bifunctional organocatalysis in the asymmetric aza-baylis...
TRANSCRIPT
Bifunctional Organocatalysis in the Asymmetric Aza-Baylis-
Hillman Reaction
Von der Fakultät für Mathematik, Informatik und Naturwissenschaften der Rheinisch-
Westfälischen Technischen Hochschule Aachen zur Erlangung des akademischen Grades
eines Doktors der Naturwissenschaften genehmigte Dissertation
vorgelegt von
Diplom-Chemiker
Pascal Buskens
aus Heerlen (Niederlande)
Berichter: Universitätsprofessor Dr. rer. nat. Walter Leitner Universitätsprofessor Dr. rer. nat. Dieter Enders
Tag der mündlichen Prüfung: 22. September 2006
Diese Dissertation ist auf den Internetseiten der Hochschulbibliothek online verfügbar.
I
II
Selected results from this thesis were already published:
(1) Bifunctional Activation and Racemization in the Catalytic Asymmetric Aza-Baylis-
Hillman Reaction
Pascal Buskens, Jürgen Klankermayer, Walter Leitner, Journal of the American Chemical
Society 2005, 127, 16762-16763.
(2) Highly Enantioselective Aza-Baylis-Hillman Reaction in a Chiral Reaction Medium
Dedicated to Professor Dieter Enders on the occasion of his 60th birthday.
Rolf Gausepohl, Pascal Buskens, Jochen Kleinen, Angelika Bruckmann, Christian W.
Lehmann, Jürgen Klankermayer, Walter Leitner, Angewandte Chemie 2006, 118, 3772-3775
(Titelbild Ausgabe 22, Mai 2006); Angewandte Chemie International Edition 2006, 45, 3689-
3692 (cover picture Issue 22, May 2006).
III
Abstract (English)
In this doctoral thesis, the mechanism of the Lewis base-mediated aza-Baylis-Hillman
reaction was examined. Intermediates of the reaction were intercepted and structurally
characterized, an extensive kinetic study was performed and the effects of Brønsted acidic co-
catalysts on the reaction mechanism were examined. In addition, other mechanistic aspects
like reversibility, stability of the stereocenter and chirality transfer from the catalytic system
to the reaction product were studied.
This mechanistic study provided useful information for the rational design of an
appropriate chiral catalytic system. Several potential catalytic systems were synthesized and
tested. The most successful system involved a reaction medium, an ionic liquid, as the source
of chirality. With this system, enantioselectivities up to 84% ee were obtained in the
triphenylphosphine-catalyzed aza-Baylis-Hillman reaction of aromatic tosylaldimines and
methylvinyl ketone.
IV
Abstract (German)
Im Rahmen dieser Doktorarbeit wurde der Mechanismus der Lewis-Basen-katalysierten aza-
Baylis-Hillman-Reaktion untersucht. Reaktionsintermediate wurden abgefangen und
strukturell charakterisiert, die Kinetik der Reaktion wurde eingehend untersucht und die
Auswirkungen von Brønsted-sauren Cokatalysatoren wurden studiert. Zusätzlich wurden
weitere mechanistische Aspekte der Reaktion wie Reversibilität, Stabilität des Stereozentrums
und Chiralitätstransfer vom katalytischen System auf das Reaktionsprodukt behandelt.
Diese mechanistische Studie lieferte wertvolle Informationen für den rationellen
Entwurf eines geeigneten chiralen Katalysatorsystems. Das erfolgreichste System umfasste
als Chiralitätsquelle ein Reaktionsmedium, eine ionische Flüssigkeit. Mit diesem System
konnten in der triphenylphosphin-katalysierten aza-Baylis-Hillman-Reaktion von
aromatischen Tosylaldiminen mit Methylvinylketon Enantioselektivitäten von bis zu 84% ee
erreicht werden.
V
VI
Acknowledgements
First of all, I want to thank my Ph.D. supervisor, Prof. Dr. Walter Leitner, for his continuous
support and the helpful discussions during the last three years. In addition, I would like to
thank him for the outstanding working conditions and the possibility to present my work at
numerous conferences.
I would like to express my thanks to Prof. Dr. Dieter Enders for the kind acceptance of the
position of second referee.
Furthermore, I would like to thank Dr. John M. Brown for allowing me to work in his group
at the Chemistry Research Laboratory (CRL) in Oxford as a Marie-Curie-Fellow and for the
numerous scientific discussions we had during this period.
I would like to express my sincere thanks to Dr. Jürgen Klankermayer for his help with the
performance of NMR spectroscopic measurements, lots of valuable discussions and proof
reading this manuscript.
Special thanks to Dipl.-Chem. Rolf Gausepohl for the nice and successful cooperation on the
CHIRAL SOLVENT PROJECT.
In addition, I would like to thank …
Dr. Barbara Odell for her assistance with NMR spectroscopic measurements during my stay
in Oxford.
Dr. Lasse Greiner for his help with the interpretation of the results from the kinetic studies on
the aza-Baylis-Hillman reaction.
Dr. Markus Hölscher for the DFT calculations on the intermediates of the reaction.
Dipl.-Chem. Christian Böing, Dipl.-Chem. Martina Peters and Dipl.-Chem. Clemens Minnich
for proof reading this manuscript.
VII
Dr. Giancarlo Franciò for a generous gift of (R)-2’-diphenylphosphanyl-[1,1’]binaphthalenyl-
2-ol and (R,S)-2-diphenylphosphanyl cyclohexane carboxylic acid methyl ester.
My lab colleagues Dr. Christian Steffens, Dr. Daniela Giunta, Dipl.-Chem. Rebekka Loschen
and Dipl.-Chem. Volker Gego for the excellent working atmosphere.
My research students Jochen Kleinen, Angelika Bruckmann, Dirk Iffland, Miriam Baumert
and Andreas Hergesell for their valuable help in the course of their research projects.
All members of the Leitner- and JMB group for the great working atmosphere.
All members of the technical staff of the ITMC and the CRL, especially Miss Jennifer Thelen,
for the pleasant working atmosphere and the valuable technical assistance.
1
Contents
1. OBJECTIVE..........................................................................................4
2. INTRODUCTION ...................................................................................5
2.1. ASYMMETRIC ORGANOCATALYSIS ................................................................................... 5
2.1.1. General Aspects........................................................................................................ 5
2.1.2. Lewis Base Catalysis ................................................................................................ 8
2.1.3. Lewis Acid Catalysis .............................................................................................. 10
2.1.4. Brønsted Base Catalysis......................................................................................... 11
2.1.5. Brønsted Acid Catalysis ......................................................................................... 12
2.1.6. Bifunctional Acid-Base Catalysis........................................................................... 13
2.2. BAYLIS-HILLMAN REACTION ......................................................................................... 14
2.2.1. General Aspects...................................................................................................... 14
2.2.2. Mechanism ............................................................................................................. 15
2.2.3. Catalysts ................................................................................................................. 19
2.3. AZA-BAYLIS-HILLMAN REACTION................................................................................. 23
2.3.1. General Aspects...................................................................................................... 23
2.3.2. Mechanism ............................................................................................................. 26
2.3.3. Catalysts ................................................................................................................. 29
2.4. CHIRAL SOLVENTS FOR ASYMMETRIC SYNTHESIS.......................................................... 32
3. RESULTS AND DISCUSSION .................................................................35
3.1. MECHANISTIC INVESTIGATION OF THE AZA-BAYLIS-HILLMAN REACTION .................... 35
3.1.1. Kinetic Study .......................................................................................................... 35
3.1.1.1. Lewis Base Catalysts........................................................................................... 35
3.1.1.2. Lewis Base-Brønsted Acid Catalysts .................................................................. 40
3.1.2. Reversibility of the Aza-Baylis-Hillman Reaction.................................................. 44
3.1.3. Racemization of the Aza-Baylis-Hillman Product ................................................. 47
3.1.4. Chirality Transfer................................................................................................... 51
3.1.5. Implications for Asymmetric Catalysis .................................................................. 54
3.2. DESIGN OF NEW CATALYTIC SYSTEMS FOR THE ASYMMETRIC AZA-BAYLIS-HILLMAN
REACTION ............................................................................................................................. 55
3.2.1. QUINAP Derivatives.............................................................................................. 55
2
3.2.2. Other phosphinocarboxylic acids........................................................................... 64
3.2.3. Chiral Brønsted Acids ............................................................................................ 65
3.2.4. Chiral Aminoalcohols ............................................................................................ 66
3.2.4.1. Synthesis.............................................................................................................. 66
3.2.4.2. Catalysis .............................................................................................................. 72
3.2.5. Chiral Solvents ....................................................................................................... 72
4. SUMMARY AND OUTLOOK..................................................................79
5. EXPERIMENTAL.................................................................................84
5.1. GENERAL METHODS, SOLVENTS AND REAGENTS........................................................... 84
5.1.1. Inert Gas Conditions .............................................................................................. 84
5.1.2. Solvents................................................................................................................... 84
5.1.3. Reagents ................................................................................................................. 85
5.2. DETERMINATION OF PHYSICAL DATA............................................................................. 85
5.2.1. NMR Spectroscopy ................................................................................................. 85
5.2.2. IR Spectroscopy...................................................................................................... 86
5.2.3. Mass Spectroscopy ................................................................................................. 86
5.2.4. Gas Chromatography ............................................................................................. 87
5.2.5. High Performance Liquid Chromatography .......................................................... 87
5.2.6. Thin Layer Chromatography.................................................................................. 88
5.3. PREPARATIVE COLUMN CHROMATOGRAPHY.................................................................. 88
5.4. SYNTHESES..................................................................................................................... 88
5.4.1. Aromatic Tosylaldimines........................................................................................ 88
5.4.2. Racemic Aza-Baylis-Hillman Products .................................................................. 91
5.4.3. Enantiomerically Enriched Aza-Baylis-Hillman Products .................................... 93
5.4.4. (R,S)-2-Diphenylphosphanyl cyclohexane carboxylic acid (140).......................... 94
5.4.5. (3-Oxobutyl)triphenylphosphonium malate (109).................................................. 95
5.4.6. [1-(3-Carboxylato-isoquinolin-1-yl)-naphthalen-2-yl]-(3-oxobutyl)-diphenyl-
phosphonium (131)........................................................................................................... 96
5.4.7. (R)-(1-Isoquinolin-1-yl-naphthalen-2-yl)-(3-oxobutyl)-diphenylphosphonium
diphenyl-acetate (172)...................................................................................................... 97
5.4.8. (R,R)- and (S,R)-{1-[3-(3-Hydroxy-2-phenylpropylcarbamoyl)-isoquinolin-1-yl]-
naphthalen-2-yl}-(3-oxobutyl)-diphenylphosphonium diphenylacetate (173) ................. 97
3
5.4.9. [1-(3-Carboxy-isoquinolin-1-yl)-naphthalen-2-yl]-{3-oxo-2-[phenyl-(toluene-4-
sulfonylamino)-methyl]-butyl}-diphenyl-phosphonium diphenylacetate (132) ............... 98
5.4.10. Methyltrioctyl ammonium dimalatoborate (166) ................................................. 99
5.4.11. trans-4-Hydroxy-(S)-proline methylester hydrochloride (155).......................... 100
5.4.12. (2S,4R)-4-Hydroxy-1-benzoylproline methylester (156).................................... 101
5.4.13. (2S,4R)-4-{[1-(tert-Butyl)-1,1’-dimethylsilyl]-oxy}-1-benzoylproline methylester
(157) ............................................................................................................................... 102
5.4.14. (2S,4R)-4-{[1-(tert-Butyl)-1,1’-dimethylsilyl]-oxy}-1-benzyl-2-hydroxymethyl-
pyrrolidine (158) ............................................................................................................ 103
5.4.15. (3R,5R)-1-Benzyl-3-(tert-butyl-dimethylsilanyloxy)-5-chloro-piperidine (159) 104
5.4.16. (3R,5R)-1-Benzyl-5-chloro-piperidin-3-ol (160) ............................................... 105
5.5. CATALYSIS ................................................................................................................... 106
5.5.1. Screening of Lewis Base-Brønsted Acid Catalysts in the Aza-Baylis-Hillman
Reaction.......................................................................................................................... 106
5.5.2. Kinetic Experiments ............................................................................................. 107
5.5.3. Screening of Brønsted Acids for Kinetics............................................................. 109
5.5.4. Catalysis in Chiral Ionic Liquids ......................................................................... 109
5.5.5. Screening of Chiral Brønsted Acidic Additives.................................................... 110
5.6. MISCELLANEOUS .......................................................................................................... 111
5.6.1. Cross-Mannich Experiment.................................................................................. 111
5.6.2. Deuteration Experiment ....................................................................................... 112
5.6.3. Racemization Experiment..................................................................................... 112
6. APPENDICES....................................................................................113
6.1. ABBREVIATIONS ........................................................................................................... 113
6.2. LIST OF COMMERCIALLY OBTAINED CHEMICALS......................................................... 116
6.3. KINETIC STUDY WITH PHENOL AS CO-CATALYST ........................................................ 117
6.4. 1H AND 13C NMR SPECTRA OF COMPOUND 160 ........................................................... 118
6.5. HPLC CHROMATOGRAM OF AZA-BH PRODUCT 106 ................................................... 120
6.6. 31P NMR SPECTRUM OF COMPOUND 172 ..................................................................... 122
6.7. 31P NMR SPECTRUM OF COMPOUND 173 ..................................................................... 123
7. LITERATURE ...................................................................................124
4
1. Objective
The objective of this Ph.D. thesis was to develop novel chiral catalytic systems for the
organo-mediated asymmetric aza-Baylis-Hillman reaction, an atom efficient C-C bond
forming reaction leading to highly functionalized chiral allylic amines.[1] The system should
be based on nitrogen- or phosphorus-containing nucleophilic Lewis base organocatalysts.
In principle two general strategies were viable to achieve this goal:
(1) A combinatorial approach involving a screening of a broad variety of potential catalyst
structures for the aza-Baylis-Hillman reaction. These compounds should either be
commercially available or attainable via a short and straightforward synthetic route.
(2) The rational design of suitable chiral catalytic systems based on insights into the
mechanism of the aza-Baylis-Hillman reaction and, more specifically, into the
mechanism of chirality transfer.
Since the first strategy had turned out to be widely unsuccessful in the search for
appropriate chiral catalysts for related organocatalytic C-C couplings like the Baylis-Hillman
reaction, the second strategy was elected.[2] There was no information available on the
mechanism of the aza-Baylis-Hillman reaction at the beginning of this Ph.D. study
(November 2003), so extensive mechanistic research in the initial stage of the project was
necessary. This involved the interception and characterization of reaction intermediates as
well as a full kinetic analysis of the reaction catalyzed by nucleophilic Lewis bases with and
without potential co-catalysts. Furthermore, aspects like chirality transfer, reversibility and
product stability were of high interest.
The implications of these mechanistic findings should provide information for the
rational design of novel chiral catalytic systems. In addition to the conventional approach of
applying chiral organocatalysts in the aza-Baylis-Hillman reaction, the use of well designed
chiral solvents as carriers of chiral information in a catalytic system should be explored in this
present work.
5
2. Introduction
2.1. Asymmetric Organocatalysis
2.1.1. General Aspects
The term ORGANOCATALYSIS was introduced by MacMillan in 2000 and is used to describe a
research area involving reactions which are mediated by metal-free, small organic
compounds.[3],[4] Scheme 1 shows a selection of typical chiral organocatalysts.
NH
CO2HN
NH
O
Bn
OH
N
N
O
1 2
8
N
NNHBoc
HNO
NHO
ON
O
HN
NHO
ONH
OHN
OO
4
N
N
N
O
BF4-
7
N
F F
F
F F
F
5
HN
S
HN
N
6
HNNH
O
ON
HN
3
PPh
9
Scheme 1. A selection of chiral organocatalysts.
6
Organocatalysis complements the classical domains of metal- and enzyme catalysis and
provides useful new strategies for organic synthesis. Organocatalysts have several advantages
over transition-metal catalysts and enzymes: they are usually robust, inexpensive and readily
available. Because of their robustness they often do not require demanding reaction conditions
like inert gas atmosphere and absolute solvents.
Whereas synthetic organic chemists have started to explore organocatalysis
systematically in the past decade, it is suggested that this field of catalysis has a long history:
Pizarrello and Weber reported evidence for a key role of organocatalytic processes in the
formation of important chiral prebiotic building blocks like sugars.[5] It was proposed that
aminoacids from carbonaceous meteorites, which carried the same sign L as terrestrial amino
acids, were delivered to the Earth in its early history via showering of the planet with
cometary and asteroidal material. As chiral organocatalysts they could be responsible for the
enantioselective synthesis of sugars. Furthermore, the authors reported that it is likely that
similar organocatalytic processes are responsible for the propagation of chirality in living
organisms.
The first examples of asymmetric organocatalytic processes, in which synthetically
useful enantioselectivities were obtained, date from the early sixties of the past century.
Pracejus reported the use of optically active amines like acetylquinine (12) as catalysts for the
reaction of phenylmethyl ketene (10) with alcohols[6] or amines (Scheme 2).[7]
OCH3OH+
12O
O
toluene, −111°C
10 11 13
OAc
N
N
O
93%74% ee
Scheme 2. Addition of methanol (11) to phenyl methyl ketene (10) as reported by Pracejus.
7
In the early seventies, both the group of Hajos and Parrish[8] at Hoffmann-La Roche
and the group of Eder, Sauer and Wiechert[9] at Schering reported the L-proline-catalyzed
intramolecular aldol reaction, which nowadays carries their names (Scheme 3).
O
O
1 (3 - 47 mol-%)
CH3CN, r.t. - 80°C
O
O
83% - quant.71 - 93% ee
14 15O
Scheme 3. The Hajos-Parrish-Eder-Sauer-Wiechert reaction.
Despite these early successes it took a long time for synthetic organic chemists to
recognize and appreciate the broad scope of asymmetric organocatalysis. Only in the past
decade enantioselective organocatalysis became a main focus of research. In 2000, List and
Barbas reported pioneering studies on organocatalytic intermolecular aldol reactions[10]
parallelled by a report of the group of MacMillan on enantioselective organocatalytic Diels-
Alder reactions[3] in the same year (Scheme 4 and 5, respectively). These studies elucidated
the promising potential of organocatalytic transformations and resulted in a large scientific
interest in this area of research.[11]
OO
1 (30 mol-%)
DMSO, r.t.+
O OH
16 17 18
97%
96% ee
Scheme 4. L-Proline-catalyzed intermolecular aldol reaction reported by Barbas and List.
8
O+
CHO
19 20 21
2 (5 mol-%)
23°C
82%94% ee (endo/exo 14:1)
Scheme 5. First enantioselective organocatalytic Diels-Alder reaction reported by the group
of MacMillan.
Several criteria can be applied to categorize the large amount of organocatalytic
reactions reported in literature in the past few years, such as the type of catalyst employed or
the type of reaction that is catalyzed.[11] The mechanistic classification by List involves a
division of the organocatalytic processes into four categories, according to their
mechanisms:[4],[12]
(1) Lewis Base Catalysis
(2) Lewis Acid Catalysis
(3) Brønsted Base Catalysis
(4) Brønsted Acid Catalysis
Despite the sometimes limited information on mechanisms of organocatalytic reactions and
the fact that not all organocatalytic processes can be described with these general reaction
mechanisms, this division will be adopted in this manuscript to give a brief survey of the large
diversity of asymmetric organocatalytic reactions reported in literature.
2.1.2. Lewis Base Catalysis
The general catalytic cycle for reactions catalyzed by Lewis bases (B:) is shown in Scheme 6.
This type of process starts with a nucleophilic addition of the Lewis base B: to the substrate S,
which leads to the adduct B+-S−. This adduct undergoes a reaction to the intermediate species
B+-P−, from which the product (P) is released. The catalyst is set free and re-enters the
catalytic cycle.
9
Scheme 6. General mechanism for Lewis base-catalyzed reactions.
Prototypical examples of reactions catalyzed by Lewis bases are the reactions shown in
Scheme 4 and 5. The intermolecular aldol reaction, shown in Scheme 4, proceeds through the
enamine intermediate 24 which is formed by deprotonation of the primarily formed iminium
ion 23 (Scheme 7).[10a],[13]
OHN
COOH
+ N
COOHOH
- H2O
N
CO2
N
COOH
+ RCHO
16 1 22
2324
25aldol
product
Scheme 7. The formation of the enamine intermediate 24 (R = alkyl, aryl).
Enamine 24 undergoes an electrophilic attack from aldehyde 25 which leads to the aldol
product after subsequent hydrolysis. Further examples of so-called ENAMINE CATALYSIS are
the Hajos-Parrish-Eder-Sauer-Wiechert reaction (Scheme 3),[8],[9] Mannich reaction,[14]
Michael addition[15] and α-functionalization of ketones and aldehydes (α-amination,[16] α-
hydroxylation,[17] α-alkylation,[18] α-halogenation).[19]
10
The Diels-Alder reaction in Scheme 5 proceeds through the iminium intermediate 26
(IMINIUM CATALYSIS,[13] Scheme 8).[3]
O + N
- H2O
20 2 26
NH
N
Bn
O
NBn O
Scheme 8. The formation of the iminium intermediate 26.
In case of the Diels-Alder reaction, shown in Scheme 5, the α,β-unsaturated aldehyde 20
forms an iminium coumpound with the chiral imidazolidinone catalyst 2. In comparison to the
unsaturated aldehyde 20, the LUMO energy of the iminium ion 26 as dienophile is lowered.[3]
In general, an iminium ion is more reactive than its corresponding carbonyl compound
and consequently facilitates reactions such as [3+2]-cycloadditions,[20] Friedel-Crafts
alkylation with pyrroles, indoles and benzenes,[21] and Mukayiama-Michael reactions.[22]
Other N-Lewis base-catalyzed processes mainly proceed through acyl-ammonium[23]
and ammonium-enolate intermediates[24] (e.g. Baylis-Hillman reaction, see chapter 2.2.2).
Although the majority of chiral Lewis bases for organocatalysis are N-based compounds, C-
(nucleophilic carbenes, generated from precursors like 7),[25], P-[26] and S-Lewis bases[27] are
also applied as chiral organocatalysts.
2.1.3. Lewis Acid Catalysis
Lewis acid catalysts (A) activate nucleophilic substrates (S:) which leads to the formation of
the adduct A−-S+. This adduct is converted into the adduct A−-P+, followed by elimination of
the product (P). This enables the catalyst (A) to re-enter the catalytic cycle (Scheme 9).
A large class of organocatalysts which can be referred to as Lewis acids are phase
transfer catalysts such as 5.[28] This catalyst was successfully applied to enantioselective α-
alkylations as well as aldol- and Michael reactions.[29] A further example of Lewis acid
catalysis is the asymmetric oxidation method reported by Shi.[30]
11
Scheme 9. General mechanism for Lewis acid-catalyzed reactions.
2.1.4. Brønsted Base Catalysis
Organocatalytic processes, initiated by Brønsted bases (B:), start with a (partial)
deprotonation of the substrate S-H. The cycle proceeds through the intermediates B+H S− and
B+H P−. Elimination of the product (P-H) enables the catalyst (B) to re-enter the catalytic
cycle (Scheme 10).
Scheme 10. General mechanism for Brønsted base-catalyzed reactions.
Prototypical examples of reactions catalyzed by Brønsted bases are hydrocyanations such as
Strecker reactions (S = CN).[31] The dipeptide species 3 was reported as a successful catalyst
for this type of reactions.[32] It is postulated that in this reaction hydrogen cyanide interacts
with the nitrogen base to form a cyanide ion, which subsequently adds to the carbonyl or
imine compound coordinated to the chiral peptide via hydrogen bonding.
12
2.1.5. Brønsted Acid Catalysis Brønsted acid-catalyzed reactions start with a (partial) protonation of the substrate (S:). The
resulting adduct A− S+H is converted into the adduct A− P+H, which undergoes an elimination
reaction to liberate the product (P) and the catalyst (A-H) (Scheme 11).[33]
Scheme 11. General mechanism for Brønsted acid-catalyzed reactions.
Jacobsen and co-workers used urea- and thiourea compounds as chiral Brønsted acids to
activate carbonyl- and imine groups in a broad variety of reactions: Strecker-,[34] Mannich-,[35]
Henry-,[36] hydrophosphonylation-,[37] and aza-Baylis-Hillman reactions.[38] These catalysts
activate carbonyl- or imine substrates by hydrogen bonding of the (thio)urea catalyst to the
carbonyl oxygen or imine nitrogen, respectively.
Rawal reported the use of TADDOL derivatives (28) as chiral catalysts for the hetero-
Diels-Alder reaction (Scheme 12).[39]
TBSO
N
O
R+
OHOH
O
O
Ar Ar
Ar Ar(20 mol-%)
toluene, −40°C - −78°C
27 25
28O
RTBSO
N
+ CH3COCl
29
30
O
RO
31
52 - 97%86 - 98% ee
Scheme 12. Hetero-Diels-Alder reaction catalyzed by TADDOL derivatives (R = aryl, alkyl).
13
Protecting one or both hydroxy-groups leads to a decrease in activity and selectivity,
indicating the involvement of both OH groups in the activation of the carbonyl compound.
McDougal and Schaus reported an enantioselective variant of the Baylis-Hillman
reaction, catalyzed by BINOL derivatives.[40] This will be discussed in more detail in chapter
2.2.3.
