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Doctoral Thesis

Ruthenium/PNNP-catalyzed asymmetric Michael addition

Author(s): Santoro, Francesco

Publication Date: 2007

Permanent Link: https://doi.org/10.3929/ethz-a-005361343

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Diss. ETHNo. 17024

Ruthenium/PNNP-Catalyzed Asymmetric

Michael Addition

A dissertation submitted to the

SWISS FEDERAL INSTITUTE OF TECHNOLOGY ZURICH

For the degree of

DOCTOR OF SCIENCE ETH

Presented by

Francesco Santoro

Dipl. Chem. ETH Zurich

Born on July 15, 1979

Accepted on Recommendation of

Prof. Dr. Antonio Togni, Examiner

Dr. Antonio Mezzetti, Co-Examiner

Prof. Dr. Peter Chen, Co-Examiner

Zurich 2007

Acknowledgements

I would like to express my gratitude to Prof. Dr. Antonio Togni for giving me the privilege

to carry out my Ph.D. in his group, for always being available whenever I had questions, and for the

interesting discussions about chemistry and other topics.

A special thanks to Dr. Antonio Mezzetti, who supervised my Ph.D. project, and

significantly contributed to my scientific formation. His critic and zealous direction of my work

stimulated, through numerous events, the continuous need for personal and professional

improvements.

I wish to thank Prof. Dr. Peter Chen for accepting to co-referee this thesis.

I thank all the people who contributed to the development of this thesis through their

technical expertise: Dr. Heinz Ruegger and Serena Filippuzzi for the NMR spectroscopy; Dr.

Isabelle Haller, Dr. Sebastian Gischig, and Pietro Butti for the X-ray crystallography.

I wish to thank all the members of the Togni group for the stimulating and pleasant working

environment, and for the many lovely activities inside and outside the laboratory (including:

dinners, holidays, conferences, ski weekends, weddings, concerts, cheese-and-wine(-and-movie)

evenings, expovina excursions, dancing nights, all-night-up-and-cheeseburger-at-5-o'clock nights,

etc.). In particular, I wish to thank my lab-mates, Patrick Eisenberger and Dr. Céline Réthoré, for

the infinite patience and friendship shown every day. A big thanks to Pietro Butti and Marco

Ranocchiari for the exceptional friendship we developed, which is very important to me.

I would like to thank all my friends outside the group for their support and sincere friendship

during my stay in Zürich. Among them, I have to express my gratitude to Luca Cereghetti, who had

the guts to live under the same roof with me for 9 years (!!!!), and to Marco Abbondio, a true friend

since childhood and very talented artist, who keeps inviting me to exquisite home-made dinners

knowing that I could never keep up with his cooking standards.

Infine vorrei ringraziare di cuore i miei genitori, mia sorella e Isabelle per avermi sostenuto,

incoraggiato e amato incondizionatamente anche - e soprattutto - durante i periodi piu bui.

List of Publications

"Chiral Dicationic Bis(aqua) Complexes [Ru(OH2)2(PNNP)]2 : The Effect of Double Chloride

Abstraction on Asymmetric Cyclopropanation", C. Bonaccorsi, F. Santoro, S. Gischig, A. Mezzetti,

Organometallics 2006, 25 (8), 2002-2010.

"Chiral Ruthenium PNNP Complexes of Non-Enolized 1,3-Dicarbonyl Compounds: Acidity and

Involvement in Asymmetric Michael Addition", M. Althaus, C. Bonaccorsi, A. Mezzetti, F.

Santoro, Organometallics, 2006, 25 (13), 3108-3110.

"Chiral Ruthenium PNNP Complexes in Asymmetric Michael Addition", F. Santoro, M. Althaus,

C. Bonaccorsi, A. Mezzetti; in preparation.

1 Table of Contents

Table of Contents

Abstract iii

Zusammenfassung vRiassunto vii

1 Introduction 1

1.1 Lewis Acids in Organic Synthesis 1

1.1.1 The Strength of Lewis Acids 3

1.1.2 Carbonyl Groups Coordination to Lewis Acid 6

1.1.3 C-H Acidity Enhancement by Lewis Acids Coordination 8

1.1.4 Lewis Acids Coordination to Enones - Conjugate Addition 9

1.2 Michael Addition 15

1.2.1 Discovery and Definition 15

1.2.2 Asymmetric Michael Addition 17

1.2.3 Asymmetric Catalytic Michael Addition 18

1.3 Heterofunctionalization of 1,3-Dicarbonyl Compounds 34

1.4 Ruthenium/PNNP-Catalyzed Organic Transformations^^_

39

1.4.1 Chiral Tetradentate Ligands 39

1.4.2 Epoxidation of Olefins 42

1.4.3 Cyclopropanation of Olefins_______

44

1.4.4 Fluorinationof ß-Keto Esters 47

1.4.5 Hydroxylation of ß-Keto Esters and oc-Acyl Lactams 50

1.5 Aims__

51

1.6 Literature____^^^_^^^__„__„_„„__„

54

2 Ruthenium/PNNP-Catalyzed Michael Addition 612.1 Ruthenium/PNNP Complexes of 1,3-Dicarbonyl Compounds

_______________

61

2.1.1 Complexes of Non-Enolized 1,3-Dicarbonyl Compounds 61

2.1.2 Enolato Complexes 622.1.3 Note on the Rarity of Complexes With Non-Enolized 1,3-Dicarbonyl Compounds 65

2.2 Catalytic Michael Addition 68

2.2.1 Discussion on the Substrate Screening 70

2.3 Activation Screening 73

2.4 Stoichiometric Reactions 77

2.4.1 Reaction of 3 with Methyl Vinyl Ketone.____m_____________^_

77

2.4.2 Reaction of 4 with Methyl Vinyl Ketone 782.5 Enolato Complexes as Catalyst Precursors 80

2.6 The Effects of Polar Additives as Proton-Transfer Agents^_^^__„_„„

82

2.7 Solvent Effect______^^_

83

2.8 NMR Investigations of the Reaction of [RuCl2(la)] with (Et30)PF6 (2 equiv) 85

2.9 pKa Determination of 1,3-Dicarbonyl Complexes 3 and 17 89

2.9.1 Method^_^_____

90

2.9.2 Involvement in the Michael Addition 93

2.10 Deuteration and Protonation of Enolate Complex 4 at Low Temperature 93

2.10.1 Method 95

2.10.2 Deuteration with CF3C02D....

95

Table of Contents ii

2.10.1i Deuteration with D2S04 96

2.10.' Protonation with HBF^EtîO 98

2.11 Concluding Remarks 100

2.12 Literature 101

3 Developing New Lewis Acids Based on Nitrosyl Complexes3.1 Introduction

103

103

3.1.1 Counting Electrons 104

3.1.2

3.1.3

3.1.4

Frontier Molecular Orbitals Interpretation of Nitrosyl-Metal complexes

Nitrosyl Complexes of Transition-Metals as Lewis Acids

Metal Nitrosyl Complexes as Electron-Switch

105

108

110

3.2 Synthesis of rRuCl(PNNP)(NO)l 112

3.2.1

3.2.2

3.2.3

Synthesis of [Ru(dppe)2(NO)l+ (97a)Attempted Synthesis of [RuCl(la)(NO)l (100)

Synthesis of [RuCl(lb)(NO)] (7) and Attempted Synthesis of [Ru(lb)(NO)]+

112

114

115

3.2.4

3.2.5

3.2.6

Crystal Structure of rRuCl(lb)(NO)l (7)

Crystal Structure of rRuCl(N02)(lb)l (8)

Catalytic Attempts

117

122

124

3.3 Rh/PNNP Complexes 127

3.3.1

3.3.2

3.3.3

3.3.4

Attempted Synthesis of [Rh(PNNP)(NO)l2+ (113)Crystal Structure of rRh(la)lPFrt (9)

Synthesis of [Rhi2(la)l+ (10) and Catalytic AttemptsSynthesis of rRhMeI(la)l+ (11)

128

129

130

133

3.3.5

3.4

Reaction of [Rh(la)]+ with (Me30)BF4: Synthesis and Characterization of 12Conclusion and Outlook

136

139

3.5 Literature 141

4 Experimental Part 143

4.1 General 143

4.2 Chapter 2 145

4.2.1 Complexes 145

4.2.2 Substrates 150

4.2.3 Catalysis Products 154

4.2.4 Activation Screening 157

4.2.5 Stoichiometric Reactions 158

4.2.6

4.2.7

4.3

Measurement of the pKa of Complex 17

Deuteration and Protonation at Low Temperature

Chapter 3

159

160

160

4.4 Literature 166

5 Appendix 167

5.1 List of Abbreviations 167

5.2 List of Substances 168

5.3 Crystallographic Data 169

5.3.1 rRuCl(lb)(NO)l (7) 169

5.3.2 [RuCl(N02)(lb)l (8) 172

5.3.3 |Rli(la)lPFfi (9PF6) 175

5.4 Curriculum Vitae 179

iii Abstract

Abstract

The first part of this thesis (chapter 2) is focused on the application of the ruthenium

complex [RuCl2(la)] (2) bearing a chiral tetradentate PNNP ligand (la) as catalyst precursor in the

asymmetric Michael addition of 1,3-dicarbonyl compounds to methyl vinyl ketone.

Previous studies revealed that the activation of [RuCl2(la)] (2) with halide scavengers gives

a Lewis acidic catalyst that has been employed in the asymmetric fluorination and hydroxylation of

1,3-dicarbonyl compounds. Differently than analogous systems, the ß-keto ester 5a coordinates to

the activated ruthenium fragment in the ^o/7-enolized form to give 3. The structure of 3 was

disclosed by comparing its NMR spectroscopic data with those of its enolato analogue 4, which was

structurally characterized. Complex 3 catalyzes the Michael addition of 1,3-dicarbonyl compounds

to methyl vinyl ketone in CH2C12 with quantitative yield and up to 93 % ee.

QN

^-^Ph2 Ph2x=/1a

0 O

| 1) (Et30)PF6 (2 equiv)

N7, l~N^

^P | P^CI&x ®&

~\2+

NEt,

OFT

2 + 2(Et30)PF6

(5 mol-%)

R2

5

up to >99 % yield, 93 % ee

Stoichiometric and catalytic experiments show that the enolato adduct 4 is not nucleophilic

enough to react with the enone. The p/Ca of two 1,3-dicarbonyl-ruthenium adducts was measured

and, although the acidity of the p-keto ester is enhanced by about 8 orders of magnitude, it is still at

least 6 orders of magnitude lower than that of methyl vinyl ketone. This strongly suggests that the

enone is not protonated to a significant extent in the reaction mixture. Taken together, these data

suggest that complex 3, rather than 4, is an intermediate in the catalytic reaction.

