pale yellow solid

7b in quantitative yield (0.43 g, 99 %). 31P-NMR spectrum shows total conversion.

mp = 155 – 157 ºC

P(S)Cy

Experimental Part

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103

1H-NMR (500 MHz, CDCl3): δ = 0.84 – 1.02 (m, 2H, CH2), 1.06 – 1.13 (m, 2H, CH2), 1.18

– 1.27 (m, 4H, CH2), 1.28 – 1.34 (m, 1H, CH), 1.42 – 1.58 (m, 5H, CH, CH2), 1.59 – 1.69

(m, 4H, CH2), 1.70 – 1.73 (m, 2H, CH), 1.77 – 1.80 (m, 2H, CH2), 2.60 (s, 6H, N(CH3)2),

6.99 – 7.12 (m, 3H, ArH), 7.25 – 7.35 (m, 2H, ArH), 7.36 – 7.45 (m, 1H, ArH), 7.49 (m,

1H, ArH), 8.65 (q, J = 7.4 Hz, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 25.3 – 28.1 (10C), 37.0 – 38.1 (2C), 44.1 (2C), 117.4

(ArC), 121.3 (ArC), 126.7 (ArC), 126.8 (ArC), 129.0 (ArC), 130.5 (ArC), 130.6 (ArC),

132.8 (ArC), 133.1 (ArC), 133.2 (ArC), 137.0 (ArC), 137.1 (ArC)

31P-NMR (200 MHz, CDCl3): δ = 69.74 (P-C coupling), 69.86 (P,P(S)Cy2), 69.98 (P-C

coupling)

M/z (calculated) = 425.6

MS (EI / 200 ºC, R=1000): m/z (%) = 425.2 [M+] (45), 381.1, 349.2, 310.2, 299.1, 260.1,

216.0, 194.1, 183.0, 83.1, 55.0

5.5.8 X-Phos oxide derivative 8a (Table 3.19, Entry 3)

X-Phos ligand (8) (0.34 g, 0.72 mmol) and 10 mL CH2Cl2 were placed in a 100 mL

round-bottomed flask. To the cooled solution 3 mL H2O2 (35 %) was added at 0 ºC. The

mixture was stirred at 0 ºC than room temperature overnight. Afterwards 10 mL water

was added. Aqueous phase was extracted with 3x3 mL CH2Cl2. The organics phases

were dried over MgSO4 and evaporated to gain a white powder 8a (0.35 g, 99 %).

mp = 213 - 215 ºC

P(O)Cy2

Experimental Part

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104

1H-NMR (500 MHz, CDCl3): δ = 0.96 (d, J = 6.7 Hz, 6H, CH2), 1.05 – 1.24 (m, 6H, CH2),

1.26 – 1.33 (m, 12H, CH3), 1.34 – 1.46 (m, 4H, CH2), 1.64 – 1.68 (m, 2H, CH2), 1.75 –

1.79 (m, 8H, CH2), 1.84 – 1.95 (m, 2H, CH2), 2.45 (m, 2H, CH(CH3)2), 2.95 (m, 1H,

CH(CH3)2), 7.0 (s, 2H, ArH), 7.15 – 7.20 (m, 1H, ArH), 7.39 – 7.51 (m, 2H, ArH), 7.69 (t,

J = 7.5 Hz, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 22.8 (2C), 24.1 (2C), 25.8 (2C), 26.0 – 26.8 (10C), 30.8

(2C), 34.1 (1C), 37.5 (1C), 37.9 (1C), 120.2 (2C, ArC), 125.9 (ArC), 126.0 (ArC), 129.7

(ArC), 131.8 (ArC), 133.5 (ArC), 133.6 (ArC), 145.2 (ArC), 147.7 (ArC), 147.7 (ArC),

147.9 (ArC)

31P-NMR (500 MHz, CDCl3): δ = 44.07 (P-C coupling), 44.24 (P,P(O)Cy2), 44.39 (P-C

coupling)

M/z (calculated) = 492.7

MS (EI / 200 ºC, R=1000): m/z (%) = 492.2 [M+] (23), 449.2, 367.1, 349.1, 334.1, 278.1,

263.1, 233.1, 214.1, 181.0, 133.0, 83.1, 55.0

IR (KBr):

[cm-1] = 2939, 1751, 1608, 1450, 1357, 1317, 1261, 1191, 1124, 1072, 947,

890, 871, 823, 769, 739, 669, 544, 495

5.5.9 X-Phos sulfide derivative 8b (Table 3.19, Entry 4)

0.43 g (0.9 mmol) X-Phos ligand (8) and elemental sulphur (0.36 g, 1.38 mmol) were

stirred in 10 mL toluene at 95 ºC for 12 hours. The mixture was cooled down and then

filtered and dried over MgSO4. Afterwards it was evaporated to obtain a pale yellow solid

8b in quantitative yield (0.46 g, 99 %). 31P-NMR spectrum shows total conversion.

