Download Hydrogenation, Transfer Hydrogenat- ion and Hydrogen Transfer Reactions

Hydrogenation, Transfer Hydrogenation and Hydrogen Transfer Reactions
Catalyzed by Iridium Complexes.
Xu Quan
©Xu Quan, Stockholm University 2015
ISBN 978-91-7649-255-0
Printed in Sweden by Holmbergs, Malmö 2015
Distributor: Department of Organic Chemistry, Stockholm University
To my parents and Ling Jin
谨以此论文献给我的父母和妻子
Abstract
The work described in this thesis is focused on the development of new bidentate iridium complexes and their applications in the asymmetric reduction
of olefins, ketones and imines. Three new types of iridium complexes were
synthesized, which included pyridine derived chiral N,P-iridium complexes,
achiral NHC complexes and chiral NHC-phosphine complexes. A study of
their catalytic applications demonstrated a high efficiency of the N,P-iridium
complexes for asymmetric hydrogenation of olefins, with good enantioselectivity. The carbene complexes were found to be very efficient hydrogen
transfer mediators capable of abstracting hydrogen from alcohols and subsequently transfer it to other unsaturated bonds. This hydrogen transferring
property of the carbene complexes was used in the development of C–C and
C–N bond formation reactions via the hydrogen borrowing process. The
complexes displayed high catalytic reactivity using 0.5–1.0 mol% of the
catalyst and mild reaction conditions. Finally chiral carbene complexes were
found to be activated by hydrogen gas. Their corresponding iridium hydride
species were able to reduce ketones and imines with high efficiency and
enantioselectivity without any additives, base or acid.
i
List of Publications
This thesis is based on the following publications, which are referred to in
the text by their Roman numerals.
I.
Iridium Catalysts with Chiral Bicyclic Pyridine-Phosphane
Ligands for the Asymmetric Hydrogenation of Olefins. Xu
Quan, Vijay Singh Parihar, Milan Bera, and Pher G. Andersson.
European Journal of Organic Chemistry, 2014, 140–146.
II. Highly Enantioselective Iridium Catalyzed Hydrogenation of
α, β Unsaturated Esters. Jia-Qi Li, Xu Quan, and Pher G. Andersson. Chemistry-A European Journal, 2012, 10609–10616.
III. Chiral Hetero- and Carbocyclic Compounds from the Asymmetric Hydrogenation of Cyclic Alkenes. J. Johan Verendel, JiaQi Li, Xu Quan, Byron Peters, Taigang Zhou, Odd R. Gautun,
Thavendran Govender, and Pher G. Andersson. Chemistry-A European Journal, 2012, 6507–6513.
IV. C-C Coupling of Ketones with Methanol Catalyzed by a NHeterocyclic Carbene-Phosphine Iridium Complex. Xu Quan,
Sutthichat Kerdphon, and Pher G. Andersson. Chemistry-A European Journal, 2015, 3576–3579.
V. C-N Coupling of Amides with Alcohols Catalyzed by NHeterocyclic Carbene-Phosphine Iridium Complexes. Sutthichat Kerdphon, Xu Quan, Vijay Singh Parihar, and Pher G. Andersson. Journal of Organic Chemistry (Submitted)
VI. Highly Active Cationic NHC, Phosphine Iridium Catalysts for
Base Free Asymmetric Hydrogenation of Ketones. Xu Quan,
Sutthichat Kerdphon, Janjira Rujirawanich, Suppachai Krajangsri,
and Pher G. Andersson. (Manuscript)
Manuscript not included in this thesis:
VII. The Thiazole, Imidazole and Oxazole Based N, P-Ligands for
the Palladium Catalyzed Cycloisomerization of 1,6-Enynes.
Xu Quan, Jianguo Liu, Wangchuk Rabten, Simone Diomedi, and
Pher G. Andersson. (Manuscript)
ii
Abbreviations
*
Ac
Ar
BArFBINAL-H
Bu
BuLi
t-Bu
Cat.
COD
Conv.
Cp*
Cy
DCM
DIBAL
DMF
DMSO
dppf
dppp
ee
equiv.
Et
i-Pr
LDA
L
m
Me
Mes
NHC
o
S
Tol
p
Stereogenic center
Acetyl
Aryl
Tetrakis[3,5-bis(trifluoromethyl)phenyl]borate
1,1’-Bi-2-naphtolaluminum hydride
Butyl
Butyl lithium
tert-Butyl
Catalyst
1,5-Cyclooctadiene
Conversion
Pentamethylcyclopentadienyl
Cyclohexyl
Dichloromethane
Di-iso-butylaluminum hydride
Dimethylformamide
Dimethyl sulfoxide
1,1’-Bis(diphenylphosphino)ferrocene
1,3-Bis(diphenylphosphino)propane
Enantiomeric excess
Equivalent
Ethyl
iso-Propyl
Lithium di-iso-propylamine
Ligand
Meta
Methyl
Mesityl
N-heterocyclic carbene
Ortho
Solvent
Tolyl
Para
iii
Ph
PHOX
Py
r.t.
THF
Phenyl
Phosphinooxazolines
Pyridine
Room temperature
Tetrahydrofuran
iv
Contents
1. Introduction ............................................................................................. 1 1.1 Catalysis1 .............................................................................................................. 1 1.3 Asymmetric Hydrogenation .................................................................................. 4 1.2 1.4 1.5 Chirality ................................................................................................................. 2 Hydrogen Transfer Alkylation ............................................................................... 7 Aim of this Thesis ................................................................................................. 9 2. Development of Pyridine Based N, P-Iridium Catalysts for the
Asymmetric Hydrogenation of Olefins (Paper I) ........................................... 10 2.1 Synthesis of Novel Pyridine Derived Ligands and their Iridium Complexes ....... 12 2.3 Conclusion .......................................................................................................... 17 2.2 Evaluation of the Iridium Catalysts in Asymmetric Hydrogenation ..................... 14 3. Asymmetric Hydrogenation of α-Substituted Conjugated Esters (Paper
II) .............................................................................................................. 18 3.1 Catalyst Screening ............................................................................................. 20 3.3 Conclusion .......................................................................................................... 25 3.2 Study of the Substrate Scope ............................................................................. 21 4. Synthesis of Chiral Heterocyclic Compounds by Iridium Catalyzed
Hydrogenation (Paper III) ............................................................................. 26 4.1 Asymmetric Hydrogenation of Conjugated Lactones and Ketones .................... 26 4.3 Conclusion .......................................................................................................... 28 4.2 Asymmetric Hydrogenation of 2-Substituted Quinolines .................................... 27 5. Iridium Catalyzed Alkylation of Ketones and Amides with Alcohols, via
Hydrogen Transfer Reactions (Paper IV and V) .......................................... 29 5.1 Methylation of Ketones with Methanol (Paper IV) .............................................. 30 5.1.1 Catalyst screening and optimization .......................................................... 30 5.1.3 Mechanistic study ....................................................................................... 35 5.1.2 5.2 N-Alkylation of Amides with Alcohols (Paper V) ................................................. 37 5.2.1 5.2.2 5.3 Study of substrate scope ............................................................................ 32 Study of reaction conditions ....................................................................... 37 Study of substrate scope ............................................................................ 39 Conclusion .......................................................................................................... 43 6. Chiral Bidentate NHC, Phosphine-Iridium Complexes and their Catalytic
Activities in Hydrogenation Reactions (Paper VI) ........................................ 44 6.1 6.2 A Class of Novel Bidentate Chiral NHC, Phosphine-Iridium Complexes. ........... 45 Evaluation of Chiral NHC-P Iridium Complexes ................................................. 47 6.2.1 6.2.2.
6.3 Hydrogenation of alkenes .......................................................................... 47 Hydrogenation of ketones and imines ....................................................... 48 Conclusion .......................................................................................................... 58 7. Concluding Remarks and Outlook ........................................................ 59 Contribution List ........................................................................................... 60 Acknowledgments ........................................................................................ 62 Summary in Swedish ................................................................................... 64 References ................................................................................................... 65 1. Introduction
1.1 Catalysis1
Catalysis is the process that facilitates a chemical reaction, and was first
introduced by Jöns Jacob Berzelius in 1835.2 A catalyst is an additive that
triggers and participates in the reaction to make the reaction go faster by
decreasing the activation energy, without itself being consumed. It does not
change the equilibrium of reaction system, but accelerates the reaction by
stabilizing the transition state. As it is not included in the product, only substoichiometric amounts of catalyst can be enough to accelerate a reaction,
thus generating less waste. In addition, the catalyst can often be used to control the chemo-, regio-, stereo- and enantioselectivity of a reaction.
Generally, catalysis is classified as being either homogeneous or heterogeneous. In homogeneous catalysis, the catalyst and reactants are in the same
phase; whereas for heterogeneous catalysis, the catalyst is in a different
phase from the reactant. Homogeneous catalysis often provides good reactivity and selectivity; however, it is difficult to separate the catalyst from the
reaction mixture once the reaction is complete. Heterogeneous catalysis eases the recovery of the catalyst.
Altogether, efficient, environmentally friendly and economical catalytic
processes make great contributions and receive extensive attention from both
chemical industry and academic research.
1
1.2 Chirality
The word “chirality” is derived from the Greek, χειρ (kheir) which means
“hand”. Our hands cannot be superimposed onto each other but are mirror
images of each other. Chirality can be traced back to the beginning of the
1900s, when the phrase was first introduced by Lord Kelvin,3 whose original
statement was “I call any geometrical figure, or group of points, ‘chiral’ and
say that it has chirality if its image in a plane mirror, ideally realized, cannot be brought to coincide with itself.” Since then, the concept of “chirality”
has received tremendous interest in a number of fields like chemistry, physics and biology. As shown in Figure 1, a molecule is referred to as “chiral”
when it is not superimposable on its mirror image. If two molecules are mirror images of each other and not superimposable, then these two molecules
are called enantiomers.
(R )-limonene
The two enantiomers
(S )-limonene
Figure 1. Chiral molecules
Chiral molecules exist in Nature and the human body also contains many
chiral compounds. Biologically, proteins in our bodies exhibit different responses to two enantiomers, for example, (R)- and (S)-limonene, smell of
orange and lemon, respectively.