On the other hand, the catalytic performances are influenced by the presence of a polar co-

solvent such as Et20. Low temperature deuteration and protonation of the enolato complex 4

suggest the existence of a thermally disfavored tautomer of 3, that we tentatively identify as the

coordinated enol compound 3'.

Abstract iv

3 n 3.

A preliminary reaction mechanism is proposed in which 3' is the active species in the C-C

bond formation step that activates and attacks the enone in a single step. Thus, Et20 is proposed to

act either as proton shuttle to assist the deprotonation of 3, or to favor the tautomerization of 3 to 3'.

The fact that the speed and enantioselectivity enhancement of the catalysis are dependent by the

kind of ether used supports this hypothesis.

The second part of this thesis describes the efforts to prepare new Lewis acidic catalysts

based on tetradentate PNNP ligands for the asymmetric cyclopropanation and epoxidation of

olefins. In this context, two strategies have been undertaken.

Firstly, it has been attempted to use the bending of the nitrosyl in {MNO}8 complexes to

promote the transfer of a carbene or an oxo ligand from a reactive source to the metal, and then to

the substrate. To that end, a nitrosyl complex of formally ruthenium(O) (7) was prepared and

structurally characterized. To the best of our knowledge, 7 is the first {RuNO}8 compound with

octahedral geometry and bent mctal-nitrosyl bond. Complex 7 reacts readily with molecular oxygen

to give the nitro complex 8, which was also structurally characterized.

As second strategy, we prepared new rhodium-PNNP complexes to be used as Lewis acidic

catalysts, in analogy with the ruthenium-PNNP chemistry, but with the advantage of the double

positive charge. To that end, complexes [RhI2(la)]PF6 (10), [RhIMe(la)]PF6 (11), and

[RhMe(la)](PF6)2 (12) were prepared. Moreover, the structure of the precursor 9 was determined.

Q

1b

/IN',, ' ,,'INn

CI 7

hJLh

\* I VCI 8

/=N N-

\Jriph2 Ph2

1a

cN>op pP'

9

n +

V Zusammenfassung

Zusammenfassung

Der erste Teil dieser Dissertation (Kapitel 2) umfasst die Anwendung des

Ruthenium-Komplexes [RuCi2(la)] (2) als Katalysator für die asymmetrische Michael Addition

von 1,3-Dicarbonylverbindungen an Methylvinylketon.

Wie bereits berichtet, führt die Aktivierung von [RuCbCla)] (2) mit Chloridabstraktoren zur

Bildung eines Lewis-aziden Katalysators, der für die asymmetrische Fluorierung und

Hydroxyherung von 1,3-Dicarbonylverbindungen angewendet wurde. Im Gegensatz zu analogen

Systemen koordiniert ß-Ketoester 5a in seiner nicht-enolisierten Form ans Ru/PNNP-Fragment (3).

Die Charakterisierung von Komplex 3 erfolgte mittels NMR-Spektroskopie und des Vergleiches

mit den NMR-Daten des analogen Enolatokomplexes 4, dessen Struktur kristallographisch

bestimmt wurde. Komplex 3 katalysiert die Michael Addition von 1,3-Dicarbonylverbindungen an

Methylvinylketon in CH2CI2 mit quantitativen Ausbeuten und Enantioselektivitäten bis 93 % ee.

QN=

\}~p p

^-yPh2 Ph2

1a

O O

CI 1)(Et30)PF6(2equiv

cfe>2> °H2+

CI

2

OR^

R2

5

2 + 2(Et30)PF6

(5 mol"%bis zu >99 % Ausbeute

93 % ee

Stöchiometrische und katalytische Experimente zeigen, dass der Enolatokomplex 4 nicht mit

Methylvinylketon reagiert, weil er nicht nucleophil genug ist. Der pKa von 3 wurde gemessen und

zeigt, dass die Azidität des a-protons des ß-Ketoesters in 3 um acht Grössenordnungen größer ist

als in freiem 5a. Trotzdem, Methylvinylketon ist immer noch sechs Grössenordnungen saurer als 3.

Diese Vergleiche legen nahe, dass Methylvinylketon unter den Reaktionsbedingungen nicht

protoniert wird. Es zeigt sich daher, dass Komplex 3, und nicht 4, ein Zwischenprodukt in der

katalytischen Reaktion ist.

Anderseits beeinflusst die Anwesenheit von polaren Lösungsmitteln wie Et20 die

katalytischen Eigenschaften des beschriebenen Systems. Tieftemperatur-Deuterierungen und

Protonierungen des Enolatokomplexes 4 weisen auf die Existenz eines thermodynamisch

unbevorzugten Tautomers von 3 hin, das wir als den Enol-Komplex 3' formuliert haben.

Zusammenfassung vi

N^\~|2+-h-tQ

3 n 3'

Ein Reaktionsmechanismus wurde vorgeschlagen, in dem 3' die reaktive Spezies in der

Bildung der C~C Bindung ist, wobei das Enon gleichzeitig durch Wasserstoffbrücken aktiviert und

vom Nucleophil angegriffen wird. Es wird daher vorgeschlagen, dass Diethylether entweder als

Protonentransfer-Reagenz wirkt, oder die Tautomerisierung von 3 zu 3' fördert. Die Abhängigkeit

der Katalyseeigenschaften von der Art des Esthers unterstützt diese Hypothese.

Der zweite Teil dieser Dissertation befasst sich mit dem Versuch, neue Lewis-azide

Katalysatoren, basierend auf PNNP Liganden, für die asymmetrische Cyclopropanierung und

Epoxidierung zu synthetisieren. Zwei verschiedene Strategien wurden dabei verfolgt.

Erstens wurde versucht, die Koordinationseigenschaften des Nitrosylliganden in {MNO}

Komplexen anzuwenden, um die Übertragung eines Carben- oder Oxo-Liganden aus einer

entsprechenden reaktiven Quelle zum Metall und dann zum Substrat zu fördern. Ein formal

Ruthenium(0)-Nitrosylkomplex (7) wurde synthetisiert und dessen Kristallstruktur bestimmt. Nach

unserem bestem Wissen ist 7 das erste Beispiel eines {RuNO}8 Komplexes mit oktaedrischer

Geometrie und gewinkelter Metall-Nitrosyl Bindung. Komplex 7 reagiert mit molekularem

Sauerstoff zum Mitrit-Komplex 8, dessen Struktur kristallographisch untersucht wurde.

Der zweite Ansatz befasst sich mit der Synthese von Rhodium/PNNP-Komplexen als

Analoge zu den Ruthenium/PNNP Komplexen, aber mit dem Vorteil, dass sie zweifach geladen

sind. Die Komplexe [RhI2(la)]PF6 (10), [RhIMe(la)]PF6 (11) und [RhMe(la)](PF6)2 (12) wurden

synthetisiert und die Struktur von Komplex 9 wurde kristallographisch bestimmt.

\}~p p"\ /^-?

Ph2 Ph2x=/

1b

nCT^Ns

c.\ -,

N

p

Vil Riassunto

Riassunto

La prima parte di questa tesi (capitolo 2) è incentrata sull'applicazione del complesso di

rutenio [RuChfla)] (2) contenente un legante tetradentato chirale PNNP (la) quale precursore del

catalizzatore nell'addizione di Michael asimmetrica di composti 1,3-dicarbonilici al metil¬

vinilchetone.

E' stato osservato in precedenti studi che l'estrazione di un legante cloro da [RuC^la)] (2)

produce degli acidi di Lewis che sono stati utilizzati corne catalizzatori nella fluorurazione e

idrossilazione asimmetrica di composti 1,3-dicarbonilici. A differenza di sistemi catalitici analoghi,

il ß-chetoestere 5a si coordina al complesso attivo di rutenio nella forma non enolizzata per dare il

complesso 3. La struttura di 3 è stata dedotta confrontando i dati di spettroscopia NMR con quelli

dell'analogo enolato complesso 4, per il quale è stato possibile determinare la struttura cristallina. Il

complesso 3 catalizza l'addizione di Michael di composti 1,3-dicarbonilici al metilvinilchetone con

rese quantitative e fino al 93% di eccesso enantiomerico (ee).

Q/=N N=n

1a

1)(Et30)PF6(2equiv)

"db^,,' oy, y*

ClV~y

5a

0 0O

2 + 2(Et30)PF6

OR3+ ^JL (5 m°' %) , R1 ,/\ ORJ fino a >99 % di resa, 93 % ee

R2

5

Esperimenti stechiometrici e catalitici hanno dimostrato che l'enolato complesso 4 non è

abbastanza nucleofilo per reagire con l'enone. È stato misurato il pK^ di due addotti di rutenio con i

substrati 5a e 5g e, per quanto l'acidità del substrata sia stata incrementata di otto ordini di

grandezza, è sempre minore dell'acidità dell'acido coniugato dell'enone di almeno un fattore 6.

Questo suggerisce che l'enone non venga significativamente protonato durante la catalisi. In

conclusions queste osservazioni suggeriscono che 3 (e non 4) sia un intermedio del ciclo catalitico.

È stato osservato che la reazione catalitica è influenzata dalla presenza di solventi polari

quali per esempio Et20. Analisi NMR délia reazione di deuterazione e protonazione dell'enolato

complesso 4 a bassa temperatura suggeriscono la presenza di un tautomero di 3

termodinamicamente sfavorito. Si presuppone che questo composta sia l'enolo complesso 3'.

Riassunto vin

3 n 3.

Si propone quindi, in via präliminare, un meccanismo di reazione in cui 3' è la specie attiva

nella la tormazione del nuovo legame carbonio-carbonio, che al tempo stesso attiva e attacca

1'enone. Di conseguenza si è ipotizzato che l'etere assista la prototropia: promuovendo la

deprotonazione di 3 0 favorendo la tautomerizzazione da 3 a 3'. Questa ipotesi è supportata dal fatto

che la velocità e la stereoselettività della reazione catalitica dipendano dal tipo di etere usato.

La seconda parte di questa tesi descrive i tentativi di sviluppo di nuovi acidi di Lewis basati

su complessi di leganti tetradentati PNNP quali catalizzatori asimmetrici per la ciclopropanazione e

l'cpossidazione di olefine. Questo obiettivo è stato perseguito attraverso due stratégie.