2.1.6. Bifunctional Acid-Base Catalysis
In the past few years, several groups showed that the incorporation of a basic and an acidic
moiety in one chiral molecule can facilitate a synergistic interaction between the functional
groups and thereby lead to an efficient bifunctional chiral organocatalyst.
One of the first examples of a bifunctional chiral organocatalyst was reported by the
group of Takemoto in 2003.[41] They used catalyst 34 which contains an amine moiety and a
thiourea group (Scheme 13).
NO2
CO2Et
CO2Et+
HN
S
HNF3C
CF3
N
(10 mol-%)toluene, r.t.
NO2
CO2EtEtO2C
86%93% ee
32 33
34
35
Scheme 13. Michael addition of diethyl malonate (33) to trans-β-nitrostyrene (32).
In this system, the amino group serves as a Brønsted base and activates the nucleophile via
(partial) deprotonation. The thiourea group − a Brønsted acidic catalyst − coordinates to the
nitro function of the α,β-unsaturated olefin. The results obtained with catalyst 34 in the
Michael addition of malonates to a range of different nitroolefins are good to excellent (up to
93% ee).
Since then, bifunctional organocatalysts were successfully applied to a wide range of
reactions. Catalysts containing both a Brønsted basic- and a Brønsted acidic group were
applied to Michael additions,[42] Henry reactions,[43] aza-Henry reactions,[44] Strecker
reactions[45] and kinetic resolution of azlactones.[46] The combination of a Lewis basic
14
(nucleophilic) and a Brønsted acidic group works well for Baylis-Hillman (see chapter
2.2.3.)[47] and aza-Baylis-Hillman reactions (see chapter 2.3.3.).[48]
2.2. Baylis-Hillman Reaction
2.2.1. General Aspects
The Baylis-Hillman (BH) reaction was first described by Morita et al.[49] and later, in a
German patent, by Baylis and Hillman.[50] It involves the atom-efficient coupling of an
activated alkene in its α-position with a carbonyl compound and is mediated by a nucleophilic
Lewis base. As prototypical example of the BH reaction, the coupling of benzaldehyde (36)
with methylvinyl ketone (MVK, 37) catalyzed by 1,4-diazabicyclo[2.2.2]octane (DABCO,
38) is shown in Scheme 14.
OO
+
NN
OH O
36 37 39
38
Scheme 14. BH reaction of benzaldehyde (36) with MVK (37) catalyzed by DABCO (38).
The reaction shows an enormous diversity in substrates.[2] As activated alkenes alkyl vinyl
ketones, alkyl (aryl) acrylates, acrylonitrile, vinyl sulfones, acryl amides, allenic esters, vinyl
sulphonates, vinyl phosphonates, acrolein, crotonitrile, crotonic acid esters and phenyl vinyl
sulfoxide can be used.[2] They couple with aliphatic, aromatic and heteroaromatic aldehydes,
α-keto esters, non-enolizable 1,2-diketones and fluoroketones.[2] Simple ketones require high
pressure to react as electrophiles in the BH reaction.[51] The BH coupling of activated alkenes
with imines – the aza-BH reaction – is discussed in chapter 2.3. A further variant of the BH
reaction involves the coupling of activated alkenes with sp3 hybridized electrophiles (alkyl
halogenides) – the so-called BH alkylation.[52]
The products of the BH reaction are highly functionalized chiral allylic alcohols of
type 39. They are useful intermediates for the synthesis of more complex organic structures
like anti-tumor agents,[53] anti-biotics[54] and natural products.[55] The potential of the reaction
15
is further illustrated by its application in industrial processes. tert-Butyl-2-
(hydroxymethyl)propenoate, a key intermediate in Pfizer’s synthetic route to the Zn-
metallaprotease inhibitor Sampatrilat, is prepared via BH coupling on a 40 kg scale.[56]
In principle, the reaction can be mediated by various types of catalysts. In all cases, a
nucleophilic Lewis base, which can be an amine,[57] phosphine,[58] sulphide[59] or selenide,[59]
is part of the catalytic system. Lewis-[60] and Brønsted acids[40] can be added as co-catalysts.
With sulfides and selenides, it is necessary to use a Lewis acidic co-catalyst (e.g. TiCl4) to
obtain a useful catalytic activity.[59] The research described in this thesis focuses solely on
phosphine- and amine catalysts and Brønsted acids as potential co-catalysts.
2.2.2. Mechanism
Several studies contribute to the understanding of the mechanism of the BH reaction. The
generally accepted reaction intermediates have been intercepted and structurally characterized
by using electrospray ionization with mass and tandem mass spectroscopy.[61] Further
experimental evidence is delivered by the group of Drewes through isolation of the second
zwitterionic intermediate (type-41, see Scheme 15) as coumarine salt.[62] The catalytic cycle
of the BH reaction based on the intermediates, which are intercepted and characterized in
these studies, is shown for the prototypical reaction of benzaldehyde (36) with MVK (37)
(Scheme 15).
The reaction starts with a 1,4-addition of the nucleophilic catalyst 38 to the activated
olefin 37, which leads to the formation of the zwitterionic 3-ammonium enolate 40. Enolate
40 is then converted to the second zwitterionic intermediate 41 by aldol-type coupling with
36. The last step involves a proton migration from the α-carbon to the alcoholate oxygen and
release of the catalyst (38) which provides the BH product 39. There is some discussion in
literature regarding the configuration of 40 and 41. Some groups report evidence for an open
isomer as the reactive species, [52b],[63] other groups postulate a (Z)-isomer with a Nu+-O−
stabilization.[64] In Scheme 15, the enolate geometry is therefore left undefined which is
indicated by a wavy bond.
16
O
NN
OOH O
36
3738
39
NN
O
4041
NN
O
Ph O
O
NN
OOH O
36
3738
39
NN
O
4041
NN
O
Ph O
Scheme 15. Catalytic cycle for the BH reaction of 36 with 37 based on the intercepted and
characterized intermediates.
All steps of the catalytic cycle are potentially reversible.[65] The reaction has a high
negative activation volume which explains the increase of the reaction rate of the typically
slow BH reaction under high-pressure conditions (about 5-15 kbar) reported by several
groups.[66] In some cases, even stereo- and enantioselectivity are affected by a change in
pressure.[67],[51b]
Three mechanistic models are postulated to explain the results obtained in different
kinetic studies. The first model – the so-called CLASSICAL MODEL – was developed by Kaye
and co-workers to interpret the kinetic data obtained for the BH reaction of acrylate esters
with pyridine carboxaldehydes in CDCl3.[68] They monitored the reaction via NMR
spectroscopy and observed a first-order dependence in catalyst, aldehyde, and acrylate and
17
postulated a mechanism which contained the intermediates shown in Scheme 15 with the
aldol-coupling as the rate determining step (RDS).
The second model – the so-called HEMI-ACETAL MODEL – was developed by the group
of McQuade to explain their kinetic results.[69] They investigated the reaction of various
aromatic aldehydes with methyl acrylate (42) both in non-protic polar solvents like DMSO
and THF and under protic conditions. With rate- and isotope data, they showed that the
reaction is second order in aldehyde and that the α-C-H bond breaks in the RDS. To include
the second equivalent of aldehyde, they altered the cycle shown in Scheme 15 and proposed
the formation of an additional hemi-acetal type intermediate – intermediate 43 – which
preceded the proton migration (Scheme 16). This model was further supported by the
observation of dioxanones as typical by-products of the BH reaction when the acrylate ester
was a reasonable leaving group and the aldehyde concentration was high.[70] Furthermore,
they reported a first order dependence on solvent and a solvent-induced acceleration which
roughly followed the dielectric constant of the solvent or solvent mixture. They explained
these results as a medium effect in which the ionic transition states of the BH reaction were
stabilized in the presence of polar solvents.
O
O O
Ar
O Ar
NN
H 2 eq. aldehyde1 eq. acrylate
1 eq. DABCO
C-H bond broken
43
Scheme 16. Hemi-acetal intermediate 43 as postulated by McQuade.
The third proposed mechanism is the so-called AUTOCATALYSIS MODEL.[71] Aggarwal
and Lloyd-Jones investigated the reaction between benzaldehyde (36) and ethyl acrylate (44)
catalyzed by quinuclidine (45) without the use of a solvent. In a competition experiment with
α-deuterated ([D]44) and non-deuterated ethyl acrylate (44), they observed a substantial
increase of the mole fraction of [D]44 in the early stages of the reaction (< 20% conversion).
As the reaction proceeded, the ratio 44/[D]44 reached a constant level. This was explained
with a scenario where in the early stage of the reaction, the proton migration was rate limiting
but became increasingly efficient during the course of the reaction which ultimately resulted
18
in a shift of the RDS from the proton migration to the aldol-type coupling. They rationalized
these findings by a model in which the product serves as a co-catalyst through facilitation of
the proton migration from the α-keto methine to the alkoxide making the reaction
autocatalytic. They postulated a proton transfer via transition state 46 (Scheme 17).
R
O
R3N
HE
HO R
46
Scheme 17. Transition state for product-assisted proton migration according to Aggarwal and
Lloyd-Jones (product = ROH).[71]
The AUTOCATALYSIS MODEL, including the TS depicted in Scheme 17, also explained the
large rate enhancements in the BH reaction caused by water and other protic solvents or
additives.[72] At the end of their report, the authors postulated a model for enantioselective BH
reactions with bifunctional chiral catalysts containing a Lewis basic and a Brønsted acidic
moiety and discussed the implications of their mechanistic findings for asymmetric catalysis
(Scheme 18).
RCHO + OR
O
Nu
OHR
O
Nu
O
ORH
HO
D1
D2
D3
D4
fast
slow
slow
slow
type-41
***
*
Scheme 18. Model for enantioselective BH reactions by Aggarwal and Lloyd-Jones (Nu∩OH
= chiral bifunctional catalyst).
Since the second intermediate of the BH reaction (type 41) contained two centers of chirality,
four diastereoisomers could be formed with an enantiopure catalyst. The authors suggested
that all four diastereoisomers (D1-4) of the “type-41 intermediate” should be formed during
the reaction, but only one had the hydrogen-bond donor suitably positioned to allow an
19
effective proton transfer. The other diastereoisomers would revert back to the starting
materials and eventually the reaction would “filter” through the pathway that leads to fast
elimination. This implied that the proton migration step determined the enantioselectivity of
the reaction and that the reaction itself could be regarded as a dynamic kinetic resolution of
the intermediate of type 41 which is shown in Scheme 18. Other models explaining the
enantioselectivity in catalytic asymmetric BH reactions for specific catalyst systems are
discussed in the next chapter.
2.2.3. Catalysts
As already mentioned, the BH reaction can be mediated by nucleophilic Lewis bases or by
combined Lewis base/Lewis acid or Lewis base/Brønsted acid systems. Only the systems
based on N- and P-Lewis bases (in combination with Brønsted acids) will be discussed here in
more detail.
Suitable N-Lewis base catalysts for the BH reaction are compounds like DABCO
(38),[73] quinuclidine (45),[74] 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU, 47),[75] imidazole
(48)[76] and 4-dimethylaminopyridine (DMAP, 49) (Scheme 19).[77]
NN
NN N
N
N
NHN
38 45 47 48 49
Scheme 19. Typical N-Lewis base catalysts for the BH reaction.
These Lewis bases can be divided into two categories. The first group contains highly
nucleophilic and unhindered Lewis bases like DABCO (38) and quinuclidine (45). Because of
their high nucleophilicity they enable the efficient formation of the 3-ammonium enolate
(type-40) which leads to a high overall reaction rate. The second group consists of catalysts
which can stabilize this 3-ammonium enolate by delocalization of the positive charge on
nitrogen (e.g. 47-49) (Scheme 20).
20
NN
OO
NN
OO
50 50
Scheme 20. Stabilization of the DBU-containing 3-ammonium enolate (50) of methyl
acrylate (42).
Typical P-containing Lewis bases for the BH reaction are trialkylphosphines like P(n-
Bu)3 (51),[78] PEt3 (52) and the air-stable trialkylphosphine 1,3,5-triaza-7-phosphaadamantane
(PTA, 54) (Scheme 21).[79] Due to their reduced nucleophilicity, triarylphosphines like PPh3
(53) can only initiate the reaction in the presence of a suitable co-catalyst like phenol.[80]
NN
P
NP
P
P
51 52 53 54
Scheme 21. Typical P-Lewis base catalysts for the BH reaction.
As already mentioned before, Brønsted acids are efficient co-catalysts for the BH
reaction and lead to significant rate enhancements. Typical protic additives which are used to
increase the efficiency of BH reactions are for example methanol,[81] water,[82] (thio)ureas,[83]
and phenols.[40] Both catalytic moieties can also be incorporated in one catalyst. A simple
example is 3-quinuclidinol (55), which in general shows a much higher catalytic activity than
quinuclidine (45) itself due to the formation of hydrogen bonds in the corresponding
intermediates.[84] This concept of applying a bifunctional catalyst in BH reactions has proven
to be successful in asymmetric catalytic variants.
The first successful chiral catalyst that resulted in synthetically useful
enantioselectivities in the BH reaction has been developed only recently. 1999, Hatakeyama
and co-workers applied the cinchona alkaloid derivative 56 as catalyst for the BH reaction of
various aldehydes with 1,1,1,3,3,3-hexafluoroisopropyl acrylate (57) (Scheme 22).[47b]
21
At −55°C in DMF they obtained the corresponding products (58) in enantioselectivities up to
99% ee.
RCHO +O
O
CF3
CF3
N
NO
OH
R
OH O
O
CF3
CF3
O O
R
R O
+
57
56
58 59
−55°C, DMF
yield up to 58%up to 99% ee
(10 mol-%)
25
Scheme 22. Reaction of various aldehydes with 57 under the catalytic influence of 56 (R =
C6H5, p-NO2C6H4, CH3CH2, C6H11 etc).
The explanation for the high enantioselectivity as given by the authors was based on three
features of catalyst 56:
(1) its increased nucleophilicity in comparison to related compounds like quinidine
(2) the presence of the free phenolic-OH group at the quinoline ring
(3) the anti-open conformation of catalyst 56
The authors postulated that the anti-open conformation allowed an optimal stabilization of
zwitterion 60 through intramolecular hydrogen bonding (Scheme 23).
NN
O
O H O
O
O
CF3
CF3
R
60
A
B
Scheme 23. Postulated stabilization of intermediate 60 with Hatakeyama’s catalyst 56.
22
Since the chirality of the catalyst is fixed and intermediate 60 contains two chiral centers, A
and B, four diastereoisomers can be formed in this stage of the reaction. The authors
postulated that diastereoisomer 60, depicted in Scheme 23, is the most stable and has a nearly
ideal conformation for the subsequent elimination reaction. Elimination from the catalyst in
intermediate 60 leads to the BH product with the stereoconfiguration of 58. A major
disadvantage of Hatakeyama’s catalytic system is the formation of relatively large amounts of
the dioxanone by-product 59 which suppresses the yield of the BH product 58. These
dioxanone by-products are formed in opposite stereoconfigurations and worse
enantioselectivities as compared to 58. This dioxanone formation, however, contributed to the
mechanistic understanding of the BH reaction (cf. HEMI-ACETAL MODEL). Catalyst 56 was
subject of further studies to expand the scope of substrates[85] and has also been applied in the
synthesis of natural products.[86] Other bifunctional chiral catalysts for the BH reaction which
contain both catalytic moieties in one chiral molecule, are the cinchona-alkaloid derivative 61
(pseudo-enantiomer to 56),[87] N-methylprolinol (62)[88] and the amine-thiourea catalyst 63
(Scheme 24).[89]
NH
S
NH
CF3
CF3NN
OH
up to 94% ee
N
OH
N
O
up to 91% ee up to 78% ee61 62 63
Scheme 24. Recent examples for bifunctional chiral catalysts for the BH reaction.
Examples of efficient systems with chiral Brønsted acidic co-catalysts in combination
with simple achiral nucleophiles like DABCO (38) and PEt3 (52) are based on L-proline
(1),[90] BINOL derivatives (64),[40] the bis-thiourea compound 65[91] and pipecolinic acid (66)
(Scheme 25).[92]
23
NH
CO2H
66
up to 84% ee (with methylimidazol)
NHS
HN
CF3
CF3
NH
S
NH
CF3
CF3
65up to 90% ee (with DABCO)
NH
CO2H
1up to 81% ee
(with methylimidazol-modified peptide)
X
OH
X
OH
64
up to 96% ee (with PEt3)
Scheme 25. Chiral co-catalysts for the BH reaction (X = H, Br, Ph etc).
There are only few non-bifunctional chiral catalyst systems for the BH reaction
reported in literature. Hayashi and co-workers reported a chiral diamine catalyst with
enantioselectivities up to 75% ee.[93] As a chiral biphosphine catalyst, BINAP resulted in
enantioselectivities up to 44% ee.[94]
2.3. Aza-Baylis-Hillman Reaction
2.3.1. General Aspects
The aza-Baylis-Hillman (aza-BH) reaction – the coupling of activated alkenes with imines –
was first reported by Perlmutter and Teo in 1984 (Scheme 26).[1] This atom-efficient C-C
bond forming reaction is, in analogy to the BH reaction, usually catalyzed by nucleophilic
Lewis bases like DABCO (38) and leads to highly functionalized chiral allylic amines (68).
NTos
+O
O
NN
NH O
O38
4467 68
Tos
Scheme 26. Aza-BH reaction of N-benzylidene-4-methylbenzenesulfonamide (67) with ethyl
acrylate (44), catalyzed by DABCO (38).
24
The reaction is flexible towards the choice of starting materials. As electrophiles,
various activated aromatic aldimines like tosyl-,[48b],[93] nosyl-[38] and phosphinoylimines[95]
can be used. The reaction can also be performed as a three component reaction in which
aldehyde, activated alkene and tosylamide[96] or diphenylphosphinamide[97] are coupled in one
pot. Furthermore, sulfinimines[98] and azadicarboxylates[99] can be applied in the aza-BH
reaction.
The spectrum of Michael acceptors, which can be used for this reaction, is even
broader.[100] MVK, acrolein, phenyl acrylate, α-naphthyl acrylate, methyl acrylate, 2-
cyclopentenone and 2-cyclohexenone as well as other β-substituted activated alkenes were
reported as suitable Michael acceptors.[101] Also, activated allenes and alkynes are appropriate
substrates.[102]
In the presence of P(n-Bu)3 (51) as Lewis base the aza-BH reaction of aldimines like
67 with cyclic α,β-unsaturated ketones like 2-cyclohexenone (69) can result in the formation
of the expected aza-BH product 70 along with the bicyclic by-product 71 (Scheme 27).[103]
NTos
+NH
51
6967 70
TosO P(n-Bu)3 (20 mol-%) O+
MeOH, 40°C
O 67 O
Ph
NTos
N
O
Tos
Ph
H+
72 73 71
N
O
Tos
Ph
71
Scheme 27. Formation of the bicyclic compound 71 under aza-BH reaction conditions.
The mechanism postulated for the formation of 71 starts with a Mannich-type coupling of 72
and 67 which results in the formation of 73. In the next step, intermediate 73 undergoes
intramolecular Michael addition and subsequent protonation to form 71.
Another substrate combination which can lead to unexpected (by-)products under aza-
BH reaction conditions is 67/MVK (37) (Scheme 28).[104] In the case of PPh3 (53) as catalyst,
the expected aza-BH product 77 was the only observed reaction product. With P(n-Bu)3 (51)
25
as catalyst under otherwise identical reaction conditions, the only observed products were 74
and 75. The proposed mechanism that explains the formation of these products involves the
hemi-aminal intermediate 78. In case of the BH reaction, a similar intermediate (hemi-acetal)
is postulated to explain the formation of dioxanones as by-products as well as specific kinetic
results (see chapter 2.2.2. and 2.2.3.).
NTos
+ 51
3767
O P(n-Bu)3 (20 mol-%)
THF, r.t.N HNTos
Ph
Ph
O
Ph
Ph O
74 75
O
R3P
NPhTos
76
- PPh3 (53) NH OTos
77
(R = Bu)67
PBu3
NPhTos
N
Ph
Tos
O
78
- PBu3 (51)
PBu3
NPhTos
HN
Ph
Tos
O
79
NTos Ph
NHTos
Ph
O
74 + 75
80
Scheme 28. Unexpected products for the reaction of 67 with 37.
The synthetic potential of the aza-BH reaction is illustrated by its integration into
synthetic routes. It is, for example, used for the synthesis of PEG-supported α-methylene-β-
aminoesters,[105] substituted pyrroles[106] and 2,5-dihydropyrroles.[107]
26
2.3.2. Mechanism
At the beginning of this Ph.D. study (November 2003) no information was available on the
mechanism of the aza-BH reaction. It was assumed that the catalytic cycle of the reaction
contained intermediates similar to those commonly accepted for the BH reaction (Scheme 29).
NN
NH O
O
Tos
67
443868
NN
O
O
8182
NN
O
O
Ph NTos
O
O
NTos
NN
NH O
O
Tos
67
443868
NN
O
O
8182
NN
O
O
Ph NTos
O
O
NTos
Scheme 29. Assumed catalytic cycle for the aza-BH reaction.
In parallel to the work described in this thesis, Jacobsen and co-workers investigated the
reaction between the aromatic nosyl-aldimine 83 and methyl acrylate (42) (Scheme 30).[38]
They published their results almost simultaneously with our first communication on the
reaction mechanism.
27
NNos
+CO2Me
38 +
N
O
tBu
NH
S
NH
BnN
HO
But tBu NHCO2Me
Nos(1 eq.) (20 mol-%)
84
xylene, r.t.
55%97% ee
83 42 85
Scheme 30. Reaction of the nosyl imine 83 with methyl acrylate (42), catalyzed by DABCO
(38) and thiourea 84.
As catalyst they used a combined system of the Lewis basic nucleophile DABCO (38) and the
Brønsted-acidic chiral thiourea 84 in xylene. They observed a yellow precipitate during the
course of the reaction and spectroscopically identified it as the second intermediate of the
catalytic cycle 86 (Scheme 31). Upon treatment with an excess of hydrochloric acid, they
could isolate and characterize the dihydrochloride salt 87 as a glassy solid.
CO2MePh
NNos
NN
HCl CO2MePh
NHNos
NN
H
2 Cl-
86 87
Scheme 31. Isolation and characterization of the dihydrochloride salt 87 of intermediate 86 by
the group of Jacobsen.
Intermediate 86 (and its corresponding dihydrochloride salt 87), which resulted from a
Mannich-type coupling of the corresponding zwitterionic 3-ammonium enolate with imine 83
was obtained in high diastereomeric purity (d.r. > 10/1) with a relative stereochemistry of the
major isomer assigned as anti. Furthermore, they disclosed that 86 could racemize under turn-
over conditions. This stereochemical lability was explained by the reversibility of the
28
Mannich-type coupling step which would create a racemization pathway for 86 in which the
Brønsted acidic co-catalyst did not play a role (Scheme 32).
CO2MePh
NHNos
NN
H
2 Cl-
87
DBU (47)rac-85 + 83 42+
trace amount
Scheme 32. Racemization under turn-over conditions.
Because the reaction mixture for the reaction disclosed in Scheme 30 was not
homogeneous, kinetic experiments could not be performed for that exact system. Therefore
the group of Jacobsen studied the reaction of imine 83 with methyl acrylate (42) without co-
catalyst in CHCl3 which provided a homogeneous mixture during the complete course of the
reaction. They monitored the conversion by GC analysis and analyzed their data with the
method of initial reaction rates.[108] The reaction showed a first order kinetic dependence on
both DABCO (38) and methyl acrylate (42). In contrast to the BH reaction, they observed rate
saturation for the imine 83 as electrophile.
In kinetic isotope effect studies using α-deuterated methyl acrylate ([D]42) they
disclosed a prominent primary kinetic isotope effect (kH/kD = 3.81), which strongly suggested
that a cleavage of the α-CH(D) bond was involved in the RDS (RDS = proton
migration/elimination).
To determine the influence of the electrophile on the elimination reaction, they
investigated the DBU (47)-mediated elimination of 87 in methanol via IR spectroscopy. They
found a first-order reaction rate profile for more than 4 half-lives, which was consistent with a
rapid and irreversible deprotonation of 87 to 86, followed by intramolecular proton transfer.
Since added imine had no effect on the rate of elimination, they concluded that the
electrophile did not play a role in mediating the elimination step thereby excluding a pathway
similar to the HEMI-ACETAL MECHANISM postulated by McQuade for the BH reaction.[69]
Further mechanistic investigations were carried out by the groups of Sasai and Shi
focussing on the origin of enantioselectivity in their specific systems. The results of these
studies will be discussed in the next chapter.
29
2.3.3. Catalysts
In accordance with the BH reaction, the aza-BH reaction can be mediated by nucleophilic
Lewis bases, by Lewis bases in combination with Lewis acids[109] and by combined Lewis
base/Brønsted acid systems. Only the systems based on N- and P-Lewis bases (with Brønsted
acid) will be discussed here in more detail.
In general, the achiral nucleophilic N- and P-containing Lewis bases, which were
discussed as catalysts for the BH reaction, can also be applied to mediate the aza-BH reaction.
For the asymmetric aza-BH reaction, however, different catalytic systems are applied.