OH
O
OH
N
H
HO
H
N
HO
(R)-Propranolol
(R)-Albueterol
Figure 2. Examples of the chiral medicines
However, interactions between enantiomers and our bodies do not always
result in just delightful experiences, such as different taste and smell. As
drugs, they can also have significantly discrepant effects and cause serious
problems. Currently, a number of optically pure chiral compounds are used,
primarily in the pharmaceutical industry, 4 such as the β2-adrenergic receptor
agonist (R)-Albuterol and (R)-Propranolol for the treatment of hypertension
and panic (Figure 2). Progressive demand and interest from industry and
2
academic research toward chiral molecules has led to the development of
efficient, economically and environmentally friendly methods to generate
optically pure chiral compounds.
There are two general methods to obtain enantiomerically pure or enriched
compounds: resolution and asymmetric synthesis.5
Resolution is the separation of a racemic mixture. An optically pure molecule is introduced to a mixture of enantiomers to form diastereomers. The
newly generated diastereomers can be separated due to their different chemical properties. In classical resolution, preparation of the desired enantiomer
by resolution means the production of an equal amount of the other enantiomer, though in some cases, it could be resolved by dynamic kinetic resolution.
In asymmetric synthesis, as the term suggests, the target chiral molecule is
synthesized by creating new stereogenic centers. Naturally available optically pure compounds can be used as building blocks for the target molecule;
this is referred to as the chiral pool method. Scheme 1 shows an example of
the use of an optically pure chiral pool starting material (S)-phenylalanine6 to
synthesize the chiral dipeptide 1, in which the stereogenic center from the
starting material remains in the final product.
O
H 2N
OH
Bn
94%
O
O
1) BnCl, K 2CO 3 Bn N
2
2) MeCN, NaNH 2
OBn
Bn
Bn 2N
78%
O
3) BnMgCl
CN
Bn
Bn 2N
NH 2
Bn
Bn
(S)-phenylalanine
4) NaBH 4, MsOH
5) NaBH 3(OTFA)
OH
Bn 2N
NH 2
Bn
Bn
mixture of diastereomers
6) Pd/C, HCO 2NH 4
7) H +
60% in 4 steps
OH
H 2N
NH 2
2HCl
Bn
Bn
1
Scheme 1. An example of the chiral pool method
Another technique in asymmetric synthesis is the strategy of asymmetric
induction. Pre-existing chirality can be used to induce a stereoselective bond
formation and generate the desired stereoisomer. The source of chirality can
stem from a reagent, the substrate or the catalyst. For example, chiral alcohol
(R)-3 was obtained using the chiral LiAlH4 derivative BINAL-H7 in a reagent-based asymmetric reduction (Scheme 2a). An alternative is to use a
chiral auxilliary, such as Evans’ oxazolidinones.8 These control the configuration of an enolate and direct the electrophile to react with the enolate enantioselectively. Starting from oxazolidinone 4, compound 5 was obtained in
high diastereometric excess, and could then be hydrolyzed and recrystallized
to yield the enantiomerically pure chiral acid 6 (Scheme 2b). The third chiral
induction method is asymmetric catalysis, in which the asymmetry stems
from the catalyst. Compared to the previously mentioned asymmetric synthesis, it differs from reagent- and substrate-based induction in that it uses
3
only a catalytic amount of chiral material. The Sharpless Epoxidation is a
well-known and successful method (Scheme 2c).9 It converts an allylic alcohol into a chiral epoxide with high enantiomeric excess, and is catalyzed by
chiral titanium metal complexes. The chirality of the product is controlled by
the stereoconfiguration of the catalyst.
a)
Reagent-based induction
O
OH
BINAL-H
2
b)
O
OEt
Al
O
H
(R)-3, 91% yield, 87% ee
BINAL-H
Substrate-based induction
O
HN
O
O
i-Pr
Bn
i-Pr
Cl
N
2) NaHMDS
O
Br
i-Pr
CO2t-Bu
t-BuO2C
Bn
N
Bn
O
O
3) LiOH, H 2O2
i-Pr
recrystallization
t-BuO2C
5, 74% yield, >95% de
4, oxazolidinone
c)
O
O
O
O
1) BuLi
OH
6, 91% yield, >99% ee
Asymmetric catalysis
R
O
OH
D-(-)-tartrate (6-7.5mol%),
Ti(Oi-Pr)4 (5mol%),
t-BuOOH
R
OH
L-(+)-tartrate (6-7.5mol%),
Ti(Oi-Pr)4 (5mol%),
t-BuOOH
R
O
OH
Scheme 2. Examples of asymmetric synthesis
1.3 Asymmetric Hydrogenation
Since enantiomerically pure compounds are very important building blocks,
their preparation by asymmetric synthesis using transition metal catalysts is
a very attractive research area. Transition–metal–catalyzed asymmetric hydrogenation is a straightforward approach to create a stereogenic carbon
center by reducing prochiral C=C, C=N or C=O bonds. The two major processes are direct hydrogenation of the unsaturated substrate by hydrogen gas
and transfer hydrogenation with other hydrogen sources (Figure 3).
Catalyst,
H2
X
a)
R1
R1
X
b)
R1
XH
R2
Catalyst
XH
R2
R1
OH
R2
R2
O
Figure 3. Direct hydrogenation (a) and transfer hydrogenation (b)
4
Rhodium, ruthenium and iridium catalysts have achieved great success in
stereoselective homogeneous hydrogenation.10 The study of homogeneous
iridium catalysis was initiated in the 1960s with IrCl(CO)(PPh3)2 (Vaska’s
complex) by Lauri Vaska.11 Under hydrogen pressure, it formed the dihydride complex IrH2Cl(CO)(PPh3)2 via oxidative addition. Wilkinson’s analog
IrCl(PPh3)3 showed similar reactivity towards hydrogen gas, produced
IrH2Cl(PPh3)3. However, neither of the iridium hydride complexes showed
good catalytic activity for the hydrogenation of olefins, mainly because the
dissociation of triphenylphosphine was extremely difficult.12 Shrock and
Osborn13 observed good catalytic activity of the rhodium complex
[Rh(COD)L2]+ (L = PR3) in hydrogenation of olefin in coordinating solvents.
Further investigation implied that the active rhodium species [RhH2S2L2]+ (L
= PR3) was formed by the solvent–assisted dissociation of a phosphine,
which provided an active site for the alkene. However, the corresponding
iridium complexes did not show catalytic reactivity towards hydrogenation,
possibly due to the high stability of the solvent complex [IrH2S2L2]+. Crabtree14 hypothesized that if [IrH2S2L2]+ was almost inactive due to strong coordination of the metal to the solvent, the properties of the complex may be
changed by loosening or removing this coordination. His study of iridium
complexes in non-coordinating or weakly coordinating solvents demonstrated that chlorinated solvents such as chloroform and dichloromethane enhanced the reactivity dramatically, not only for unhindered alkenes but also
for the sterically more bulky tri- and tetra-substituted olefins. Later modification15 resulted in the iridium complex [Ir(COD)PCy3(Pyridine)], which is a
very efficient catalyst for the hydrogenation of alkenes (Table 1).
Table 1. Reactivity comparisons and development of Crabtree’s catalyst
substrate and hydrogenation rate a
Catalyst precursor
Solvent
[Rh(COD)(PPh 3)]PF6
CH2Cl2
10
-
0
[Ir(COD)(PMePh 2)2]PF6
CH2Cl2
3800
1900
50
Me 2CO
0
0
0
CH2Cl2
4500
3800
4000
[Ir(COD)PCy 3(Pyridine)]PF 6
a In
mol of substrate reduced (mol of catalyst)-1h -1
5
These discoveries opened up the possibility of asymmetric hydrogenation.
Pfaltz introduced the first chiral N, P-ligated cationic iridium catalyst for the
asymmetric hydrogenation of non-functionalized olefins with good enantioselectivity.16 Compared with rhodium and ruthenium17 catalysts, the iridium
complexes did not require that the substrates have coordination groups in
order to achieve high levels of high reactivity and enantioselectivity. Iridium
catalyzed hydrogenation of non-functionalized olefins proved itself an alternative, offering an outstanding advantage, and this method greatly expanded
the scope of the asymmetric hydrogenations available for the preparation of
a range of optically active compounds. Arising from these studies, a number
of iridium complexes were developed as catalysts for the homogeneous
asymmetric hydrogenation of olefins with non- and weakly coordinating
substitutions. 18
PF 6
PF 6
O
Ar
P
N
Ar
Ir
N
Ir PCy 3
R
1998, [Ir(COD)PHOX][PF 6]
developed by Pfaltz
1977, Crabtree's catalyst
Figure 4. Crabtree’s catalyst and PHOX-ligated iridium catalyst
Transition–metal–catalyzed asymmetric hydrogenation and transfer hydrogenation, were also applied in the preparation of enantiomerically enriched
alcohols and amines. Noyori, Ikariya and co-workers19 have developed ruthenium diamine and ruthenium BINAP/diamine catalysts for the asymmetric hydrogenation and transfer hydrogenation of ketones (Figure 5).
ArAr
Cl
P
Ru
P
Cl
ArAr
H2
N
Ph
N
H2
Ph
Ts
N
Ts
N
Ru
N
H2
Cl
Ir
N
H2
Cl
Figure 5. Noyori’s ruthenium and iridium catalysts
High enantioselectivity and reactivity were observed, and these methodologies have been applied in numerous industrial processes.20 In 2001, Noyori
shared the Nobel Prize in Chemistry, with Knowles and Sharpless because of
his great contributions to asymmetric hydrogenation. The design of new
6
ligands and their transition metal complexes, as well as investigations of
their mechanism, have been extensively studied. 17c, 21
Iridium-based asymmetric reduction has more recently attracted attention.
An array of iridium complexes having P,P- , P,N- or N,N- are good catalysts
for asymmetric ketone reductions.22 The first example of an iridium catalyzed asymmetric hydrogenation of a ketone with good enaniomeric excess
(ee) was reported by Takaya and co-workers.23 Over 90% ee was obtained
using a cationic IrI diphosphine complex. The five- and six- membered cyclic ketones were hydrogenated with 84-95% ee. In transfer hydrogenation,
pioneering work has been done using achiral bispyridine and phenanthroline
ligated IrI complexes.24 However, more success has been achieved with
IrIII(Cp∗)/diamine (Cp∗= pentamethylcyclopentadienyl) catalysts (Figure 5,
right).25 Major efforts have been made to employ ruthenium analogue systems in combination with various chiral amine and imine ligands. Formate
salts, i-PrOH and formic acid are commonly used as hydrogen donors. When
using i-PrOH as reductant, the reaction is carried out at low concentration to
suppress the reversible oxidation of the product.