Inizialmente si è cercato di sfruttare le modalité di coordinazione del nitrosile nei complessi

del tipo {MNO}8 per promuovere il trasferimento di un carbene 0 ossene da reagenti reattivi al

métallo, e quindi al substrato. A questo scopo è stato preparato un complesso nitrosilico di rutenio

(7), del quale è stata determinata la struttura crystallina. Per quanto ci risulta, 7 è il primo composto

del tipo {RuNO}8 ad avere una geometria ottaedrica e un legame M-N-0 piegato. II complesso 7

reagisce velocemente con ossigeno molecolare producendo il nitro complesso 8, la cui struttura

cristallina è stata ugualmente determinata.

Come seconda strategia sono stati preparati dei nuovi complessi di rodio con leganti PNNP

da usare come catalizzatori in maniera analoga ai succitati complessi di rutenio, awalendosi

dell'incremento di acidità di Lewis dovuto alla doppia carica positiva. A questo scopo sono stati

sintetizzati i complessi [RhI2(la)JPF6 (10), [RhIMe(la)]PF6 (11) e [RhMe(la)](PF6)3 (12). La

struttura cristallina del complesso 9 è stata determinata.

Qtfi

,

£&Ph2 Ph2W1b

CI 7

h^Lh-N.„ I „>N>

Cp-^P)CI 8

Qn +

1

tfg=N N=

9

1 Introduction 1

1 Introduction

This thesis is focused on the development of an asymmetric Michael addition catalyzed by

Lewis-acidic ruthenium/PNNP complexes. Therefore, the introduction will cover the relevant

aspects of Lewis acids in organic chemistry, an overview on the Michael addition with focus on its

asymmetric version, and the application of the ruthenium/PNNP catalysts developed in our

laboratory.

1.1 Lewis Acids in Organic Synthesis

G. N. Lewis published in 1923 a landmark essay laying the foundation for our modern

understanding of the valence bond.1 In this work, he formulated the concept of the chemical bond

by the sharing of electron pairs and provided the following definition of donors and acceptors:

"...with complete generality we may say that a basic substance is one which has a lone pair of

electrons which may be used to complete the stable group of another atom, and that an acidic

substance is one which can employ a lone pair from another molecule in completing the stable

group of one of its own atoms." In modern terms, a Lewis acid is a chemical entity with an empty

orbital that is able to accept an electron-pair from the filled orbital of another molecule—the base.

Although the concept of Lewis acidity is different from the definition of Bransted acidity, it must be

noted that there is no such difference between Lewis bases and Bronsted bases. Both concepts are in

fact equivalent because all species able to donate an electron-pair are, to a certain extent, proton

acceptors.

The involvement of Lewis acids in organic chemistry is associated with their complexation

with organic molecules, usually, at electron-rich heteroatomic functional groups. Among these, the

interaction between Lewis acids and carbonyl groups received the greatest attention from the

scientific community because of its central role in synthetic organic chemistry. The importance of

Lewis acids in synthetic organic chemistry is indicated by the tremendous amount of publications

available in books,3"6 reviews, and articles. Scientific accounts concerning Lewis acids appear in

virtually every edition of major chemistry journals.

Initially, the Lewis acids applied for the promotion of Diels-Alder reactions were mainly

halides of B(I1I), Sn(IV), Ti(IV), lanthanides, Zn(II), and Mg(II).7 At that time, stoichiometric or

*

In 1988 the International Union of Pure and Applied Chemistry (IUPAC) suggested to use the term "proton"

only in relation to the cation of the isotope 'H and to use the word "hydron" in the case of isotope mixtures.2 However,

the term "proton" is still by far the most commonly used expression to indicate the naturally occurring cation. For that

reason, only the word "proton" will be used in this thesis.

2 1 Introduction

greater amounts of the Lewis-acidic reagent were employed to compensate for the decomposition

by hydrolysis and, thus, to achieve the highest acceleration.

However, the interest in Lewis-acidic compounds is mainly owed to their application as

molecular catalysts. Lewis acids can catalyze an enormous number of different reactions, thus, any

serious attempt to comprehensively survey all aspects of this chemistry is a frightful task. However,

one of the most important contributions of Lewis acids in synthetic chemistry is their application in

the formation of new carbon-carbon bonds.

There is no need to point out the importance of the formation of new carbon-carbon bonds in

organic synthesis. Classical reactions such as the Friedel-Crafts alkylation and acylation, Diels-

Alder cyclization, ene reaction, Mukaiyama aldol reaction, epoxide opening, and conjugate

additions are only a selection of the most important transformations promoted by Lewis acids such

as BF3, AlCb, TiCl4, SnCl4, FeCl3 (Scheme 1.1).3"6

R'

o

XR2 ;

+ R2-X

OR

Friedel-Crafts

Acylation

Friedel-Crafts

Alkylation

Die Is-Alder

Reaction

O^OR

X = Halogen

X = Halogen

ROH

+ J^ ene ReactionOH

C02R

OTMS O

+ AH R

Mukaiyama

aldol Reaction AX

Scheme 1.1: Examples of key organic transformations catalyzed by Lewis acids

Unfortunately, these "classical" Lewis acids often do not provide the chemo-, regio-, or

stereoselectivity required by modern organic synthesis. For that reason, the research in this field has

been characterized in the last years by an impressive expansion in the development of more

1 Introduction 3

selective, reactive, and versatile catalysts. To that end, a Lewis acid can be coordinated to

specifically designed ligands allowing the fine tuning of the reagent properties in terms of acidity

strength, chemo-, stereo-, and, by means of chiral ligands, enantioselectivity. An exhaustive

discussion on the role of Lewis acids in organic synthesis can be found in the books of Schinzer,

and Santelli and Pons.4

In the next paragraphs, it will be introduced how a Lewis acid can activate a substrate to

promote reactions. To that end, the discussion will concern the concept of Lewis acidity and some

attempts made to measure it. In a second part, it will be shown how Lewis acids can activate

carbonyl compounds in three model reactions—the 1,2-addition to carbonyl groups, the a-

functionalization of carbonyl groups, and the conjugate addition. In each case, the function of the

Lewis acid will be highlighted by focusing on the interactions between the Lewis acid and the

organic substrates.

1.1.1 The Strength of Lewis Acids

After the discovery by Yates and Eaton8 in 1960 that Lewis acids accelerate Diels-Alder

reactions, chemists were interested in giving a quantitative classification of Lewis acids according

to their strength. The idea of putting Lewis-acidic compounds in tables ordered by their acidity

strength, as it has been done for Bransted acids, was an appealing task. Unfortunately, the strength

of a Lewis acid is a more complicated concept than the strength of a Bransted acid.

For instance, the latter is defined as the extent of proton dissociation in a solvent of

reference. Bronsted acids can thus be ordered according to their strength by comparing the

equilibrium constant of the proton transfer reaction reported in equation 1.1 with B being the

solvent molecule.

AH + B - A" + BH+ (Eq. 1.1)

However, according to Lewis's concept of acids and bases, equation 1.1 is a particular case

of the general base-exchange reaction formulated in equation 1.2 in which the only Lewis acid is

H+. Thus, the comparison of Bronsted acidity means to compare the proton affinity of different

compounds.

AB1 + B2 - B1 + AB2(Eq 1,2)

In the general case when the acid is not H+ but any Lewis acid, the equilibrium constant /Ceq

in equation 1.2 is determined the by difference in the standard free energies of adducts AB1 and

AB2.

4 1 Introduction

Measure ofStandard Gibb 's Free Energy

Satchell and Satchell reported in 1969 a first attempt of quantitative measurement of Lewis

acidity according to the equilibrium constants Keq of the association of a Lewis acid with a series of

different bases in solution.9 This might still be described by equation 1.2 in which the base B1 is the

solvent. The measure of equilibrium constants is inherently a measure of the standard Gibb's free

energy AG0 according to equation 1.3.

AG° = -RT\n(Keq) (Eq. 1.3)

A major drawback of this method is the competing association of the solvent to the Lewis

acid. In fact for solubility reasons, it was not always possible to use non-coordinating solvents such

as benzene or hexane, and polar solvents such as acetone or diethyl ether had to be used. The

authors fairly argued that within a series of experiments—that is, same Lewis acid, same solvent,

different bases—all solvent effects were expected to be much the same, also because interactions of

the solvent with the base are usually negligible.

This method offers the possibility to compare the affinity of a Lewis acid for different bases

but no direct comparison between Lewis acids is meaningful because each acid interacted

differently with the solvent. Moreover, the method was restricted to 1:1 adducts.

For that reason, this approach failed to give a satisfying quantitative scale of Lewis acidity

strength.

Measure ofStandard Enthalpy

Drago et al. developed a method for the quantitative measurement of Lewis acidity based on

the enthalpy difference AH° of the Lewis acid-base association reaction in the gas phase or in non-

coordinating solvents (equation 1.4).10"13

A + B AB

(Eq. 1.4)-AH = EAEB + CACB-W

The acid A and the base B were characterized by the empirical parameters E and C. The

enthalpy of the reaction was partitioned into two terms EA EB and CA CB which were said to

correspond to the electrostatic (ionic and dipole-dipole interaction) and covalent contribution in the

acid-base interaction, respectively. The relative scales of parameters E and C for both the acid and

the base have been fixed from four arbitrarily chosen reference values, and then statistically

optimized from a large set of enthalpy values of adduct formations. A third parameter W has been

1 Introduction 5

introduced later to account for processes independent from the actual acid-base association reaction.

For example in the reaction of the dimer [RhCl(CO)2]2 with a base B to give the adduct

[RhCl(B)(CO)2], /^corresponds to the enthalpy of cleaving the dimer.

In the case one or both reaction partners are charged, there is a significant stabilization by

the partial charge-transfer between the acid and the base, which causes a poor fit of the

experimental data. To account for this phenomenon, the third term W was replaced with RaTb

where RA is the "receptance" of the acid and Tü the "transmittance" of the base (equation 1.5).14

-AH = EAEB+ CA CB + RATB (Eq. 1.5)

This model predicts satisfyingly the enthalpy of the association reaction between Lewis acids

and bases, albeit only in the gas phase or very weakly-coordinating solvents such as CCU or

benzene. The enthalpy of reactions carried out in more polar solvents can deviate substantially from

the calculated value.13

Anyway, this approach shows, basically, that the nature of the Lewis acid-base interaction is

composed by electrostatic attraction, covalent bond resulting from the energy match and overlap

between the filled donor orbital and the empty acceptor orbital, and charge-transfer stabilization

energy.