One of the most successful chiral catalytic systems for the aza-BH reaction was
developed by Shi and co-workers in 2003.[110] They developed the P-based catalyst 88 which
carried a Brønsted acidic phenol moiety and tested it initially for the coupling of aromatic
tosylaldimines like 67 with simple Michael acceptors like MVK (37) and phenyl acrylate
(Scheme 33). Depending on the substitution pattern of the aromatic tosylaldimine,
enantioselectivities up to 97% ee were obtained.
NTos
O+
OHPPh2
NH OTos
67 37
88
89
(10 mol-%)
THF, −30°C, MS 4A, 24 h
83%83% ee
Scheme 33. Reaction of the aromatic tosylaldimine 67 with MVK (37), catalyzed by 88.
In further studies, the substrate scope of this catalytic system was investigated.[48b],[111]
Besides aromatic tosylaldimines like 67, aromatic mesyl-, p-chlorobenzenesulfonyl- and β-
trimethylethanesulfonyl (SES) aldimines could be used. The catalyst was inactive in reactions
with aliphatic aldimines.
As Michael acceptor, MVK, ethyl vinyl ketone (EVK), phenyl acrylate, α-naphthyl
acrylate, β-naphthyl acrylate and acrolein could be used. Reactions with methyl acrylate
30
proceeded in a very sluggish way with low enantioselectivities (typically about 20% ee). β-
Substituted Michael acceptors proved inactive with 88. Replacement of the PPh2 group with a
more nucleophilic PMe2 group, however, resulted in a suitable chiral catalyst system for
reactions with this type of Michael acceptors.
In addition, the authors carried out some mechanistic investigations on their system.
The phenolic OH group turned out to be crucial for the success of the catalyst.[112] The
introduction of substituents in 3, 6 or 6’ position of 88 did not result in significant changes in
activity and selectivity. Replacement of the PPh2 group with a P(o-tolyl)2 group, however,
yielded an inactive system, which indicated that the steric bulk around the P-atom played a
key role in initiating the aza-BH reaction. Furthermore, the authors characterized the “type-81
intermediate” of 88 with 37 via NMR spectroscopy. They suggested a stabilization of this
intermediate by hydrogen bond interaction of the phenolic OH group with the enolate oxygen.
They explained the success of their chirality transfer with a model similar to that postulated
by Hatakeyama and co-workers for catalyst 56 (page 21).
A second system based on a phosphorus-containing Lewis base was developed by
Sasai and co-workers in 2006.[113] They attached a phosphine unit through an aromatic ring to
the 3-position of (S)-BINOL as a chiral Brønsted acid and tested the system for the reaction of
imine 67 with MVK (37) (Scheme 34).
NTos
O+
NH OTos
67 37
90
89
(10 mol-%)
MTBE, −20°C,9 d
97%87% ee
OH
PPh2OH
Scheme 34. Reaction of imine 67 with MVK (37) catalyzed by 90.
They obtained enantioselectivities up to 95% ee, albeit with a very slow reaction rate. When
both catalytic moieties of this bifunctional catalyst were positioned in a way that no
31
synergistic interaction between the Lewis base and the Brønsted acid could occur in an
intramolecular fashion, the selectivity decreased dramatically.
Similar results were reported by the same group for a nitrogen containing bifunctional
system which was introduced in 2005.[114] They investigated the reaction of aromatic
tosylaldimines like 67 with MVK (37) catalyzed by the bifunctional catalyst 91 (Scheme 35).
NTos
O+
NH OTos
67 37
91
89
(10 mol-%)
toluene:CPME (1:9), −15°C, 168 h
93%87% ee
OHOH
NN
Scheme 35. Reaction of 67 with 37 catalyzed by the bifunctional catalyst 91.
In a mixture of toluene and cyclopentyl methyl ether (CPME) at −15°C, enantioselectivities
up to 96% ee could be obtained for aza-BH reactions between aromatic tosylaldimines and
simple Michael acceptors like MVK, EVK and acrolein. The authors showed that activity and
enantioselectivity of the catalytic system were severely dependent on the exact position of the
active units within the catalyst.[48a] Many similar catalysts which contained different spacers
between the catalytic moieties and/or different positions of the pyridine nitrogen relative to
the Brønsted acidic group were often inactive and non-selective. Only when both catalytic
functions were correctly positioned within the organocatalyst, a synergistic interaction was
possible which resulted in an efficient bifunctional chiral catalyst. In a more extensive
mechanistic study, they disclosed that the catalytically active groups of catalyst 91 are the
pyridine-N atom and the phenolic OH group in 2’-position.[48a]
A fourth bifunctional system which proved effective in mediating the aza-BH reaction
of aromatic tosylaldimines involves the BH catalyst 56. Both the group of Shi[115] and the
group of Adolfsson[116] showed that catalyst 56 did not only efficiently catalyze the BH but
also the aza-BH reaction. The substrate scope of this catalytic system was fairly broad: MVK,
32
EVK, acrolein, methyl acrylate, phenyl acrylate and naphthyl acrylates could be used as
Michael acceptors. Furthermore, the reaction could be performed enantioselectively as a three
component coupling of aldehyde, tosylamide and activated alkene. With catalyst 56,
enantioselectivities up to 99% ee were obtained. This successful transfer of chirality was
explained by a mechanistic model similar to that for the BH reaction with 56 as catalyst.
In principle, it is also possible to decouple both catalytic moieties. As already partially
described in 2.3.2., Jacobsen and co-workers used chiral thiourea derivatives like 84 in
combination with simple achiral nucleophiles like DABCO (38).[38] They investigated the
coupling of aromatic nosylaldimines like 83 with methyl acrylate (42) and obtained the
corresponding reaction products in enantioselectivities up to 99% ee. The activity of this
catalytic system, however, was low to moderate. Furthermore, the observed inverse
relationship between chemical- and optical yield for this system leaves no room for
improvement. In addition, the substrate scope is, to date, very limited.
2.4. Chiral Solvents for Asymmetric Synthesis
A chemical reaction that leads to enantiomerically enriched products can in principle be
carried out with a source of chirality in any of the involved components – starting
materials,[117] catalysts,[118] or solvents.[119] The strategy of applying chiral solvents in
asymmetric synthesis was pioneered by Seebach and Oei.[120] They used a chiral aminoether
as the solvent in the electrochemical reduction of ketones but observed only low
enantioselectivities (up to 23.5% ee). Since then, all attempts to apply chiral solvents in
asymmetric synthesis have resulted in similar or lower enantioselectivities, which led to the
generally accepted conclusion that “asymmetric induction caused by chiral solvents is usually
rather small”.[119]
As ionic liquids (ILs), however, recently attracted a lot of attention as a new class of
solvents,[121] the incorporation of chiral information in these media has caught the interest of
several groups.[122] A selection of chiral ions, used for the synthesis of chiral ILs, is shown in
Scheme 36.
The first contribution to this area of research was made by the group of Seddon and
co-workers in 1999.[123] They introduced [bmim] lactate (92) as anion-chiral IL, which was
prepared by ion metathesis of sodium lactate with [bmim] chloride. Application of this IL as a
solvent for the Diels-Alder reaction of ethyl acrylate with cyclopentadiene, however, did not
result in a transfer of chirality from the reaction medium to the corresponding reaction
33
product. Although this first application of a chiral IL as reaction medium was rather
unsuccessful, Seddon’s study initiated the synthesis of a broad spectrum of chiral ILs, as
shown in Scheme 36.
NO
R'RN
HO
CO2-
OHH CO2
-
R O
OP
O
OSO3
- O
92 93 94 95
Seddon, 1999 Dorta, 2005 Dorta, 2005Ohno, 2005
96 97
N N
98
OO
H
NC10H21
R
H
99
Wasserscheid, 2001 Wasserscheid, 2001 Saigo, 2002 Plaquevent, 2005
Scheme 36. A selection of chiral ions which are used for the synthesis of chiral ILs.
In 2001 Wasserscheid and co-workers developed a first set of ILs containing chiral
cations including ephedrinium based ILs (96).[124] Very recently, Vo-Thanh and co-workers
used these ILs as solvent for the DABCO-catalyzed BH reaction of benzaldehyde and methyl
acrylate.[125] With this IL, they obtained the first significant asymmetric induction caused by a
chiral IL as the only source of chirality in an asymmetric reaction. The corresponding BH
product 101 was obtained in an enantiomeric excess of up to 44% (Scheme 37).
34
O O
O+38 (1 eq), 30°C, 7 d
O
O
OH
60%44% ee
36 42 101
NHO
C8H17
100OTf
Scheme 37. BH reaction in the ephedrinium IL 100.
Further examples of asymmetric induction caused by cation-chiral ILs as solvents were
reported by Armstrong and co-workers (photoisomerization of
dibenzobicyclo[2.2.2]octatriene diacid, ee up to 11%)[126] and by the group of Bao (Michael
additions of malonates to enones, ee up to 25%).[127] No significant asymmetric induction has
been reported so far for anion-chiral ILs.
The comparatively high enantioselectivities obtained in the BH reaction of
benzaldehyde and methyl acrylate indicate that the application of chiral ILs as the source of
chirality in organocatalytic processes can be a promising strategy to obtain the corresponding
products in valuable enantioselectivities. A potential reason for the comparatively high
enantioselectivity in this reaction may be a strong interaction of the zwitterionic reaction
intermediates (transition states) with the chiral ions of the solvent. Possible modes of
interaction with ILs are electrostatic attraction and, in case of IL 100, hydrogen bonding.
35
3. Results and Discussion
3.1. Mechanistic Investigation of the Aza-Baylis-Hillman Reaction
3.1.1. Kinetic Study
3.1.1.1. Lewis Base Catalysts
In initial experiments, kinetic measurements were performed on the catalytic system which
contained only a Lewis base catalyst. As a model reaction, the aza-BH coupling of N-(3-
fluorobenzylidene)-4-methylbenzenesulfonamide (102) with MVK (37) in the presence of
triphenylphosphine (53) as catalyst was examined (Scheme 38). The reaction was carried out
in THF at room temperature.
F
N TosO
+
PPh3, C6F6
THF, r.t.
F
NH OTos
102 103
10453
37
− 112.6 −114.1−164.0δ (19F) ppm
Scheme 38. Model reaction for kinetic study of the Lewis base-catalyzed aza-BH reaction.
The first method considered for this study was on-line IR spectroscopy. In cooperation
with Patrick Bäuerlein from the group of Dr. Lasse Greiner, the reaction could be monitored
via IR spectroscopy in an Argon-glovebox. For this purpose, an ATR-IR sensor from the
company INFRARED FIBER SENSORS was used, which measures the wave-length dependent
attenuation of the intensity of the IR signal for the total reflection at a diamond crystal.[128]
The laser beam was injected and released through a fiber optical cord. The probe and the
setup in the glovebox are depicted in Figure 1.
36
Figure 1. ATR-IR probe from INFRARED FIBER SENSORS, mounted for reaction monitoring in
a glovebox.
The main advantage as compared to other potential analysis techniques (e.g. NMR
spectroscopy, vide infra) was the velocity of the measurement and the high flexibility of the
probe as a result of the attached fiber optics. A major disadvantage, however, was the
complexity of the handling and analysis of the obtained data involving operations like base
line corrections and curve fitting. Furthermore, an external reference was necessary for an
appropriate quantification. Although the data that were obtained with this technique were in
accordance with data obtained from 1H NMR spectroscopic studies, the disadvantages of this
method outweighed its advantages for the aza-BH reaction.[129]
As a second method NMR spectroscopy was considered. A general advantage of
NMR- over IR-spectroscopy was the easy data handling. An important drawback of this
technique, however, was the inability to obtain data during the first minutes of a reaction due
to experimental factors (lock/shim). Since the aza-BH reaction was a relatively slow process,
this disadvantage played only a minor role in this kinetic study. Consequently, NMR
spectroscopy was elected as the method of choice for these investigations. Furthermore, the
use of the fluorinated electrophilic coupling partner 102 allowed reaction monitoring via 19F
NMR spectroscopy. In consequence, the use of large amounts of expensive deuterated
solvents like [D8]THF which would be necessary for 1H NMR spectroscopic measurements,
could be avoided. Hexafluorobenzene (104) was applied as internal standard.
Typical concentration-time profiles that were obtained with 19F NMR spectroscopy,
are shown in Figure 2.
37
0,000
0,020
0,040
0,060
0,080
0,100
0,120
0,140
0 100 200 300 400 500 600 700
t / min
c / (
mol
/l)
48 mol-%64 mol-%78 mol-%105 mol-%
Figure 2. Typical concentration-time profiles. Starting concentrations: c (102) = 0.1514
mol⋅l−1, c (37) = 0.1531 mol⋅l−1, c (104) = 0.0285 mol⋅l−1, c (53) = 0.0724 - 0.1595 mol⋅l−1.
The concentration-time profiles were fitted with a polynomial of fourth order
(Equation 1). The initial reaction rate was determined through differentiation (Equation 2).
pdtctbtattc ++++= 234)( ℜ∈pdcba ,,,, Equation 1
ddt
tdcdctbtatdt
tdc
t
=⎟⎠⎞
⎜⎝⎛⇒+++=
=0
23 )(234)( ℜ∈pdcba ,,,, Equation 2
The initial reaction rate was analyzed as a function of the starting concentration of the
individual components. The corresponding plots are shown in Figure 3a-d.
38
0,000E+00
1,000E-04
2,000E-04
3,000E-04
4,000E-04
5,000E-04
6,000E-04
0,000 0,050 0,100 0,150 0,200 0,250 0,300
c (imine) / (mol / l)
r(0)
/ [m
ol /
(l*m
in)]
Figure 3a. Partial order in imine 102. Starting concentrations: c(53) = 0.0501 mol⋅l−1, c(37) =
0.1438 mol⋅l−1, c(104) = 0.0243 mol⋅l−1, c(102) = 0.0998-0.2530 mol⋅l−1.
log r(0) = 0,4685log c(imine) + 3,0243R2 = 0,9908
3,00
3,10
3,20
3,30
3,40
3,50
3,60
0,50 0,60 0,70 0,80 0,90 1,00 1,10
log c(imine)
log
r(0)
Figure 3b. Partial order in imine (double-logarithmic).
39
r(0) = 0,0027*c(MVK)R2 = 0,9909
0,000E+00
1,000E-04
2,000E-04
3,000E-04
4,000E-04
5,000E-04
6,000E-04
7,000E-04
8,000E-04
9,000E-04
0,00 0,05 0,10 0,15 0,20 0,25 0,30 0,35
c(MVK) / (mol/l)
r(0)
/ [m
ol/(l
*min
)
Figure 3c. Partial order in MVK (37). Starting concentrations: c(53) = 0.0500 mol⋅l−1, c(102)
= 0.1506 mol⋅l−1, c(104) = 0.0214 mol⋅l−1, c(37) = 0.1712 – 0.3163 mol⋅l−1.
r(0) = 0,00698*c(catalyst)R2 = 0,98780
0,000E+00
2,000E-04
4,000E-04
6,000E-04
8,000E-04
1,000E-03
1,200E-03
0,00 0,02 0,04 0,06 0,08 0,10 0,12 0,14 0,16 0,18
c(catalyst) / (mol/l)
r(0)
/ [m
ol/(l
*min
)]
Figure 3d. Partial order in PPh3 (53). Starting concentrations: c(37) = 0.1531 mol⋅l−1, c(102)
= 0.1514 mol⋅l−1, c(104) = 0.0285 mol⋅l−1, c(53) = 0.0724 – 0.1595 mol⋅l−1.
40
These results demonstrated that the reaction showed a first order dependence in Michael
acceptor (37) and catalyst (53). To determine the non-integer order in imine (102), the data
were analyzed by using a double-logarithmic plot (Figure 3b).[130] The gradient of this plot
corresponded to a partial reaction order of approximately 0.5 (Equation 3).
)()()(5.0 hosphinepcacceptorMichaelcimineckr obs ⋅−⋅⋅= Equation 3
A comparison of these data to the kinetic results obtained by Aggarwal and Lloyd-Jones for
the autocatalytic BH reaction revealed that the aza-BH coupling was no autocatalytic process
under the conditions applied in this kinetic study.[71] A HEMI-ACETAL MECHANISM, as
proposed by McQuade for the BH reaction in aprotic solvents, could also be ruled out.[69]
Based on the rate law in Equation 3, however, no autonomous mechanism for the Lewis base-
catalyzed aza-BH reaction could be postulated. A mechanistic interpretation of these data will
be provided in the next chapter by comparison to the kinetic data of the aza-BH reaction
mediated by a bifunctional Lewis Base-Brønsted acid catalyst system. Similar kinetic results
for the aza-BH reaction catalyzed by nucleophilic Lewis bases were independently reported
by the group of Jacobsen.[38]
3.1.1.2. Lewis Base-Brønsted Acid Catalysts
In a second set of experiments, the influence of Brønsted acidic additives (co-catalysts) on the
reaction of N-(4-bromobenzylidene)-4-methylbenzenesulfonamide (105) with MVK (37) in
[D8]THF was examined (Scheme 39).
N TosO
+
PPh3, Brønsted acid
[D8]THF, r.t.
NH OTos
Br Br37
53
105 106
Scheme 39. Reaction of imine 105 with MVK (37), catalyzed by the system PPh3
(53)/Brønsted acid.
A set of Brønsted acids with pKA values in the range of 4 to 16 was screened as potential
additives for this model reaction.[131] Approximately one equivalent of Brønsted acid per
41
imine was used. A strong influence of strength of the Brønsted acid on the rate of the reaction
was observed (Table 1, Figure 4).
Table 1. Influence of Brønsted acidic additives on the reaction rate.
entry additive pKA relative initial rate 1 malic acid 3.6 0.1 2 - - 1.0 3 aza-BH product (106) n.a. 1.2 4 water 15.4 2.4 5 methanol 15.5 3.7 6 N-methyl-tosylamide 11.7 4.8 7 benzoic acid 4.2 6.5 8 phenol 9.9 7.3 9 3,5-bis(CF3)phenol 8.0 13.9
Starting concentrations: c(37) = 0.150 mol⋅l−1, c(105) = 0.125 mol⋅l−1, c(53) = 0.0125 mol⋅l−1
and 0.172 mol⋅l−1 Brønsted acid in [D8]THF.
0,0
2,0
4,0
6,0
8,0
10,0
12,0
14,0
16,0
0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0
pKa
rela
tive
initi
al r
ate
malic acid
benzoic acid
3,5-bis(CF3)phenol
phenol
N-methyl-tosylamide
water
methanol
0,0
2,0
4,0
6,0
8,0
10,0
12,0
14,0
16,0
0,0 2,0 4,0 6,0 8,0 10,0 12,0 14,0 16,0 18,0
pKa
rela
tive
initi
al r
ate
malic acid
benzoic acid
3,5-bis(CF3)phenol
phenol
N-methyl-tosylamide
water
methanol
Figure 4. Influence of Brønsted acidic additives on the reaction rate.
42
A comparison of the relative initial rate of the reaction with the aza-BH product 106 as
additive (entry 3) to the relative initial rate of the reaction without co-catalyst (entry 2)
confirmed that the reaction was not autocatalytic under the applied conditions. A maximum in
reaction rate was observed with 3,5-bis(CF3)phenol (107) (pKA ≈ 8, entry 9) as additive,
corresponding to a 14-fold rate enhancement as compared to the reaction without additive
(entry 2). Less acidic compounds showed a smaller effect (entry 4-6, 8). Additives, which
were more acidic than 3,5-bis(CF3)phenol (107), ultimately even inhibited the reaction (entry
1).
NMR studies showed that this was mainly due to a protonation of the first zwitterionic
reaction intermediate and to a minor extent to protonation of the nucleophilic catalyst itself
(Scheme 40).
O+
2 HX
[D8]THF, r.t.
O
3753
2 PPh3
Ph3PX
+ HPPh3+X−
108
109 110
Scheme 40. Protonation of the nucleophilic catalyst and the first zwitterionic reaction
intermediate.
Treatment of a 1:1-mixture of PPh3 (53) with MVK (37) in [D8]THF at r.t. with one
equivalent of malic acid resulted in a mixture of the corresponding 3-phosphonium enolate in
its protonated form (109) and the triphenylphosphonium salt 110. After 5 min all PPh3 was
converted. A comparison of the signal intensities in the 31P NMR spectrum showed that the
ratio 109/100 corresponded to a value of 95/5. These results are i.a. supported by a report
from Wasserscheid and co-workers. They described a similar reaction as side reaction during
the preformation of their metal-phosphine catalytic system for acrylate dimerisation.[132]
Additionally, the rate law of the reaction was determined in the presence of phenol
(111) as prototypical additive. The reaction was monitored by 19F NMR spectroscopy. The
dependence of the initial rate on the starting concentration of imine is depicted in Figure 5.
43
r(0) = 0,0111*c(imine)R2 = 0,9906
0,000E+00
2,000E-04
4,000E-04
6,000E-04
8,000E-04
1,000E-03
1,200E-03
1,400E-03
1,600E-03
1,800E-03
2,000E-03
0,0000 0,0200 0,0400 0,0600 0,0800 0,1000 0,1200 0,1400 0,1600 0,1800
c(imine) in [mol/l]
r(0)
in [m
ol/(l
*min
)]
Figure 5. Initial rate as function of starting concentration of the imine 102 in the presence of
phenol as Brønsted acidic co-catalyst. Starting concentrations: c(53) = 0.0294 mol⋅l−1, c(37) =
0.1502 mol⋅l−1, c(111) = 0.1584 mol⋅l−1, c(104) = 0.0341 mol⋅l−1, c(102) = 0.0962 – 0.1479
mol⋅l−1.
For the other curves r(0) = f(c(x)) {x = MVK (37) and phenol (111)}, see Appendix 3.
A first order dependence in all components was observed, including the imine and Brønsted
acid (Equation 4).
)()()()('' acidcphosphinecacceptorMichaelcimineckr obs ⋅⋅−⋅⋅= Equation 4
These results are in line with the results obtained by Kaye in the so-called CLASSICAL MODEL
for the amine-catalyzed BH reaction of pyridinecarboxaldehydes with acrylate esters.[68] This
indicates, that the RDS of the aza-BH reaction catalyzed by the combined system Lewis Base-
Brønsted acid is the C-C coupling step, the Mannich reaction.
A comparison of these results to the results obtained with a Lewis base catalyst alone
(Equation 3), clearly indicates that the mechanism undergoes a change upon addition of the
44
Brønsted acidic co-catalyst. A potential mechanistic interpretation of the change in the rate
law – the partial order in imine changed from 0.5 to 1 – involves a shift of the RDS from the
proton migration to the Mannich-type coupling reaction. Addition of a Brønsted acid
facilitates the proton transfer which ultimately becomes so fast that it is not rate limiting
anymore. This hypothesis is supported by the data, provided by Aggarwal and Lloyd-Jones in
their mechanistic study on the BH coupling.[71] A plausible transition state, which explains the
facilitation of the proton transfer, is shown in Scheme 41. Without Brønsted acid, the proton
migration step most likely proceeds either through a 4-membered cyclic TS or in an
intermolecular fashion. Addition of a suitable Brønsted acid (ROH) enables a facilitation of
the migration step via 6-membered cyclic TS.
H O
HN
OR
Tos
PPh3
112
F
Scheme 41. Postulated transition state for the Brønsted acid-mediated proton transfer.
Furthermore, the partial order of 1 in Brønsted acid indicates that the Brønsted acid also plays
a role in the Mannich type reaction, probably through activation of the imine. At
approximately one equivalent of Brønsted acid per imine, a start of saturation was observed
(see Appendix 3).
3.1.2. Reversibility of the Aza-Baylis-Hillman Reaction
To assess the reversibility of the aza-BH reaction, both cross-Mannich (Scheme 42) and
racemization experiments (Scheme 43) with the catalytic system PPh3 (53)/phenol (111) were
performed.
45
PPh3, phenol
THF, r.t.
NH OTos
Br
53
F
N Tos
+111
F
NH OTos
Br
N Tos
+
106 105102 103
Scheme 42. Cross-Mannich experiments with the catalytic system PPh3 (53)/phenol (111).
Reaction conditions: 30.0 mg (0.0735 mmol, 1.00 eq) 106, 203.7 mg (0.735 mmol, 10.0 eq)
102, 19.3 mg (0.0735 mmol, 1.00 eq) 53, 34.6 mg (0.367 mmol, 5.00 eq) 111, 2 ml (2.7
ml⋅mmol−1) THF, r.t., n h.
Figure 6 shows a direct comparison of kinetic results that were obtained with imine 102 and
105, respectively, in the reaction with MVK (37). As catalytic system, the combined system
PPh3 (53)/phenol (111) was applied.
0
0,05
0,1
0,15
0,2
0,25
0 10 20 30 40 50 60 70
t / min
conv
ersi
on in
[%]
106103
Figure 6. Kinetic results obtained with imine 103 and 106, respectively. Starting
concentrations: c(37) = 0.15 mol⋅l−1, c(103/106) = 0.13 mol⋅l−1, c(53) = 0.014 mol⋅l−1,
c(111) = 0.15 mol⋅l−1in THF.
46
These results showed that the reactivity of imine 102 was higher than the reactivity of 105.
Under turn-over conditions, however, the product of cross-Mannich reaction (103) was not
observed even after prolonged reaction times (t = 72 h).
A further probe for the reversibility of the reaction was the stability of the stereocenter
of the aza-BH product 106 under turn-over conditions (Scheme 43). With the catalytic system
PPh3 (53)/phenol (111), racemization of enantiomerically enriched 106 (ee = 88% (S)) was
observed under turn-over conditions (Figure 7). The absence of cross-Mannich products under
these conditions indicated that the racemization of the aza-BH product 106 was independent
from the catalytic cycle. Further experiments to elucidate the mechanism of racemization are
described below.