1.4 Hydrogen Transfer Alkylation
As mentioned above, the hydrogen transferring properties of certain iridium
complexes permit these catalysts to take hydrides from i-PrOH and then
transfer them to unsaturated ketone, imine or olefin substrates.
Alcohols are readily available compounds but are considered to be very poor
electrophiles. Normally, an extra chemical transformation is needed to increase their reactivity. For example, the alkylation of an amine with alcohol
would normally require the activation of the alcohol by converting the hydroxyl group to a better leaving group (halide, tosylate etc) or oxidation to
the aldehyde. This implies that the reaction efficiency and atom economy is
compromised because an extra step is involved and stoichiometric byproducts are generated.
Transition–metal–catalyzed hydrogen transfer reactions could be a good
solution to this problem. By using the redox activity of a transition metal, the
alcohol is converted to a more electrophilic substrate, an aldehyde, which
reacts with the nucleophile to form a new bond and subsequently the metalhydride species transfers the hydride to an acceptor in order to finish the
catalytic cycle. As an example in Figure 6, the metal catalyst removes the
hydrogen atoms from an alcohol to form an aldehyde, which condenses with
nucleophile–amine. The metal hydride produced from the oxidation of the
alcohol reduces the in situ generated imine intermediate to give the final
product.
7
R
OH
R
N
H
R'
[M]
H
[M]-H or [M]-H
R
R
O
R'NH 2
N
R'
H 2O
Figure 6. Alkylation of an amine with alcohol via the hydrogen transfer reaction
This method can be employed not only for C–N bond formation but also for
C–C bond formation. In general, because the catalyst “borrows” the hydrogen from the reactant and transfers the hydride to the product, this method is
called “hydrogen borrowing” or “hydrogen transfer” reaction. In 1981, Grigg
and co-workers26 reported the use of the RhH(PPh3)4 in the N-alkylation of
amines with alcohols. They also implied that iridium and ruthenium complexes could be active catalysts. In the same year, RuCl2(PPh3)3 was studied
by Watanabe and co-workers.27 However, a high temperature (180 ºC) was
required and the substrate scope was limited to anilines with simple aliphatic
alcohols. Currently, considerable research has been focused on transition –
metal–catalyzed hydrogen transfer alkylations.28 Williams et al. developed
the alkylation of amines with alcohols in the presence of the [Ru(pcymene)Cl2]2 with bidentate phosphine ligands.29 Fujita and Yamaguchi30
first investigated [IrIII(Cp∗)Cl2]2 in the intramolecular alkylation of amines
using alcohols, and further studies demonstrated that a wide range of substrates including primary and secondary amines could be alkylated with simple alcohols. Carbon nucleophiles have also been used in a similar manner as
amines in the hydrogen–transfer reaction. For example, the combination of
[Ir(COD)Cl]2 with phosphine ligands permitted the catalytic Wittig reaction
and α-alkylation of the ketones with alcohols. 31
R2
R1
+
OH
Ph 3P
R3
[Ir(COD)Cl] 2 (5.0mol%),
dppp (5.0mol%),Cs 2CO 3 (5.0mol%)
Toluene, 150 oC
R2
R1
R3
up to 71% yield
Scheme 3. Example of C–C bond formation via the hydrogen–transfer reaction
8
1.5 Aim of this Thesis
The aim of the work presented in this thesis concerns the development of
new iridium complexes for asymmetric hydrogenation and hydrogen transfer
reactions, as well as the development of new approaches towards synthetically useful chiral compounds via iridium catalyzed asymmetric hydrogenation reaction.
Novel, chiral iridium N,P-complexes have been synthesized and evaluated
for the asymmetric hydrogenation of olefins. The substrate scope has been
expanded to include conjugated esters and cyclic olefins with good to excellent enantiomeric excess. Further research has focused on the development
of N-heterocyclic carbene (NHC), phosphine-iridium catalysts. A series of
NHC-iridium complexes have been prepared and evaluated as catalysts in
the hydrogen transfer reaction. Achiral bidentate NHC-iridium complexes
were found to have high catalytic activity and selectivity in both C–C and C–
N bond formation via the hydrogen transfer process. In addition, chiral
NHC-iridium catalysts showed good reactivity and enantioselectivity for
hydrogenation of ketones under mild and base-free conditions.
9
2. Development of Pyridine Based N, PIridium Catalysts for the Asymmetric
Hydrogenation of Olefins (Paper I)
In 1998, Pfaltz and co-workers first reported the chiral N,P- iridium catalyst
[Ir(COD)PHOX][PF6] for the asymmetric hydrogenation of olefins with
non- or weakly coordinating substituents.16 The activity and stability of the
catalyst could be further improved by using the more bulky and weakly coordinating anion BArF-. The catalyst loading could also be decreased to 1.0
mol% or even lower.32 Initiated by Pfaltz study, a number of iridium catalysts containing nitrogen-phosphine, nitrogen-carbene, nitrogen-phosphite
ligands have been developed and employed in hydrogenation of a wide range
of olefin substrates.18
O
R
P
1
R
N
1
R
R2
N
N
R1
O
N
N
O
R2
N
P
1
N
R2
R1
n
N
N
R1
R1
O
Ph
R2
O
O
O
O
P
O
O
Ph
O
n=0, 1
Ph
P
R1
N O
R
O
O P
O
N
O
O
O
R1
P
R1
N
N
R2
O
PPh 2
R2
N
Ph
Ph
=
O
R2
O
O P
O
R1 R1
O
N
O
R3
R3
O
O
O
O
R3
R3
R4
R2
R4
Figure 7. Examples of the N,P-ligands developed for the Ir-catalyzed asymmetric
hydrogenation of olefins
Intensive mechanistic study has been carried out both computationally 33 and
experimentally,34 and has resulted in good insights on the mechanism of the
10
reaction. Catalytic cycles were first proposed by Andersson and Burgess.33a-e
These computational studies supported Ir(III)/Ir(V) catalytic cycles (Figure
8) that started from A. One molecule of hydrogen and one olefin replace the
two solvent molecules to give B. The alkene inserts into the iridium hydride–
bond, and this is accompanied by simultaneous oxidative addition of the
hydrogen molecule to iridium to generate C. Intermediate C undergoes reductive elimination to form iridium species D, which releases the product to
regenerate A and close the catalytic cycle. Recent NMR experiments from
Pfaltz group provided data to support this mechanism.34d
N
Ir
P
H2
H
H
H2
H
P
Ir
S
H
S
N
2S
2S
A
H
P
Ir
H
H
H
D
H
P
Ir
H
H H
B
N
N
H
P
Ir
H
H
H
C
N
S= solvent
Ir(III)/Ir(V)
Figure 8. Proposed Ir(III)/Ir(V) mechanism, BArF- omitted for clearity.
Based on this mechanism, the enantioselectivity could be rationalized and
predicted by the four-quadrant selectivity model developed by the Andersson
group as shown in Figure 9.33a,d The bulky substituent on the heterocyclic
ring occupies quadrant iii, which is the most hindered quadrant, while the
other two quadrants (i and iv) are relatively open. The substituent on the
phosphorus occupies the partly hindered quadrant ii. When the olefin is superimposed on this selectivity model, the most bulky substituents are positioned towards the open quadrant i and iv, so that the smallest substituent,
hydrogen, is located in the most sterically hindered quadrant iii and the other
group in quadrant ii.
11
i
ii
i
ii
R2
P
N
R2
Ir
H
H
R1
iii
iv
iii
iv
Figure 9. Selectivity model
2.1 Synthesis of Novel Pyridine Derived Ligands and
their Iridium Complexes
A series of N,P-iridium catalysts (Figure 10) has been developed and evaluated in the asymmetric hydrogenation of olefins by the Andersson group
over the last few years.35 Various heterocycles such as thiazole, imidazole
and oxazoline have been employed as N-donors, and have resulted in high
reactivity and enantioselectivity for a number of substrate classes.
PAr 2
O
PAr 2
N
N
N
PAr 2
S
PAr 2
N
N
S
N
R
O
R
N
Ph
S
PAr 2
PAr 2
N
Ph
S
R
O
N
PAr 2
N
Ph
Ph
N
PAr 2
R
R
N
Ph
Figure 10. N,P-ligands previously developed in the Andersson group
Pyridine, being one of the most common heterocycles, has also been studied
in this group as the component of N-donating ligand.36 Previous pyridine
derived hydrogenation catalysts which were prepared from (-)-pinocarvone
provided moderate to good ee but low reactivity. In this part of the thesis, the
preparation of a new class of pyridine derived iridium complexes with bicyclic scaffolds and their evaluation for asymmetric hydrogenation of olefins,
are described. The synthesis of the iridium complexes began with the corresponding pyridine derivatives 7a and 7b (Scheme 4). These were lithiated
with LDA and BuLi, and then dimethyl carbonate was added to form com12
pounds 8a and 8b. The optically pure pyridine alcohols 9a and 9b were obtained by resolution of the racemic esters 8a and 8b, followed by reduction
using DIBAL-H. The phenyl group was introduced by a Suzuki coupling,
giving good isolated yields.
O
N
OH
OMe
Cl a) LDA, BuLi then
(MeO) 2CO, Et 2O
N
Cl
n
7a, n=1
7b, n=2
n
8a, n=1, 86%
8b, n=2, 90%
OH
d) PhB(OH) 2, dppf,
PdCl 2, K 2CO 3,
Toluene, H 2O
N
b) Resolution
c) DIBAL-H, Et 2O
Cl
n
9a, n=1, 87%
9b, n=2, 90%
OTs
N
Ph
N
e) TsCl, Et 3N,DCM
n
Ph
n
10a, n=1, 78%
10b, n=2, 80%
11a, n=1
11b, n=2
Scheme 4. Initial synthetic route
Initially, the tosyl group was chosen as the leaving group, but the tosylates
were only produced in low yields. As an alternative, the chiral alcohols 10a
and 10b were converted to iodinated compounds 12a and 12b in 87% and
90% isolated yield, and were then substituted with in situ prepared
Ar2P(BH3)Li to obtain the borane-protected N,P-ligands 13a–13d. The borane group was removed by treatment with diethylamine.