It must be noted that this model elegantly includes the concept of hard and soft acids and

bases (HSAB),15'16 which is a very important feature governing Lewis acids-bases interactions. In

fact, a hard acid or base will have a larger E- and a smaller C-value, whereas a soft acid or base will

have a smaller E- and a larger C-value. In other words, interactions between hard acids and bases

are prevalently of electrostatic nature, whereas interactions between soft acids and bases are

essentially of covalent nature.

Measure ofNMR Chemical Shifts

In 1982, Childs17 offered a fundamentally original method for the determination of Lewis-

acidic strength. He observed the chemical shifts differences in oc,ß-unsaturated carbonyl compounds

upon coordination to Lewis acids. For example he observed that, for crotonaldehyde, the magnitude

of the shift of the H signal upon complexation is the greatest, whereas those of H2 and H4 are

smaller but still linearly related to the shift of the H3 signal. Instead, the shift of the H1 signal

induced by coordination appeared to vary randomly (Figure 1.1).

6 1 Introduction

3

44h-Y T 'HiH H

4 2

Figure 1.1

Based on the shifts of the H3 resonances of various bases, the authors proposed the following

scale of Lewis acidity: BBr3 > BC13 > SbCl5 > A1C13 > BF3 > EtAlCfe > TiCl4 > Et2AlCl > SnCL, >

Et3Al.

In 1990, Laszlo18 provided some theoretical support to the experimental work of Childs,

Calculations of Lewis acid adducts of crotonaldehyde and methyl acrylate showed a direct

correlation between the shifts of the H3 resonances with the LUMO (71*) energy of the oc,ß-

unsaturated carbonyl substrate.

The experimental confirmation of the reliability of such method was reported shortly after.

The observed pseudo first-order rate constant k of the ene reaction catalyzed by Lewis acids showed

a linear relation with the calculated energy of the LUMO orbital of methyl acrylate (Scheme 1.2).19

Most importantly, the activity of the Lewis acids tested in this experiment showed the same trend as

predicted by Childs.

^% -U, Lewis acid (10 mol-%)Scheme 1.2: Lewis acid-catalyzed ene reaction

In conclusion, the NMR method developed by Childs has the considerable merit to provide a

direct measurement of the strength of a Lewis acid expressed as activation power, which is most

valuable in the prediction of catalytic activity.

1.1.2 Carbonyl Groups Coordination to Lewis Acid

Understanding the nature of the interactions between a Lewis acid and a carbonyl group is a

necessary prerequisite to fully appreciate the function of Lewis acids in catalysis. Carbonyl

compounds interact with Lewis acids primarily through a-coordination with one lone pair of the

oxygen atom. Rare examples of ^-coordination through the C-0 double bond building a if-

metalloxirane complex are also known but they are not relevant for the purpose of this discussion,7

1 Introduction 7

Representative examples of a- and 7t-bonded complexes of Lewis acid with carbonyl groups are

illustrated in Figure 1.220,21

^-coordination

Ri" R2

X

7i -coordination R2'/

R

M

!X-b Ar'

Figure 1.2: The a- and ^-coordination modes of Lewis acids with carbonyl groups

The most important consequence of carbonyl coordination to a Lewis acid is the increase of

electrophilicity at the carbonyl C-atom. The concept of enhanced electrophilicity of a carbonyl

group upon Lewis acid coordination was explained by Reetz20 for the coordination of BF3 to

acetaldehyde by means of semi-empirical MNDO calculations.

H,C

n* LUMO

-0.776 °-585

E = +0.76 eV

-0.827

E=-1.59eV

BF,

Figure 1.3: MNDO energies and coefficients of the LUMO of CH3CHO and CH3CHO-BF3

The results showed that the BF3 complex had a lower LUMO energy and increased positive

charge at the carbonyl C-atom (Figure 1.3 and Figure 1.4). As result of the altered electronic

distribution, Lewis acids can promote the nucleophilic attack at the carbonyl C-atom and, thus,

catalyze the 1,2-addition to carbonyl groups.

H3C'S+0.242

H3C H

+0.363

-BF,

Figure 1.4: MNDO-computed charges of the carbonyl C-atom

8 1 Introduction

The addition to C-0 double bonds is a very important chemical transformation because of its

very broad applicability. In fact, countless different carbon- and heteronucleophiles have been

successfully added to carbonyl groups. Among the additions of carbon nucleophiles catalyzed by

Lewis acids, the most important ones are the Mukaiyama aldol reaction, the reduction of the

carbonyl group, and the alkylation, allylation, cyanation, and phenylation of aldehydes, ketones, and

esters (Scheme 1.3).

O Lewis acid OH

Rl + r*ar3 Ar

OSiMe3

R1 = R^^ H" CN" AlkyP Ar"Mukaiyama reduction cyanation alkylation arylationaldol reaction

Scheme 1.3: Examples of nucleophilic addition to carbonyl compounds catalyzed by Lewis

acids

1.1.3 C-H Acidity Enhancement by Lewis Acids Coordination

The interaction of Lewis acids with non-conjugated carbonyl groups results in the increase

of the acidity of the a-proton. This effect derives from the change in the charge distribution within

the molecule and from the stabilization of the enolate (Scheme 1.4).

n

-H ?"r

.—-

^yRH H H

LA^ LA.O CT

R ^ü J^R

H H H

Scheme 1.4: Effect of the coordination of a carbonyl to a Lewis acid on the adjacent a-

proton

An example of exploitation of this effect in organic synthesis is the aldol condensation via

boron enolates.22 In this reaction, a ketone is smoothly converted to the corresponding enolato-

boron complex by deprotonation with an amine such as N'Pr2Et. The enolato-boron complex reacts

then with the aldehyde to give the expected aldol product with high stereo- and regioselectivity

(Scheme 1.5).

1 Introduction 9

BR2(OS02CF3) BR,„Xu

0 (lequiv) 0'2 R H 0 OH Q OH

riA^r2iprNB R1^ Ri^Y^RS

+ Rl^Y^R32

R2 R2 R2

R' = Alkyl Z/E ratio up to 99-1 erythro/threo ratio up to 97:3

Scheme 1.5: Boron-promoted aldol reaction

aq»-aBy complexation with the boron reagent, the a-H acidity of the ketone (normally pATa'

-19-20)23 is increased by at least 8-9 pK3 units, so that 'Pr2EtN (pKam = ~\ l)24 is sufficiently basic

to carry out the deprotonation. However, the Lewis acid must be used in stoichiometric amounts to

avoid self-condensation along with other side-reactions, which rules out the development of a

catalytic version of the direct aldol reaction.

Enhancement of acidity by complexation with Lewis acids is particularly evident with 1,3-

dicarbonyl compounds. These compounds already contain an acidic C-H group (pKa = 10-15) and,

upon coordination with a Lewis acid, they usually enolize spontaneously without the need of a

supplementary base. The synthetic applications of the Lewis acid activation of 1,3-dicarbonyl

compounds will be discussed in Paragraphs 1.2 and 1.3.

1.1.4 Lewis Acids Coordination to Enones - Conjugate Addition

A particular class of substrates that can be activated by coordination to Lewis acids are

a,ß-unsaturated carbonyl compounds. This interaction promotes two classic organic

transformations: the Diels-Alder reaction and the conjugate addition. For the purpose of this

introduction, only the conjugate addition will be discussed here.

The nucleophilic addition to a conjugated system is of paramount importance in organic

synthesis because it is one of the oldest and most frequently used methods for the formation of new

C-C bonds.25,26 Differently to classical 1,2-additions, the conjugate addition occurs at the

extremities of the conjugated system (Scheme 1.6).

1,2-additionX-Y - ^s^^O-

X

1,4-addition

^^° + X-Y - X^^/0.y

Scheme 1.6: Simplified concept of 1,2-addition versus 1,4- or conjugate addition

10 1 Introduction

For example, the cyanide ion, which normally adds to the carbonyl bond in aldehydes and

ketones, can add to a C-C double bond of a conjugated system (Scheme 1.7).25

EtOH

Ph^^^O + KCN » Ph^\^0Ph CN Ph

Scheme 1.7: Conjugated addition of cyanide

Although the reaction appears to be a 1,2-addition to the C-C double bond, the mechanism

actually involves the 1,4-addition of HCN to the conjugated system followed by tautomerization of

the enolate intermediate to the more stable keto form (Scheme 1.8).25

Ph^^\^0 + HCN - Ph^^^OH __—^ Ph^/\^0Ph CN Ph CN Ph

Scheme 1.8: Stepwise addition of HCN to the conjugated system showing the enol

intermediate

The electrophile is typically an a,ß-unsaturated carbonyl compound (ketone, aldehyde, or

ester), but alkenes with other electron withdrawing groups such as nitro, cyano, or sulfonyl are also

reactive electrophiles in the conjugate addition. Similarly, different kinds of nucleophiles such as

amines, phosphines, silanes, alkoxides, and sulfides have also been used (Scheme 1.9).

Nu^^^EWG 1) Nu~ l

R^

2) H+

Nu = -C, -N,-P,-Si, -O, -S...

EWG = -CHO, -COR, -C02R, -CONR2, ~N02, -CN, -S02R

Scheme 1.9: Generalized conjugate addition

The concept of conjugate addition can be extended to longer conjugated systems, as

demonstrated in the examples reported in Scheme 1.10.27,2 However, it must be noted that these are

rare reactions as compared to the classical 1,4-addition.

1 Introduction 11

<,C02Et 1,6-addition

CQ2Et

0 02S'^OH

1,8-addition

Scheme 1.10: Examples of 1,6- and 1,8-conjugate additions

Frontier Molecular Orbital Considerations

Most of the early studies on the coordination of Lewis acids to a,ß-unsaturated carbonyl

compounds were performed in association with Diels-Alder reactions. However, some of these

findings are also relevant to the conjugate addition.