PPh3, phenol
THF, r.t.
NH OTos
Br
53 111
(S)-106
NH OTos
Br
(R)-106
Scheme 43. Racemization experiments with the catalytic system PPh3 (53)/phenol (111).
Reaction conditions: 38.1 mg (0.0933 mmol, 1.00 eq) 106, 24.5 mg (0.0933 mmol, 1.00 eq)
53, 26.3 mg (0.280 mmol, 3.00 eq) 111, 0.75 ml (8.0 ml⋅mmol−1) THF, r.t., n h.
0,0
2,0
4,0
6,0
8,0
10,0
12,0
0,00 5,00 10,00 15,00 20,00 25,00
t / h
enan
tiom
eric
rat
io S
/R
Figure 7. Racemization under turn-over conditions. Starting concentrations: c(106) = 0.125
mol⋅l−1, c(53) = 0.125 mol⋅l−1, c(111) = 0.373 mol⋅l−1 in THF.
47
3.1.3. Racemization of the Aza-Baylis-Hillman Product
Firstly it was investigated whether the C-C, C-H or C-N bond at the stereogenic center was
broken during the racemization process. To obtain this information, the aza-BH product rac-
106 was treated with PPh3 (53) in [D4]methanol. The result of this experiment is shown in
Scheme 44.
PPh3
CD3OD, r.t., 5h
O
Br
53O
Br
NHTos NDTosH D
D D
106 [D4]106
Scheme 44. Deuteration of rac-106 with [D4]methanol. Reaction conditions: 20.4 mg (0.050
mmol, 1.00 eq) 106, 13.1 mg (0.l050 mmol, 1.00 eq) 53, 1.0 ml (20 ml⋅mmol−1)
[D4]methanol, r.t., 5 h.
As shown in Scheme 44, a proton-deuterium exchange was observed in several positions of
106, also at the stereogenic center. This indicated that the C-H bond at the stereogenic center
broke during the racemization process and thereby confirmed that racemization of the aza-BH
product was not caused by retro-Mannich reaction.
In a further set of experiments, the role of all components in the racemization was
investigated. The results are shown in Table 2. These experiments showed that racemization
was not caused by simple deprotonation at the stereogenic center (entry 6). Also the presence
of triphenylphosphine alone did not lead to product racemization (entry 1). Besides a
nucleophilic catalyst a Brønsted acidic additive (entry 3) and/or imine (entry 4, 5) was
necessary for racemization. With Shi’s phosphinyl-BINOL catalyst 88, however, no
racemization was observed under the same conditions, even though the catalytic system
contained all components identified in the model reaction. This indicated that the spatial
arrangement of a bifunctional catalytic system is of major importance for the prevention of
racemization. This provides important information for the efficient design of successful chiral
catalyst systems
48
Table 2. Role of all reaction components in the racemization process.
entry system yes no
1 PPh3 x
2 phenol x
3 PPh3 + phenol x
4 PPh3 + imine x
5 PPh3 + phenol + imine x
6 KOH x
Reaction conditions: 40.0 mg (0.107 mmol, 1.00 eq) (S)-4-methyl-N-[2-methylene-1-(4-
nitrophenyl)-3-oxobutyl]-benzenesulfonamide (114), 28.0 mg (0.107 mmol, 1.00 eq) PPh3
(53), 30.2 mg (0.321 mmol, 3.00 eq) phenol (111), 16.3 mg (0.053 mmol, 0.50 eq) N-(4-nitro-
benzylidene)-4-methylbenzenesulfonamide (113), 0.85 ml THF, r.t., 24 h. The experiment
with KOH was performed in a biphasic system water/diethylether.
To assess the influence of the Brønsted acidic additive on the rate of racemization, a
screening of additives with pKA values of 4-16 was performed.[131] The influence of the
Brønsted acidic additive on the racemization rate was determined by single point
measurements of the enantiomeric ratio. The results are shown in Figure 8.
The results depicted in Figure 8 show a clear dependency of the rate of racemization
on the pKA value of the additive. Rapid and nearly complete racemization was observed with
phenol (pKA = 9.90) as additive. Weak Brønsted acids like water and methanol caused no
significant racemization on a relevant time scale. Stronger acidic additives resulted in a
slower rate of racemization ultimately leading to a non-significant racemization.
49
0
2
4
6
8
10
12
no additive 3,6 (malic acid) 4,2 (benzoic acid) 9,9 (phenol) 15,4 (methanol) 15,5 (water)
Additive
Ena
ntio
mer
ic r
atio
S/R
Figure 8. Single point measurements for comparison of the influence of different Brønsted
acidic additives on the rate of racemization. Reaction conditions: 38.1 mg (0.0933 mmol, 1.00
eq) 106 (e.r. = 11.4 (S)), 211.1 mg (0.0933 mmol, 1.00 eq) PPh3 (53), 0.2799 mmol (3.00 eq)
Brønsted acid, 0.75 ml THF, r.t., t = 24 h.
A plausible model which explains these findings involves a racemization pathway in
which both the nucleophilic catalyst and the conjugated base of the Brønsted acid play a
crucial role (Scheme 45). All steps in this model are equilibrium reactions. When the
Brønsted acid is strong (e.g. malic acid, pKA = 3.6), the conjugated base is relatively weak. It
is easily formed but not able to deprotonate the stereogenic center. In case of very weak
Brønsted acids (e.g. methanol, water, pKA ≈ 15.5), a protonation of enolate 115/116 does not
take place and consequently the conjugated base, which is necessary for deprotonation at the
stereogenic center, is not formed. Only for a small spectrum of Brønsted acids of medium
strength, the concentration and strength of the conjugated base such as 117 is suitable to
deprotonate type-118 intermediates and hence cause racemization. This base-generation
hypothesis is supported by the mechanistic work of Bergman and Toste on the phosphine-
catalyzed hydration and hydroalkylation of activated olefins.[133]
50
PPh3 +OTosHN
OH
O+
H OTosHN H
PPh3
OTosHN H
PPh3
H
− PPh3, phenol
OH NHTos
X X
XX
53 (S)-106 (X = Br)(S)-114 (X = NO2)
115 (X = Br)116 (X = NO2)
111
117118 (X = Br)119 (X = NO2)
(R)-106 (X = Br)(R)-114 (X = NO2)
53 111
Scheme 45. Potential racemization pathway involving phenol (111) /phenolate (117).
The stability of the stereocenter of the product upon treatment with successful bifunctional
catalysts like Shi’s phosphinyl-BINOL catalyst 88 indicates that the spatial arrangement of a
bifunctional catalytic system is of major importance for the prevention of racemization
(Scheme 46). A possible explanation for this phenomenon involves the intramolecular
coordination of the enolate-oxygen by the phenolic OH group of catalyst 88. This may form a
stabile adduct like 120/121 and thereby prevent the formation of the conjugated phenolate
base which is postulated as a key intermediate in the racemization of the aza-BH product.
PPh2 +OTosHN H
O
TosHN H
PX X
88 (S)-106 (X = Br)(S)-114 (X = NO2)
120(X = Br)121 (X = NO2)
HO
*
OH
*
Scheme 46. Model for the prevention of racemization with Shi’s catalyst 88 (compound 88 is
represented as HO^PPh2).
In absence of a Brønsted acid, an imine-mediated racemization takes place (Table 2,
entry 4). A possible mechanism, which explains this racemization pathway, might involve a
51
hemi-aminal intermediate. Similar intermediates have been suggested by McQuade and co-
workers in the so-called HEMI-ACETAL MECHANISM for the BH reaction. Furthermore, the
occurrence of cyclic products in the aza-BH reaction was explained by the formation of hemi-
aminals (page 25). There is, however, not enough direct experimental evidence available to
unequivocally identify such kind of mechanism at the present stage.
3.1.4. Chirality Transfer
Representative for the chirality transfer models that are reported in literature is the hypothesis
by Shi and co-workers involving catalyst 88.[48b] This model is depicted in Scheme 47.
OH
PPh2
OO
PPh2
OH
ArCH=NTosArCH=NTos
O
PPh2
HN
H
ArHTos
OO
PPh2
HN
H
HArTos
O
Ar
NH OTos
Ar
NH OTos
88 37 122
125124
123 123
(S)-126 (R)-126
P
O HN
ArH
Tos
O
PhPh
P
O H**
N
HAr
Tos
O
PhPh
124' 125'
+
S RRR
S R
R R
Scheme 47. Model by Shi and co-workers for the chirality transfer in the aza-BH reaction.
52
They postulated that compound 88 acts as a bifunctional chiral catalyst in the aza-BH
reaction. The phosphine atom acts as a Lewis base and the phenolic OH group as a Brønsted
acid. The Lewis basic moiety initiates the aza-BH reaction whereas the Brønsted acid
stabilizes both intermediates of the catalytic cycle (122 and 124/125) through hydrogen
bonding to the enolate-oxygen and imine-nitrogen, respectively. During the Mannich-type
coupling step, 4 diastereoisomers can in principle be formed. In Shi’s model, only the (R,S,R)-
and the (R,R,R)-diastereoisomers 124 and 125 are considered. Because of the steric
repulsions between the C(O)Me group with the aromatic group and the aromatic group with
the two phenyl groups at phosphorus in intermediate 125, the authors suggest that the
activation energy for the pathway through 125’ is higher than through 124’. This kinetic
selection implements the necessity of a reversible Mannich-type coupling. In accordance with
the model reported by Aggarwal and Lloyd-Jones, the reaction would “filter” through the
elimination pathway.[71]
Shi’s model, however, comprehends several ambiguities. The first ambiguity involves
the consideration of only two of four diastereoisomeric intermediates that may result from the
Mannich-type coupling of enolate 122 and imine 123. This selection is not motivated in their
report. Therefore, the relative energies of all four diastereoisomers that may result from the
Mannich type coupling of N-benzylidene-4-methylbenzenesulfonamide (67) with enolate 122
were determined in a computational study using DFT calculations in the present work.[134],[135]
The results are shown in Figure 9.
The (R,S,R)- and (R,R,S)-diasteroisomers were significantly higher in energy (6.2 and
8.3 kcal⋅mol−1, respectively) relative to the lowest energy conformer of the (R,S,S)-form. The
energy of the (R,R,R)-diastereoisomer, however, was only 1.2 kcal⋅mol−1 above the energy of
the (R,S,S)-form. Accordingly we re-optimized the structures of the (R,S,S)- and (R,R,R)-
diastereoisomers using the larger TZVP basis set by Ahlrichs and co-workers.[136a] For these
optimizations (Turbomole 5.7)[136b] the BP86[136c,d] functional was used (Turbomole 5.7 was
used simply for efficiency considerations). Again the energy difference between (R,S,S)- and
(R,R,R)-form was small (0.5 kcal⋅mol−1), now with the (R,R,R)-diastereoisomer being the
more stable compound.
53
(R,S,S) 0.0 (R,R,R) 1.2
(R,S,R) 6.2 (R,R,S) 8.3
(R,S,S) 0.0 (R,R,R) 1.2
(R,S,R) 6.2 (R,R,S) 8.3
Figure 9. Calculated structures of all four diastereoisomers (relative energies in kcal⋅mol−1).
Following Shi’s explanation, in which the stability of the intermediates correlates directly
with the relative energies of the transition states that lead to elimination of the aza-BH
product, the (R)-product should be formed in a fairly low enantiomeric excess of about
48%.[137] The observed enantioselection for this reaction, however, corresponded to an
enantiomeric excess of 83% (S) at −30°C.[48b]
A further requirement for the validity of Shi’s model is the reversibility of the
Mannich-type coupling. For the model system PPh3 (53)/phenol (111), no products from
cross-Mannich reactions were observed under turn-over conditions. Therefore, it is unlikely
that the Mannich coupling is reversible with Shi’s catalyst 88. Consequently, a model in
which the enantioselection is fully determined in the Mannich type coupling step seems a
more plausible alternative.
Furthermore, it is noteworthy that the phenolic OH group of catalyst 88 tends to
coordinate to the SO oxygen rather than to the imine nitrogen in the calculated structures
54
depicted in Figure 9. This illustrates that the activating group on the imine might play a vital
role in the chirality transfer from the catalyst to the aza-BH product.
3.1.5. Implications for Asymmetric Catalysis
All successful chiral catalysts to date contain two catalytic moieties: a Lewis basic and a
Brønsted acidic one. The Brønsted acidic co-catalyst is necessary to obtain an effective
system with regard to the catalyst’s activity and selectivity. In contrast to the results obtained
by Aggarwal and Lloyd-Jones for the BH reaction, there is no evidence for autocatalysis.
Competitive catalysis by the reaction product can therefore be ruled out. The work of Sasai
and Shi shows that a suitable positioning of both catalytically active groups is necessary to
obtain a high enantiomeric excess. The Mannich-type coupling can lead to four
diastereoisomers. There are two scenarios to explain the enantioselectivity of the reaction:
(1) All four diastereoisomers are formed, and because of the spatial arrangement only one
undergoes a fast proton transfer. The others then revert back to the starting materials and
the proton transfer serves as a selective “filter” for the reaction.
(2) A second pathway involves the selective formation of one (or two) diastereoisomers
leading directly to the product with the desired configuration.
The first route is dependent on the reversibility of the C-C coupling step – the Mannich
reaction. In the cross-Mannich experiments performed in this mechanistic study no cross-
Mannich products were observed which makes this explanation very unlikely.
Considering the limitations of the model, in which the proton migration step
determines the enantioselectivity of the reaction, it seems more likely that the enantioselection
takes place in the C-C coupling step. This, however, could not yet be validated in
experimental or theoretical studies.
A potential reason for the small success rate in the design of chiral catalysts for the
aza-BH reaction may lie in the lability of the product’s stereocenter. The results obtained with
Shi’s catalyst 88 in comparison to the model system triphenylphosphine (53)/phenol (111)
show that the spatial arrangement of a bifunctional catalyst is not only important for an
efficient transfer of the chiral information but also for the prevention of racemization.
55
3.2. Design of New Catalytic Systems for the Asymmetric Aza-Baylis-Hillman Reaction
3.2.1. QUINAP Derivatives
QUINAP (127), a powerful and versatile ligand for asymmetric transition-metal catalysis, was
developed by Brown and co-workers in 1993.[138] This axially chiral aminophosphine has
been successfully applied as P,N-ligand in Rh-catalyzed hydroboration and
hydroboration/amination reactions [139],[140] and Pd-catalyzed allylic substitutions.[141]
Since the binaphthyl backbone has proven to be a valuable lead structure for chiral
bifunctional organocatalysts for the aza-BH reaction,[48] the use of QUINAP (127) and
QUINAP-type derivatives seemed interesting. The structures depicted in Scheme 48 − (R)-
QUINAP (127), rac-1-(2-diphenylphosphanylnaphthalen-1-yl)isoquinoline-3-carboxylic acid
(128) and 1-(2-diphenylphosphanylnaphthalen-1-yl)isoquinoline-3-carboxylic acid (3-
hydroxy-2-phenylpropyl)amide (129) − were tested as catalysts in the aza-BH reaction of the
aromatic aldimines 67 (unsubstituted), 102 (m-F) and 113 (p-NO2) with MVK (37), methyl
acrylate (42) and cyclopentenone (130) as Michael acceptors (Scheme 49).
N
PPh2
127
N
COOH
PPh2
128
N
PPh2
O
HN OH
Ph
129
Scheme 48. QUINAP-derivatives as catalysts for the aza-BH reaction.
A starting concentration of 0.125 mol imine per l THF was applied. The reaction was
performed on a 2 ml scale. Conversion (conv.) was determined via 1H- and/or 19F NMR
spectroscopy, the enantiomeric excess of the reaction product was analyzed via chiral HPLC
(only in case of conv. > 15%).
56
N Tos
X EWGEWG
NHTos
X+
catalyst (10 mol-%)
THF, r.t.
127, 128, 129
67 (X = H) 102 (X = m-F)113(X = p-NO2)
37 (EWG = C(O)CH3)42 (EWG = C(O)OCH3)130 (cyclopentenone)
Scheme 49. Aza-BH reaction with QUINAP-derivatives.
In a first set of experiments, the scope of the catalysts towards different Michael acceptors
was tested. The results are depicted in Table 3.
Table 3. Screening of different Michael acceptors.
entry imine alkene catalyst catalyst [mol-%]
alkene [eq]
t / h conv. [%]
1 113 42 128 10 1.2 24 0 2 113 42 129 10 1.2 24 0 3 113 130 128 10 1.2 24 0 4 113 130 129 10 1.2 24 0 5 113 37 128 10 1.2 24 11 6 113 37 129 10 1.2 24 7
Reaction conditions: 38.0 mg (0.125 mmol, 1.00 eq) imine 113, 0.150 mmol (1.20 eq) alkene,
0.0125 mmol (0.10 eq) catalyst, 2.0 ml (16.0 ml⋅mmol−1 113) THF, r.t., t = 24 h.
These results showed that the QUINAP-derivatives 128 and 129 displayed a low activity in
comparison to similar bifunctional catalysts like 88.[48b] Furthermore, the scope of these
catalysts towards the activated alkenes was rather limited. The only system that displayed any
activity was obtained with MVK as Michael acceptor.
To verify whether the low activity of 128 and 129 in the aza-BH reaction was intrinsic
or due to catalyst deactivation, the reaction time was prolonged. The results for the coupling
of imine 102 with the activated alkenes 37, 42 and 130 are shown in Table 4.
57
Table 4. Coupling of imine 102 with the activated alkenes MVK (37), methyl acrylate (42)
and cyclopentenone (130), catalyzed by 129.
entry imine alkene catalyst catalyst [mol-%]
alkene [eq]
t / h conv. [%]
ee [%]
1 102 37 129 10 1.2 24 10 n.d. 2 102 37 129 10 1.2 67.5 24 6.0 3 102 37 129 20 5.0 24 50 6.0 4 102 42 129 20 5.0 24 0 n.d. 5 102 130 129 20 5.0 24 0 n.d.
Reaction conditions: 69.4 mg (0.250 mmol, 1.00 eq) imine 102, 2.0 ml (8.0 ml⋅mmol−1 102)
THF, r.t.
These results show, that the catalyst was not completely deactivated after 24 h in the coupling
of imine 102 with MVK (37) (entry 1, 2). Furthermore, a reasonable yield within 24 h could
be achieved by a 4-fold increase of the amount of MVK (37) and a 2-fold increase of the
amount of catalyst 129 (entry 3). Under these reaction conditions, however, catalyst 129 still
showed no activity in the coupling of imine 102 with methyl acrylate (42) and cyclopentenone
(130) (entry 4, 5). The enantioselectivity in the aza-BH reaction of imine 102 with MVK (37)
was very poor and independent from the reaction time, the amount of catalyst, and Michael
acceptor (entry 2, 3).
To determine the relative activity and selectivity of all three catalysts, they were tested
in the coupling of the imines 67 and 102 with MVK (37) under the reaction conditions,
displayed in entry 3 of Table 4 (20 mol-% catalyst, 5.0 eq MVK). The results are shown in
Table 5.
These results showed that the activity of all three catalysts was rather low in
comparison to similar bifunctional catalysts reported in literature.[48b] The best results with
respect to catalytic activity were obtained with catalyst 128, the QUINAP-derivative with
carboxylic acid group (128 > 129 > 127). The enantioselectivity that was obtained with the
enantiopure catalysts 127 and 129 was very poor.
58
Table 5. Coupling of the imines 67 and 102 with MVK (37).
entry imine catalyst Conv. [%] ee [%] 1 67 127 12 rac 2 67 128 47 - 3 67 129 34 rac 4 102 127 43 rac 5 102 128 94 - 6 102 129 50 6.0
Reaction conditions: 0.250 mmol (1.00 eq) imine, 104.1 μl (1.250 mmol, 5.00 eq) MVK,
0.050 mmol (0.20 eq) catalyst, 2.0 ml (8.0 ml⋅mmol−1 102) THF, r.t., 24 h.
QUINAP does not contain an acidic moiety which can serve as co-catalyst for the aza-
BH reaction. Therefore, its low activity and enantioselectivity was not unexpected. By
protonation of the quinoline-nitrogen, however, one would create a side group with a pKA
similar to the pKA of phenol.[132] This would result in a catalyst, which is structurally related to
Shi’s catalyst 88 and contains an acidic group with a pKA value similar to that of the phenolic-
OH group in 88. Selective N-protonation of QUINAP (127) requires a Brønsted acid of
medium strength. Strong Brønsted acids would deactivate the catalyst by protonation of the
phosphino-group. Phenol (111) was chosen as Brønsted acid to generate the protonated
QUINAP derivative in situ. The results are shown in Table 6.
Table 6. Catalysis results with N-protonated QUINAP.
entry imine catalyst Conv. [%] ee [%] 1 67 127 12 rac 2 67 127/111 35 rac 3 102 127 43 rac 4 102 127/111 88 rac
Reaction conditions: 0.250 mmol (1.00 eq) imine, 104.1 μl (1.250 mmol, 5.00 eq) MVK,
0.050 mmol catalyst (0.20 eq), 2 ml THF (8.0 ml⋅mmol−1 imine), r.t., 24 h.
These results show that the activity of the catalyst increased significantly through addition of
phenol (111) (entry 2, 4). The enantioselectivity, however, remained unchanged.
59
Although the activity and selectivity of these catalysts in the asymmetric aza-BH reaction was
rather low, catalyst 128 could be used to intercept and characterize the intermediates of the
phosphine-catalyzed aza-BH reaction for the first time (Scheme 50).
N
COO
P
O
Ph Ph
N
COOH
P
O
Ph PhPh
NH
Tos
131 132
Scheme 50. The intermediates of the aza-BH reaction of imine 67 with MVK (37), catalyzed
by QUINAP-derivative 128, in their protonated forms.
The first intermediate 133 results from a Michael type addition of the phosphine
catalyst 128 to MVK (37). It could be intercepted in its protonated form (131) by addition of
one equivalent of MVK (37) to a solution of catalyst 128 in CDCl3. The solution was stirred
for 5 min at room temperature (Scheme 51).
N
COOH
P
O
Ph Ph
133
N
COOH
PPh2+ O
CDCl3, r.t., 5 min N
CO2−
P
O
Ph Ph
13137128
Scheme 51. Interception of intermediate 133 in its protonated form (131).
The protonated intermediate 131 was identified via multinuclear NMR- and high-resolution
electrospray ionization mass spectroscopy (HR-ESI-MS). The 1H- and 31P NMR spectra are
shown in Figure 10 and 11, respectively.
In the 1H NMR spectrum, the signals which correspond to the PCH2CH2 moiety were
positioned between 3 and 5 ppm. Due to the chirality of catalyst 128 this moiety consisted of
four protons in a 1:1:1:1 ratio.
60
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 ppm
N
CO2−
P
O
Ph Ph
131
2.02.53.03.54.04.55.05.56.06.57.07.58.08.59.09.510.0 ppm
N
CO2−
P
O
Ph Ph
131
Figure 10. 1H NMR spectrum of the reaction mixture containing intermediate 131.
-10-530 25 20 15 10 5 0 ppm
N
CO2−
P
O
Ph Ph
131
N
COOH
PPh2
128
134
-10-530 25 20 15 10 5 0 ppm
N
CO2−
P
O
Ph Ph
131
N
COOH
PPh2
128
134
Figure 11. 31P NMR spectrum of the reaction mixture containing intermediate 131.
61
The 31P signal of catalyst 128 at −13.7 ppm disappeared nearly completely. This
demonstrated that catalyst 128 was almost completely converted to intermediate 131 (δ = 26.9
ppm) under these reaction conditions. The remaining signal at 30.3 ppm corresponds to the
phosphine oxide (134).
The second intermediate (135), which results from a Mannich-type coupling of enolate
133 with imine 67 could in principle be obtained both from the side of the starting materials
and the reaction product. In systems with Brønsted acidic co-catalysts, however, the Mannich-
type coupling is the RDS. This implied that intermediate 135 would be formed after the RDS
and therefore most likely be difficult to intercept. Thus, starting from the reaction product in a
Michael-type reaction seemed more promising (Scheme 52).
N
COOH
PPh2
128
ONHTos
N
COOH
P
O
Ph PhPh
NH
Tos
132
+
N
COOH
P
O
Ph PhPh
NH
Tos
135
H+
77
Scheme 52. Interception of intermediate 135 in its protonated form (132).
For this reaction diphenylacetic acid was used as an additional proton source. The resulting
reaction mixture contained only a small amount of 132 (about 13% of the P-containing
species in solution). A characterization of 132, however, was possible via multinuclear NMR
and HR-ESI-MS. The (1H, 31P)-correlation spectrum, the 1H spectrum and the 31P spectrum
are shown in Figure 12, 13 and 14, respectively.
62
ppm
3.03.54.04.55.05.56.06.57.07.5 ppm
19.5
20.0
20.5
21.0
21.5
22.0
22.5
23.0
23.5
24.0
132
1H
31P
ppm
3.03.54.04.55.05.56.06.57.07.5 ppm
19.5
20.0
20.5
21.0
21.5
22.0
22.5
23.0
23.5
24.0
132
1H
31P
Figure 12. (1H, 31P)-correlation spectrum of the reaction mixture with 132.
x
xxo
x
xx
x
xxo
N
COOH
P
O
Ph PhPh
NH
Tos
132
x
xxo
x
xx
x
xxo
N
COOH
P
O
Ph PhPh
NH
Tos
132
Figure 13. 1H NMR spectrum of the reaction mixture with 132 (x = from (1H,31P)-correlation
spectrum, o = from (1H,1H)-COSY and TOCSY).