OH
P(BH 3)Ar2
I
N
Ph a) I 2, PPh 3,imidazole,
DCM
n
N
b) Ar2P(BH 3)H, BuLi
Ph
THF
c)Et2NH
d) [Ir(COD)Cl] 2, DCM
e) NaBArF, H 2O
13a, n=1, Ar= Ph, 91%
13b, n=1, Ar=o -Tol, 60%
13c, n=2, Ar= Ph, 99%
13d, n=2, Ar=o -Tol, 54%
12a, n=1, 87%
12b, n=2, 90%
Ar
Ar P
Ph
n
n
10a, n=1, 78%
10b, n=2, 80%
N
BArF
Ir
N
Ph
n
14a, n=1, Ar=Ph, 76%
14b, n=1, Ar=o -Tol, 80%
14c, n=2, Ar=Ph, 89%
14d, n=2, Ar=o -Tol, 87%
Scheme 5. The synthetic route to 14a–14d
13
The deprotected N,P-ligands were then treated with [Ir(COD)Cl]2 and anion
exchange was achieved by adding NaBArF to give iridium N,P complexes
14a-14d.
2.2 Evaluation of the Iridium Catalysts in Asymmetric
Hydrogenation
The newly synthesized iridium complexes 14a-14b were evaluated for
asymmetric hydrogenation of various olefins. Table 2 contains the results
with non-functional substrates. The trans-methylstilbene 15 (Table 2, entry
1) was hydrogenated in full conversion and 99% ee by complex 14b, and
84% conversion and 97% ee by complex 14a. However, the six-membered
bicyclic catalysts 14c and 14d resulted in lower reactivity and enantioselectivity. The conversions were less than 30% (>12 h) and the ee decreased to
76% and 87%, respectively. For alkene 16, the conversion was good, but the
ee decreased slightly. A possible explanation is that, in comparison to substrate 15, the replacement of the phenyl group with methyl decreased the
selectivity of the compound, which led to a slight drop in ee. Over 90% enantioselectivity was observed for all catalysts except 14c, which gave 35%
ee. The more unreactive cyclic olefin 17 was also hydrogenated with good
results, giving full conversions with 91% and 76% ee using the fivemembered bicyclic catalysts 14a and 14b. The hydrogenation products were
observed with 87% and 97% conversion for 14c and 14d with 77% and 48%
ee.
Table 2. Asymmetric hydrogenation of unfunctionalized olefins with 14a–14d
Ar
Ar P
Ir catalyst 14a-14b (1mol%),
H 2(50 bar),DCM,12hours
R1
R3
14a
Entry
Substrate
N
R1
R3
R2
BArF
Ir
R2
Ph
14a, n=1, Ar=Ph
14b, n=1, Ar=o -Tol
14c, n=2, Ar=Ph
14d, n=2, Ar=o -Tol
n
14b
14c
14d
conv.
ee
conv.
ee
conv.
ee
conv.
ee
84%
97% (S)
99%
99% (S)
17%
76% (S)
26%
87% (S)
99%
93% (S)
99%
90% (S)
91%
35% (S)
99%
90% (S)
99%
91% (R)
99%
76%(R)
87%
77% (R)
97%
48% (R)
Ph
1
Ph
2
Ph
15
16
3
17
14
Next, olefins containing functional groups were evaluated using catalysts
14a–14d (Table 3). In general, the catalysts 14a and 14b performed better
for this type of substrate than 14c and 14d. The β-methyl cinnamate 18 was
hydrogenated by 14a and 14b with good conversion (94% and 99%) and
moderate ee (80% and 78%), whereas poor activity and enantioselectivity
were given by 14c and 14d. The results for the corresponding allylic alcohol
19 and acetate 20 were better, with full conversion and up to 99% ee (Table
3, entries 2 and 3).
Table 3. Asymmetric hydrogenation of functionalized olefins with 14a–14d
Ar
Ar P
Ir catalyst 14a-14b (1mol%),
H 2(50 bar),DCM,12hours
R1
R3
R2
14a
Entry
Substrate
CO2Et
1
Ph
OH
Ph
14a, n=1, Ar=Ph
14b, n=1, Ar=o -Tol
14c, n=2, Ar=Ph
14d, n=2, Ar=o -Tol
n
14b
14c
14d
conv.
ee
conv.
ee
conv.
ee
conv.
ee
94%
80% (S)
99%
78% (S)
17%
50% (S)
35%
65% (S)
99%
94% (S)
99%
84% (S)
99%
99% (S)
99%
87% (S)
99%
94% (S)
99%
79% (S)
99%
90% (S)
99%
92% (S)
46%
78% (R)
99%
77% (R)
< 5%
33%
99% (S)
99%
75% (S)
42%
31% (S)
62%
66% (S)
48%
77% (S)
99%
76% (S)
50%
14% (S)
67%
46% (S)
19
OAc
3
Ph
18
2
Ph
N
R1
R3
R2
BArF
Ir
20
CO2Et
4
Ph
21
< 5%
OH
5
Ph
22
OAc
6
Ph
23
Most of the catalysts showed good enantioselectivity, of up to 99% ee, with
full conversions. However, when the methyl group on the substrate was in
the α-position (Table 3, entries 4, 5 and 6), hydrogenation became more difficult. A remarkable difference in catalyst activity was demonstrated by 14a
and 14b. These differed only in the phosphine substituent, which was phenyl
group in 14a and an o-Tol group on the phosphine in 14b; however, the latter hydrogenated 21-23 to full conversion, where <50% of conversion was
observed for 14a. The conjugated ester 21 was hydrogenated by 14a and 14b
in 78% and 77% ee; low conversion was obtained for 14c and 14d. Excellent
15
ee was obtained for alcohol 22 using 14a, but with only 33% of the product
being formed. The best result for acetate 23 was obtained using catalyst 14b,
with full conversion and 76% ee. More electron-deficient olefins (Figure 11)
were screened, but catalysts 14a-d were not successful with these olefins,
even under harsh reaction conditions.
O
R
MeO
O
O
O
O
R
25, R= CO2Et
26, R= Ph
24
27, R= Ph
Figure 11. Unreactive electron-deficient olefins
The selectivity model that had been previously developed in the group could
be used to explain the absolute configuration of the products with 14a-d.
Catalyst 14a and trans-methylstilbene 15 are used as an example in this
model (Figure 12). The phenyl ring on the pyridine occupies quadrant iii,
which becomes the most hindered site, while other two quadrants ii and iv
are least hindered and the phenyl ring on the phosphorus is partly located in
quadrant I (Figure 12a). The trans-methylstilbene is positioned so that the
two most sterically demanding phenyl groups are positioned towards the
least hindered sites (ii and iv). Thus the smallest substituent on the olefin,
hydrogen, is directed to the most hindered quadrant iii and the methyl group
is in quadrant i. When using this model, formation of the (S)-configured
product is predicted and agrees with the experimental result.
Me
i
Me
ii
H
a)
iii
iv
major product
Sterically favorable
i
P
Ir
ii
N
iv
iii
b)
H
i
ii
Me
Me
iv
iii
minor product
Sterically unfavorable
Figure 12. Selectivity model used to explain the absolute configuration of the hydrogenation product
16
2.3 Conclusion
New chiral N,P-ligated iridium complexes were prepared from pyridine derivatives via a mild and efficient synthetic route. These iridium complexes
were evaluated as catalysts for the asymmetric hydrogenation of various
olefins. Good conversions and enantioslectivities were obtained and generally 14a and 14b, which contained five-membered bicyclic moieties, performed better than complexes 14c and 14d, which contained six-membered
carbocycles. The hydrogenation results were comparable with those obtained
from previously developed systems and the configuration of the products
could be rationalized using the selectivity model developed for these systems.
17
3. Asymmetric
Hydrogenation
of
Substituted Conjugated Esters (Paper II)
α-
Optically pure esters with a stereogenic center in the α-position are key
structures of many natural products and pharmaceutical compounds.37
Through simple chemical transformations, the ester groups can be converted
to various functional groups such as alcohol, acid and amide. The catalytic
asymmetric hydrogenation of conjugated esters generates optically pure
esters in a highly straightforward and efficient manner. Previous studies on
this reaction are summarized in Scheme 6.
CO2R
a)
H 2 (50bar),
[IrCODL*][BArF ](1.0mol%)
L=
Ph
Ph
P(t-Bu)2
O
N
CO2R
R=Me/ Et/ i -Pr
ee up to 99%
CO2R
b)
H 2 (20atm),
[IrCODL*][BArF ](1.0mol%)
R2
N
CO2R
L=
N
R=Et/ Benzyl
ee up to 73%
O
c)
Ar
O
H 2 (20atm),
[IrCODL*][BArF ](1.0mol%)
i-Pr
N
i-Pr
O
R1
O
Ar
R1
R
O
n
n
n=0,1
ee 71%-95%
N
L=
PAr 2
O
Scheme 6. Iridium catalyzed hydrogenation of α-substituted unsaturated esters
Pfaltz (Scheme 6a)38 reported the hydrogenation of α-methyl substituted
cinnamate derivatives. Burgess (Scheme 6b)39 has two examples in his study
with moderate ee. Neither of the catalysts reported covers a wide range of
conjugated esters having various substituents. In Zhang’s investigation,40 the
substrate scope was limited to exocyclic compounds (Scheme 6c). Additionally, Zhou41 has developed a series of chiral spiro iridium/phosphineoxazoline complexes and successfully hydrogenated α, β-conjugated acids in
18
high enantioselectivities, but he found that esters were completely unreactive
with his catalysts.