Lewis acids can promote the conjugate addition as indicated by the example reported in

Scheme 1.11. Here, the addition of AlEt3 to the reaction mixture leads to a faster reaction (6 vs. 29

hours) and to the smooth formation of the conjugate adduct (>99 % vs. 67 % yield) even when the

ß-carbon of the enone is highly substituted.29

HMethod A: HCN, NH4CI. 29 h

Method B: HCN, AICI3, 6 h

CN

Method A: 67 % yield, 1:2 cis/trans ratio

Method B: >99 % yield, 1:9 cis/trans ratio

Scheme 1.11: Comparison of conjugate addition ofHCN with and without Lewis acid

It must be considered that a,ß-unsaturated carbonyl compounds are ambidentate

electrophiles because the nucleophilic attack can occur either at the ß-carbon or at the carbonyl

carbon atom. Although the conjugate addition affords more stable products, the electron deficiency

at the carbonyl carbon is greater than at the ß-carbon. Despite that, the conjugate addition is the

12 1 Introduction

most commonly observed process. The factors that favor the 1,2-regioselectivity as compared to the

1,4-addition have been elucidated by Anh and co-workers according to the frontier molecular

orbitals (FMO) theory.30"33 DFT calculations performed on acrolein as standard substrate revealed

that the FMO coefficient of the LUMO is larger at the ß-carbon.34 For soft nucleophiles, such as

delocalized carbanions, the frontier orbital interaction is more important than electrostatic effects;

thus, the attack at the ß-carbon predominates. In other words, the conjugate addition is an orbital

controlled process.

Houk34 and Ottenbrite35 performed DFT calculations on acrolein as model substrate and

compared the frontier molecular orbitals (FMO) of the free compound with its BF3-complex and the

protonated species. The results showed that, upon coordination of a Lewis acid or protonation, the

most noticeable change in the electronic structure of the aldehyde is the considerable decrease of

the energy of the LUMO (Figure 1.5).

.^\-^-0 j^-^'Z'O^ ^\^-0*

E = +5.96eV E = +3.33eV E=-6.5eV

Figure 1.5: FMO energies of acrolein, acrolein-BF3 complex, and acroleinium ion

The reduced energy gap between the HOMO of the diene and the LUMO of the dienophile is

believed to be responsible for the observed enhancement of the reaction rate.

Conjugate Addition ofReactive Carbanions

To form new C-C bonds, the nucleophile must be a carbanion. It is possible to divide

carbanions in two classes. Stabilized carbanions are those in which the negative change is stabilized

by derealization with a near electron withdrawing group such as ketones, aldehydes, esters, nitro

groups, cyano groups, etc. The anions of relatively acidic C-H groups belong to this category. Non-

stabilized carbanions are compounds in which the negative charge is localized. It is the case, for

example, of simple alkyl or aryl organometallic reagents (Figure 1.6).

AUS

« , ... .

i^\- 1^ 02N. _ NC. R102S\_Stabilized carbanions R] R^l ] | l

R2 R2 RR R2

Non-stabilized carbanions RLi ZnR2 RMgBr Li[R2Cu] AIR3

Figure 1.6: Examples of stabilized and non-stabilized carbanions

1 Introduction 13

The conjugate addition of organometallic carbanions such as organolithium, organozinc,

Grignard, and cuprate reagents to a,ß-unsaturated carbonyl compounds represents one of the most

investigated reaction class and constitutes a conspicuous chapter in the literature of C-C bond

formation. ' •- The conjugate addition with organometallic compounds is a strategic

transformation from a synthetic point of view because it offers the possibility to form a new C-C

bond with high chemo- and regioselectivity by using highly reactive reagents that are generally

readily available from simple alkyl halides (Scheme 1.12). Very often, the addition of a catalytic

amount of a copper salt dramatically improves the regioselectivity in favor of the 1,4-adduct and

increases the rate of the reaction.

MR

copper catalyst

MR = RMgBr of RMgCI, ZnR2, RLi

R = alkyl, aryl

Scheme 1.12: Generalized copper-catalyzed conjugate addition of organometallic

carbanions

The relevant literature on the mechanism of the conjugate addition of organocuprates to

enones has been reviewed by Woodward38 and Nakamura and Mori39 in 2000. Recently, Minnaard

and Feringa also reported an article on the mechanism of the copper-catalyzed conjugate addition of

Grignard reagents to enones.40

In general, the first step involves the transmetallation of the MR fragment to form an

organocuprate intermediate that contains the substructure [R2Cu]~. This cuprate fragment binds to

the "soft" C-C double bond as in 19, whereas the resulting free metal cation M+ (Li+, MgX+, RZn+,

etc.), being a hard Lewis acid, coordinates to the "hard" oxygen atom. This intermediate has been

directly observed by low-temperature NMR spectroscopy.41 In the following step, one alkyl group

is transferred to the ß-position of the conjugated system (Scheme 1.13).

MNR-Cu-R

,MO O'

, SRpu--j| _CuR

R

19

Scheme 1.13: General mechanism of 1,4-cuprate addition to enones

14 1 Introduction

The actual mechanism of alkyl group transfer from the copper complex to the enone is still

matter of discussion. However, two mechanistic possibilities have been proposed. One mechanism

involves the formation of the Cu(III)-peralkyl intermediate 20 by formal oxidative addition,

42-44followed by reductive elimination to the adduct 22.

"

Alternatively, a 1,2-migratory insertion of

the alkyl group that leads to the carbocuprated complex 21, followed by a rearrangement to the n-

adduct 22, is also a viable hypothesis (Scheme 1.14).45

Ai

R.\

/,Cui—

19

-CuR

22

R 21

Scheme 1.14: Possibilities of the C-C bond forming step in the cuprate conjugate addition

The importance of the activation of the enone by the Lewis acid is fundamental. This is

proved by the fact that the cuprate salt [Li(12-crown-4)2][CuPli2] 23 containing a coordinatively

saturated Li+ does not react with enones, whereas the corresponding cuprate reagent 24 with free

Li+ as counterion reacts readily.38

^~9'A

1 Introduction 15

covalent auxiliaries,26,46 the attention of scientists turned to the development of a catalytic version

using chiral ligands in substoichiometric amounts.7"

Phosphorus ligands are by far the most widely investigated chiral source. Any source of

trivalent phosphorus (phosphines, phosphites, phosphorami dites, phosphonites) has been found to

strongly accelerate the reaction.50 The ideal ratio has been found to be 2 equivalents of P per Cu.47

A very large amount of chiral bidentate phosphine ligands has been tested in the

Cu-catalyzed conjugate addition of dialkylzink to enones along with various P,N- and tetradentate

ligands bearing a P,N,N or P,N,S donor-atom set.47 Moreover, great contributions to this chemistry

have been achieved with the application of chiral monodentate phosphonite, phosphinite, and

phosphoramidite ligands derived from biphenol, binaphthol, or TADDOL (Figure 1.7).

P-R

0

( P-OR'(NR'2)V0

( P-OR'(NR'2) ( P-OR'(NR'2)

Figure 1.7

An example of copper-catalyzed 1,4-additions of diethylzinc to 2-cyclohexenone with a

chiral phosphoramidite ligand is illustrated in Scheme 1.16.51

Et2Zn

toluene, -30°C

L =

Cu(OTf)2 (0.5 mol-%) \/\/ f^TÏT0 )~*L (1 mol-%)

I I II

>98 % ee

Scheme 1.16: Example of highly enantioselective copper-catalyzed conjugated addition

1.2 Michael Addition

1.2.1 Discovery and Definition

The first example of conjugate addition of diethyl sodium malonate to diethyl

ethylidenemalonate was reported by Komnenos in 1883. However, this chemistry really began a

few years later in 1887 with the work of Arthur Michael. In his first publication, he reported his

study on the addition of sodium malonate diethyl ester to cinnamic acid ethyl ester.53 In his

observations he proposed that this reaction could be applied as a general synthetic method for the

formation of new carbon-carbon bonds.

16 1 Introduction

O 9 £ 1)EtOH, reflux, 6h J Jph^^A0B + EtCf^f^OEt 2)h2o "etO^Sr^OEt

H PhAMichael Michael ^LappBn(m H„r

O OEtacceptor donor

Scheme 1.17: First conjugate addition reported by A. Michael

Since then, this reaction attracted very much attention from the scientific community and

many efforts have been devoted to its study and development. It has been found that the general

concept of nucleophilic addition to enones could be applied to a large variety of compound classes

and is generally accepted as one of the most useful constructive methods in organic synthesis.54

For such a broad range of reactions, it is appropriate to define a convention of terms.

"Conjugate addition or 1,4-addition" refers to the addition of any class of nucleophiles, including

reactive carbanions, to an unsaturated system in conjugation with any electron withdrawing group

such as those of Chapter 1.1.3. "Michael addition or Michael reaction" refers to the addition of

stabilized carbanions to unsaturated systems in conjugation with carhonyl groups.

In organic synthesis, the Michael addition is performed usually by deprotonating the acidic

ot-carbon with a strong base such as an alkali metal, alkoxide, or amine. After the addition of the

enone, the product is obtained by hydrolysis with water. To favor the proton exchange, the reaction

often requires the use of protic solvents such as EtOH. The generalized reaction mechanism is

depicted in Scheme 1.18.

Base 9" 9 Q 9~ H+Ri __ >^r1 + ^^ —- A^^K —"R2

H r2 R1 R2 R1 R2

31 32

Scheme 1.18: The generalized mechanism of the base-catalyzed Michael addition

Unlike other nucleophilic C-C bond forming reactions such as the aldol condensation, which

require a stoichiometric formation of the enolate, in the Michael reaction the base can also be used

in catalytic amounts. This allows for milder reaction conditions and, thus, better tolerance toward

sensitive groups. When a catalytic amount of base is used, every reaction step becomes reversible

and the reaction proceeds with thermodynamic control of the enolate formation. This is because the

intermediate enolate species 32, generated by the nucleophilic attack to the ß-carbon, is more basic

1 Introduction 17

than the original enolate compound 31. The protonation of 32 under the reaction conditions drives

the reaction to completion.

1.2.2 Asymmetric Michael Addition

The most appealing feature of the Michael addition is that, with the appropriate substituents,

it leads to the generation of one or two stereogenic centers. As the formation of quaternary carbon

centers is a very attractive achievement from a synthetic point of view, considerable efforts have

been committed to the development of efficient diastereo- and enantioselective Michael reactions.

There are essentially three different strategies to control the absolute configuration of the new

stereocenter in a general conjugate addition (Scheme 1.19).

diastereo selective

reactions

Chiral catalyst R^EWG^

» R^EWG

Scheme 1.19: Strategies for the stereoselective conjugate

The first two approaches, which represent the earliest attempts of stereocontrol in this

reaction, involve the use of chiral reaction partners. The corresponding product contains, thus, at

least two stereogenic centers and the reaction proceeds diastereoselectively. The use of chiral

auxiliaries, which are covalently bonded to the substrates and cleaved at the end of the reaction,

belongs to this group.