The signals marked with “x” were unambiguously assigned to the aliphatic protons of
intermediate 132 in α- and β-position to the P-atom via (1H, 31P)-correlation. The fourth
signal, marked with “o”, was assigned to the proton in γ-position through (1H, 1H)-correlation
and TOCSY.
63
-10-530 25 20 15 10 5 0 ppm
N
COOH
PPh2
128
N
COOH
P
O
Ph PhPh
NH
Tos
132
134
-10-530 25 20 15 10 5 0 ppm
N
COOH
PPh2
128
N
COOH
P
O
Ph PhPh
NH
Tos
132
134
Figure 14. 31P NMR spectrum of the reaction mixture with 132.
This was the first time that both intermediates of the phosphine-catalyzed aza-BH reaction
were intercepted and structurally characterized. The first intermediate (type-131) was also
obtained for various other phosphine catalysts in combination with MVK (37) and an external
acid source (Table 7). Conv. (31P) is the conversion of the starting phosphine to the
corresponding adduct (type-131), derived from the 31P NMR spectra.
Table 7. Intercepted first intermediate of the aza-BH reaction.
entry phosphine acid acid:alkene δ 31P (phosph./add.) [ppm]
Conv. (31P) [%]
1 53 malic acid 1.0 -5.4 / 25.5 95.0 2 127 diphenyl acetic acid 1.0 -14.1 / 26.4 52.6 3 128 - 0.0 -13.7 /26.9 64.3 4 129 diphenyl acetic acid 1.0 -13.4 /26.0 32.3
Reaction conditions: 1.00 eq phosphine, 1.00 eq MVK, 1.00 eq diphenylacetic acid, NMR
solvent, r.t., 5 h.
64
3.2.2. Other phosphinocarboxylic acids
As a model system to verify the catalytic potential of phosphinocarboxylic acids with various
distances between both functionalities in the aza-BH reaction, 2-, 3- and 4-
diphenylphosphanyl benzoic acid were tested as catalysts (Scheme 53).
COOH
Ph2P
COOH
PPh2
COOH
PPh2
PPh3COOH
+
136 137 138 53 139
0% 70% 38% 86%
Scheme 53. Diphenylphosphanyl benzoic acids as catalysts for the aza-BH reaction of imine
102 (m-F) with MVK (37). Reaction conditions: 69.33 mg (0.250 mmol, 1.00 eq) imine 102,
7.66 mg (0.0250 mmol, 0.10 eq) diphenylphosphanyl benzoic acid, 25.0 μl (0.300 mmol, 1.20
eq) MVK, 2.0 ml (8.0 ml⋅mmol−1) THF, r.t., 24 h.
These results clearly indicated that the activity of the catalyst was dependent on its geometry:
compound 136, in which both catalytic moieties are positioned ortho to each other, was
inactive. The “meta-catalyst” 137 was the most active compound albeit its catalytic activity is
still lower than the activity of the 1:1 system PPh3 (53)/benzoic acid (139). This results in
following trend in activity: 53/139 > 137 > 138 > 136.
As chiral phosphinocarboxylic acid, (R,S)-2-diphenylphosphanyl-cyclohexane-
carboxylic acid (140) was tested as catalyst for the coupling of imine 105 with MVK (37)
(Scheme 54).
Br
N TosO
+
Br
NH OTos
COOH
PPh2
(10 mol-%)
r.t., THF, 24 h
105 37
140
106
86%rac
Scheme 54. Coupling of imine 105 with MVK (37), catalyzed by phosphinocarboxylic acid
140. Reaction conditions: 51.0 mg (0.125 mmol, 1.00 eq) imine 105, 12.5 μl (0.150 mmol,
1.20 eq) MVK, 3.90 mg (0.0125 mmol, 0.10 eq) catalyst 140, 1.0 ml (8.0 ml⋅mmol−1) THF,
r.t., 24 h.
65
Although the activity of the system is higher than the activity of Shi’s catalyst 88 under the
same conditions (60% yield), the product is obtained as racemate.[48b] Racemization of
enantiomerically enriched aza-BH product 106 under the influence of catalyst 140 was
excluded in the corresponding control experiment. Consequently, the reason for the formation
of racemic product was the low intrinsic enantioselectivity of catalyst 140.
3.2.3. Chiral Brønsted Acids
The use of a combined system Lewis base/chiral Brønsted acid proved to be a valuable
strategy for obtaining high enantioselectivities in the BH- and aza-BH reaction (cf. Jacobsen’s
urea-catalysts, Schaus’ BINOL system), although the risk of subsequent racemization of the
aza-BH product is high as compared to catalysts that combine both functionalities suitably
positioned in one chiral compound.[38], [40]
As Brønsted acids, chiral alcohols were tested as co-catalysts in the PPh3-catalyzed
coupling of imine 105 (p-Br) with MVK (37) (Scheme 55). In all experiments, the
enantiomeric excess of the corresponding reaction product was very poor. The best result (ee
= 11%) was obtained with (R)-BINOL as additive.
OHOH
OHOHO
OO
O
OHHO O O
HO OHH H
141 142 143 144
97%11% ee
40%rac
31%rac
66%6% ee
Scheme 55. Chiral co-catalysts for the PPh3-catalyzed aza-BH coupling of imine 105 with
MVK (37). Reaction conditions: 51.0 mg (0.125 mol, 1.00 eq) imine 105, 12.5 μl (0.150
mmol, 1.20 eq) MVK, 3.28 mg (0.0125 mmol, 0.10 eq) PPh3, 0.0375 mmol (0.30 eq)
Brønsted acid, 1.0 ml (8.0 ml⋅mmol−1 105) THF, r.t., 24 h.
66
3.2.4. Chiral Aminoalcohols
3.2.4.1. Synthesis In accordance with previous reports in literature (page 29) [38], [88], [114]-[116] and the mechanistic
investigations described above, aminoalcohols of type-145 are potential bifunctional
asymmetric catalysts for the aza-BH reaction. Besides a Lewis basic tertiary amino group,
they contain an alcohol moiety as co-catalyst. Kinetic- and racemization studies with weak
acids like alcohols in the phosphine-catalyzed aza-BH reaction showed that they are able to
serve as co-catalyst – methanol causes rate acceleration by a factor of 3.7 – but that their
acidic strength is insufficient to induce racemization of the reaction product. An efficient
access to this class of aminoalcohols must be straightforward and substitution diversity should
be possible without major changes of the synthetic route. One flexible strategy to obtain this
type of aminoalcohols is shown in Scheme 56.
This strategy involves an ex-chiral-pool synthesis starting from the chiral building
block hydroxyproline. In step A the acid group would be protected by esterification, followed
by protection of the aminogroup of aminoester 152 in step B. For step F it is required that the
aminogroup carries an electron donating group. This should be considered in the choice of an
appropriate protecting group R’. In step C, the OH group of 151 should be protected, followed
by a reduction of the ester moiety in step D. The OH group of the corresponding vic-
aminoalcohol 149 would then be transformed into a leaving group (e.g. via mesylation). In an
intramolecular SN2 reaction followed by a ring opening of the corresponding aziridinium-ion
147, compound 146 would be formed as a product of ring expansion. Deprotection of the OH
group would then lead to the desired class of aminoalcohols 145.
67
NR'
HO X* *
NR'
O X* *PG
NR'
OH
OPG*
*
NR'
OR
OPG*
*NR'
OR
HO*
*
ONH
OR
HO*
*
O
B C
D
FGH
145 146 147 148
150151152
NH
OH
HO*
*
O
153
A
O
NR'
LG
OPG
* *
E
149
NR'
OPG ** LG
Scheme 56. Strategy for the synthesis of aminoalcohol 145.
For the synthesis, trans-4-hydroxy-L-proline (154) was used as starting material. In the first
step, compound 154 was converted into the corresponding methyl ester. This was isolated in
form of its hydrochloride salt 155.
NH
OH
HO
ONH2
O
HO
O Cl−
154 155
SOCl2
CH3OH, 0°C - r.t., 24 h
> 99%
Scheme 57. Synthesis of the methylester 155.
According to a procedure reported by Enders and co-workers, 155 was prepared by addition
of trans-4-hydroxy-L-proline to a solution of thionylchloride in methanol at 0°C.[142] After
warming to room temperature, the mixture was stirred for 24 h. Then, the excess SOCl2 and
methanol was removed in vacuo. Subsequently compound 155 was crystallized from a
mixture of methanol and diethylether and isolated in quantitative yield.
The second step consisted of protection of the amino group of 155 via benzoylation
(Scheme 58).[142] 155 was dissolved in dichlormethane at room temperature and treated with a
68
large excess of triethylamine. After stirring the mixture for 1.5 h at room temperature, DMAP
and benzoylchloride were added. The resulting reaction mixture was stirred overnight.
Precipitation from dichloromethane/pentane yielded compound 156 as a colorless precipitate
in 80% yield.
NH2
O
HO
O Cl-NEt3, DMAP, PhC(O)Cl
DCM, r.t., 14 hN
O
HO
OO
155 15680%
Scheme 58. Benzoyl-protection of the amino group in 155.
In the third step, 156 was converted into the corresponding tert-butyldimethylsilyl
(TBS) ether 157 (Scheme 59).[142]
TBSCl, imidazol
DMF / toluene, r.t., 43 hN
O
HO
OO
156
NO
O
OO
157
Si
> 99%
Scheme 59. Conversion of 156 into its corresponding TBS-ether 157.
Amide 156 and imidazole were dissolved in DMF and stirred at room temperature for 3 h.
Then, a solution of tert-butyldimethylsilyl chloride (TBSCl) in toluene was added dropwise
and the resulting mixture was stirred at room temperature for 40 h. After removal of the
volatiles in vacuo, the residue was taken up in ether and underwent a standard organic
workup. The resulting organic residue was recrystallized from dichloromethane/pentane.
Compound 157 was obtained in quantitative yield in form of colorless crystals.
In the next step, the ester moiety was reduced to the corresponding primary alcohol
(Scheme 60). Under the employed conditions, the benzoyl group was reduced as well.[142]
69
LAH
THF, rfl, 1.5 hN
O
O
OO
157
Si
NOH
O
158
Si
> 99%
Scheme 60. Reduction of 157 with lithium aluminiumhydride (LAH).
To a suspension of LAH in THF, a solution of ester 157 in THF was carefully added. The
resulting mixture was heated under reflux for approximately 1.5 h. After hydrolysis with 20-
% aqueous KOH solution and standard organic workup, the compound was obtained as
colorless oil in quantitative yield. Aminoalcohol 158 was used without further purification.
The vic-aminoalcohol 158 was treated with methanesulfonyl chloride (MsCl) to
convert the OH group to an appropriate leaving group for nucleophilic substitution (Scheme
61).
MsCl, NEt3
THF, 0°C - rfl, 12 hNOH
O
158
Si
NOMs
OSi
− HNEt3MsO
N
OSi
Cl
N
ClOSi
15957%
+ HNEt3Cl
Scheme 61. Reaction of 158 with MsCl.
MsCl and triethylamine were added to a solution of aminoalcohol 158 in THF at 0°C. After
0.5 h, the reaction mixture was heated to reflux for 12 h. Then, the suspension was cooled to
room temperature and poured into an aqueous 2.5 M-NaOH solution. After standard organic
70
workup, the resulting oil was purified via column chromatography and isolated as yellow oil
in 57% yield. The NMR spectra of the resulting compound provide proof for the formation of
one single diastereoisomer. The absolute configuration was assigned via NOESY (Figure 15).
The NOESY spectrum was recorded at −40°C in CDCl3 and displayed a clear NOE contact
between the Si-CH3 group and the proton in α-position to the Cl-atom. This, in combination
with the fixed R-configuration for the stereocenter adjacent to the silyl group, unambiguously
proved the (R,R)-configuration of compound 159.
NMR-, GC- and GC-MS analysis proved that the intermediate aziridinium ion was
solely attacked by chloride anions. The corresponding amino mesylate (159, Cl = OMs) could
not be detected. Similar results were obtained by the group of Cossy.[143] They postulated the
involvement of a tight ion pair to explain this chemoselectivity.
In the last step, the TBS-ether was cleaved according to standard procedure with tetra-
n-butyl ammonium fluoride (TBAF) in THF (Scheme 62).[144]
TBAF
DCM, r.t., 14 hN
ClOSi
159
N
ClHO
16081%
Scheme 62. Cleavage of the TBS-ether 159.
TBAF was added to a solution of TBS-ether 159 in dichloromethane. The mixture was stirred
at room temperature overnight. After standard organic workup, the resulting colourless solid
was purified via column chromatography. Aminoalcohol 160 was isolated as a colourless
solid in 81% yield.
ppm
4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
N
H
H
O
HH
HH
Cl
Ph
H
H
Si
ppm
4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 ppm
1.0
1.5
2.0
2.5
3.0
3.5
4.0
4.5
N
H
H
O
HH
HH
Cl
Ph
H
H
Si
Figure 15. NOESY spectrum of compound 159 in CDCl3 at −40°C.
In conclusion, vic-aminoalcohol 160 could be synthesized in a 6 step-synthesis with an
overall yield of 37%. In principle, all four diastereoisomers of this compound can be
selectively produced starting from hydroxyproline precursors with different stereochemistry.
3.2.4.2. Catalysis
Both the TBS protected vic-aminoalcohol 159 and the deprotected aminoalcohol 160 were
tested as catalysts for the aza-BH coupling of imine 113 (p-NO2) with MVK (37) in THF at
room temperature. With a catalyst loading of 10 mol-% and a ratio of MVK : imine = 1.2 : 1,
no conversion was observed within 24 h. Several parameters were varied to increase the
system’s reactivity: the catalyst loading was increased up to a stoichiometric amount (100
mol-%), the ratio MVK : imine was varied in the range of 1.2 - 5.0, the temperature was
increased up to 60°C and the substitution pattern (X = p-NO2, m-F, p-Br, p-Me) of the imine
was varied. In all cases, no conversion could be detected. A possible reason for this
unexpected result could be the nucleophilicity of the amino group. In case of non-sufficient
nucleophilicity, the catalyst cannot initiate the Michael addition as first step of the catalytic
cycle and remains unactive.
A possible strategy to overcome this problem involves the introduction of different
protecting groups at the Nitrogen atom. It was, however, decided to focuss on a different
strategy to create a new enantioselective system for the aza-BH reaction – the design and
application of a chiral reaction medium. In future investigations, vic-aminoalcohol 160 as well
as its precursor 159 may serve as chiral backbone chiral for the formation of catalysts for
other organocatalytic processes as well as ligands for homogeneous transition metal catalysis.
3.2.5. Chiral Solvents
ILs, often referred to as DESIGNER SOLVENTS, offer the possibility of adapting their solvent
properties to a given chemical need through structural variations of one or both ions.[145] The
investigations on the mechanism of the aza-BH reaction provided useful information for the
design of a chiral solvent for this process. It was shown that a bifunctional interaction of the
catalyst with the zwitterionic reaction intermediates (transition states) is beneficial for
obtaining high enantioselectivity and preventing subsequent racemization of the reaction
product. In conventional systems, this can be achieved by incorporating both the nucleophilic
catalyst and the Brønsted acidic co-catalyst in one chiral molecule. ILs, however, might offer
73
the possibility of obtaining a bidentate interaction by incorporating the acidic center in the
chiral solvent, allowing simple monofunctional achiral nucleophiles to be used as catalysts in
the enantioselective aza-BH reaction (Scheme 63). A long and complicated synthesis of a
suitable bidentate catalyst can then be avoided.
PRRR
OHO
R'
161
Scheme 63. Illustration for a possible bifunctional interaction of the first zwitterionic 3-
phosphoniumenolate intermediate of the aza-BH reaction with the anion of an anion-chiral IL
containing a hydrogen bond donor.
Apart from the structural requirements elucidated above, the chiral reaction
medium has to meet some general stipulations. It should be cheap, easy to prepare and stable
under reaction conditions. Furthermore, the chiral building block should preferably be
available in both enantiomeric forms to obtain a selective access to both optical antipodes of
the desired product. These considerations led to the application of an anion-chiral IL derived
from malic acid (162). In a straight-forward ex-chiral-pool synthesis developed by Rolf
Gausepohl, the desired reaction medium was obtained as a colorless room-temperature IL
(Scheme 64).[146]
The first step involved the preparation of the corresponding sodium dimalatoborate
salt (165) by stirring an aqueous solution of boric acid (164), sodium hydroxide (163) and L-
(−)-malic acid (162) in an open flask at 100°C. After complete evaporation (within
approximately 4 h), sodium dimalatoborate (165) was isolated as a colourless salt in
quantitative yield. The dimalatoborate anion contained exclusively five-membered rings and
consisted of a nearly 1:1-mixture of diastereoisomers. This resulted from the fixed chirality at
the asymmetric carbon atoms and the labile chirality at the boron center of this spiro-type
compound. Configurational lability of orthoborates has been described earlier in literature by
Boeseken and Mijs.[147]
74
OHO
HO
O OH
B(OH)3 + NaOH + 2
O O
OO
O
OO O
Na
H2O, 100°C, 4h
MtOA Cl, acetone,
rt, 14h
- NaCl(s)
> 99%
B
[MtOA]
164 163 162 165
166
O
OHH
O O
OO
O
OO OB
O
OHH
Scheme 64. Two-step synthesis of methyltrioctyl ammonium dimalatoborate (166) (only the
(S,S,S)-diastereoisomer is shown).
The second step involved a cation-exchange replacing the sodium ion with a cation
typically used for the formation of ILs: the methyltrioctyl ammonium ion. The reaction took
place with Aliquat 336® (≡ methyltrioctyl ammonium chloride, 167) in acetone. Under the
precipitation of sodium chloride the desired compound 166 was isolated as a hygroscopic and
viscous colorless liquid (C = 72 ± 2%, determined from 1H NMR spectroscopy).[148]
The aza-BH reaction between MVK (37) and the aromatic tosyl-aldimines 105, 168
and 113 was performed in this new reaction medium (166) (Scheme 65).
N TosONHTos
+chiral solvent 166, r.t., 24 h
105 (X = Br) 168 (X = CH3)113 (X = NO2)
O
37
PR3 (10 mol-%)
X X
106 (X = Br) 169 (X = CH3)114 (X = NO2)
Scheme 65. Reaction between the aromatic tosylaldimines 67, 168 and 113 and MVK (37) in
methyl trioctylammonium dimalatoborate (166) (R = C6H5, o-CH3C6H4, etc).
75
As nucleophilic catalysts the commercially available, achiral triarylphosphines PPh3, P(o-
tolyl)3 and (C6F5)PPh2 were applied. The best results were obtained with imine 105 (X = Br)
and triphenylphosphine (53) as catalyst. Using 1.2 eq of MVK (37) and 10 mol-% of
phosphine 53, the corresponding chiral allylic amine (R)-106 (X = Br) was obtained with a
reasonable conversion and a high enantiomeric excess.[149] In a series of four independent
experiments using various batches of IL 166, conversion varied between 34-39% and the
enantioselectivity ranged from 71-84% ee. The highest ee of 84% observed in these
experiments corresponds to an enantiomeric ratio of er = 11.5 and hence an energetic
differentiation of ΔΔG‡ = 6.05 kJ·mol-1 for the formation of the two enantiomers.[137] So far,
this is the highest level of enantioselectivity obtained with a chiral solvent as the sole source
of chirality. It exceeds the asymmetric induction reported in the work by Loupy and co-
workers for the BH reaction of benzaldehyde with methyl acrylate by a factor of 3.2.[125]
Although a variation of the achiral catalyst (PPh3, P(o-tolyl)3 and (C6F5)PPh2) did not
cause a significant change in enantioselectivity, conversion dropped with a decrease in
nucleophilicity of the phosphine (P(o-tolyl)3 ≈ PPh3 > (C6F5)PPh2) (Table 8).
Table 8. Different phosphine catalysts for the coupling of imine 105 (X = Br) with MVK (37)
in IL 166.
entry phosphine conv. [%] ee [%] 1 PPh3 37 77 (R) 2 P(o-tol)3 35 74 (R) 3 (C6F5)PPh2 9 71 (R)
Reaction conditions: 51.0 mg (0.125 mol, 1.00 eq) imine 105, 12.5 μl (0.l50 mmol, 1.20 eq)
MVK, 0.0125 mmol (0.10 eq) phosphine, 1.0 ml (8.0 ml⋅mmol−1 105) IL 166, r.t., 24 h.
In contrast, the influence of the p-substituent X of the imine on the enantioselectivity of the
reaction is very pronounced. Although increasing the electron density of the aromatic imine
by substituting the Br- for a Me group in the para-position caused no large difference in
conversion (C = 30% after 24 h) and enantioselectivity (ee = 64% (R)), a strong decrease of
the enantiomeric excess was observed upon introduction of the highly electron-withdrawing
nitro moiety (ee = 10% (R)) (Table 9).
76
Table 9. Influence of the para-substituent X of the aromatic tosylaldimine on conversion and
enantioselectivity.
entry X conv. [%] ee [%] 1 Br 37 77 (R) 2 CH3 39 64 (R) 3 NO2 38 10 (R)
Reaction conditions: 0.125 mmol (1.00 eq) imine, 12.5 μl (0.l50 mmol, 1.20 eq) MVK, 3.28
mg (0.0125 mmol, 0.10 eq) PPh3, 1.0 ml (8.0 ml⋅mmol−1 imine) IL 166, r.t., 24 h.
Since the stability of the stereogenic center of the aza-BH product under turn-over
conditions is likely to decrease with the introduction of electron-withdrawing groups, one of
the possible explanations for the dramatic drop of the enantiomeric excess could be a
subsequent racemization of the allylic amine 114 (X = NO2). A control experiment with the
enantiomerically enriched reaction product 114 (X = NO2), however, excluded this possibility
indicating that the dependence of the enantioselectivity on the nature of the substituent X is a
reaction intrinsic phenomenon. A similar decrease in optical induction was described by Vo-
Thanh and co-workers for the mechanistically related BH reaction of p-nitrobenzaldehyde and
methylacrylate in ephedrinium based cation-chiral ionic liquids.[125] They explained the drop
in enantioselectivity by the formation of a hydrogen bond between the OH group of the chiral
ion and the NO2 function of the substrate.
To investigate whether methyltrioctyl ammonium dimalatoborate (166) acts as a chiral
additive rather than a chiral solvent, the MtOA-IL 166, its corresponding sodium salt 165 and
L-malic acid (162) were tested as additives for the triphenylphosphine-catalyzed aza-BH
reaction of imine 105 (X = Br) with MVK (37) in THF. In all cases, racemic product (106, X
= Br) was obtained in low conversions (Table 10).
77
Table 10. PPh3-catalyzed reaction of imine 105 and MVK (37) with malic acid-based chiral
additives.
entry additive conv. [%] ee [%] 1 166 10 rac 2 165 10 rac 3 162 8 rac
Reaction conditions: 51.0 mg (0.125 mmol, 1.00 eq) imine 105, 12.5 μl (0.l50 mmol, 1.20 eq)
MVK, 3.28 mg (0.0125 mmol, 0.10 eq) PPh3, 0.0125 mmol (0.10 eq) additive, 1.0 ml (8.0
ml⋅mmol−1) THF, r.t., 24 h.
Consequently, neither the IL 166 nor any of its chiral precursors (165, 162) can be used as
additive for the aza-BH reaction in conventional organic solvents, which clearly underlines
the necessity of using the IL 166 as a solvent for this process.
In the discussion of the structural requirements for an ideal IL for the aza-BH reaction,
the necessity of a hydrogen bond donor group in the anion of the solvent was postulated for a
benificial interaction with the zwitterionic transition states of this reaction (vide supra). To
validate this hypothesis, the structurally related anion-chiral ILs 170 and 171 without a
hydrogen bond donor, prepared by Gausepohl in a procedure which is similar to the synthesis
of 166, were tested.[145] The results obtained with these solvents in the PPh3-catalyzed aza-BH
coupling of imine 67 (X = Br) with MVK (37) are depicted in Scheme 66.
[MtOA][MtOA] [MtOA]
O
O OOB
O
O
O
O
OO
O
O O O
OO
O OB
O O
OO
O
OO OB
O
OHH
170 171 16614% 15%
rac rac up to 84% ee
up to 39%
Scheme 66. ILs containing chiral anions without a Brønsted acid group. Reaction conditions:
51.0 mg (0.125 mol, 1.00 eq) imine 105, 12.5 μl (0.l50 mmol, 1.20 eq) MVK, 3.28 mg
(0.0125 mmol, 0.10 eq) PPh3, 1.0 ml (8.0 ml⋅mmol−1 105) IL, r.t., 24 h.
78
Notably, the structurally related ILs 170 and 171 resulted in lower conversions (14% and 15%
respectively) and formation of racemic product 106 (X = Br), which indicates the necessity of
a Brønsted acidic moiety within the chiral ion.
In conclusion, it is shown that the strategy of applying chiral solvents in asymmetric
synthesis can be a valuable strategy for obtaining chiral products with high enantioselectivity.