P(S)Cy

Experimental Part

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105

mp = 224 – 226 ºC

1H-NMR (500 MHz, CDCl3): δ = 0.96 (d, J = 6.7 Hz, 6H, CH2), 1.06 – 1.22 (m, 6H, CH2),

1.24 – 1.30 (m, 6H, CH3), 1.31 – 1.35 (m, 6H, CH2), 1.37 – 1.51 (m, 4H, CH2), 1.53 –

1.64 (m, 4H, CH2), 1.74 – 1.79 (m, 4H, CH2), 1.84 – 1.86 (m, 2H, CH2), 1.98 – 2.08 (m,

2H, CH2), 2.41 (m, 2H, CH(CH3)2), 2.95 (m, 1H, CH(CH3)2), 7.0 (s, 2H, ArH), 7.15 – 7.21

(m, 1H, ArH), 7.39 – 7.49 (m, 2H, ArH), 7.99 – 8.04 (m, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 21.5 (2C), 24.2 (2C), 25.8 (2C), 26.6 – 27.2 (10C), 30.8

(2C), 34.2 (1C), 34.6 (1C), 39.8 (1C), 120.3 (2C, ArC), 125.3 (ArC), 126.2 (ArC), 131.6

(ArC), 132.8 (ArC), 132.9 (ArC), 135.5 (ArC), 137.9 (ArC), 145.4 (ArC), 146.0 (ArC),

148.4 (ArC)

31P-NMR (200 MHz, CDCl3): δ = 59.58 (P,P(S)Cy2)

M/z (calculated) = 508.8

MS (EI / 200 ºC, R=1000): M/z (%) = 508.2 [M+] (14), 465.1, 383.1, 255.7, 191.8, 159.8,

127.8, 95.9, 63.9

5.5.10 Reduction procedure of standard Dave-Phos oxide derivative 7a

305 mg (0.75 mmol) Dave-Phos oxide (7a) was solved in 5 ml xylene and 3 ml (0.02

mol) NEt3. This was heated to 60 °C under reflux then a mixture of 5 ml (0.05 mol)

trichlorosilane and 5 ml xylene was added slowly to the suspension. It was heated and

stirred overnight at 110 °C. Afterward reaction mixture was cooled to room temperature

and solved in 15 mL CH2Cl2. Then the solution was cooled to 0 °C and NaOH (10 w/w

%) was added dropwise until pH=10 was reached. The suspension was filtered under

argon atmosphere over 5 g Al2O3 (90 active, acidic). The organic phase was collected in

a second flask and the water phase was extracted with 20 mL CH2Cl2. The collected

dichloromethane phases were washed 2x10 mL water under argon atmosphere. The

organic layer was reduced to a volume of 10 mL in vacuo. Organic layer was dried over

MgSO4 and completely removed under reduced atmosphere, thus 7 was obtained as a

pale yellow powder (245 mg, 83 %). Conversion of reduction: 83 %.

Experimental Part

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106

1H-NMR (500 MHz, CDCl3): δ = 0.88 – 0.95 (m, 2H, CH2), 1.12 – 1.16 (m, 4H, CH2), 1.27

– 1.32 (m, 4H, CH2), 1.50 – 1.67 (m, 7H, CH, CH2), 1.72 – 1.78 (m, 2H, CH2), 1.81 –

1.83 (m, 2H, CH2), 2.03 – 2.10 (m, 1H, CH), 2.48 (s, 6H, N(CH3)2), 6.94 – 7.11 (m, 3H,

ArH), 7.28 – 7.37 (m, 3H, ArH), 7.40 – 7.44 (m, 1H, ArH), 7.75 – 7.62 (m, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 25.9 – 30.8 (10C), 33.3 – 36.7 (2C), 43.2 (2C), 117.3

(ArC), 120.7 (ArC), 125.8 (ArC), 128.1 (ArC), 130.5 (ArC), 130.8 (ArC), 132.4 (ArC),