On the other hand, when the asymmetric element is located on the catalyst, the optically pure

component, which is usually the most valuable, can be employed in a substoichiometric amount.

Among the enantioselective Michael additions, it is possible to distinguish further classes

with respect to the site at which the stereogenic center is generated. In Type I, the stereogenic center

is formed on the oc-carbon of the nucleophile, whereas in Type II it is formed on the Michael

acceptor side (Scheme 1.20).55

Nu

Chiral conjugate acceptor p'^^^W^ , ^

18 1 Introduction

Type l

Z_,H

R

C02Et +

^Z'

0

R H

^^C02Et

Z^H + R^^Z' Z^M_Z'Z H

Type II

Et02C^/C02Et +PK

Ph O

EtQ2C

C02Et

Scheme 1.20: Types of enantioselective Michael addition

1.2.3 Asymmetric Catalytic Michael Addition

The function of the catalyst is also an important factor to classify Michael reactions. For

Type A reactions, the catalyst activates the Michael donor and generates a chiral nucleophile. In

Type B reactions instead, the catalyst interacts with the Michael acceptor and directs the side of

approach of the nucleophile. Recently, some catalysts have been called bifunctional to underline the

simultaneous activation of both nucleophile and electrophile. As we shall see, this is not such a rare

condition as it is claimed to be.

Type A

RO OR

Type B

R02C

R02C

Scheme 1.21: Types of activation in the catalytic Michael addition

Catalytic reactions of Type A correspond typically to a stereocontrol of Type I. To this group

belong all the basic catalysts (amine, phase transfer catalysts, alkoxide, ect...), most transition and

rare-earth-metal-catalysts, and the proline-derived catalysts that follow the enamine pathway (see

1 Introduction 19

below). On the other hand, reactions of Type B correspond to a stereoselectivity of Type II and are

catalyzed by certain transition-metal complexes and proline-derived compounds that follow the

iminium pathway.

Basic Catalysts

After the first report by Bergson,36 who investigated the Michael addition catalyzed by the

chiral amine 33, Wynberg57 studied a series of cinchona alkaloids as chiral catalysts and found that

(-)-quinine (34) promoted the Michael addition of ethyl indanone-2-carboxylate to methyl vinyl

ketone affording the product in excellent yield and with 76 % ee (Scheme 1.22).

34(1 mol-%)

CCI4, -21"C

6h

99 % yield, 76 % ee

OH

33 34

(-)-quinine

Scheme 1.22: Michael addition catalyzed by the chiral base

The Michael addition catalyzed by chiral amines has been developed since. In particular,

cinchona alkaloids derivatives, in which the nitrogen atom is alkylated to give a chiral salt, have

been used as phase transfer catalysts.58

Achiral Bases with Chiral Crown Ethers

An interesting variation of the base-catalyzed Michael addition was reported by Cram in

1981. Instead of using chiral bases, he showed that asymmetry is induced by achiral potassium

bases such as KO'Bu or KM-I2 in combination with chiral crown ethers such as 35, which acts as

chiral host (Scheme 1.23) for the potassium cation.59

20 1 Introduction

^=^ 36 35

Scheme 1.23: Asymmetric Michael addition with chiral crown ether as K+ host

The crown ether is coordinated to the potassium-enolate intermediate 36 after the

deprotonation of the acidic a-proton and provides the necessary asymmetric environment to afford

excellent enantioselectivity for the substrate tested, 5h (up to 99 % ee). This strategy has been

further developed, including the use of elaborate sugar-annulated crown ether derivatives.60"63

However, these systems are characterized by a narrow reaction scope, being effective only with

specific substrates.

Proline Catalysts

After numerous accounts on the use of proline as chiral ligand in asymmetric transition-

metal-catalyzed reactions, it has been discovered that proline itself can be a powerful

organocatalyst. Many aspects of the proline-catalyzed reactions have attracted the interest of the

scientific community. Apart from the obvious reasons that proline is an abundant chiral molecule, is

very inexpensive, and is available in both enantiomeric forms, the most appealing feature in the

proline structure is the simultaneous presence of a base and of a Bransted acid. A review of various

asymmetric reactions catalyzed by proline was published by List in 2002.64

The modes of reaction are very similar for all the proline-related catalysts and can be divided

in two groups according to the nature of the reactive intermediate, which is either an iminium ion or

an enamine, as illustrated in Scheme 1.24.

1 Introduction 21

iminium pathway N co2H enamine pathway R^/^%.TypeB Type A V^^C\EWG

R' V_ Nu"^

Scheme 1.24: Proline catalysis, the two reaction pathways

In 1991, Yamaguchi65 began his study on asymmetric Michael additions of malonates to a

series of a,ß-unsaturated ketones catalyzed by L-prolinate salts of alkali metals. The best reactivity

and enantioselectivity were observed with the rubidium salt 37 as illustrated in Scheme 1.25.66'67

Unfortunately, prolinate salts were only moderately active and, except the example in Scheme 1.25,

the extent of asymmetric induction was quite low.

POzR,

COzR-i

Os.

37 or 38 (5-10 mol- %) R2 O

R3 Ri02Cy^Ar/

/—N

/"n C02HPh H

COzRt

37: up to 62 % yield, 77 % ee

38: up to 93 % yield, >99 % eeN C02RbH

37 38

Scheme 1.25: Enantioselective Michael addition catalyzed by proline-related

organocatalysts

Noteworthy improvements were obtained by J0rgensen,68 who used the imidazolidine 38 as

organocatalyst. This molecule, prepared from phenylalanine, was of more general applicability and

afforded the desired Michael adducts in excellent yield and enantioselectivity.

In the proposed mechanism, the catalyst reacts with the carbonyl compound to give the

iminium intermediate 39 shown in Scheme 1.26. The nucleophilicity at the ß-carbon of the iminium

ion is increased as compared to the a,ß-unsaturated carbonyl. At the same time, the asymmetric

environment directs the approach of the nucleophile onto the Sï-face (Scheme 1.26).

75

Nu

SI face approach

Scheme 1.26: Mode of reaction of imidazolidine catalyst involving an iminium pathway

22 1 Introduction

Some attempts to use proline for the Type B Michael addition were also made. Kozikowski

and Momose70 reported the intramolecular Michael additions of unactivated ketones to a,ß-

unsaturated enones catalyzed by proline. However, the reaction required prolonged reaction times

and a stoichiometric amount of proline. Despite that, the highest enantioselectivity observed was

34 % ee. Later, List71 and Enders72 applied this methodology to the intermolecular addition of

unactivated ketones to nitroolefins and obtained excellent diastereo- and good enantioselectivities

(Scheme 1.27).

NO;

+

R i Ro R'

^N^C02HH

9 R3

(>15 mol-%) R1 R2

up to 74 % yield,

16:1 dr, 76 % ee

Scheme 1.27: Asymmetric Michael addition of ketones to nitroolefins catalyzed by proline

Cobalt/Chiral Diamine

The first example of transition-metal-catalyzed Michael addition was reported by

Watanabe "' in 1980. In his paper, he reported the clean formation of the Michael adduct from

nitromethane and calchone catalyzed by a series of Co(II) and Ni(II) salts coordinated to various

achiral amines.

In 1984, Brunner75 extended this methodology by using chiral diamine ligands coupled with

[Co(acac)2] to attain the first asymmetric transition-metal-catalyzed Michael addition. The degree of

asymmetric induction was moderate and markedly dependent on the structure of the 1,3-dicarbonyl

compound. The best performances were obtained with the chiral diamine 40 and the indanone

derivative 5h (Scheme 1.28), however, with moderate asymmetric induction (66 % ee). Treatment

of [Co(acac)2] with a stoichiometric amount of chiral diamine 40 in toluene afforded the octahedral

complex [Co(acac)2(40)] (41) as observed by means of MS analysis. Following this

observation, he proposed that the active intermediate is the cobalt complex 41 containing

two coordinated enolates of the 1,3-dicarbonyl substrate.

1 Introduction 23

OEt

5h

NH2

NH;

40

[Co(acac)2] (3 mol-%)

40 (3 mol-%)^

Toi, -50, 64 h

>P •*H2

24 1 Introduction

L =^T "n Ph

OH

42

Q o [Cu(L)]2'H20

(1-10 mol-%)

CCI4, 2-3 d

L = 42: rac.43: 50 % ee

44: 70 % ee45: 70 % ee

Scheme 1.29: Copper-catalyzed Type I Michael addition reported by Desimoni

The mechanism suggested is analogous to that of Brunner's system. Upon addition of the ß-

keto ester to the copper(II) catalyst, the octahedral complex 46 is formed, in which the tetradentate

ligand has A-configuration. The attack of the enone was again thought to be directed onto the Re

face of the substrate by assistance of hydrogen-bond interactions with the equatorial alcohol group

(Figure 1.8).

46

Figure 1.8: The reactive intermediate proposed in the Cu-catalyzed Michael addition

Recently, J0rgensen reported the first Michael additions of cyclic 1,3-dicarbonyl compounds

to 2-oxo-3-butenoate esters catalyzed by copper(II)/bisoxazoline (BOX) complexes; this is a rare

example of a metal-catalyzed Type B Michael addition.77 This methodology afforded the Michael

adducts in high yield and high enantioselectivity (Scheme 1.30).

1 Introduction 25

[Cu(OTf)2(BOX)] 0H ph o(10mol-%)

C02Me C&+C02Me

BOX =

98 % yield, 84 % ee

,0-^\-Q

lBu tBu pu~Q tBu

approach

Scheme 1.30: Copper/BOX-catalyzed Michael addition

The structure of the cyclic 1,3-dicarbonyl unit does not allow the bonding in a bidentate

fashion to the metal center as in the acyclic analogues. Therefore, it has been proposed that the

copper binds to the enone to form the intermediate compound depicted in Scheme 1.30. This model

also accounts for the observed absolute configuration of the Michael products: in the structure of

the proposed intermediate, the S7-face of the double bond is shielded by one tert-buty\ group of the

ligand whereas the i?e-face is open for the nucleophile approach.

However, cyclic 1,3-dicarbonyl compounds are completely enolized and their further

activation is not needed. There is no report of a similar reaction with less enolized 1,3-dicarbonyl

compounds.

Shibasuki 's Catalysts

Shibasaki contributed to the development of the Type II enantioselective Michael addition

(Scheme 1.20, page 18) with a new kind of catalysts based on heterobimetallic-BINOL systems.