With the specifically designed methyltrioctyl ammonium dimalatoborate IL 166, the aza-BH
product 106 could be obtained with enantioselectivities up to 84% ee.
79
4. Summary and Outlook
In this thesis, the rational development of a new enantioselective catalytic system for the
asymmetric aza-BH reaction was described (Scheme 67).
N Tos
EWGNHTos
+ EWG *chiral catalyst/chiral solvent
X X
Scheme 67. Aza-BH reaction of aromatic tosylaldimines with activated alkenes (X = H, p-
NO2, m-F etc; EWG = C(O)CH3, C(O)OCH3 etc).
Since no mechanistic details on this reaction were known at the beginning of this work, an
extensive study on the reaction mechanism was performed. This showed that the mechanistic
details of the aza-BH reaction (see Scheme 29) did not fit into any of the existing mechanistic
hypotheses for the related BH coupling.
Detailed kinetic investigations via 19F NMR spectroscopy yielded rate law equations
for the phosphine-catalyzed aza-BH reaction with and without Brønsted acidic co-catalysts
(Scheme 68).
F
N TosO
+
PPh3, C6F6, (acid)
THF, r.t.
F
NH OTos
102 103
10453
37
− 112.6 −114.1−164.0δ (19F) ppm
Scheme 68. Model reaction for kinetic study of the aza-BH reaction.
A comparison of these equations enabled the localization of the RDS in both cases:
without co-catalyst, proton migration was involved in the RDS. Upon addition of a Brønsted
acidic co-catalyst, this reaction step was considerably facilitated leading to a shift of the RDS
to the Mannich-type coupling. Additionally, a set of Brønsted acids with pKA values in the
range of 4-16 was screened. An evaluation of these results showed that a maximum in
reaction rate was obtained with 3,5-bis(CF3)phenol (pKA ≈ 8) as additive, corresponding to a
80
14-fold rate enhancement as compared to the reaction without additive. Weakly acidic
additives like methanol and water caused only a small rate enhancement; highly acidic
additives like malic acid inhibited the reaction by protonation of the nucleophilic catalyst
itself and the 3-phosphonium enolate.
In addition to this kinetic study, investigations towards the reversibility of the reaction
were performed. Cross-Mannich experiments were carried out and evaluated. In none of these
reactions, however, cross-over products were observed under turn-over conditions. This
provided strong evidence for the irreversibility of this coupling step under these conditions.
Racemization experiments showed that the stereocenter of the aza-BH product was not
always stable under turn-over conditions (Scheme 69).
PPh3, phenol
THF, r.t.
NH OTos
Br
53 111
(S)-106
NH OTos
Br
(R)-106
Scheme 69. Racemization of the aza-BH product 106 under the influence of PPh3 and phenol.
When the reaction was performed in [D4]methanol, an H/D-exchange occurred at the
stereogenic center. This demonstrated that the C-H bond at the stereogenic center was labile
under turn-over conditions and that the racemization process is independent from the catalytic
cycle. Further investigations on the rate of racemization and the influence of different reaction
parameters displayed that either a Brønsted acid or remaining starting material (imine) in
combination with the Lewis basic catalyst is necessary for product racemization. The results
from more elaborate studies on the influence of the nature of the Brønsted acid on the rate of
racemization provided information for the postulation of a mechanism, in which the
conjugated base of the Brønsted acid played a vital role.
Information on the transfer of chirality from a bifunctional catalyst to the reaction
product was obtained by studying Shi’s successful phosphine-BINOL catalyst 88 (see Scheme
47).[48b] Shi’s mechanistic proposal was proven incomplete and amended. Furthermore, it was
demonstrated via DFT calculations that bifunctional stabilization of the second intermediate
of the aza-BH reaction through coordination of the phenolic OH group to the negatively
charged imine nitrogen was very unlikely (see Figure 9). In the calculated structures the OH
group coordinated to the SO2 moiety of the activating tosylgroup. This might have wide-
81
ranging consequences for the influence of the activating group on the enantioselectivity of the
reaction.
The results from these mechanistic investigations provided useful information for the
design of novel enantioselective systems. As potential chiral catalysts phosphinoarboxylic
acids, chiral Brønsted acidic co-catalysts and QUINAP derivatives were tested. Although the
obtained enantioselectivities were very poor in all cases, a more extensive study on the
QUINAP-type system enabled the interception and characterization of all commonly accepted
intermediates of the phosphine-catalyzed aza-BH reaction.
Furthermore, the chiral aminoalcohol 160 was synthesized in a six-step sequence
starting form trans-4-hydroxy-L-proline (Scheme 70). The overall yield of this successful and
modular synthesis was 37%. Evaluation of this compound as a catalyst for the aza-BH
reaction, however, displayed this vic-aminoalcohol as inactive.
NH
HO
COOH NH
HO Cl
37%
6 steps
154 160
Scheme 70. Synthesis of vic-aminoalcohol 160.
A complementary approach was chosen with the application of a solvent as the sole
source of chirality for the aza-BH reaction. An anion-chiral IL with an acidic side group was
specifically designed for this process. The PPh3-catalyzed aza-BH coupling of tosylaldimines
with MVK yielded the corresponding reaction products in enantioselectivities up to 84% ee
(er = 11.5; ΔΔG‡ = 6.05 kJ·mol-1) in IL 166 (Scheme 71).
N TosONHTos
+166, r.t., 24 h
O
37
PR3 (10 mol-%)
X Xup to 84% ee
[MtOA]
O O
OO
O
OO OB
O
OHH
166
Scheme 71. Aza-BH reaction in methyltrioctyl dimalatoborate (166) (X = CH3, Br, NO2; PR3
= PPh3, P(o-tolyl)3, (C6F5)PPh2).
82
So far, this is the highest enantioselectivity obtained with a chiral solvent as the sole source of
chirality for an asymmetric reaction.
In future experiments, the racemization process should be investigated more intensively.
Especially, a detailed study towards the rate law for this process would provide valuable
additional information for processing the aza-BH reaction in an enantioselective way.
Additionally, the mechanism of chirality transfer should be readdressed. To determine the
exact influence of the activating group and fully clarify the mechanism, additional theoretical
and experimental studies, e.g. on matched-mismatched effects of succesfull catalysts with S-
chiral sulfinimines, are required.
Regarding the chiral vic-aminoalcohols based on trans-4-hydroxy-L-proline, a
variation of the protecting group on the Nitrogen atom seems a viable strategy for tuning the
nucleophilicity of these compounds. It is expected that increasing the nucleophilicity of the
aminogroup leads to an active catalyst for the aza-BH reaction. Furthermore, vic-
aminoalcohol 160 as well as its TBS-protected precursor 159 may serve as chiral backbone
chiral for the formation of catalysts for other organocatalytic processes as well as ligands for
homogeneous transition metal catalysis.
Concerning the reaction in anion-chiral ILs, a more extensive screening of substrates
would provide valuable information on the flexibility of this catalytic system. Furthermore,
mechanistic investigations on the structure and dynamics of these solvents and their
interaction with dissolved substances are inevitable for the clarification of the mechanism of
chirality transfer in these media. Useful experiments in this respect are:
1. Dilution experiments with conventional, achiral ILs: How does the activity and
enantioselectivity of the system depend on the fraction of chiral IL in the solvent
mixture?
2. Controlled addition of impurities: What are the influences of impurities like water on
the system’s activity and enantioselectivity?
3. NMR spectroscopic studies: Is there a signal shift upon dissolution of a compound in
the IL and does this correlate to the coordination strength of the IL?
In summary, a detailed insight into the mechanism of the aza-BH reaction under bifunctional
activation was obtained. This provided useful information for the development of the first
efficient enantioselective system in which the solvent is used as the sole source of chirality.
83
Based on these results, future synthetic and mechanistic work in this research area seems very
promising.
84
5. Experimental
5.1. General Methods, Solvents and Reagents
5.1.1. Inert Gas Conditions
All reactions involving air-sensitive chemicals were performed under Argon atmosphere
using standard Schlenk techniques. Glassware was heated in vacuo and subsequently purged
with Argon. The addition of reagents and solvents was carried out with polypropylene
syringes equipped with V2A steel needles under an Argon stream. Sensitive chemicals like
MVK were degassed and stored under Argon at −30°C.
5.1.2. Solvents
The following solvents were dried and purified by distillation under Argon according to
standard procedures (Table 11).[150] For the purification of the corresponding deuterated
solvents, identical procedures were applied.
Table 11. Purification conditions for solvents.
entry solvent conditions 1 tetrahydrofurane heated under reflux over sodium benzophenone ketyl,
followed by distillation under Argon 2 diethylether heated under reflux over sodium benzophenone ketyl,
followed by distillation under Argon 3 toluene heated under reflux over sodium benzophenone ketyl,
followed by distillation under Argon 4 benzene heated under reflux over sodium benzophenone ketyl,
followed by distillation under Argon 5 chloroform heated under reflux over calcium hydride,
followed by distillation under Argon 6 dichloromethane heated under reflux over calcium hydride,
followed by distillation under Argon 7 pentane heated under reflux over calcium hydride,
followed by distillation under Argon 8 acetone heated under reflux over calcium chloride,
followed by distillation under Argon
85
N,N-Dimethylformamide (DMF) and dimethylsulfoxide (DMSO) were purchased from
Aldrich in following quality:
(a) DMF: puriss, absolute, over MS 4Å (H2O ≤ 50 ppm) under nitrogen
(b) DMSO: water-free (H2O ≤ 50 ppm) under nitrogen
Furthermore, all solvents for column chromatography, recrystallization and reaction workup
were distilled prior to use.
5.1.3. Reagents
The commercially obtained reagents which were used in this Ph.D. project were obtained
from various suppliers and in different qualities. Appendix 2 contains a detailed list with
reagent, supplier and quality.
(R)-2’-diphenylphosphanyl-[1,1’]binaphthalenyl-2-ol (88) and (R,S)-2-diphenylphos-
phanyl cyclohexane carboxylic acid methyl ester were provided by Dr. Giancarlo Franciò.
(R)-QUINAP (127) and its derivatives 128 and 129 were donated by Dr. John M. Brown FRS.
The diphenylphosphinocarboxylic acids 136, 137 and 138 were kindly allocated by Dr.
Christian Steffens. The chiral ILs 170 and 171 were donated by Dipl.-Chem. Rolf Gausepohl.
5.2. Determination of Physical Data
5.2.1. NMR Spectroscopy
1H-, 13C-, 31P-, 19F- and 11B NMR spectra were recorded on Bruker DPX 200, DPX 300, AV
400, AV 500 and AV 600 spectrometers. The operating frequencies of these spectrometers for
NMR measurements are listed in Table 12. For 1H- and 13C NMR spectroscopy, the chemical
shifts δ are given in ppm using the residual solvent signals as internal standard. For 31P- and 19F-NMR spectroscopy the chemical shift values δ are given in ppm relative to 85%
phosphoric acid and hexafluorobenzene as external standard, respectively. The multiplicity of
the signals was assigned assuming spectra of first order. The coupling constant J is given in
Hertz. For the description of the multiplicity of the signal following abbreviations are used: s
86
= singulet, d = doublet, t = triplet, q = quadruplet, m = multiplet, br = broad. The proton
which belongs to the signal is underlined in the added structure section. Unless indicated
otherwise, the spectra are recorded at room temperature.
Table 12. Operating Frequencies of NMR spectrometers.
entry spectrometer operating frequency /
MHz
1H 13C 31P 19F 11B 1 DPX 200 200.1 50.3 81.0 188.3 64.2 2 DPX 300 300.1 75.5 121.5 282.4 96.3 3 AV 400 400.1 100.6 162.0 376.5 128.4 4 AV 500 500.1 125.8 202.5 470.6 160.5 5 AV 600 600.1 150.9 242.9 564.7 192.5
5.2.2. IR Spectroscopy
IR spectra were recorded with a Perkin-Elmer spectrometer (PE 1720X, PE 1760 FT). The
measurements were carried out on a film between two plates of KBr for liquids, in CHCl3 for
oils and KBr pills for solids. The positions of the absorption signals are listed in cm−1. Only
signals with a transmission T ≤ 80% are reported. The peak intensity is characterized using
the following abbreviations: vs (very strong, 0% ≤ T ≤ 20%), s (strong, 20% < T ≤ 40%), m
(medium, 40% < T ≤ 60%), w (weak, 60% < T ≤ 80%).
5.2.3. Mass Spectroscopy
Mass spectroscopic (MS) measurements were performed on a Finnigan SSQ 7000 (EI 70 eV,
CI 100 eV) or Fisons Platform spectrometer (Electrospray mode). High-resolution MS
measurements were carried out on a Finnigan MAT 95 or Micromass QTOF Micro
spectrometer (Electrospray mode).
The mass of fragments (m/z) is given using a number without dimension with the
relative peak intensity added in brackets. For high-resolution MS, the mass of the molecule
ion is given. The error Δ is given in ppm (Equation 5).
87
calc
calcobs
mmm −
=Δ 610 Equation 5
Δ = error (in ppm)
mobs = observed mass
mcalc = calculated mass
5.2.4. Gas Chromatography
GC analysis was performed on a HP5890 (serie 2) using a Si 54 column of 25 m length.
Following temperature program was applied: 50°C (1 min) – 8°C/min – 250°C (5 min).
5.2.5. High Performance Liquid Chromatography
HPLC analyses of the aza-BH products 106 (p-Br), 169 (p-CH3), 114 (p-NO2), 89 (H) and
103 (m-F) were performed on Diacel Chiralcel OD-H, AD-H or Chiralpack IA column at
20°C.
106 (p-Br): 223 nm, heptane/isopropanol = 85/15, flow rate 0.5 ml/min, t(S) = 31.4 min, t(R)
= 35.1 min (Diacel Chiralcel OD-H)
169 (p-CH3): 223 nm, heptane/ethanol = 90/10, flow rate 0.5 ml/min, t(S) = 52.1 min, t(R) =
60.7 min (Chiralpack IA)
114 (p-NO2): 223 nm, heptane/ethanol = 80/20, flow rate 0.7 ml/min, t(S) = 39.6 min, t(R) =
61.1 min (Chiralpack IA)
89 (H): 223 nm, heptane/isopropanol = 85/15, flow rate 0.5 ml/min, t1 = 42.6 min, t2 = 49.0
min (Chiralcel AD-H)
103 (m-F): 223 nm, heptane/isopropanol = 85/15, flow rate 0.5 ml/min, t1 = 38.0 min, t2 =
46.5 min (Chiralcel AD-H)
88
5.2.6. Thin Layer Chromatography
For Thin Layer Chromatography (TLC), POLYGRAM SIL G/UV254 plates from Macherey
and Nagel with a silica layer of 0.2 mm were used. Vizualization was realized through UV or
permanganate treatment.
5.3. Preparative Column Chromatography
For preparative column chromatography, KIESELGEL 60 from Merck with a particle size in
the range of 0.040 – 0.063 mm was used. The chromatographic purification was carried out
according to the general procedure by Still and co-workers.[151]
5.4. Syntheses
5.4.1. Aromatic Tosylaldimines
N SO
ON S
O
O
Br
N SO
O
N SO
O
O2N
N SO
O
F
67 168 105
113102
Synthesis of N-Benzylidene-4-methylbenzenesulfonamide (67) as prototypical procedure:
According to Love and co-workers,[152] tosylamide (8.56 g, 50.0 mmol, 1.00 eq) was added to
a mixture of benzaldehyde (5.07 ml, 50.0 mmol, 1.00 eq) and tetraethoxysilane (11.7 ml, 52.5
mmol, 1.05 eq) under inert gas conditions. The resulting suspension was heated in a
89
distillation apparatus to 170°C and stirred overnight. Ethanol was continuously removed by
distillation. The product was isolated by crystallization from a mixture of ethyl acetate and
pentane.
Yield: 9.72 g (37.5 mmol, 75%)
1H NMR (300 MHz, CDCl3): δ = 9.05 (s, 1H, imine-H), 7.96-7.89 (m, 4H, Ar), 7.63 (m, 1H,
Ar), 7.50 (dd {3JHH = 7.7 Hz, 3JHH = 7.3 Hz}, 2H, Ar), 7.37 (d {3JHH = 8.6 Hz}, 2H, Ar), 2.45
(s, 3H, tos-CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 170.2, 144.7, 135.1, 135.0, 132.4, 131.3, 129.8, 129.2,
128.1, 21.7 ppm.
TLC: Rf = 0.40 (pentane/ethyl acetate = 5/1)
N-(4-Methylbenzylidene)-4-methylbenzenesulfonamide (168)
Yield: 58%
1H NMR (300 MHz, CDCl3): δ = 9.00 (s, 1H, imine-H), 7.90 (d {3JHH = 8.2 Hz}, 2H, Ar), 7.83
(d {3JHH = 8.2 Hz}, 2H, Ar), 7.35 (d {3JHH = 8.2 Hz}, 2H, Ar), 7.30 (d {3JHH = 8.2 Hz}, 2H,
Ar), 2.45 (s, 3H, CH3), 2.44 (s, 3H, CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 170.0, 146.4, 144.5, 135.4, 131.4, 130.0, 129.9, 129.8,
128.0, 22.0, 21.7 ppm.
TLC: Rf = 0.37 (pentane/ethyl acetate = 5/1)
N-(4-Bromobenzylidene)-4-methylbenzenesulfonamide (105)
Yield: 65%
90
1H NMR (300 MHz, CDCl3): δ = 8.90 (s, 1H, imine-H), 7.80 (d {3JHH = 8.3 Hz}, 2H, Ar), 7.70
(d {3JHH = 8.5 Hz}, 2H, Ar), 7.55 (d {3JHH = 8.5 Hz}, 2H, Ar), 7.27 (d {3JHH = 8.3 Hz}, 2H,
Ar), 2.36 (s, 3H, tos-CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 168.8, 144.8, 134.8, 132.6, 131.2, 130.3, 129.9, 128.2, 21.7
ppm.
TLC: Rf = 0.43 (pentane/ethyl acetate = 5/1)
N-(3-Fluorobenzylidene)-4-methylbenzenesulfonamide (102)
Yield: 79%
1H NMR (300 MHz, CDCl3): δ = 9.03 (s, 1H, imine-H), 7.91 (d {3JHH = 8.4 Hz}, 2H, Ar), 7.83
(d {3JHH = 8.4 Hz}, 1H, Ar), 7.71-7.65 (m, 2H, Ar), 7.49 (m, 1H, Ar), 7.38 (d {3JHH = 8.4
Hz}, 2H, Ar), 2.46 (s, 3H, tos-CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 168.8 (d {JCF =3.1 Hz}), 162.8 (d {JCF = 249.1}), 145.0,
134.7, 134.5 (d {JCF = 7.6 Hz}), 130.9 (d {JCF = 8.0}), 129.9, 128.2, 127.9 (d{JCF = 3.1 Hz}),
121.9 (d {JCF = 21.8 Hz}), 116.6 (d {JCF = 22.5 Hz}), 21.7 ppm.
19F NMR (282.4 MHz, CDCl3): δ = −112.6 ppm.
TLC: Rf = 0.35 (pentane/ethyl acetate = 5/1)
N-(4-Nitrobenzylidene)-4-methylbenzenesulfonamide (113)
Yield: 86%
1H NMR (300 MHz, CDCl3): δ = 9.04 (s, 1H, imine-H), 8.26 (d {3JHH = 8.7 Hz}, 2H, Ar), 8.04
(d {3JHH = 8.7 Hz}, 2H, Ar), 7.84 (d {3JHH = 8.3 Hz}, 2H, Ar), 7.31 (d {3JHH = 8.3 Hz}, 2H,
Ar), 2.39 (s, 3H, tos-CH3) ppm.
91
13C NMR (75.5 MHz, CDCl3): δ = 167.3, 145.4, 137.4, 134.1, 131.9, 130.0, 129.9, 128.4,
124.2, 21.7 ppm.
TLC: Rf = 0.26 (pentane/ethyl acetate = 5/1)
5.4.2. Racemic Aza-Baylis-Hillman Products
NH OSO
O NH OSO
ONH OS
O
O
Br
NH OSO
O
O2N
NH OSO
O
F
89 169 106
103 114
Synthesis of 4-Methyl-N-(2-methylene-3-oxo-1-phenylbutyl)-4-methylbenzenesulfon-
amide (89) as prototypical procedure:
N-Benzylidene-4-methylbenzenesulfonamide (67) (1.647 g, 5.00 mmol, 1.00 eq), DABCO
(56.1 mg, 0.50 mmol, 0.10 eq) and phenol (47.1 mg, 0.50 mmol, 0.10 eq) were dissolved in
dry THF (10 ml, 2 ml⋅mmol−1). Then, MVK (0.499 ml, 6.00 mmol, 1.20 eq) was added to this
solution. The reaction was stirred at room temperature. Conversion of the starting material 67
to the corresponding aza-BH product 89 was monitored via TLC (pentane/ethylacetate = 5/1).
After complete conversion, all volatiles were removed in vacuo and the solid residue was
purified via column chromatography (pentane/ethyl acetate = 4/1 – 2/1).
1H NMR (300 MHz, CDCl3): δ = 7.57 (d {3JHH = 8.3 Hz}, 2H, Ar), 7.11 (m, 5H, Ar), 7.02 (m,
2H, Ar), 6.02 (s, 1H, CHH), 6.01 (s, 1H, CHH), 5.73 (d {3JHH = 8.7 Hz}, 1H,CHNH), 5.21 (d
{3JHH = 8.7 Hz}, 1H,CHNH), 2.33 (s, 3H, tos-CH3), 2.07 (s, 3H, C(O)CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ =198.8, 146.5, 143.3, 138.8, 137.4, 129.5, 128.5, 128.2,
127.6, 127.3, 126.4, 58.7, 26.3, 21.5 ppm.
92
TLC: Rf = 0.14 (pentane/ethyl acetate = 5/1)
4-Methyl-N-(2-methylene-3-oxo-1-p-tolyl-butyl)-benzenesulfonamide (169)
1H NMR (300 MHz, CDCl3): δ = 7.58 (d {3JHH = 8.3 Hz}, 2H, Ar), 7.15 (d {3JHH = 8.6 Hz},
2H, Ar), 6.92 (m, 4H, Ar), 6.03 (s, 1H, CHH), 6.02 (s, 1H, CHH), 5.48 (d {3JHH = 8.4 Hz},
1H, CHNH), 5.16 (d {3JHH = 8.4 Hz}, 1H, CHNH), 2.34 (s, 3H, tos-CH3), 2.19 (s, 3H, p-
CH3), 2.09 (s, 3H, C(O)CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 198.9, 146.6, 143.3, 137.4, 135.9, 129.5, 129.2, 128.0,
127.3, 126.3, 58.7, 26.4, 21.5, 21.0 ppm.
TLC: Rf = 0.12 (pentane/ethyl acetate = 5/1)
N-[1-(4-Bromophenyl)-2-methylene-3-oxobutyl]-4-methylbenzenesulfonamide (106)
1H NMR (300 MHz, CDCl3): δ = 7.55 (d {3JHH = 8.0 Hz}, 2H, Ar), 7.22 (d {3JHH = 7.8 Hz},
2H, Ar), 7.16 (d {3JHH = 8.0 Hz}, 2H, Ar), 6.88 (d {3JHH = 7.8 Hz}, 2H, Ar), 6.00 (m, 3H,
CHH and CHNH), 5.16 (d {3JHH = 8.5 Hz}, 1H, CHNH), 2.33 (s, 3H, tos-CH3), 2.05 (s, 3H,
C(O)CH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 198.8, 146.2, 143.6, 138.1, 137.5, 135.9, 131.3, 129.6,
128.6, 128.3, 127.2, 121.5, 58.0, 26.3, 21.5 ppm.
TLC: Rf = 0.12 (pentane/ethyl acetate = 5/1)
N-[1-(3-Fluorophenyl)-2-methylene-3-oxobutyl]-4-methylbenzenesulfonamide (103)
1H NMR (300 MHz, CDCl3): δ = 7.58 (d {3JHH = 8.3 Hz}, 2H, Ar), 7.16 (d {3JHH = 8.3 Hz},
2H, Ar), 7.10 (m, 1H, Ar), 6.80 (m, 3H, Ar), 6.02 (s, 1H, CHH), 6.01 (s, 1H, CHH), 5.76 (d
{3JHH = 8.8 Hz}, 1H, CHNH), 5.19 (d {3JHH = 8.8 Hz}, 1H, CHNH), 2.35 (s, 3H, tos-CH3),
2.09 (s, 3H, C(O)CH3) ppm.
93
13C NMR (75.5 MHz, CDCl3): δ = 198.8, 162.6 (d {JCF = 245 Hz}), 146.0, 143.6, 141.5 (d
{JCF = 6.8 Hz}), 137.4, 130.0 (d{JCF = 8.4 Hz}), 129.6, 128.9, 127.3, 122.0 (d {JCF = 2.8
Hz}), 114.2 (d {JCF = 21.2 Hz}), 113.7 (d {JCF = 22.8 Hz}), 58.6, 26.3, 21.5 ppm.
19F NMR (282.4 MHz, CDCl3): δ = −114.1 ppm.