132.8 (ArC), 135.8 (ArC), 135.9 (ArC), 149.5 (ArC), 151.5 (ArC)

31P-NMR (200 MHz, CDCl3): δ = -9.59 (P,PCy2), 47.78 (P(O)Cy2)

5.5.11 Reduction procedure of standard X-Phos oxide derivative 8a

112 mg (0.23 mmol) X-Phos oxide (8a) was solved in 5 ml xylene and 3 ml NEt3. This

resulting was heated to 60 °C under reflux then a mixture of 4 ml (0.04 mol)

trichlorosilane and 4 ml xylene was added slowly to the suspension. It was heated and

stirred overnight at 110 °C. Afterward reaction mixture was cooled to room temperature

and solved in 8 mL CH2Cl2. Then the solution was cooled to 0 °C and NaOH (10 w/w %)

was added dropwise until pH=10 was reached. The suspension was filtered under argon

atmosphere over 5 g Al2O3 (90 active, acidic). The organic phase was collected in a

second flask and the water phase was extracted with 10 mL CH2Cl2. The collected

dichloromethane layers were washed two times with 10 mL water under argon

atmosphere. The organic layer was reduced to a volume of 5 mL in vacuum. Organic

phase was dried over MgSO4 and removed under reduced atmosphere, thus 8 was

obtained as a white powder (92 mg, 84 %). Conversion of reduction: 85 %.

1H-NMR (500 MHz, CDCl3): δ = 1.00 – 1.07 (d, J = 6.7 Hz, 6H, CH2), 1.24 – 1.29 (m, 6H,

CH3), 1.30 – 1.42 (m, 16H, CH2, CH3), 1.59 – 1.66 (m, 2H, CH2), 1.71 – 1.85 (m, 8H,

CH2), 1.87 – 1.91 (m, 2H, CH), 2.48 (m, 2H, CH(CH3)2), 2.98 (m, 1H, CH(CH3)2), 7.06 (s,

2H, ArH), 7.17 – 7.26 (m, 1H, ArH), 7.36 – 7.39 (m, 2H, ArH), 7.65 (t, J = 7 Hz, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 22.9 (2C), 24.1 (2C), 25.9 (2C), 26.0–26.8 (10C), 30.9

(2C), 34.1 (1C), 37.5 (1C), 38.0 (1C), 120.2 (ArC), 125.8 (ArC), 129.8 (ArC), 130.9

Experimental Part

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107

(ArC), 131.7 (ArC), 132.4 (ArC), 134.7 (ArC), 136.5 (ArC), 136.6 (ArC), 145.8 (ArC),

146.0 (ArC), 147.7 (ArC)

31P-NMR (200 MHz, CDCl3): δ = - 12.11 (PCy2), 44.58 (P(O)Cy2)

5.5.12 Examined separation procedures of product (6) after the amination

Vacuum distillation of the product 6 at 200 ºC (14 mbar), the temperature of the cooler

was adjusted to 60 ºC.

Column chromatography over silica gel with 1:1 CH2Cl2 / EtOAc, (Rf(6) = 0.9, Rf(7a, 8a) =

0.3) as eluent provided the ligand oxide derivative 7a, 8a.

Separation of the ligand 7 and 8 by protonation: the reaction was run overnight and after

that 200 mL water was added to make phase separation. The catalyst complex was

filtered. After the phase separation, the organics phase was treated with 5 mL HCl (37

%) to protonate the ligand. The solution was neutralized with a mixture of 1.8 g NaOH in

5 mL water. The ligand was in the water phase after the protonation.

Water was removed and the residue was solved in 30 mL dichloromethane (inorganic

salt remained in the flask) and oxidized with 5 mL H2O2 (35 %). Water was added to

perform phase separation and the organic layer was dried over MgSO4 and completely

removed. Yellow solid was obtained using both ligand (7, 8) but not confirmed by NMR

measurements as pure ligand oxide derivatives of 7a or 8a.

5.5.13 Recycling method using X-Phos ligand (Table 3.20, Entry 1)

The amination reaction was conducted in threefold bigger scale under argon with 2.45

mL (26.8 mmol) aniline and 2.82 mL (26.8 mmol) bromobenzene were added in a 200

mL round-bottomed flask to 75 mL toluene. Afterwards 3.9 g (40.5 mmol) NaOtBu as a

base and a mixture of 0.37 g (0.40 mmol) Pd2(dba)3 and 0.375 g (0.82 mmol) X-Phos (8)

Experimental Part

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108

in 15 mL toluene were placed to the solution. The reaction was taken place at 100 °C

overnight.