The α-substituted conjugated esters are difficult to hydrogenate with iridium
catalysts. Since the C=C bond is polarized by conjugation with the carbonyl,
there are electronic effects that have to be taken into consideration together
with steric effects. The configuration of the product was the opposite to what
was predicted by the selectivity model, probably due to the electronic effect
that prevented the hydride insertion at the electron-rich terminus of the C=C
bond. The selectivity model, shown in Figure 13 in combination with methyl
cinnamate 21 illustrates this phenomenon. If only the steric feature is considered, then substrate 21 could be aligned in the selectivity model as shown
in Figure 13. However, this would lead to a hydride insertion taking place on
the electron rich carbon, which would form the sterically predicted but electronically disfavored product. However, the experimental result always produced predominantly the opposite enantiomer, which implied that the stereoselectivity of the product was governed via an electronically matched but
sterically mismatched process. The poor enantioselectivity and reactivity
problem from the mismatch of the electronic/steric effects inspired us to
investigate and modify our iridium catalyst library to also include αsubstituted conjugated esters.
electronically unfavored hydride addition
ii
i
N
ii
i
P
Ir
HP
iv
iii
EtO 2C
N
Sterically favored
arrangement
Ir
EtO 2C
Ph
Ph
EtO 2C
iv
Ph
iii
21
Ph
Ph
P Ir
N
(S)-product
Sterically favored,
electronically unfavored
product
BArF
Ph
CO2Et
CO2Et
Ph
Experimental result
Ph
(R)-product
conv. 46%
ee 78%
Figure 13. The predicted product and experimental results for the hydrogenation of
cinnamic ester 21
19
3.1 Catalyst Screening
The α-methylcinnamic ester 21 was used as the benchmark substrate for the
catalyst screening. The first result was obtained using imidazole ligand L-1,
which provided good catalytic activity with 86% ee. The o-Tol derivative L2 resulted in a decrease of both the activity and selectivity. Thiazole L-3
provided 50% conversion with moderate 77% ee, and o-Tol L-4 further increased the ee to 80% with full conversion. Introduction of the more sterically bulky group 3,5-dimethylphenyl on the thiazole ring (Table 4, L-5 and L6) failed to improve the results further. The open-chain skeleton (Table 4, L7) for the thiazole did not provide better the enantioselectivity, nor did ligand
L-8 which had a nitrogen linked to the phosphorus. The iridium catalyst with
bicyclic thiazole L-9 was unreactive to cinnamic ester 21. The pyridine
based N,P- ligands L-10 to L-13 could not hydrogenate the ester to 80% ee.
The cinnamic ester 21 was completely hydrogenated using ligands with bicyclic oxazoline moieties (Table 4, L-14 to L-16) and an ee of up to 90%
was achieved with L-16. Further modification of L-16 by replacing the phenyl group with o-Tol (Table 4, L-17) enhanced the result to 95% ee and a
complete reaction in 15 h. Using ligand L-17, it was also possible to decrease the catalytic loading to 0.5 mol% without losing either yield or selectivity.
Table 4. Catalyst screening
CO2Et
CO2Et 1.0 mol% [Ir(COD)L*][BArF]
Ph
21
PPh 2
Ph
N
PPh 2
P(o-Tol)2
N
N
N
L-2
PPh 2
N
N
PPh 2
N
Ph
S
Ph
S
L-7
Conv. 60%
ee 67%
P(o-Tol)2
N
L-8
Conv. 36%
ee 39%
N
P(o-Tol)2
O
L-13
Conv. less than 5%
20
L-14
Conv. 99%
ee 53%
Ph
N
PPh 2
Ph
N
Ph
tBu
L-9
Conv. less than 10%
P(o-Tol)2
N
Ph
P(o-Tol)2
N
S
N
Ar
S
L-6, Ar= 3,5-Me-Ph
Conv. 35%
ee 77%
L-5, Ar= 3,5-Me-Ph
Conv. less than 10%
PPh 2
N
N
Ar
S
L-4
Conv. 99%
ee 80%
PPh 2
P(o-Tol)2
N
S
L-3
Conv. 50%
ee 77%
N
PPh 2
Ph
S
Conv. 43%
ee 34%
21a
N
Ph
Ph
Ph
P(o-Tol)2
N
L-1
Conv. 99%
ee 86%
0.25 M substrate in CH2Cl2
50 bar H 2, r.t., 15 h
L-10
Conv. 46%
ee 78%
N
PPh 2
N
N
O
L-11
Conv. 99%
ee 77%
O
L-15
L-16
Conv. 99%
ee 59%
Conv. 99%
ee 90%
N
Ph
Ph
L-12
Conv. less than 5%
P(o-Tol)2
N
O
L-17
Conv. 99%
ee 95%
Ph
Ph
3.2 Study of the Substrate Scope
Next, α-methyl unstaturated esters with various ester substituents (Table 5)
were investigated using L-17 as the ligand in iridium catalyzed hydrogenation. The preparation of the substrates are not discussed in this section, but
are reported in Paper II, as well as the characterization data of all compounds. All the substrates were completely hydrogenated in 15 hours, in the
presence of 0.5 mol% catalyst.
Table 5. Hydrogenation of the conjugated esters 21, 28-38a
O
R1
O
0.5 mol% [Ir(COD)L-17][BArF]
OR3
Me
0.25 M substrate in CH2Cl2
H 2, r.t., 15 h
21, 28-38
R1
N
OR3
Me
CO2R
Ph
CO2R
2
Ph
Ph
L-17
Conv.
ee
21, R=Et
28, R=Bn
29, R=i-Pr
30, R=t-Bu
31, R=H
99%
99%
99%
99%
99%
95%
97%
93%
99%
99%
32, R=Et
33, R=i-Pr
34, R=Bn
99%
99%
99%
97%
93%
99%
Substrate
1
N
O
21a, 28a-38a
Entry
P(o-Tol)2
O
3
R
O
Ph
35, R=Ph
36, R=Me
99%
99%
99%
93%
O
Ph
37, R=Ph
38, R=Me
99%
99%
99%
91%
O
4
R
a) 50 bar of H 2 was used for the substrates 21, 28-31, 35 and 37; 20 bar of H 2 was used for
the substrates 32-34, 36 and 38.
Benzyl ester 28 gave a slightly increased enantioselectivity of 97% ee while
the more bulky ester i-propyl group 29 decreased ee to 93%. The highest ee
was obtained from the t-butyl derivative 30 with 99% ee, but the reaction
mixture included 7% of the hydrolysis product (a chiral acid). Although it
was not clear if the hydrolysis occurred before the hydrogenation of substrate 30 or after, it implied the catalyst could survive acidic conditions. Hydrogenations of conjugated acid 31 were successful with full conversion and
99% ee. The dimethyl acrylic esters (Table 5, entry 2) were also hydrogenated with full conversion and excellent ee. It displayed the same trend: benzyl
21
ester 34 gave higher ee than ethyl ester 32, while i-propyl ester 33 lowered
the enantioselectivity slightly. The addition of one stereogenic center on the
ester did not have a significant effect on the selectivity of the reaction. Hydrogenation over ran any chiral induction from the existing stereogenic centre of the substrates. For the α-methylcinnamic esters 35 and 37 with both
racemic and (S)-configuration, excellent stereoselectivity on the α-carbon
was observed. The enantioselectivity was only slightly affected by the chiral
center in 36 and 38. For the pure enantiomeric substrate 38, 91% ee was
observed, which dropped by 2% when using the racemic substrate 36.
The substrate scope was expanded to include a variety of unsaturated esters
(Table 6). Three different cinnamate derivatives (Table 6, entries 1-3) were
synthesized and their hydrogenations took place in full conversions with
high ees. For the ethyl and propyl derivatives 39 and 40, the ee increased to
96%, and hydrogenation with i-butyl substituted 41 gave 90% ee. Iridium
catalyst L-17 also hydrogenated aliphatic conjugated esters with good results. From the results (Table 6, entries 4-7), it clearly shows the remarkable
effect of the alkyl substituent on the β-position is having on the enantioselectivity. Compound 42 with an ethyl substituent (Table 6, entry 4) had high
enantioselectivity of 96% ee, which decreased to 93% ee when the substituent changed to propyl (Table 6, entry 5). It decreased further to 84% ee for
substrate 44, accompanied also with a lower conversion (50%). For the ipropyl group (Table 6, entry 7), 62% ee was observed. The exocyclic esters
46 and 47 gave excellent results. Hydrogenations were complete in 15 hours
with 99% and 96% ee, respectively.
Table 6. The study of the substrate scopea
O
R1
0.5 mol% [Ir(COD)L-17][BArF ]
OR3
R2
0.25 M substrate in CH2Cl2
H 2, r.t., 15 h
Entry
Substrate
N
O
R1
P(o-Tol)2
N
OR3
R2
O
L-17
Conv.
ee
99%
96%
99%
96%
99%
90%
O
1
Ph
OEt
39
Et
O
2
Ph
OEt
nPr
40
O
3
Ph
OEt
i-Bu
22
41
Ph
Ph
Table 6. The study of the substrate scope (continued)a
O
R1
0.5 mol% [Ir(COD)L-17][BArF]
OR3
R2
0.25 M substrate in CH2Cl2
H 2, r.t., 15 h
Entry
Substrate
N
O
R1
P(o-Tol)2
N
OR3
R2
O
Ph
Ph
L-17
Conv.
ee
99%
96%
99%
93%
50%
84%
99%
62%
99%
99%
99%
96%
O
4
Et
OEt
Me
42
O
5
nPr
OEt
Me
43
O
6
4
OEt
Me
44
O
7
OEt
Me
45
O
8
O
46
O
9
Ph
O
47
a) 50 bar of H 2 was used for the substrates 39-41 and 47, 20 bar of H 2 was used for
the substrates 42-46.
When (Z)-45 was tested (Scheme 7a), (S)-45a was formed as the major enantiomer and the hydrogenation reaction mixture contained 6% of the (E)-45.
Interestingly, the result was the same when (E)-45 is used, which again implies that the α-substituted esters reacts via a different mechanism than most
other olefins. It implied that when (Z)-45 was hydrogenated by the iridium
catalyst, the hydride insertion was hindered due to steric and electronic mismatch, of (Z)-45, hence the alkene isomerization product from the competitive β-hydride elimination was detected.
23
0.5 mol% [Ir(COD)L-17][BArF ]
CO2Et
a)
CO2Et
0.25 M substrate in CH2Cl2
H 2, r.t., 15 h
(Z)-45
45a
Yield 57%
ee 35%
0.5 mol% [Ir(COD)L-17][BArF ]
CO2Et
b)
CO2Et
+
(E)-45
Yield 6%
CO2Et
0.25 M substrate in CH2Cl2
H 2, r.t., 15 h
(E)-45
45a
Yield 99%
ee 62%
Scheme 7. Hydrogenation of (Z)-45
Substrate 45 was investigated by other iridium catalysts containing a similar
bicyclic skeleton (Table 7). An increase of the ee was obtained when introducing more steric bulkiness on the oxazoline (Table 7, entries 1-3). Full
conversion and 29% ee were achieved from L-14, 38% ee was attained with
the more bulky ligand L-15 with t-butyl group on the oxazoline. The enantioselectivity was further enhanced to 62% ee with L-17.