TLC: Rf = 0.14 (pentane/ethyl acetate = 5/1)
4-Methyl-N-[2-methylene-1-(4-nitrophenyl)-3-oxobutyl]-benzenesulfonamide (114)
1H NMR (300 MHz, CDCl3): δ = 8.09 (d {3JHH = 8.7 Hz}, 2H, Ar), 7.68 (d {3JHH = 8.3 Hz},
2H, Ar), 7.39 (d {3JHH = 8.7 Hz}, 2H, Ar), 7.28 (d {3JHH = 8.3 Hz}, 2H, Ar), 6.10 (m, 3H,
CHNH and CHH), 5.35 (d {2JHH = 9.4 Hz}, 1H, CHNH), 2.45 (s, 3H, tos-CH3), 2.18 (s, 3H,
C(O)CH3) ppm.
13C NMR (300 MHz, CDCl3): δ = 198.7, 147.2, 146.3, 145.5, 143.9, 137.3, 129.7, 129.6,
127.3, 127.2, 123.6, 58.7, 26.2, 21.5 ppm.
TLC: Rf = 0.03 (pentane/ethyl acetate = 5/1)
5.4.3. Enantiomerically Enriched Aza-Baylis-Hillman Products
NH OSO
ONH OS
O
O
O2NBr(S)-114(S)-106
Synthesis of (S)-N-[1-(4-bromophenyl)-2-methylene-3-oxobutyl]-4-methylbenzene-
sulfonamide (106) as prototypical procedure:
N-(4-Bromobenzylidene)-4-methylbenzenesulfonamide (105) (338.2 mg, 1.00 mmol, 1.00 eq)
and (R)-2’-diphenylphosphanyl-[1,1’]binaphthalenyl-2-ol (88) (45.4 mg, 0.10 mmol, 0.10 eq)
were dissolved in THF (8.0 ml, 8.0 ml⋅mmol−1) under inert gas conditions. After addition of
94
MVK (99.9 μl, 1.20 mmol, 1.20 eq), the reaction mixture was stirred at room temperature for
24 h. Then, all volatiles were removed in vacuo and the residue was purified via column
chromatography (pentane/ethyl acetate = 4/1 – 2/1).
Yield: 60%
Enantiomeric excess: 88% (S)
NMR data: see rac-106
(S)-4-Methyl-N-[2-methylene-1-(4-nitrophenyl)-3-oxobutyl]-benzenesulfonamide (114)
Yield: 98%
Enantiomeric excess: 74% (S)
NMR data: see rac-114
5.4.4. (R,S)-2-Diphenylphosphanyl cyclohexane carboxylic acid (140)
COOH
PPh2
140
(R,S)-2-diphenylphosphanyl cyclohexane carboxylic acid methyl ester (326.0 mg, 1.00 mmol,
1.00 eq) was dissolved in ethanol (4 ml, 4 ml⋅mmol−1 ester) under Argon at room temperature.
Then, a solution of KOH (98.2 mg, 1.75 mmol, 1.75 eq) in degassed water (3.5 ml, 2
ml⋅mmol−1 KOH) was added dropwise and the resulting mixture was heated under reflux for 4
h. After removal of all volatiles in vacuo, degassed water was added (4 ml, 4 ml⋅mmol−1 ester)
and the aqueous phase was extracted with dichloromethane (3 x 8 ml, 3 x 2 ml⋅mmol−1 ester)
under Argon. The organic phase was separated and dried over Na2SO4. All volatiles were
removed in vacuo and (R,S)-2-diphenylphosphanyl cyclohexane carboxylic acid (140) was
isolated as a colorless crystalline solid.
95
Yield: 309 mg (0.99 mmol, 99%)
1H NMR (300 MHz, [D8]THF): δ = 7.58 (m, 4H, Ar), 7.42 (m, 6H, Ar), 2.85 (m, 1H,
CHPPh2), 2.35 (m, 1H, CHCOOH), 2.10 (m, 1H, CHHCHCOOH), 1.85 (m, 1H, CHHCHP),
1.75 (m, 1H, CHHCHCOOH), 1.50 (m, 1H, CHHCHHCHP), 1.42 (m, 1H,
CHHCHHCHCOOH), 1.35 (m, 1H, CHHCHHCHP), 1.22 (m, 1H, CHHCHP), 1.10 (m, 1H,
CHHCHHCHCOOH) ppm.
13C NMR (75.5 MHz, [D8]THF): δ = 174.8 (d {JPC = 5.4 Hz}), 136.8 (d {JPC = 15.0 Hz}),
135.8 (d {JPC = 18.0 Hz}), 134.2 (d {JPC = 21.1 Hz}), 132.0 (d {JPC = 17.5 Hz}), 128.3, 127.7
(d {JPC = 5.6 Hz), 127.5 (d {JPC = 7.5 Hz}), 127.3, 44.2 (d {JPC = 19.9 Hz}), 34.6 (d {JPC =
15.1}), 28.2 (d {JPC = 10.5 Hz}), 25.6 (d {JPC = 3.4 Hz}), 24.3, 24.1 (d {JPC = 0.9 Hz}) ppm.
31P NMR (121.5 MHz, [D8]THF): δ = −6.11 ppm.
5.4.5. (3-Oxobutyl)triphenylphosphonium malate (109)
O
Ph3P
O
OHO
O
OH
109
Triphenylphosphine (15.7 mg, 0.060 mmol, 1.00 eq) and MVK (4.99 μl, 0.060 mmol, 1.00 eq)
were dissolved in [D8]THF under Argon. After addition of L-(−)-malic acid (8.0 mg, 0.060
mmol, 1.00 eq), the mixture was stirred at room temperature for 5 minutes and transferred
into an NMR tube under Argon. The mixture was analyzed via NMR spectroscopy.
Conversion: 95%
1H NMR (300 MHz, [D8]THF): δ = 9.62 (br. s., 1H, COOH), 7.78 (m, 3H, Ar), 7.63 (m, 12H,
Ar), 3.98 (dd {2JHH = 9.3 Hz, 2JHH = 4.9 Hz}, 1H, CHOH), 3.55 (dt {2JPH = 12.9 Hz , 3JHH =
7.3 Hz}, 2H, PCH2CH2), 2.95 (dt {3JPH = 12.9, 3JHH = 7.3 Hz}, 2H, PCH2CH2), 2.57 (d {3JHH
= 4.9 Hz} 1H, CHHCOOH), 2.55 (d {3JHH = 9.3 Hz}, 1H, CHHCOOH), 2.05 (s, 3H,
C(O)CH3) ppm.
96
13C NMR (75.5 MHz, [D8]THF): δ = 203.9 (d {JPC = 10.8 Hz}), 178.1, 173.9, 133.4 (d {JPC =
10.0 Hz}), 130.7 (d {JPC = 12.7 Hz}), 118.3, 117.2, 66.2, 41.3, 35.4 (d {JPC = 3.1 Hz}), 29.6,
21.6 (d {JPC = 56.4}) ppm.
31P NMR (121.5 MHz, [D8]THF): δ = 25.3 ppm.
5.4.6. [1-(3-Carboxylato-isoquinolin-1-yl)-naphthalen-2-yl]-(3-oxobutyl)-diphenyl-
phosphonium (131)
N
P
O
Ph Ph
O
O131
MVK (4.16 μl, 0.050 mmol, 1.00 eq) was added to a solution of rac-1-(2-
diphenylphosphanylnaphthalen-1-yl)-isoquinoline-3-carboxylic acid (128) (24.0 mg, 0.050
mmol, 1.00 eq) in CDCl3 (0.7 ml, 14 ml⋅mmol−1). The mixture was stirred at room
temperature for 5 min. After filtration, the resulting solution was analyzed via NMR
spectroscopy and High-Resolution MS.
Conversion: 64%
1H NMR (300 MHz, CDCl3): δ = 8.05 (dd {3JHH = 8.8 Hz, 3JHP = 2.7 Hz}, 1H, Ar), 7.94 (m,
2H, Ar), 7.84 (m, 2H, Ar), 7.72 (m, 2H, Ar), 7.60 (m, 4H, Ar), 7.49 (m, 4H, Ar), 7.20 (m, 6H,
Ar), 4.76 (m, 1H, PCHHCHH), 3.94 (m, 1H, PCHHCHH), 3.30 (m, 1H, PCHHCHH), 3.09
(m, 1H, PCHHCHH), 2.02 (s, 3H, C(O)CH3) ppm
13C NMR (75.5 MHz, CDCl3): δ = 37.4 (d {JPC = 4.0}), 29.7, 16.8 (d {JPC = 55.7 Hz})
ppm.[153]
31P NMR (162.0 MHz, CDCl3): δ = 26.8 ppm.
97
HR-MS (ESI+): (m/z)obs = 554.1866 (Δ = 2.4 ppm)
5.4.7. (R)-(1-Isoquinolin-1-yl-naphthalen-2-yl)-(3-oxobutyl)-diphenylphosphonium diphenyl-
acetate (172)
N
PPh2
O
O
O
172
MVK (4.2 μl, 0.050 mmol, 1.00 eq) was added to a solution of (R)-QUINAP (127) (22.0 mg,
0.050 mmol, 1.00 eq) and diphenyl acetic acid (10.7 mg, 0.050 mmol, 1.00 eq) in CDCl3 (0.5
ml) under Argon. The reaction mixture was stirred at room temperature for 1 h. After
filtration of the resulting suspension, the solution was analyzed via NMR spectroscopy.[154]
Conversion: 15%
1H NMR (400 MHz, CDCl3): δ = 5.06 (s, 1H, Ph2CH), 3.36 (m, 2H, PCH2CH2), 3.22 (m, 1H,
PCH2CHH), 2.64 (m, 1H, PCH2CHH), 2.29 (s, 3H, C(O)CH3) ppm.
31P NMR (162.0 MHz, CDCl3): δ = 26.43 ppm.
5.4.8. (R,R)- and (S,R)-{1-[3-(3-Hydroxy-2-phenylpropylcarbamoyl)-isoquinolin-1-yl]-
naphthalen-2-yl}-(3-oxobutyl)-diphenylphosphonium diphenylacetate (173)
N
PPh2
O
HN OH
PhO
O
O
173
A 1:1-mixture of (R,R)- and (S,R)-1-(2-diphenylphosphanylnaphthalen-1-yl)-isoquinoline-3-
carboxylic acid (3-hydroxy-2-phenylpropyl)-amide (129) (60.3 mg, 0.100 mmol, 1.00 eq)
and MVK (8.32 μl, 0.100 mmol, 1.00 eq) were dissolved in [D6]benzene (1.5 ml) under
98
Argon. After addition of diphenyl acetic acid (21.3 mg, 0.100 mmol, 1.00 eq), the mixture
was stirred at room temperature for 5 min, filtered and transferred into a NMR tube under
inert gas. The resulting solution was analyzed via NMR spectroscopy.[154]
Conversion: 32%
1H NMR (400 MHz, [D6]benzene): δ = 3.48 (m, 2H, PCH2CH2), 3.00 (m, 2H, PCH2CH2),
2.02 (s, 3H, C(O)CH3) ppm.
31P NMR (162.0 MHz, [D6]benzene): δ = 26.0 ppm.
5.4.9. [1-(3-Carboxy-isoquinolin-1-yl)-naphthalen-2-yl]-{3-oxo-2-[phenyl-(toluene-4-
sulfonylamino)-methyl]-butyl}-diphenyl-phosphonium diphenylacetate (132)
N
COOH
P
O
Ph PhPh
NH
Tos O
O
132
rac-1-(2-Diphenylphosphanylnaphthalen-1-yl)-isoquinoline-3-carboxylic acid (128) (30.2 mg,
0.050 mmol, 1.00 eq), rac-4-Methyl-N-(2-methylene-3-oxo-1-phenylbutyl)-4-methylbenzene-
sulfonamide (89) (16.5 mg, 0.050 mmol, 1.00 eq) and diphenylacetic acid (10.7 mg, 0.050
mmol, 1.00 eq) were dissolved in 0.7 ml [D8]toluene. The mixture was stirred at room
temperature for 8 h, filtered and subsequently analyzed via NMR spectroscopy and High-
Resolution MS.[153]
Conversion: 13%
1H NMR (400 MHz, [D8]toluene): δ = 5.93 (m, 1H, PCHHCH), 4.90 (m, 1H, PCHHCHCH),
4.68 (m, 1H, PCHHCH), 4.17 (m, 1H, PCHHCH) ppm.
31P NMR (162.0 MHz, [D8]toluene): δ = 22.2 ppm.
99
HR-MS (ESI+): (m/z)obs = 813.2544 (Δ = 0.3 ppm)
5.4.10. Methyltrioctyl ammonium dimalatoborate (166)
[MtOA]
O O
OO
O
OO OB
O
OHH
166
The synthesis was performed according to the procedure developed by Gausepohl.[146]
Sodium dimalatoborate (165): L-(−)-malic acid (10.73 g, 80.0 mmol, 2.00 eq) was dissolved
in water (10 ml, 0.125 ml⋅mmol−1 malic acid) and treated with boric acid (2.47 g, 40.0 mmol,
1.00 eq). Then, a solution of sodium hydroxide (1.60 g, 40.0 mmol, 1.00 eq) in water (30 ml,
0.75 ml⋅mmol−1 NaOH) was added. The reaction mixture was stirred in an open flask at
100°C. After evaporation of the water (ca. 4 h), sodium dimalatoborate (165) was isolated as a
colorless powder.
Yield: 11.92 g (40.0 mmol, > 99%)
1H NMR (600 MHz, [D6]DMSO): δ = 12.24 (s, 2H, COOH), 4.32 and 4.31 (dd {3JHH,cis = 3.3
Hz, 3JHH,trans = 8.8 Hz}, 2H, CHOB), 2.53 and 2.49 (dd {3JHH,cis = 3.3 Hz, 2JHH = 15.8 Hz},
2H, CHH), 2.27 and 2.25 (dd {3JHH,trans = 8.8 Hz, 2JHH = 15.8 Hz}, 2H, CHH) ppm.
13C NMR (150 MHz, [D6]DMSO): δ = 178.3 and 178.2, 172.6, 72.7 and 72.4, 39.6 and 39.5
ppm.
11B NMR (192.5 MHz, D2O): δ = 9.85 ppm.
Methyltrioctyl ammonium dimalatoborate (166): Methyltrioctyl ammonium chloride
(Aliquat 336®, 3.54 g, 8.75 mmol, 1.00 eq) was dissolved in acetone (20 ml, 2.3 ml⋅mmol−1)
and treated with a solution of the sodium borate salt 165 (2.61 g, 8.75 mmol, 1.00 eq) in
100
acetone (20 ml, 2.3 ml⋅mmol−1). The reaction mixture was stirred at room temperature
overnight. During this period sodium chloride precipitated as a colorless solid. The reaction
mixture was filtered and the solvent was removed in vacuo to yield the IL 166 as a highly
viscous, hygroscopic colorless liquid.
Conversion: 72 ± 2% (determined from 1H NMR)
1H NMR (600 MHz, [D6]DMSO): δ = 12.24 (s, 2H, COOH), 4.32 and 4.31 (dd {3JHH,cis = 3.3
Hz, 3JHH,trans = 8.8 Hz}, 2H, CHOB), 3.22 (tt {3JHH = 8.2, 4JHH = 4.6 Hz}, 6H, C1-H2), 2.96 (s,
3H, C9-H3), 2.54 and 2.50 (dd {3JHH,cis = 3.3 Hz, 2JHH = 15.8 Hz}, 2H, CHH), 2.28 and 2.26
(dd {3JHH,trans = 8.8 Hz, 2JHH = 15.8 Hz}, 2H, CHH), 1.62 (m, 6H, C6-H2), 1.26 (m, 30H, [C2-
C5+C7]-H2) , 0.87 (tt {3JHH = 6.7 Hz, 4JHH = 2.2 Hz}, 9H, C8-H3) ppm. [155]
13C NMR (150 MHz, [D6]DMSO): δ = 178.3 and 178.2, 172.6, 72.7 and 72.4, 60.4, 47.9, 39.6
and 39.5, 31.1, 28.7, 28.7, 25.7, 22.0, 21.3, 13.9 ppm.
11B NMR (192.5 MHz, [D6]DMSO): δ = 9.85 ppm.
5.4.11. trans-4-Hydroxy-(S)-proline methylester hydrochloride (155)
NH2 O
O
HO
Cl−
155
Thionylchloride (48.33 ml, 662.6 mmol, 3.13 eq) was carefully dissolved in methanol (250
ml) at 0°C. Then, trans-4-hydroxy-L-proline (24.33 g, 211.3 mmol, 1.00 eq) was added to this
solution in small portions. The resulting mixture was stirred at 0°C for 0.5 h. After warming
to room temperature, the mixture was stirred for additional 24 h and subsequently
concentrated in vacuo. The residue was taken up in methanol and diethyl ether was added
until the product precipitated as a white solid. The solid was collected on a filter and washed
with small portions of ether. The mother liquor was concentrated and a second crystallization
furnished the product in quantitative yield.
101
Yield: 38.00 g (209.2 mmol, 99%)
1H NMR (600 MHz, [D6]DMSO): δ = 9.95 (br. s, 2H, NH2), 5.67 (br. s, 1H, OH), 4.42 (m, 2H,
CHOH and CHC(O)OCH3), 3.73 (s, 3H, C(O)OCH3), 3.35 (dd {2JHH = 12.1 Hz, 3JHH = 3.6
Hz}, 1H, NH2CHHCH(OH)), 3.03 (br. d {2JHH = 12.1 Hz}, 1H, NH2CHHCH(OH)), 2.18 (m,
1H, CH(OH)CHHCHC(O)OCH3), 2.07 (m, 1H, CH(OH)CHHCHC(O)OCH3) ppm.
13C NMR (150 MHz, [D6]DMSO): δ = 169.5, 69.8, 58.4, 53.7, 53.0, 37.2 ppm.
5.4.12. (2S,4R)-4-Hydroxy-1-benzoylproline methylester (156)
NO
O
HO
O
156
Triethylamine (29.0 ml, 206.5 mmol, 2.50 eq) was added to a solution of trans-4-hydroxy-(S)-
proline methylester hydrochloride (155) (15.00 g, 82.6 mmol, 1.00 eq) in dichloromethane
(90 ml, 6 ml⋅g−1 ester). The resulting mixture was stirred for 1.5 h at room temperature. After
addition of DMAP (0.463 g, 4.1 mmol, 5 mol-%), benzoylchloride (9.52 ml, 82.6 mmol, 1.00
eq) was added dropwise. The reaction mixture was stirred for 12 h at room temperature. The
resulting suspension was washed with water (30 ml), hydrochloric acid (5%, 20 ml), 0.5 M
NaOH (20 ml) and again water (30 ml). The organic phase was dried over Na2SO4 and
concentrated in vacuo. The resulting residue was taken up in a small amount of
dichloromethane. From this solution, the product was isolated as a white solid through
precipitation with pentane.
Yield: 16.48 g (66.1 mmol, 80%)
1H NMR (300 MHz, CDCl3): δ = 7.55 (m, 2H, o-H), 7.40 (m, 3H, m-H and p-H), 4.82 (m, 1H,
CHCO(O)CH3), 4.39 (m, 1H, CH(OH)), 3.75 (s, 3H, C(O)CH3), 3.50 (m, 2H,
102
NCHHCH(OH)), 3.27 (s, 1H, CH(OH)), 2.35 (m, 1H, CH(OH)CHHCHC(O)OCH3), 2.10 (m,
1H, CH(OH)CHHCHC(O)OCH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 172.9, 170.3, 135.5, 130.4, 128.3, 127.5, 70.2, 58.0, 52.4,
37.7 ppm.
5.4.13. (2S,4R)-4-{[1-(tert-Butyl)-1,1’-dimethylsilyl]-oxy}-1-benzoylproline methylester (157)
NO
O
O
O
Si
157
(2S,4R)-4-Hydroxy-1-benzoylproline methylester (156) (10.00 g, 40.12 mmol, 1.00 eq) and
imidazole (6.83 g, 100.3 mmol, 2.50 eq) were dissolved in DMF (50 ml, 5 ml⋅g−1 alcohol) and
stirred at room temperature for 3 h. Then, a solution of tert-butyl-dimethylsilyl chloride in
toluene (50 wt-%, 17.5 ml, 50.15 mmol, 1.25 eq) was added dropwise. The resulting mixture
was stirred for 40 h at room temperature. After concentration in vacuo, the residue was
dissolved in ether (60 ml) and washed with water (30 ml), diluted acetic acid (1M, 30 ml),
saturated NaHCO3 solution (30 ml) and again water (2 x 30 ml). After that, the organic phase
was dried over Na2SO4 and the solvent was removed in vacuo. The obtained colorless residue
was used in the next step without further purification.
Yield: 14.37 g (39.53 mmol, 99%)
1H NMR (300 MHz, CDCl3): δ = 7.52 (m, 2H, Ar), 7.36 (m, 3H, Ar), 4.78 (t {3JHH = 8.2 Hz},
1H, CHC(O)OCH3), 4.40 (m, 1H, CHOSi), 3.76 (s, 3H, C(O)OCH3), 3.72 (m, 1H,
NCHHCHOSi), 3.37 (m, 1H, NCHHCHOSi), 2.25 (m, 1H, SiOCHCHHCHC(O)OCH3), 2.05
(m, 1H, SiOCHCHHCHC(O)OCH3), 0.79 (s, 9H, SiC(CH3)3), 0.00 (s, 3H, SiCH3), −0.08 (s,
3H, SiCH3) ppm.
103
13C NMR (75.5 MHz, CDCl3): δ = 172.9, 170.2, 135.9, 130.3, 128.3, 127.4, 70.7, 58.1, 57.9,
52.3, 38.4, 25.6, 17.8, −4.8, −5.0 ppm.
5.4.14. (2S,4R)-4-{[1-(tert-Butyl)-1,1’-dimethylsilyl]-oxy}-1-benzyl-2-hydroxymethyl-
pyrrolidine (158)
NOH
OSi
158
A suspension of LAH (3.445 g, 90.77 mmol, 3.30 eq) in THF (55 ml, 16 5 ml⋅g−1 LAH) was
heated under reflux for 15 min. Then, a solution of (2S,4R)-4-{[1-(tert-butyl)-1,1’-
dimethylsilyl]-oxy}-1-benzoylproline methylester (157) (10.00 g, 27.51 mmol, 1.00 eq) in
THF (15 ml, 1.5 ml⋅g−1 ester) was added at a rate keeping the mixture under gentle reflux.
After complete addition, the mixture was heated under reflux for 1 h, cooled to room
temperature and carefully hydrolyzed with 20%-KOH solution (15 ml, 1.5 ml⋅g−1 157). The
solid was filtered off and extracted with ether under reflux for 1 h. The combined organic
phase was concentrated and ether (50 ml, 5 ml⋅g−1 ester) was added. After drying over
Na2SO4 and evaporation of the volatiles under reduced pressure, the obtained colorless oil
was used in the next step without further purification.
Yield: 8.75 g (27.41 mmol, 99%)
1H NMR (300 MHz, CDCl3): δ = 7.28 (m, 5H, Ar), 4.25 (m, 1H, CHOSi), 3.95 (d {2JHH = 12.9
Hz}, 1H, NCHHPh), 3.63 (dd {2JHH = 11.1 Hz, 3JHH = 3.4 Hz}, 1H, CHH(OH)), 3.45 (d {2JHH
= 12.9 Hz}, 1H, NCHHPh), 3.36 (dd {2JHH = 11.1 Hz, 3JHH = 1.5 Hz}, 1H, CHHOH), 3.11
(dd {2JHH = 9.8 Hz, 3JHH = 5.5 Hz}, 1H, NCHHCHOSi), 3.05 (m, 1H, NCHCH2), 2.34 (dd
{2JHH = 9.8 Hz, 3JHH = 5.7 Hz}, 1H, NCHHCHOSi), 2.05 (m, 1H, NCHCHH), 1.82 (m, 1H,
NCHCHH), 0.86 (s, 9H, SiC(CH3)3), 0.02 (s, 3H, SiCH3), 0.00 (s, 3H, SiCH3) ppm.
104
13C NMR (75.5 MHz, CDCl3): δ = 139.1, 128.7, 128.4, 127.1, 70.7, 68.0, 63.4, 62.3, 61.0,
58.7, 37.9, 25.8, 18.0, −4.7, −4.8 ppm.
5.4.15. (3R,5R)-1-Benzyl-3-(tert-butyl-dimethylsilanyloxy)-5-chloro-piperidine (159)
N
ClOSi
159
Methanesulfonylchloride (0.904 ml, 11.68 mmol, 1.10 eq) and triethylamine (5.93 ml, 42.48
mmol, 4.00 eq) were added dropwise to a solution of (2S,4R)-4-{[1-(tert-butyl)-1,1’-
dimethylsilyl]-oxy}-1-benzyl-2-hydroxymethylpyrrolidine (158) (3.415 g, 10.62 mmol, 1.00
eq) in THF (87 ml, 8.2 ml⋅mmol−1 alcohol) at 0°C. The mixture was heated under reflux for
12 h. After cooling to room temperature, the reaction mixture was poured into 2.5 M NaOH
solution (30 ml). After extraction with dichloromethane, the combined organic phase was
dried over Na2SO4 and concentrated in vacuo. The resulting dark brown oil was purified via
column chromatography with pentane/ethyl acetate = 3/1.