Spectra of product 6:

1H-NMR (500 MHz, CDCl3): δ = 5.83 (s, 1H, NH), 7.25 (t, J = 7.3 Hz, 2H), 7.34 (d, J = 7.5

Hz, 4H), 7.56 (t, J = 7.4 Hz, 4H)

13C-NMR (125 MHz, CDCl3): δ = 118.2 (4C), 121.3 (2C), 129.7 (4C), 143.5 (2C)

After the reaction, at room temperature 3x20 mL water was added to perform phase

separation. The organic phase was evaporated and distilled under reduced atmosphere

(200 °C, 14 mbar). 3.208 g (70 %) product 6 was separated from the ligand 8.

Afterwards the residue containing this ligand was solved in 15 mL CH2Cl2 and oxidized

by 7.5 mL H2O2 (35 %) at 0 °C overnight. Then 25 mL water and additional 5 mL CH2Cl2

were added to the phase separation. The organic layer was evaporated and dibutylether

(10 mL) was added to precipitate the Pd-derivative (PdO2) from the ligand oxide 8a. The

liquid was stirred and heated for 2 hours at 140 °C then it was cooled down slowly. After

the filtration, the solid was washed with 10 mL dibutylether and the filtrate was dried over

MgSO4 and completely distilled off in vacuo. 265 mg (70 %) 8a was obtained as white

solid.

mp = 209 – 211 °C

1H-NMR (500 MHz, CDCl3): δ = 0.98 (d, J = 6.7 Hz, 6H, CH2), 1.04 – 1.23 (m, 6H, CH2),

1.23 – 1.34 (m, 12H, CH3), 1.36 – 1.56 (m, 4H, CH2), 1.58 – 1.70 (m, 2H, CH2), 1.74 –

1.76 (m, 8H, CH2), 1.84 – 1.97 (m, 2H, CH2), 2.47 (m, 2H, CH(CH3)2), 2.93 (m, 1H,

CH(CH3)2), 7.01 (s, 2H, ArH), 7.15 – 7.24 (m, 1H, ArH), 7.37 – 7.51 (m, 2H, ArH), 7.71

(t, J = 7.5 Hz, 1H, ArH)

13C-NMR (125 MHz, CDCl3): δ = 22.8 (2C), 23.9 (2C), 25.5 (2C), 26.0 – 26.8 (10C), 30.6

(2C), 34.1 (1C), 37.4 (1C), 37.9 (1C), 120.2 (2C, ArC), 126.0 (ArC), 126.5 (ArC), 129.8

(ArC), 131.8 (ArC), 134.1 (ArC), 135.9 (ArC), 141.9 (ArC), 145.2 (ArC), 147.6 (ArC),

148.0 (ArC)

31P-NMR (200 MHz, CDCl3): δ = 44.52 (P(O)Cy2)

Experimental Part

______________________________________________________________________________

109

5.5.14 Recycling method using X-Phos ligand (Table 3.20, Entry 2)

The amination reaction was conducted in threefold bigger scale under argon with 4.1 mL

(44.7 mmol) aniline and 4.7 mL (44.5 mmol) bromobenzene were added in a 200 mL

round-bottomed flask to 80 mL toluene. Afterwards 6.45 g (67.5 mmol) NaOtBu as a

base and a mixture of 0.62 g (0.66 mmol) Pd2(dba)3 and 0.625 g (1.3 mmol) X-Phos (8)

in 15 mL toluene were placed to the solution. The reaction was taken place at 100 °C

overnight.

Spectra of product 6:

1H-NMR (500 MHz, CDCl3): δ = 5.81 (s, 1H, NH), 7.08 (t, J = 7.3 Hz, 2H), 7.21 (d, J = 7.5

Hz, 4H), 7.41 (t, J = 7.4 Hz, 4H)

13C-NMR (125 MHz, CDCl3): δ = 118.1 (4C), 121.2 (2C), 129.5 (4C), 143.2 (2C)

After the reaction, at room temperature 3x30 mL water was added to perform phase

separation. The organic phase was evaporated and distilled under reduced atmosphere

(200 °C, 14 mbar). 6.34 g (84 %) product 6 was separated from the ligand 8. Afterwards

the residue containing this ligand was solved in 15 mL CH2Cl2 and oxidized by 12 mL