Table 7. Hydrogenation of substrate 45
O
0.5 mol% [Ir(COD)L*][BArF ]
OEt
(R) or (S)-45a
P(o-Tol)2
1
Conv.
ee
OEt
99%
29%
OEt
99%
38%
OEt
99%
62%
25%
57%
Config. of the major product
L
N
OEt
0.25 M substrate in CH2Cl2
H 2 (20bar), r.t., 15 h
45
Entry
O
O
N
O
L-14
2
N
P(o-Tol)2
N
O
3
N
L-15
N
N
O
P(o-Tol)2
O
Ph
Ph
L-17
PPh 2
4
N
tBu
S
L-9
24
O
O
OEt
Surprisingly, when the catalyst with L-9 was tested, the major product was
shown as the opposite configuration, although the same enantiomer would be
expected. The configuration of the major products during the study of the
substrate scope (Table 5 and 6) all followed the electronically matched but
sterically mismatched pathway, that is, the esters gave the opposite enantiomers against the enantiomers to that predicted from the selectivity model.
Ligand L-9 was the only exception where the configuration of the product
from experimental data agreed with the predicted outcome for “normal”
substrates.
3.3 Conclusion
Iridium catalysts were evaluated in the asymmetric hydrogenation of (E)-αsubstituted conjugated esters. The iridium catalyst with ligand L-17 showed
excellent reactivity and selectivity with high conversions and up to 99% ee.
The substrate scope was studied and included a variety of unsaturated esters
having different ester groups including chiral groups, with excellent results.
Sterically bulky ester groups had little effect on the enantioselectivity as well
as the addition of another chiral center on the ester alcohol group. Alkyl and
aryl substituted substrates were hydrogenated with high selectivities. The
configuration of the products obtained was compared using the selectivity
model. This implied the α-substituted conjugated esters were hydrogenated
through the electronically matched but sterically mismatched process, which
results in the opposite enantiomers to the predicted model. The only exception was ligand L-9 which corresponded with the selectivity model and experimental data. When the (Z)-45 was tested under the same reaction conditions, hydrogenation was slow and accompanied with the observation of the
corresponding isomer (E)-45, and a decrease in ee to 35%.
25
4. Synthesis
of
Chiral
Heterocyclic
Compounds
by
Iridium
Catalyzed
Hydrogenation (Paper III)
Since chiral heterocyclic compounds are abundant both in natural products
and pharmaceuticals, their preparation is of major interest in both academic
research and industry. With the rapid development of transition metal catalyzed hydrogenation, intense research has been focused on the application of
this methodology to synthesize chiral heterocyclic compounds. 42
4.1 Asymmetric
Hydrogenation
Lactones and Ketones
of
Conjugated
Asymmetric hydrogenation of cyclic alkenes containing double bonds conjugated with carbonyl groups presented more complications than normal
alkenes. In most cases, low reactivity and moderate to good enantioselectivity was achieved. The synthesis and characterization of the substrates investigated as well as the hydrogenation products are available in the Supporting
Material of Paper(III). The discussion in this chapter is focused on the hydrogenation results.
Lactones were evaluated with various iridium catalysts and some representative results are summarized (Table 1, entries 1 and 2). In general, the hydrogenation of conjugated lactones resulted in moderate to good ee but the reactions were very slow. Five-membered-ring lactones 48 and 49 were hydrogenated with 24% and 20% conversions, albeit with good ee (85% and
92%). The six-membered lactone 50 was hydrogenated by iridium catalyst
with L-2 and gave 79% ee, however only 15% of phenyl substituted lactone
51 was hydrogenated with 93% ee. Dramatic loss of reactivity was also observed with five-membered ketones. Methyl substituted 52 was hydrogenated in only 18% in 24 hours. The best ee was attained by L-3, however only
5% conversion was achieved. Conjugated ketone 53 with a phenyl substituent was extremely difficult to reduce with iridium catalysts, even under
harsh conditions. Results improved tremendously when using six-membered
cyclic ketones. Full conversions with above 90% ee were obtained with methyl, butyl and phenyl substituted cyclic ketones (Table 8, entry 4).
26
Table 8. Asymmetric hydrogenation of the lactones and cyclic ketones
O
R
O
[Ir(COD)L]+[BArF ]- (1mol%)
X H 2 (50 bar), 24hours
PPh 2
N
N
Substrate
O
1
O
L-7
L
R
N
P(oTol) 2
N
S
L-3
Entry
P(oTol) 2
Ph
S
L-2
N
N
Ph
Ph
n
48a-55a
PPh 2
P(oTol) 2
N
R
n
48-55
R=Me, Ph
n=1, 2
X=CH2, O
X
N
Ph
S
L-14
L-18
ee (config.)
Conv.
Me 48
L-18
24
85% (S)
Ph 49
L-18
20
92% (R)
Me 50
L-2
99
79% (S)
Ph 51
L-2
15
93% (S)
Me 52
L-7
18
89% (R)
L-3
5
93% (S)
10
62% (S)
O
R
O
2
O
R
O
3
L-2
R
Ph 53
O
4
R
4.2 Asymmetric
Quinolines
L-2 to L-18
<5
Me 54
L-2
99
94% (S)
Bu 55
L-2
99
92% (S)
L-2
99
92% (S)
Ph 56
Hydrogenation
of
2-Substituted
Two quinoline derivatives 57 and 58 were also evaluated against different
iridium catalysts. First, most of the iridium complexes provided good activities for the 2-phenyl substituted quinoline 57 with over 90% conversions.
For catalysts with ligands L-15 and L-18, less than 50% of the starting material was hydrogenated. The best enantioselectivity was from ligand L-17
with 45% ee and 91% conversions. Methyl quinoline 58 was more difficult
and it seldom reached 50% conversion. Ligand L-3 led to the highest reactivity with 58 and provided 74% conversion, but only 15% ee was obtained.
27
Table 9. Asymmetric hydrogenation of 2-substituted quinolines
[Ir(COD)L][BArF ] (1.0 mol%)
H 2 (50 bar), 15 hours.
N
N
R
H
57a, R= Ph
58a, R= Me
R
57, R= Ph
58, R= Me
Entry
L
Conv.
ee
Entry
99%
37%
6
PPh 2
1
Ph
S
N
L-3
R=Me
74%
93%
15%
12%
S
87%
20%
18%
L-19
8%
R=Ph
34%
22%
91%
45%
N P(oTol) 2
Ph
S L-7
R=Ph
99%
28%
R=Me
35%
15%
R=Ph
99%
16%
8
Ph
L-15
9
N P(oTol) 2
N
O
L-11
Ph
Ph
R=Ph
R=Me
Less than 5%
L-17
PPh 2
R=Ph
N
N
O
P(oTol) 2
N
R=Ph
R=Me
Ph
O
L-8
N
5
16%
L-4
N
7
PPh 2
N
99%
PPh 2
Ph
S
R=Ph
N
O
R=Ph
N
4
ee
Ph
PPh 2
3
Conv.
P(oTol) 2
R=Ph
N
2
L
99%
5%
10
N P(oTol) 2
L-1
R=Ph
N
Ph
S
38%
racemic
Ph
L-18
4.3 Conclusion
Prochiral lactones, cyclic ketones and quinolines have been evaluated in the
asymmetric hydrogenation with iridium catalysts. The iridium catalysts successfully hydrogenated conjugated lactones and ketones with high enantioselectivities however the reaction rate was generally slow. On the other hand,
iridium catalysts showed high reactivity to 2-substituted quinolines but with
poor enantioselectivity.
28
5. Iridium Catalyzed Alkylation of Ketones
and Amides with Alcohols, via Hydrogen
Transfer Reactions (Paper IV and V)
Hydrogen transfer or hydrogen borrowing is an efficient and convenient
process for functional group interconversion without introducing an extra
step. The catalyst oxidizes the starting material by removing hydrogen to
generate a more reactive intermediate, which can subsequently lead to bond
formation via reaction with a nucleophile. Transition metals such ruthenium,
rhodium and iridium have received much attention for hydrogen transfer
reactions.28 Initiated by pioneering studies from Grigg26 and Watanabe27, a
number of the transition metal catalysts have been developed for this type of
transformation. Recent results28,43 have demonstrated hydrogen transfer reactions to be an efficient and direct route to the formation of C-N bond from
unreactive starting materials in an environmentally friendly and atom economical manner. More recently, this process has also been applied to C-C
bond formation (Scheme 8),28c,e which allows alkylation of ketones, esters,
and amides etc. via the direct use of alcohols as electrophiles.
O
+
Ar
HO
R
O
[Ru(DMSO) 4]Cl2 (2.0mol%)
Ar
KOH (1.0 equiv.),80oC
R
up to 93% yield
O
+
t-BuO
HO
R
[Ir(COD)Cl] 2 (5.0mol%),
PPh 3 (15.0mol%)
O
t-BuO
t-BuOK, 150 oC
R
up to 89% yield
HN P(t-Bu)2
N Ir
O
R1
N
R2
Cl
COE
O
+
HO
R3
HN P(t-Bu)2
2.0 mol%
R1
t-BuOK, 120 oC
N
R2
R3
up to 88% yield
Scheme 8. Example of the C-C bond formation with alcohol44
29
5.1 Methylation of Ketones with Methanol (Paper IV)
The first study of alkylation via the hydrogen transfer process primarily used
benzylic alcohol or predominantly long-chain primary alcohols as electrophiles.45 Methanol, being the simplest alcohol, has rarely been reported in
the application of C-C bond formation and only few reports on its use can be
found in literature. Jun46 reported rhodium catalyzed dialkyl ketone formation with methanol, and Krische47 described C-C bond formation using
methanol with allenes. Recently, Donohoe48 and Obora49 independently reported the alkylation of ketones with methanol using [RhIII(Cp∗)Cl2]2 and
[IrIII(Cp∗)Cl2]2 as the pre-catalysts. However, 5 mol% of dimer of the catalyst was required to achieve the good results. Previous reports from the Andersson group demonstrated that the N-heterocyclic carbene (NHC) iridium
complex could alkylate amines with an alcohol at room temperature with the
catalyst loading as low as 1.0 mol%. It was decided to investigate if the
NHC-iridium complex could also be used for C-C bond formation via the
hydrogen transfer reactions.