Yield: 2.058 g (6.05 mmol, 57%)
1H NMR (300 MHz, CDCl3): δ = 7.28 (m, 5H, Ar), 4.34 (m, 1H, CHOSi), 4.09 (m, 1H,
CHCl), 3.68 (d {2JHH = 13.7 Hz}, 1H, NCHHPh), 3.50 (d {2JHH = 13.7 Hz}, 1H, NCHHPh),
2.68 (dd {2JHH = 11.7 Hz, 3JHH = 2.7 Hz}, 1H, NCHHCHOSi), 2.55 (m, 2H, NCHHCHOSi
and NCHHCHCl), 2.33 (dd {2JHH = 11.3 Hz, 3JHH = 6.1 Hz}, 1H, NCHHCHCl), 1.92 (m, 2H,
SiOCHCHHCHCl), 0.86 (s, 9H, SiC(CH3)3), 0.02 (s, 3H, SiCH3), 0.00 (s, 3H, SiCH3) ppm.
13C NMR (75.5 MHz, CDCl3): δ = 137.9, 128.8, 128.2, 127.0, 65.9, 62.0, 59.7, 59.6, 54.8,
42.3, 25.8, 18.1, −4.7, −4.8 ppm.
GC: t = 12.96 min
MS (CI): m/z (%) = 340 (M+1, 100), 304 (49), 282 (17).
105
MS (EI): m/z (%) = 339 (M, 14), 304 (77), 296 (17), 290 (12), 282 (95), 134 (17), 91 (100),
73 (12).
HR-MS: (m/z)obs = 339.1785 (Δ = 0.2 ppm)
IR (kap): ν = 2943 (vs), 2794 (w), 2352 (m), 1645 (m), 1461 (m), 1369 (w), 1258 (s), 1096
(vs), 1038 (vs), 836 (vs), 782 (m) cm−1.
5.4.16. (3R,5R)-1-Benzyl-5-chloro-piperidin-3-ol (160)
N
ClHO
160
(3R,5R)-1-benzyl-3-(tert-butyl-dimethylsilanyloxy)-5-chloro-piperidine (159) (339.9 mg, 1.00
mmol, 1.00 eq) was dissolved in THF (15 ml, 15 ml⋅mmol−1 159) at room temperature. Then,
a solution of tetra-n-butylammonium fluoride in dichloromethane (1 M, 2.00 ml, 2.00 mmol,
2.00 eq) was added dropwise. After stirring at room temperature overnight, the reaction
solution was poured into a biphasic mixture of aqueous NH4Cl and ether. The organic phase
was separated and the resulting aqueous phase was extracted with ether. Then, the combined
organic phases were washed with water and dried over Na2SO4. After removal of the solvent
in vacuo, the remaining residue was purified via column chromatography with pentane/ethyl
acetate = 1/1.
Yield: 183.1 mg (0.811 mmol, 81%)
1H NMR (300 MHz, CDCl3): δ = 7.33 (m, 5H, Ar), 4.25 (m, 1H, CHCl), 4.02 (m, 1H, OH),
3.62 (s, 2H, NCH2Ph), 3.13 (m, 1H, CHOH), 2.81 (m, 1H, HOCHCHHCHCl), 2.30 (m, 4H,
NCH2CHOH and NCH2CHCl), 1.72 (m, 1H, HOCHCHHCHCl) ppm.
106
13C NMR (75.5 MHz, CDCl3): δ = 137.2, 129.0, 128.5, 127.5, 66.0, 62.1, 60.9, 58.6, 52.5, 41.6
ppm.
MS (CI): m/z (%) = 226 (M+1, 100), 190 (16).
MS (EI): m/z (%) = 225 (M, 66), 190 (13), 148 (16), 136 (15), 134 (58), 120 (10), 91 (100).
HR-MS: (m/z)obs = 225.0921 (Δ = 0.4 ppm)
IR (KBr): ν = 3177 (vs), 2932 (vs), 2840 (w), 2779 (vs), 2365 (s), 2342 (m), 1443 (s), 1353
(w), 1293 (vs), 1142 (m), 1075 (m), 1000 (s), 880 (w), 794 (m), 746 (s), 687 (vs), 600 (w),
482 (s) cm−1.
5.5. Catalysis
5.5.1. Screening of Lewis Base-Brønsted Acid Catalysts in the Aza-Baylis-Hillman Reaction
As prototypical example, the screening of (R,S)-2-diphenylphosphanyl-
cyclohexanecarboxylic acid (140) in the coupling of N-(4-Bromobenzylidene)-4-
methylbenzenesulfonamide (105) with MVK (37) is described:
Br
N TosO
+
Br
NH OTos
COOH
PPh2
r.t., THF, 24 h
105 37
140
106
N-(4-Bromobenzylidene)-4-methylbenzenesulfonamide (105) (51.0 mg, 0.125 mmol, 1.00 eq)
and (R,S)-2-diphenylphosphanyl-cyclohexanecarboxylic acid (140) (3.90 mg, 0.0125 mmol,
0.10 eq) were dissolved in THF under inert gas conditions. After addition of MVK (37) (12.5
μl, 0.150 mmol, 1.20 eq), the reaction solution was stirred at room temperature for 24 h. Then,
all volatiles were removed in vacuo. The composition of the resulting residue was analyzed
via 1H NMR spectroscopy (conversion) and HPLC (enantiomeric excess).
107
Conversion: 86%
Enantiomeric excess: rac
5.5.2. Kinetic Experiments
For all kinetic experiments, stock solutions were prepared to minimize the weighing error.
They were stored under Argon at −10°C.
a) Without Brønsted acid
F
N TosO
+
PPh3, C6F6
THF, r.t.
F
NH OTos
102 37 103
53 104
Prototypical example:
N-(3-Fluorobenzylidene)-4-methylbenzenesulfonamide (102) (16.60 mg, 59.9 μmol, 1.00 eq),
PPh3 (53) (7.88 mg, 30.1 μmol, 0.50 eq) and C6F6 (104) (2.71 mg, 14.6 μmol, 0.24 eq) were
dissolved in THF (0.60 ml) at room temperature. The reaction was performed in a sealed
NMR tube under Argon. After addition of MVK (37) (7.18 μl, 86.3 μmol, 1.44 eq),
conversion was monitored via 19F NMR spectroscopy for approximately 10 h.
Starting concentrations:
Partial order imine 102: c(53) = 0.0501 mol⋅l−1, c(37) = 0.1438 mol⋅l−1, c(104) = 0.0243
mol⋅l−1, c(102) = 0.0998-0.2530 mol⋅l−1.
Partial order MVK (37): c(53) = 0.0500 mol⋅l−1, c(102) = 0.1506 mol⋅l−1, c(104) = 0.0214
mol⋅l−1, c(37) = 0.1712 – 0.3163 mol⋅l−1.
108
Partial order PPh3 (53): c(37) = 0.1531 mol⋅l−1, c(102) = 0.1514 mol⋅l−1, c(104) = 0.0285
mol⋅l−1, c(53) = 0.0724 – 0.1595 mol⋅l−1.
b) With Brønsted acid = phenol
F
N TosO
+
PPh3, phenol, C6F6
THF, r.t.F
NH OTos
102 37 103
53 111 104
Prototypical example:
N-(3-Fluorobenzylidene)-4-methylbenzenesulfonamide (102) (16.01 mg, 57.7 μmol, 1.00 eq),
PPh3 (53) (4.63 mg, 17.6 μmol, 0.31 eq), C6F6 (104) (3.81 mg, 20.5 μmol, 0.36 eq) and phenol
(111) (8.94 mg, 95.0 μmol, 1.65 eq) were dissolved in THF (0.60 ml) at room temperature.
The reaction was performed in a sealed NMR tube under Argon. After addition of MVK (37)
(7.50 μl, 90.1 μmol, 1.56 eq), conversion was monitored on-line via 19F NMR spectroscopy
for approximately 10 h.
Starting concentrations:
Partial order imine 102: c(53) = 0.0294 mol⋅l−1, c(37) = 0.1502 mol⋅l−1, c(111) = 0.1584
mol⋅l−1, c(104) = 0.0341 mol⋅l−1, c(102) = 0.0962 – 0.1479 mol⋅l−1.
Partial order MVK (37): c(53) = 0.0153 mol⋅l−1, c(111) = 0.1622 mol⋅l−1, c(104) = 0.0234
mol⋅l−1, c(102) = 0.1532 mol⋅l−1, c(37) = 0.1474 – 0.2211 mol⋅l−1.
Partial order phenol (111): c(102) = 0.1264 mol⋅l−1, c(37) = 0.1527 mol⋅l−1, c(104) = 0.0350
mol⋅l−1, c(53) = 0.0154 mol⋅l−1, c(111) = 0.087 – 0.166 mol⋅l−1.
109
5.5.3. Screening of Brønsted Acids for Kinetics
For all kinetic experiments, stock solutions were prepared to minimize the weighing error.
They were stored under Argon at −10°C.
As prototypical example, the evaluation of benzoic acid as co-catalyst in the PPh3-
catalyzed coupling of N-(4-bromobenzylidene)-4-methylbenzenesulfonamide (105) with
methyl vinyl ketone (37) in [D8]THF is described:
N TosO
+
PPh3, benzoic acid
[D8] THF, r.t.
NH OTos
Br Br
105 10637
53
Benzoic acid (12.6 mg, 0.103 mmol, 1.375 eq) was added to a mixture of N-(4-
bromobenzylidene)-4-methylbenzenesulfonamide (105) (25.4 mg, 0.075 mmol, 1.00 eq) and
PPh3 (53) (2.0 mg, 0.0075 mmol, 0.10 eq) in deuterated THF (0.60 ml) at room temperature.
The reaction was performed in a sealed NMR tube under Argon. After addition of MVK (37)
(7.5 μl, 0.090 mmol, 1.20 eq), conversion was monitored online via 1H NMR spectroscopy for
700 min.
The following compounds were also tested as additives: N-[1-(4-bromophenyl)-2-methylene-
3-oxobutyl]-4-methylbenzenesulfonamide (42.1 mg), methanol (3.3 mg), phenol (9.7 mg), N-
methyltosylamide (19.1 mg), bis-3,5-(trifluormethyl)phenol (23.7 mg), water (1.9 mg), malic
acid (13.8 mg).
5.5.4. Catalysis in Chiral Ionic Liquids
As prototypical example, the PPh3-catalyzed coupling of N-(4-bromobenzylidene)-4-
methylbenzenesulfonamide (105) with MVK (37) in methyltrioctyl ammonium
dimalatoborate (166) is described:
110
Br
N TosO
+
Br
NH OTos
166, r.t., 24 h
PPh3
53
105 10637
N-(4-Bromobenzylidene)-4-methylbenzenesulfonamide (105) (42.3 mg, 0.125 mmol, 1.00 eq)
and catalyst 3 (3.3 mg, 12.5 μmol, 0.10 eq) were dissolved in methyltrioctyl ammonium
dimalatoborate (166) (1.0 ml, 6.7 ml⋅mmol−1 imine). After addition of MVK (37) (12.5 μl,
0.150 mmol, 1.20 eq), the reaction was stirred at room temperature for 24 h. After removing
excess MVK (37) in vacuo, a small sample of the reaction mixture was dissolved in
[D6]DMSO to determine the conversion by 1H NMR spectroscopy. The main part of the
reaction mixture was dissolved in a 1:1 mixture of water and methanol (5 ml). Further
methanol was added to obtain a clear solution of the reaction mixture. After (partly)
exchanging the cation on an ion-exchange resin (contact time app. 5 min), all volatiles were
removed in vacuo.[156]The resulting solid was extracted with heptane/iPrOH (85:15, 1 ml) and
the solution was directly analyzed by chiral HPLC to determine the ee of the product.
Conversion: 34 – 39%
Enantiomeric excess: 71 – 84% ee
5.5.5. Screening of Chiral Brønsted Acidic Additives
As prototypical example, the PPh3-catalyzed coupling of N-(4-bromobenzylidene)-4-
methylbenzenesulfonamide (105) with MVK (37) using L-(−)-malic acid (162) as additive
is presented:
Br
N TosO
+
Br
NH OTos
THF, r.t., 24 h
PPh3, L-(−)-malic acid
105 37 106
53 162
N-(4-Bromobenzylidene)-4-methylbenzenesulfonamide (105) (42.3 mg, 0.125 mmol, 1.00
eq), triphenylphosphine (53) (3.3 mg, 0.0125 mmol, 0.10 eq) and L-(−)-malic acid (162) (1.7
111
mg, 0.0125 mmol, 0.10 eq) were dissolved in THF (1.0 ml, 6.7 ml⋅mmol−1 105). After
addition of MVK (37) (12.5 μl, 10.5 mg, 0.150 mmol, 1.20 eq), the reaction mixture was
stirred at room temperature for 24 h. After the reaction, all volatile components were removed
in vacuo. The remaining solid was analyzed by 1H NMR (conversion) and chiral HPLC
(enantiomeric excess).
Conversion: 8%
Enantiomeric excess: ee = rac
5.6. Miscellaneous
5.6.1. Cross-Mannich Experiment
PPh3, phenol
THF, r.t.
NH OTos
Br F
N Tos
+
F
NH OTos
Br
N Tos
+
106 105 103102
53 111
N-[1-(4-Bromophenyl)-2-methylene-3-oxobutyl]-4-methylbenzenesulfonamide (106) (30.0
mg, 0.0735 mmol, 1.00 eq) and N-(3-fluorobenzylidene)-4-methylbenzenesulfonamide (102)
(203.7 mg, 0.735 mmol, 10.0 eq) were dissolved in THF (2 ml, 2.7 ml⋅mmol−1 102) under
Argon. After addition of triphenylphosphine (53) (19.3 mg, 0.0735 mmol, 1.00 eq) and
phenol (111) (34.6 mg, 0.367 mmol, 5.00 eq), the mixture was stirred at room temperature for
n h. The mixture was analyzed by 1H and 19F NMR spectroscopy.
n = 24: no cross-Mannich product (103)
n = 72: no cross-Mannich product (103)
112
5.6.2. Deuteration Experiment
PPh3
CD3OD, r.t., 24h
O
Br
O
Br
NHTos NDTosH D
D D
106 [D4]106
53
N-[1-(4-Bromophenyl)-2-methylene-3-oxobutyl]-4-methylbenzenesulfonamide (106) (20.4
mg, 0.050 mmol, 1.00 eq) and triphenylphosphine (53) (13.1 mg, 0.050 mmol, 1.00 eq) were
dissolved in [D4]methanol (1.0 ml, 20 ml⋅mmol−1) under Argon. After stirring the reaction
mixture at room temperature for 24 h, all volatiles were removed in vacuo. The residue was
dissolved in CDCl3 and characterized via NMR spectroscopy.
1H NMR (300 MHz, CDCl3): δ = 7.55 (d {3JHH = 8.0 Hz}, 2H, Ar), 7.22 (d {3JHH = 7.8 Hz},
2H, Ar), 7.16 (d {3JHH = 8.0 Hz}, 2H, Ar), 6.88 (d {3JHH = 7.8 Hz}, 2H, Ar), 6.00 (m, 3H,
CHH and CHNH), 5.16 (m, 1H, CHNH), 2.33 (s, 3H, tos-CH3), 2.05 (s, 3H, C(O)CH3) ppm.
The bold red signals showed a decrease in intensity relative to the other peaks.
5.6.3. Racemization Experiment
PPh3, phenol
THF, r.t.
NH OTos
Br
NH OTos
Br(S)-106 (R)-106
53 111
As prototypical example, the racemization of (S)-N-[1-(4-bromophenyl)-2-methylene-3-
oxobutyl]-4-methylbenzenesulfonamide (106) with the combined system PPh3
(53)/phenol (111) is presented:
To a mixture of (S)-N-[1-(4-bromophenyl)-2-methylene-3-oxobutyl]-4-methylbenzene-
sulfonamide (106) (38.1 mg, 0.0933 mmol, 1.00 eq) and triphenylphosphine (53) (24.5 mg,
0.0933 mmol, 1.00 eq) in THF (0.75 ml, 8.0 ml⋅mmol−1), phenol (111) (26.3 mg, 0.280 mmol,
3.00 eq) was added. The resulting solution was stirred at room temperature for n h and
samples were analyzed by chiral HPLC.
113
6. Appendices
6.1. Abbreviations
A acid
Ac acetyl, acetate
Ar aryl
B base
BH Baylis-Hillman
BINAP 2,2’-Bis(diphenylphosphino)-1,1’-binaphthyl
BINOL 1,1’-Bi-2-naphthol
Bmim butylmethyl imidazolium
Bn benzyl
Boc tert-butoxycarbonyl
Bu butyl
c concentration
conv conversion
calc calculated
cat. catalyst, catalytic
CI chemical ionization
COSY Correlated Spectroscopy, correlation spectrum
d doublet, day(s)
DABCO 1,4-diazabicyclo[2.2.2]octane
DBU 1,8-diazabicyclo[5.4.0]undec-7-ene
DCM dichloromethane
DFT Density Functional Theory
DMAP 4-dimethylaminopyridine
DMF N,N-dimethylformamide
DMSO dimethylsulfoxide
ee enantiomeric excess
EI electron ionisation
er enantiomeric ratio
Et ethyl
eq equivalent(s)
114
EVK ethylvinyl ketone
EWG electron withdrawing group
GC gas chromatography
h hour(s)
HPLC High Performance Liquid Chromatography
HR-MS High Resolution Mass Spectroscopy
HX acid
Hz Hertz
IL ionic liquid
IR infrared
J coupling constant
LAH lithium aluminiumhydride
Nos p-nitrobenzenesulfonyl
Nu nucleophile
m multiplet, medium
m meta
M molar
M+ molecule ion
Me methyl
Mes methanesulfonyl
min minute(s)
MVK methylvinyl ketone
MS Mass Spectroscopy, mass spectrum, molecular sieves
MTOA methyltrioctyl ammonium
n normal
n.a. not available
NMR Nuclear Magnetic Resonance
NOE Nuclear Overhauser Effect
NOESY Nuclaer Overhauser Effect Spectroscopy
o ortho
obs observed
p para
P product
PG protecting group
115
Ph phenyl
ppm parts per million
PTA 1,3,5-triaza-7-phosphaadamantane
QUINAP 1-(2-Diphenylphosphino-1-naphthyl)isoquinoline
q quartet
quant. quantitative
r reaction rate
r(0) initial reaction rate
R organic rest
RDS rate determining step
Rf ratio of fronts (TLC)
rfl. reflux
r.t. room temperature
s singulet, strong
S substrate
SES β-trimethylethanesulfonyl
t time, triplet
t tertiary
T transmission
TADDOL trans-α,α'-(Dimethyl-1,3-dioxolane-4,5-diyl)bis(diphenylmethanol)
TBS tert-butyldimethylsilyl
Tf trifluormethanesulfonyl
THF tetrahydrofurane
TLC Thin Layer Chromatography
TOCSY Total Correlated Spectroscopy
Tos p-toluenesulfonate
TS transition state
UV ultraviolet
v very
vs very strong
w weak
X halide
y yield
* symbol for a stereogenic center
116
6.2. List of Commercially Obtained Chemicals
Reagent Supplier Quality 3,5-bis-(trifluoromethyl)phenol Aldrich 95% Aliquat 336 Acros unknown benzaldehyde Avocado 99+% benzoic acid Avocado 99% benzoylchloride Avocado 99% boric acid Merck 99% p-bromobenzaldehyde Aldrich 99% 2-cyclopentene-1-one Avocado 98%
1,4-diazabicyclo[2.2.2]octane Avocado 97% p-dimethylaminopyridine Aldrich puriss, >99.0% diphenylacetic acid Avocado 99% m-fluorobenzaldehyde Aldrich 97% hexafluorobenzene Aldrich 99.9% imidazole Avocado 99% lithiumaluminium hydride Aldrich 95%, powder L-(-)-malic acid Aldrich 97% methanesulfonyl chloride Aldrich >99.7% methyl acrylate Avocado 99%
methylvinyl ketone Aldrich 99% p-nitrobenzaldehyde Aldrich 98% (pentafluorophenyl)diphenyl phosphine
Aldrich 96%
phenol Aldrich >99% tert-butyldimethylsilyl chloride Aldrich solution, 50% (w/w) in
toluene tetraethoxysilane Aldrich >99% tetra-n-butylammonium fluoride Aldrich solution, 1M in THF thionylchloride Aldrich 99% p-tolualdehyde Aldrich 97% p-toluenesulfonamide Avocado 98+% trans-4-hydroxy-L-proline Acros 99+% triethylamine Avocado 99% triphenylphosphine Acros 99% tris-(o-tolyl)phosphine Strem 99%
117
6.3. Kinetic Study with Phenol as Co-Catalyst
Teilordnung MVK_Add
r(0) = 0,0047c(0)R2 = 0,9664
0,00E+00
2,00E-04
4,00E-04
6,00E-04
8,00E-04
1,00E-03
1,20E-03
1,40E-03
0,000 0,050 0,100 0,150 0,200 0,250 0,300
c(0) in [mol/l]
r(0)
in [m
ol/(l
*min
)]
Teilordnung MVK_Add
r(0) = 0,0047c(0)R2 = 0,9664
0,00E+00
2,00E-04
4,00E-04
6,00E-04
8,00E-04
1,00E-03
1,20E-03
1,40E-03
0,000 0,050 0,100 0,150 0,200 0,250 0,300
c(0) in [mol/l]
r(0)
in [m
ol/(l
*min
)]
Teilordnung MVK_Add
r(0) = 0,0047c(0)R2 = 0,9664
0,00E+00
2,00E-04
4,00E-04
6,00E-04
8,00E-04
1,00E-03
1,20E-03
1,40E-03
0,000 0,050 0,100 0,150 0,200 0,250 0,300
c(0) in [mol/l]
r(0)
in [m
ol/(l
*min
)]
Teilordnung MVK_Add
r(0) = 0,0047c(0)R2 = 0,9664
0,00E+00
2,00E-04
4,00E-04
6,00E-04
8,00E-04
1,00E-03
1,20E-03
1,40E-03
0,000 0,050 0,100 0,150 0,200 0,250 0,300
c(0) in [mol/l]
r(0)
in [m
ol/(l
*min
)]
Phenol
r(0)= 0,0045c(0)R2 = 0,9861
0,000E+00
2,000E-04
4,000E-04
6,000E-04
8,000E-04
1,000E-03
1,200E-03
1,400E-03
0,000 0,050 0,100 0,150 0,200 0,250 0,300
c(0) in [mol/l]
r(0)
in [m
ol/l]
6.4. 1H and 13C NMR Spectra of Compound 160
1.52.02.53.03.54.04.55.05.56.06.57.07.5 ppm
N
ClHO
160
1.52.02.53.03.54.04.55.05.56.06.57.07.5 ppm
N
ClHO
160
119
4550556065707580859095100105110115120125130135 ppm
41.6
4
52.5
4
58.5
960
.87
62.1
1
65.9
8
76.6
177
.04
77.4
6
127.
5112
8.48
129.
00
137.
19
6.5. HPLC Chromatogram of Aza-BH Product 106
a) Racemate
121
b) Authentic sample (reaction in IL 166)
6.6. 31P NMR Spectrum of Compound 172
-10-525 20 15 10 5 0 ppm
-14.
19-1
4.13
-14.
07
26.1
626
.25
26.4
3
123
6.7. 31P NMR Spectrum of Compound 173
-10-530 25 20 15 10 5 0 ppm
-13.
7-1
3.6
-13.
4-1
3.4
-13.
3
20.0
22.3
24.9
26.0
26.2
27.8
28.7
29.1
30.9
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133
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137 ⎟⎠⎞
⎜⎝⎛−=ΔΔ
SRRTG ln
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and the C-signals was not possible.
135
155 For the assignment of the carbon signals, following nomenclature was used:
(C9)N+(C1C2C3C4C5C6C7C8)3 156 Preparation of the ion-exchange resin: the H-form of Marathon ® MSC (supplied by
Aldrich) was stirred with an excess of NaOH in aqueous solution. After 1h, the NaOH
solution was removed by decantation and the resin was washed with water until the
resulting aqueous phase showed a neutral pH.
136
CURRICULUM VITAE
Name: Pascal Buskens
Date of birth (place): 5th February 1980 (Heerlen, Netherlands)
Nationality: Dutch
Education
2003 – today Ph.D. study
RWTH Aachen University, Aachen (Germany)
Institute of Technical and Macromolecular Chemistry
Group of Prof. Dr. Walter Leitner
Subject: Bifunctional Organocatalysis in the Asymmetric
Aza-Baylis-Hillman Reaction
October 2004 – today Member and holder of a scholarship of the Graduate School
440 Methods in Asymmetric Synthesis
September – November 2005 Research project at the University of Oxford, Oxford (UK)
Department of Organic Chemistry
Group of Dr. John M. Brown FRS
Subject: QUINAP as Organocatalyst
2000 – 2003 Chemistry, Diplom
RWTH Aachen University, Aachen (Germany)
May – October 2003 Diploma thesis
RWTH Aachen University, Aachen (Germany)
Institute of Technical and Macromolecular Chemistry
Group of Prof. Dr. Walter Leitner
Subject: Activation and Deactivation of a Novel Non-
Classical Rutheniumhydride Catalyst for the Murai Reaction
137
January – March 2002 Research project at the University of York, York (UK)
Department of Inorganic Chemistry, Green Chemistry Group
Group of Dr. Karen Wilson
Subject: Solid Sulphonic Acid Catalysts for Esterification
Reactions
1998 – 2000 RWTH Aachen University, Aachen (Germany)
Chemistry, Vordiplom (pre-degree)
1992 – 1998 College Rolduc, Kerkrade (Netherlands)
Gymnasium