H2O2 (35 %) at 0 °C overnight. Then 40 mL water and additional 5 mL CH2Cl2 were

added to the phase separation. The organic layer was evaporated and dibutylether (10

mL) was added to precipitate the Pd-derivative (PdO2) from the ligand oxide 8a. The

liquid was stirred and heated for 2 hours at 140 °C then it was cooled down slowly. After

the filtration, the solid was washed with 2x10 mL dibutylether and the filtrate was dried

over MgSO4 and completely distilled off in vacuo. 465 mg (72 %) 8a was obtained as

white solid.

mp = 208 – 210 °C

1H-NMR (500 MHz, CDCl3): δ = 0.99 (d, J = 6.7 Hz, 6H, CH2), 1.08 – 1.18 (m, 6H, CH2),

1.24 – 1.35 (m, 12H, CH3), 1.36 – 1.43 (m, 4H, CH2), 1.61 – 1.66 (m, 2H, CH2), 1.74 –

1.79 (m, 8H, CH2), 1.86 – 1.94 (m, 2H, CH2), 2.45 (m, 2H, CH(CH3)2), 2.93 (m, 1H,

CH(CH3)2), 7.01 (s, 2H, ArH), 7.17 – 7.24 (m, 1H, ArH), 7.36 – 7.51 (m, 2H, ArH), 7.70

(t, J = 7.5 Hz, 1H, ArH)

Experimental Part

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110

13C-NMR (125 MHz, CDCl3): δ = 22.7 (2C), 24.1 (2C), 25.9 (2C), 26.0 – 26.8 (10C), 30.8

(2C), 34.1 (1C), 37.4 (1C), 38.0 (1C), 120.2 (2C, ArC), 126.0 (ArC), 126.1 (ArC), 129.8

(ArC), 131.8 (ArC), 133.5 (ArC), 133.6 (ArC), 136.0 (ArC), 145.2 (ArC), 145.7 (ArC),

147.7 (ArC)

31P-NMR (200 MHz, CDCl3): δ = 45.19 (P(O)Cy2)

Spectra

______________________________________________________________________________

111

6 Spectra

Asymmetric Hydrogenation

Spectra of substrate 1

1H-NMR spectrum of 1 (200 MHz, CDCl3):

δ = 1.29 (t, J = 7.1 Hz, 3H, C1H3), 2.27 (s, 3H, C6H3), 3.45 (s, 2H, C4H2), 4.20 (q, J = 7.1

Hz, 2H, C2H2)

Spectra of product 2

1H-NMR spectrum of 2 (200 MHz, CDCl3):

δ = 1.23 – 1.32 (m, 6H, C1,6H3), 2.44 – 2.48 (m, 2H, C4H2), 3.10 (s, 1H, OH), 4.13 – 4.24

(m, 3H, C2H2, C5H)

Buchwald-Hartwig amination

Spectra of product 6

1H-NMR (500 MHz, CDCl3): δ = 5.48 (s, 1H, NH), 7.08 (t, J = 8 Hz, 2H), 7.18 (d, J = 9.5

Hz, 4H), 7.45 (t, J = 6.9 Hz, 4H)

13C-NMR (125 MHz, CDCl3): δ = 117.9 (4C), 121.3 (2C), 129.5 (4C), 143.2 (2C)

O O

OH O

Spectra

______________________________________________________________________________

112

Spectra of Cl-MeO-Biphep ligand (3) and its phosphine oxide 3a

Spectra of 3 were assigned by 2D-NMR techniques (COSY, HMBC, HMQC) [115].

Cl-MeO-Biphep ligand (3)

1H-NMR spectrum of Cl-MeO-Biphep ligand (3)

8´

9´

11´

13´

12´

10´

9´ 11´

13´

12´

10´

Spectra

______________________________________________________________________________

113

13C-NMR spectrum of Cl-MeO-Biphep ligand (3)

31P-NMR spectrum of Cl-MeO-Biphep ligand (3)

Spectra

______________________________________________________________________________

114

1H-NMR spetrum of Cl-MeO-Biphep ligand-oxide (3a)

13C-NMR spectrum of Cl-MeO-Biphep ligand-oxide (3a)

Spectra

______________________________________________________________________________

115

31P-NMR spectrum of Cl-MeO-Biphep ligand-oxide (3a)

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116

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