5.1.1 Catalyst screening and optimization
Butyrophenone 59 was used as the benchmark substrate for the alkylation of
ketone using methanol. The reaction was carried out in the presence of 1.0
mol% of iridium catalyst 60 with a variety of bases (Table 10).
The reactivity and selectivity of the reaction depended significantly on the
base. The reaction was completely inhibited in the presence of the organic
bases, such as tertrabutylammonium chloride or pyridine (Table 10, entries 1
and 2). The reduced byproduct 59b was the sole product when using sodium
carbonate (Table 10, entry 3). Under these reaction conditions, the iridium
catalyst removed hydrogen from methanol, and then directly transferred the
hydride to the carbonyl group of the starting material 59 to form 59b instead
of 59a. Potassium carbonate (Table 10, entry 4) gave only 7% of the desired
product in combination with 37% of 59b. More than 50% of the starting
material remained. When using stronger bases (Table 10, entries 5 and 6),
sodium tert-butoxide and potassium tert-butoxide, only reduction product
59b was observed with 65% and 57% conversion. The yield of 59a increased
slightly to 11% with cesium carbonate, however 18% of 59b was obtained.
When cesium carbonate was replaced with cesium hydroxide monohydrate,
the result was an increase in reduced product 59b, while an increase in the
amount of cesium carbonate from 2 equiv. to 5 equiv. gave 63% of the desired product 59a with trace amounts of 59b.
30
Table 10. Iridium catalyzed methylation of 59 with various bases
Ir-Cat. 60 (1.0mol%),
base, MeOH, 65oC
24hours
O
O
+
Ph
Ph
59
N
OH
Ir
P
Ph
Ph
59b
60
Base
Equiv. of base
59ab
59bb
1
Bu 4NCl
2
n.d.
n.d.
2
Pyridine
2
n.d.
n.d.
61%
Entry
BArF
N
Ph
59a
Ph
3
Na 2CO 3
2
n.d.
4
K 2CO 3
2
7%
37%
5
t-BuONa
2
n.d.
65%
6
t-BuOK
2
n.d.
57%
7
Cs2CO 3
2
11%
18%
8
CsOH H 2O
2
8%
54%
9
Cs2CO 3
5
63%
Less than 1%
a) The ketone 59 (0.1mmol),base and Ir-Cat. (1.0mol%) in MeOH (2.0ml),at 65oC for 24hours;
b) NMR yield.
Iridium carbene catalysts 61 and 62 were evaluated as well (Scheme 9). The
substituent on the phosphorus was changed into a cyclohexyl group (Scheme
9, 61), which gave 53% of the product, while the benzyl group on the imidazole ring 62, gave only 33% conversion. The result improved to an excellent 99% conversion and 97% isolated yield when the reaction was carried
out at higher concentration.
Ir-Cat. (1.0mol%),
Cs2CO 3, MeOH, 65oC
O
Ph
59
N
Ph
O
Ph
Ph
59a
BArF
N
Ph
59b
BArF
N
Ir
P
Ph
Ph
63%a
60
Conv.
Conv. 99%(97%)b
Bn
BArF
N
N
N
OH
+
Ir
P
Cy
Cy
Conv.
Ir
P
Ph
Ph
61
53%a
62
Conv.
33%a
Reacton condition: a) ketone 59 (0.1mmol), Cs2CO 3 (0.5 mmol), Ir-Cat. (1.0mol%) in MeOH (2.0ml),
at 65oC for 24hours;b) ketone 59 (0.1mmol), Cs2CO 3 (0.5 mmol), Ir-Cat. (1.0mol%) in MeOH (0.5ml),
at 65oC for 24hours
Scheme 9. Methylation of 59 with iridium complexes 60-62
31
5.1.2 Study of substrate scope
A range of different ketones were tested using the optimized reaction conditions and catalyst 60. Ketones having a longer aliphatic chain (63 and 64)
(Table 11, entries 1-2) reacted favorably with excellent isolated yields. The
reactivity was unchanged with 98% and 94% yields, respectively. Addition
of one phenyl group on the ketone (Table 11, entry 3) resulted in 97% isolated yield. For ketone 66, which had two reactive α-carbons, the catalyst selectively reacted at the benzylic position to form 66a with 80% yield. It implied
that the pKa value of the α-carbon played a crucial rule on the chemoselectivity.
Table 11. Methylation of ketones 63-69
O
R2
R1
Ir-Cat. 60 (1.0mol%),
Cs2CO 3 (5 equiv.), MeOH (0.2M),
65oC, 24hours
N
O
R2
R1
63-69
63a-69a
Substrate
Product
Ph
BArF
N
Ir
P
Ph
Ph
60
Isolated yield
O
O
63
Ph
Ph
63a
98%
64a
94%
65a
97%
66a
80%
67a
96%
68a
95%
69a
95%
O
O
64
Ph
Ph
O
O
Ph
Ph
Ph
65
O
Ph
O
Ph
Ph
66
O
O
Ph
Ph
67
O
O
Ph
Ph
68
Cl
Cl
O
O
Ph
Ph
69
Ph
Ph
Reacton condition: ketone (0.1mmol), Cs2CO 3 (0.5 mmol), Ir-Cat. (1.0mol%) in MeOH (0.5ml),
at 65oC for 24hours
32
Other benzylic ketones 67 and 68 were also methylated in full conversions
and with high isolated yields. Under the optimized reaction conditions, the
mono-methylation product 69a was obtained in 95% yield in 24 hours. An
extended reaction time resulted in a complicated reaction mixture with
mono-methylated product, di-methylated product as well as reduction product. A possible explanation could be the steric hindrance of 69a which retarded the efficiency and selectivity of the iridium catalyst and led to the
iridium catalyst transferring the hydride to the carbonyl group.
Table 12. Methylation of propiophenone derivatives
Ir-Cat. 60 (1.0mol%),
Cs2CO 3 (4 equiv.), MeOH (0.2M),
65oC, 24hours
O
R1
70-86
N
O
O
Ir
P
Ph
Ph
R1
R
O
R
O
R
70
R= Me
71
70a
95%
71a
R=OMe
72
93%
72a
R= Cl
73
91%
73a
R= F
95%
74
74a
92%
R= Br
75
75a
96%
R= CF 3
76
76a
93%
R= Me
77
77a
95%
R= Cl
78
78a
92%
R= Br
79
79a
93%
R= CF 3
80
80a
90%
R= Cl
81
R= Me
82
R= F
83
R= CF 3
84
O
R
O
R
O
R
81a
89%
82a
90%
83a
88%
84a
85%
85a
91%
86a
80%
O
O
O
60
Isolated yield
Product
R= H
BArF
N
70a-86a
Substrate
Ph
85
O
O
O
O
O
86
Reacton condition: ketone (0.1mmol), Cs2CO 3 (0.4 mmol), Ir-Cat. (1.0mol%) in MeOH (0.5ml),
at 65oC for 24hours
33
A study of the substituent effect on the phenyl ring was carried out using a
number of the propiophenone derivatives in the methylation reaction (Table
12). Generally, the catalyst still maintained high activity for all derivatives.
Propiophenone 70 was alkylated using methanol in 95% yield. Para-methyl
71 and para-methoxy 72 resulted in a slightly lower yield of the desired
products. The catalyst tolerated a series of halogenated derivatives. Above
90% yields were obtained for the para-halogenated propiophenones 73-75.
Full conversion with 93% yield was attained by trifluoromethylated substrate
76. The substrate scope also included several meta-substituted ketones 77-80
without loss of catalyst reactivity. Lower yields were achieved from orthosubstituted substrates 81-84, which ranged from 85% to 90%. Under the
standard conditions, 83% of naphthyl ketone 86 was converted to 86a in
80% isolated yield.
O
Ph
87
Ir-Cat. 60 (1.0mol%),
Cs2CO 3 (4 equiv.)
MeOH (0.2M), 65oC,
24hours
O
88
O
Ph
Ph
70
70a
O
Ir-Cat. 60 (1.0mol%),
Cs2CO 3 (4 equiv.)
MeOH (0.2M), 65oC,
24hours
88a
O
Ir-Cat. 60 (1.0mol%),
Cs2CO 3 (4 equiv.)
MeOH (0.2M), 65oC,
24hours
89
89a
Ir-Cat. 60 (1.0mol%),
Cs2CO 3 (4 equiv.)
O
Ph
O
O
R
90, R=CN
91, R=OPh
92, R=TMS
93, R=SO 2Ph
MeOH (0.2M), 65oC,
24hours
O
Ph
R
90a, R=CN
91a, R=OPh
92a, R=TMS
93a, R=SO 2Ph
Scheme 10. Methylation of acetophenone and 88-93
Acetophenone 87 resulted in a mixture of the mono- and di-methylated
products as well as the starting material using the standard conditions. The
catalyst failed to control the reaction to yield only mono-methylation, but
instead, full conversion to 70a was observed in 24 hours by increasing the
catalyst loading to 3.0 mol%. Cyclic ketones 88 and 89 were unable to be
methylated using the standard conditions. For 89, aromatization occurred.
Other ketones with functional groups on the α-carbon either inhibited the
34
methylation (Scheme 10, substrate 90) or produced complex reaction mixtures (Scheme 10, substrate 91-93).
5.1.3 Mechanistic study
The catalytic cycle proposed in this study follows the generally accepted
mechanism for the hydrogen auto-transfer reaction (Scheme 11). The dehydrogenation of methanol generated one molecule of formaldehyde and an
iridium hydride species. Under the basic conditions, the aldehyde intermediate is condensed with a ketone to form a conjugated ketone, which is reduced by the iridium hydride to give the final product.
O
CH 3OH
H
H
O
Ir Cat.
Cs2CO 3
[Ir]
70
O
O
Ph
70a
+ Cs2CO 3
Ph
[Ir] H
H
Ph
- H 2O
95
O
+ H 2O
OH
Ph
94
Scheme 11. Proposed mechanism of methylation with iridium catalyst
The two proposed intermediates 94 and 95 were prepared separately and
reacted with iridium catalyst 60 under the standard reaction conditions
(Scheme 12a and b). Both were fully converted to the desired product 70a.
Additionally, use of deuterated methanol provided a clean formation of the
deuterated product 96 with more than 95% selectivity (Scheme 12c). However, formaldehyde and ketone 70 were incapable of generating either 94 or
95, when subjected to the standard reaction conditions without the iridium
catalyst (Scheme 12d). These results are in agreement with the proposed
mechanism where the reaction appears to follow a condensation pathway
and involves the dehydrogenation of the methanol and subsequent hydrogenation of the C=C bond. Since in the absence of the iridium catalyst, neither intermediates 94 and 95 were formed, it also implied that the iridium
catalyst participated in the aldol step.