The first generation of such complexes was reported in 1995 and was based on rare earth metal-

alkali metal-BINOL complexes. The most active of these was complex 47.78 The catalysts of the

second generation, with the general formula M[A1(B1N0L)2J where M is an alkali metal (M = Li:

48), were published one year later and contained aluminum as metal center.79

The most interesting feature of these catalysts is the simultaneous presence of a basic site—

the oxygen atom of the BINOL—and two Lewis-acidic sites—the metals. The performances of

these complexes represent the state of the art for this kind of reaction (Scheme 1.31).

26 1 Introduction

Bn02C^^C02BnT +

R

Na

'{ ^.Lav ^Na^0 I O

Na *

47 or 48(10mol-%)^

0°C, 24 h

OaO

47 and R = Me:

up to 91 % yield, 92 % ee

.„^C02Bn 48 and R = H:lc02Bn UP to 88 % y^'d' " % eeR

(OH

OH(R)-BINOL

47 48

Scheme 1.31: Shibasaki's bifunctional catalyst for Type II asymmetric Michael additions

The aluminum-catalyzed reaction reported in Scheme 1.31 is so efficient that it has been

possible to scale up the synthesis to 1.3 kg product still with outstanding chemo- and

stereoselectivity (91 % yield and 99 % ee).80 NMR spectroscopic investigations and molecular

mechanics calculations (UFF) disclosed the mode of reaction and the origin of the asymmetric

induction. On their basis, a similar reaction mechanism has been proposed for both complexes,

which involves the reactive intermediates 49 and 50, respectively (Scheme 1.32).

Lewis acidic sites

49

50

Na

"Na

R02C

V

C02R

Scheme 1.32: Reaction intermediates showing the basic and Lewis-acidic sites

After deprotonation of the 1,3-dicarbonyl compound by one oxygen of the BINOL ligand,

the alkali metal ion coordinates the newly-formed enolate, while the enone binds to the Lewis-

1 Introduction 27

acidic metal center. The close proximity at which the substrates are kept facilitates the Michael

addition and this can probably explain the high selectivity even when the reaction is performed at

room temperature.

Interestingly, with the second generation catalyst, it was possible to trap the aluminum

enolate intermediate by addition of an electrophile such as an aldehyde. Thus, stirring enone 51,

malonate derivative 52, and aldehyde 53 in the presence of the aluminum complex 48, it was

possible to obtain the product of the tandem Michael-aldol reaction (54) with excellent

stereoselectivity (Scheme 1.33).79

EtO OEt Ph' H

50(10mol-%)

rt, 36 h

51 52

I ?H

\^C02Et

53 Ac02Et

single diasteroisomer

64% yield, 91 % ee

Scheme 1.33: Asymmetric tandem Michael-aldol reaction catalyzed by aluminum complex

48

In 2000,81 Shibasaki reported a stable and storable modification of his catalytic system (55)

that features a tetradentate ligand obtained by linking two B1NOL units. Interestingly, the

protonated modification revealed the highest catalytic activity and selectivity ever obtained with

such systems (Scheme 1.34).

+ R

P°2R 55 (10mol-%;

C02R

n = 0-3 R^H.Me

R2 = Me, Bn

,C02R2

Ri C02R2

82-98 % yield

£ 98 % ee 55

Scheme 1.34: Third generation Shibasaki's catalyst for Michael additions

The methodology developed by Shibasaki is ineffective in the Type I Michael reactions,

indicating that the catalyst efficiently orientates the enone but does not provide any enantioface

discrimination for the 1,3-dicarbonyl compound. However, the bifunctional character of the catalyst

proved to be a successful strategy.

28 1 Introduction

Ikariya 's Ru/Bisamido Catalyst

A mechanistically interesting example of Type II Michael reaction was reported by Ikariya

in 2003.82 In fact, the reaction of dimethyl malonate with 56 formed a rare example of C-bound

enolato complex in which the 1,3-dicarbonyl compound is deprotonated by the basic amido group.

The structure of the unusual compound 57 was proven by X-ray crystallography. However, the

C-bound enolato complex is in equilibrium at room temperature with the free substrate (Scheme

1.35). Although there was no evidence of an oxygen-bound enolate, the authors did not exclude its

existence.83

Tsi

C02Me Phs^N^ ^K+ \ 1 Ru„

C02Me Ph // ''y-COjMe

O

56 57

Scheme 1.35: Equilibrium proposed by Ikariya in the formation of the ruthenium complex

57

The Michael additions catalyzed by this complex afforded the products with excellent

enantioselectivity (Scheme 1.36).

Ms i

-V* OA

C02Me+ \

C02Me

53 (1 mol-%).0

tBuOH,60°C,24h y-C02MeMe02C

99 % yield, 97 % ee

Scheme 1.36: Ikariya's catalytic Michael addition

This reaction is special also because it is the only example of Michael addition that is Type

II with respect of the position of the generated stereocenter, and Type A because the catalyst

activates the 1,3-dicarbonyl compound.

Complex 56 was originally employed by Ikariya and Noyori in the asymmetric transfer-

hydrogenation of ketones.84"92 In analogy with the author's observation in asymmetric

1 Introduction 29

hydrogénation, they proposed that the N-H moiety actively participates to the reaction by fixating

the enone in the optimal position by means of a hydrogen bond (Scheme 1.37). A similar hydrogen

bond participation from a coordinated amine has been previously described by Brunner (see

Scheme 1.28, page 23).75

C02Me

\

C02Me Ph^N^

Ph N

H

Ph" // '"'r-C02MeH H- //—OUe

0

iyis

Ptf1 N ""

30 1 Introduction

product of the Michael addition. Thus, this method allowed the direct preparation of chiral alcohols

with high diastereo- and enantioselectivity.

Sodeoka's Palladium/Hydroxo/BINAP Catalyst

Surprisingly, after the preliminary report by Brunner, the use of metal-based Lewis acid

catalysts for the Type A-I asymmetric Michael addition (that is, with both activation and

stereocontrol on the Michael donor) has not been further developed until recently.

Consiglio discovered complexes 59a and 60a and their interconversion depending on the

acidity of the medium (Scheme 1.39)94

Ph2 H Ph,~I2

Pd Pd

POP

Ph2 H Ph2

59 a

+HBF4

+H20

-HBF4

-H20

Ph2P\ /OH2

P OH2Ph2

60a

~I(BF4);

Scheme 1.39: Acid-base relation between complexes 59a and 60a

Sodeoka used chiral modifications of such complexes bearing a BINAP ligand (59b-c and

60b-c, Scheme 1.40) in asymmetric catalysis. After the development of enantioselective

95-97

Mukaiyama aldol and Mannich reactions,"

these complexes were applied to the asymmetric

Michael addition of diketones and ß-keto esters to a,ß-unsaturated ketones.

5i

59b

\

H

Pd Pd

POP

H

59

~l (OTf)2

61b

~l (OTf)2

P\ /OH2

/dsP OH2

60

6i

60b

b;Ar=4-Me-C6H4c: Ar= Ph

Scheme 1.40: Pd/BINAP-enolate formation from hydroxo or water complexes 59 or 60

1 Introduction 31

It has been observed that the reaction of either 59b or 59c with 1,3-diketone 5i formed

smoothly the corresponding enolate adducts 61b-c, as indicated by NMR spectroscopy and ESI MS

analysis. Conversely, the diaqua complex 60b reacts only partially with diketone 5i and the

formation of the enolato complex 61b is not quantitative.

Complexes 60b and 60c were tested in the Michael addition of ß-keto esters to methyl vinyl

ketone. Both complexes showed a similar reactivity with substrate 5i in CH2CI2 at -20°C, but 60b

gave a better enantioselectivity. Further studies revealed that the reactions carried out in THF

afforded the products with higher enantioselectivity than those performed in other solvents such as

CH2C12. With optimized reaction conditions, the Michael adduct 6a was isolated in 92 % yield and

92 %ee (Scheme 1.41).

9 O \60b (5 mol-%)92% yield92 % ee

5a

THF, -20°C, 24 h \—/ ''—

6a

Scheme 1.41

Interestingly, the bis(hydroxo)-bridged complexes of type 59 were found to be much less

reactive than the bisaqua-species 60 giving only 28 % of the Michael adduct after 1 week at -10°C

and 100 hours at 0°C in 66 % ee.

The screening of other substrates confirmed the broad scope of this reaction, and many ß-

keto esters with different structural features were converted to their corresponding Michael products

with more than 90 % ee. Moreover, the reaction showed good enantioselectivity with rarely

investigated substrates such as a,ß-unsaturated aldehydes and 1,3-diketones (Scheme 1.42).

60b (5 mol-%)

H MeOH,0°COMe

(4 equiv)MeO

31-73 % yield, 80-87 % ee

R2

+60b (10 mol-%)

!

THF, -10°C

(2 equiv)

up to 90 % yield, 90 % ee

Scheme 1.42: Michael reactions with unusual substrates

32 1 Introduction

Following the good performances of the previous reactions, ß-substituted enones were used

to test the palladium catalysts in the diaslereoseleclive Michael addition. The Michael products

were formed in high yield (80-98 %) and enantioselectivity (> 93 % ee). The diastereoselectivity

was generally low (1.2-3.6:1), except for 3-penten-2-one (62), with which a diastereomeric ratio of

8:1 was observed (Scheme 1.43).

60b (5 mol-%)

THF, -20°C, 24 h

5a 62

89% yield, dr = 8/1,99%ee

Scheme 1.43: Diastereo- and enantioselective Michael addition with the Pd aqua complex

60b

Interesting insights into the reaction mechanism have been gained by investigating the

reactivity of 59 and 60 in stoichiometric reactions. It has been observed that the enolato complex

61, formed in situ from the reaction of 59 and 5i, does not react with methyl vinyl ketone (2 equiv)

in THF solution. However, addition of triflic acid (1 equiv) to this solution triggers the reaction to

give the Michael adduct in 96 % yield and 97 % ee. The same experiment was carried out starting

from 60; after addition of the 1,3-diketone 5i, the NMR spectrum showed an equilibrium between

60, 5i, and 61. The addition of methyl vinyl ketone to this mixture afforded smoothly the Michael

product without the need of TfOH in comparable yield and enantioselectivity (99 %, 91 % ee).

H

f\ A SPd Pd

POPH

59

~l (OTf)2

5i

"lOTf Ol(2 equiv)

X-

+ TfOH (1 equiv)

no reaction

6i

61

tR„~IOTf

P\ /OH2Pd

P OH2

60

"I (OTf)25i

Ol(2 equiv)

61 6i

Scheme 1.44: Stoichiometric reactions with Pd-enolato complexes

1 Introduction 33

This reactivity was observed with ß-keto ester 5a as well, except that the amount of enolato

complex was significantly reduced in the case of the reaction of 5a with 60b.

Consequently, Sodeoka proposed that the palladium enolato complex was an important

intermediate in the reaction mechanism. Since the addition of TfOH started the reaction but also

triggered the formation of the equilibrium between 60 + 5i and 61, it was unclear whether the

diaqua complex 60 also acts as Lewis acid co-catalyst and activates the enone. However, this

possibility was ruled out by kinetic experiments, which showed that the reaction was first-order

with respect to the catalyst. Therefore, it has been proposed that TfOH itself, generated upon

coordination of the 1,3-dicarbonyl substrate, activates the enone by protonation. The proposed

reaction mechanism (Figure 1.9) will be discussed in detail as it is relevant to the results exposed in

this thesis.

M*.

Figure 1.9: Catalytic cycle of Sodeoka's Michael addition

Although complex 59 was not observed under the catalytic conditions, Sodeoka assumed its

formation from 60 based on the reactivity discovered by Consiglio. Complex 59 binds the ß-keto

ester in a bidentate fashion while the hydroxo group abstracts the acidic cc-proton from the

coordinated 1,3-dicarbonyl moiety to form the enolate 6161. However, the authors did not rule out

34 1 Introduction

the possibility that the Lewis-acidic activation of the 1,3-dicarbonyl compound by coordination to

palladium allowed the acidic proton to be abstracted by a weak base such as a water molecule. At

this point, the triflic acid would protonate the enone which would promote the nucleophilic attack of

the coordinated enolate fragment. After tautomerization of the unstable enol intermediate and ligand

substitution, the cycle was terminated.

1.3 Heterofunctionalization of 1,3-Dicarbonyl Compounds

In recent years, the "soft" enolization of 1,3-dicarbonyl compounds by complexation with

Lewis acids as discussed in Paragraph 1.1.3 has permitted the development of catalytic processes

other than the Michael addition. This paragraph describes some examples of asymmetric

heterofunctionalizations of 1,3-dicarbonyl compounds catalyzed by chiral Lewis acids.

In 2000, the first catalytic asymmetric fluorination of ß-keto esters was discovered in our

laboratory.99"103 By using the titanium/TADDOL complex 25 as catalyst, various 1,3-dicarbonyl

compounds have been successfully converted to their fiuorinated analogues with excellent yields

and enantioselectivities up to 90 % ee (Scheme 1.45). Selectfluor® (also called F-TEDA) has

proved to be the best source of electrophilic fluorine.

a. °-

25NP>< Cl\NPNp CK^OMeCN^I SNCMe

CI

F ~l(BF4-)2

O O ^Nt O O

° V MeCN.rt *OV°2

CH2CI

F-TEDA up to 90 % ee

Scheme 1.45: Ti-catalyzed enantioselective electrophilic fluorination of ß-keto esters

In a first mechanistic rationalization, it has been proposed that the reaction involves the

coordination of the ß-keto ester to the titanium complex in a bidentate fashion upon displacement of

one chloride and one MeCN molecule, followed by deprotonation to form an enolato

intermediate.104 The Ti-enolato complex is attacked by the electrophilic F-TEDA with high

stereoselectivity. The proposed catalytic cycle is illustrated in Scheme 1.46.

1 Introduction 35

[TiCI2(TADDOL)(MeCN)2]

25

5d-HCl

-MeCN

Ö

26

O

1"NPy>^>Np1-Np^\ CI 7^1-Np

MeCN | O ,

5d1-NPv °V ? 1-Np

1-Np

F-TEDA

MeCN

Scheme 1.46: The proposed mechanism of the titanium-catalyzed asymmetric fluorination

Starting from these hypotheses, QM/MM investigations have been carried out to better

understand the reaction mechanism.104 The calculations showed that the C-F bond formation step

involves a single electron transfer from the complex to F-TEDA. The origin of the asymmetric

induction was investigated by minimizing the energy of the structures of all the possible Ti-enolate

intermediates. The most stable diasteroisomer displayed one face-on naphthyl group of TADDOL

shielding the Re enantioface of the ß-keto ester. Therefore, F-TEDA can only approach from the Si

side. The experimental determination of the absolute configuration of the fluorinated product

supported this model.

Recently, attempts to prepare the intermediate enolato complexes to the type

[TiCl(TADDOL)(enolato)(MeCN)] from the equimolar reaction of 25 with Na or Li enolate of

some ß-keto esters gave the 1:2 adducts instead of the expected 1:1 complexes.105 These 1:2 adducts

have been characterized in solution and have been identified as a complex mixture of up to 6

possible diastereoisomers. Nevertheless, stoichiometric and catalytic reactions with these

complexes afforded the corresponding fluorinated products with the same sense of induction and

36 1 Introduction

comparable enantioselectivity as in the fluorination catalyzed by 25.105 Therefore, the identity of the

actual intermediate is still a matter of discussion.

This methodology was extended to chlorination and bromination106 (Scheme 1.47) and also

to the enantioselective geminal diheterohalogenation of unsubstituted ß-keto esters101 (Scheme

1.48).

Q O Ph

0 Ph+ N-X

[TiCI2(MeCN)2(TADDOL)] 25

(5 mol-%)

O 0 Ph

MeCN

y\ O Phx

X

X = CI: 88 % ee

Br: 23 % ee

Scheme 1.47: Chlorination and bromination of ß-keto esters catalyzed by Lewis-acidic

complex 25

^UL

1) F-TEDA

2) NCS

OBn

65 % yield

66 % eeCI F

2 BF4-

F-TEDA= FNV^N-CH2CI

[TiCI2(MeCN)2(TADDOL)] 25

(5 mol-%)

NCS =

1)NCS

2) F-TEDA

OBnF CI

60 % yield

57 % ee

N-CI

Scheme 1.48: One-pot geminal diheterohalogenation of ß-keto esters

Analogously, 25 was also applied in other a-functionalizations of ß-keto esters such as

sulfenylation and hydroxylation (Scheme 1.49).

1 Introduction 37

PhSCI

25(1.5mol-%)

5b

84 % yield, 88 % ee

25

25(1.5mol-%) 97 % yield, 94 % ee

-Nz

28

OR

Scheme 1.49: Asymmetric sulfenylation and hydroxylation of ß-keto esters catalyzed by 25

The proposed mechanism of a-hydroxylation was similar to the Ni(II)-catalyzed

hydroxylation of ß-keto esters with dimethyldioxirane previously reported by Adam and Smerz.

The authors proposed that the key step in their reaction involved the epoxidation of the C-C double

bond of the metal-bound enolate (Scheme 1.50).

Scheme 1.50: Proposed mechanism of the metal-catalyzed hydroxylation of ß-keto esters

with dimethyldioxirane

The dioxirane compound, though, was not the preferred oxidating agent for the titanium

catalytic system because traces of water, derived from the preparation of the dioxirane, deactivate

the catalyst and reduced the conversion to the desired product. This problem was solved using the

non-hygroscopic oxaziridine 28 as oxidating agent.

This protocol was efficient, however, only for substrates that do not enolize spontaneously

under neutral conditions such as 5a. The catalytic reaction with highly enolizable 1,3-dicarbonyl

compounds, such as the a-acyl-ô-valerolactam 5g, afforded the products in almost quantitative

yield but with limited enantioselectivity (Scheme 1.51). Since these substrates are present in the

enol form to a significant extent even without a Lewis acid, they react with the oxaziridine 28 in the

absence of the catalyst, thus explaining the origin of the low enantioselectivity.

38 1 Introduction

Ph02S

Y//

28

NO, 29

25 (5 mol-%)

N Ph

6g: 66 % enol*

MeCN, rt

OH

97 % yield, 94 % ee

or

N Ph

HO

97% yield, 19 % ee

30

* enol content measured by integration of the representative H NMR peaks in CDCI3

Scheme 1.51: Ti-catalyzed hydroxylation with substrates having low and high enol content

Analogous a-heterofunctionalizations of 1,3-dicarbonyl compounds catalyzed by transition

metal complexes have been reported, among others, by Sodeoka"2 (Scheme 1.52) and

Jorgensen"3,114 (Scheme 1.53). Similarly to the titanium-catalyzed reactions, in both cases the

function of the Lewis acid is to promote the formation of the enolate and to provide an asymmetric

environment for the approach of the electrophile.

NFSI

cat (2.5 mol-%)

EtOH

cat =

5b 27: 90% yield, 92% ee

H

Pd Pd

POP

H

~l (OTf)2

NFSI

Ph Ph1 1

02S^ ,so2N

1

F

N Q

or

Ar = Ph or 3,5-(CH3)2-C6H3 Ar = 3t5-CBu)2~4-W&0)-C6H2

Scheme 1.52: Enantioselective fluorination with Pd/BINAP-system reported by Sodeoka

1 Introduction 39

< T T >

XX +Bn02C

C02Bn

Ph Ph

(10mol-%)

R2 /^CC^BnBn02C-NH

up to 98% yield, 98% «

R2

Ri, R2 = alkyl

R3 = OR or alkyl

Cu(OTf)2 (10mol-%)

40 1 Introduction

zinc(II)125-130 (77 = 10.88), ruthenium(II)126''31"133 (77 = 5.86), palladium(II)134 (77 = 6.75) and

platinum(II)134 (77 = 8.0), and gold(III)135 (77 = 8.4) have been prepared and characterized.1

The simple preparation from the condensation of ethylene diamine and salicylic aldehyde

contributed to the popularity of this ligand in coordination chemistry. Additionally, the modular

synthesis allowed the preparation of a conspicuous amount of analogues, transforming the term

salen into the representative of a whole class of ligands.

The most eminent application of these ligands in catalysis is the asymmetric epoxidation of

olefins developed by Jacobsen137 by using chiral complexes of the type [MnCl(salen)] (such as 64)

as catalysts. The epoxides were obtained in excellent enantioselectivities (Scheme 1.54).

Ph+ NaOCI

64 (5 mol-%)

CH2CI2

A

Ph

92 % ee

Scheme 1.54: Jacobsen's epoxidation of olefins catalyzed by salen complex 64

Initially, Jacobsen and Katsuki rationalized the enantioselectivity with a model in which the

olefin approaches the metal-oxo bond from the side and parallel to the coordination plane (side-on

approach). Depen