35
Ir-Cat. 60 (1.0mol%),Cs2CO 3 (4 equiv.),
MeOH (0.2M), 65oC, 24 hours
O
a)
OH
Ph
O
Ir-Cat. 60 (1.0mol%),Cs2CO 3 (4 equiv.),
MeOH (0.2M), 65oC, 24 hours
Ph
95
O
c)
Ph
O
Ph
O
Ph
70a, conv. 99%
Ir-Cat. 60 (1.0mol%),Cs2CO 3 (4 equiv.),
CD 3OD (0.2M), 65oC, 24 hours
95
d)
Ph
70a, conv. 99%
94
b)
O
O
Ph
O
D
96, >95%
formaldehyde (5eq) Cs2CO 3(4eq)
MeOH (0.2M), 65oC, 24 hours
Ph
Ph
94
Ir-Cat. 60 (1.0mol%),Cs2CO 3 (4 equiv.),
MeOH (0.2M), 65oC, 24 hours
Ph
O
O
70
e)
D
OH
95
O
Ph
5 equiv. of Hg
70
70a, Conv. 97%
Scheme 12. Experiments for the mechanistic study
The homogeneous nature of the catalyst was tested in a mercury-poisoning
experiment (Scheme 12e). In the presence of 5.0 equiv. of mercury with
substrate 70, 97% conversion occurred in 24 hours, and under standard conditions, full conversion was obtained. The result clearly demonstrates that
the outcome of the reaction was not affected by the addition of mercury,
which suggests that the NHC-iridium catalyzed methylation is a homogeneous reaction.
In a time-dependent experiment, the reaction curve displayed a linear increase in the formation of the product over 24 hours (Figure 14, left). Approximately 5% of the starting material was consumed in 30 minutes (Figure
14, right), while an extremely slow reaction rate was observed during the
first 20 minutes, and gave 1% conversion. The experiment revealed that
there is a pre-activation process for iridium complex 60, which could possibly involve elimination of the COD.
36
O
Ir-Cat. 60 (1.0mol%),
Cs2CO 3 (4 equiv.), MeOH (0.2M),
65oC, 24hours
Ph
70
O
Ph
70a
70a
N
Ph
BArF
N
Ir
P
Ph
Ph
60
70
Figure 14. Kinetic study of the iridium catalyzed alkylation of ketones
5.2 N-Alkylation of Amides with Alcohols (Paper V)
Our NHC-iridium complexes were evaluated in the N-alkylation of amides
with alcohols via the hydrogen transfer process as well.
5.2.1 Study of reaction conditions
Catalyst 60, which showed the best reactivity in the previous alkylations of
amines and methylation of the ketones, was evaluated first. The N-alkylation
of amide was carried out using benzamide 97 together with benzyl alcohol
98 in the presence of base at 120oC. Several bases were tested and the results
are summarized in Table 13. The N-alkylation of benzamide 97 with benzylic alcohol 98 produced good results using several bases, with small differences in the yield. Using 0.5 equiv. of potassium or sodium bases (Table
13, entries 2-5), yields of above 60% were obtained. Potassium hydroxide
performed better with an 80% yield (Table 13, entry 5). Cesium carbonate
produced outstanding results with 88% yield in 5 hours (Table 13, entry 6).
The high activity of the catalyst was maintained even when the amount of
cesium carbonate was decreased to 0.2 equiv., with only a 4% drop in the
yield (Table 13, entry 7). The test of the temperature indicated the necessity
of an elevated temperature (Table 13, entry 8-10). Only 11% and 55% yields
37
were obtained at lower temperatures of 80oC and 100oC, while 91% was
attained at 120oC in 12 hours.
Table 13. Evaluation of base and temperaturea
Ph
N
Ir-Cat. 60 (0.5mol%),
benzyl alcohol 98 (1.2 equiv.)
O
NH 2
O
Ph
base, toluene
N
H
98a
97
Entry
Base
Ph
BArF
N
Ir
P
Ph
Ph
Ph
Equiv. of base
Temperature
Time
60
Isolated yield
1
-
-
120 oC
5h
0
2
t-BuOK
0.5
120 oC
5h
73%
3
t-BuONa
0.5
120 oC
5h
68%
4
K 2CO 3
0.5
120 oC
5h
67%
5
KOH
0.5
120 oC
5h
80%
6
Cs2CO 3
0.5
120 oC
5h
88%
7
Cs2CO 3
0.2
120 oC
5h
84%
8
Cs2CO 3
0.2
80oC
12h
11% b
9
Cs2CO 3
0.2
100 oC
12h
55%b
0.2
120 oC
12h
91%
10
Cs2CO 3
a) 1.0 M of amide in solvent, benzyl alcohol (1.2 equiv.), catalyst ( 0.5 mol%), base, heat;
b) NMR yield using 1,3,5-trimethoxybenzene as internal standard.
Several new iridium carbene complexes were prepared and evaluated for the
reaction (Scheme 13). To determine the reactivity difference, the reaction
was carried out at 100oC for 12 hours.
Ir-Cat. (0.5mol%),
benzyl alcohol 98 (1.2 equiv.)
O
Ph
NH 2
Ph
BArF
N
BArF
N
N
Ir
Ir
P
Ph
Ph
P
Ph
Ph
60
55% yielda
Ph
Cs2CO 3 (0.2 equiv.), 100 oC,
toluene, 12hours
97
N
O
N
99
31% yielda
N
N
H
98a
Ph
Ph
N
BArF
N
Ir
P
Ph
Ph
100
40% yielda
Ph
Ir
P
Ph
Ph
BArF
101
84% yielda
a) NMR yield using 1,3,5-trimethoxylbenzene as the internal standard.
Scheme 13. Screening of the NHC-iridium complexes for N-alkylation of amides
38
In comparison with catalyst 60, which gave 55% yield in 12 hours, the methyl substituted complex 99 showed a lower reactivity with only 31% yield.
While complex 100 was better than 99, only 40% yield was observed. The
pyrimidine-derived complex 101 showed the best catalytic activity and 84%
yield was achieved at 100oC in 12 hours.
The outcome of the investigations of the base, temperature and several iridium complexes revealed that complex 101 showed the highest reactivity in
the presence of 0.2 equiv. of cesium carbonate and a temperature of 120oC.
Various solvents were investigated under these reaction conditions (Table
14). The catalyst system still remained highly efficient in DMF and DMSO
with 84% and 78% yield, respectively. However, a dramatic loss in reactivity was observed when 1,4-dioxane was used. Additionally, under solvent
free conditions, the reaction proceeded in only 28% conversion. Using toluene as the solvent at 120oC, full conversion with 96% isolated yield was
achieved with iridium complex 101 in 3 hours.
Table 14. Evaluation of various solvents
Ir-Cat. 101(0.5mol%),
benzyl alcohol 98 (1.2 equiv.)
O
Ph
NH 2
97
Entry
Cs2CO 3 (0.2 equiv.), 120 oC,
toluene, 3 hours
Solvent
O
Ph
N
H
98a
Ph
Yielda (Isolated yield)
1
DMF
84%
2
DMSO
78%
3
1,4-Dioxane
32%
4
-
28%
5
Toluene
99%(96%)
a) NMR yield using 1,3,5-trimethoxylbenzene as the internal standard.
5.2.2 Study of substrate scope
The optimized reaction conditions consisted of 0.5 mol% iridium complex
101 and 0.2 equiv. of cesium carbonate with toluene as solvent. A high temperature (120oC) was necessary for quick completion of the N-alkylation of
benzamide 97 with benzyl alcohol 98 in 3 hours.
Using these conditions, benzamide 97 was examined with a wide range of
benzyl alcohol derivatives (Table 15). The various N-alkylation products
were furnished in good isolated yields regardless of the substituents on the
phenyl ring. The reactions were complete with para- and meta- substituted
benzyl alcohols with good isolated yields. Longer reaction times were required to reach high yields for the meta-methoxy- and bromo- benzyl alcohols (Table 15, 106 and 107). The alkylation was much slower with sub39
strates having ortho-substituents (Table 15, 108, 109 and 110) giving less
than 50% conversions in 3 hours. However, the results could be improved
with an extension of the reaction time to 12 hours with over 80% isolated
yields obtained for substrates 108a-110a. The high reactivity of the catalyst
system was also observed for the 3,4- and 3,5- disubstituted alcohols 111113, which provided over 90% yields.
Table 15. N-Alkylation of benzamide with different benzyl alcohol derivatives
O
Ph
NH 2
+
HO
R
Ir-Cat. 101(0.5mol%),
alcohol (1.2 equiv.)
Cs2CO 3 (0.2 equiv.), 120 oC,
toluene, 3 hours
Alcohol
R
O
Ph
Product
OH
98
102
103
104
105
106
107
108
109
110
111
112
113
R= H
R= p-Me
R= p-MeO
R= p-Br
R= m-Me
R= m-MeO
R= m-Br
R= o-Me
R= o-MeO
R= o-Br
R= 3,5-Me
R= 3,4-Me
R= 3,5-MeO
N
H
R
Isolated yield
O
Ph
N
H
R
98a
102a
103a
104a
105a
106a
107a
108a
109a
110a
111a
112a
113a
96%
95%
97%
82%
89%
77% (91%) a
59% (97%) a
35% (83%) a
20% (90%) a
37% (82%) a
98%
96%
90%
a) Reaction time was 12 hours.
Alcohols such as naphthyl, heterocyclic and aliphatic alcohols were also able
to couple with benzamide 97 (Table 16). The napthyl alcohols 114 and 115
were obtained in 96% and 87% isolated yields (Table 16, entries 1 and 2).
The iridium complex catalyzed the alkylation of the benzamide with heterocyclic alcohols such as pyridine, thiophene and furan with good to moderated yields. Excellent results were received from the pyridine and thiophene
derivatives, while 1.0 mol% of the catalyst was used for the furan compounds 121 and 122 and gave 63% and 72% yields, respectively. One example of an aliphatic alcohol 123 is shown with 70% isolated yield.
40
Table 16. N-Alkylation of benzamide with various alcohols
Ir-Cat. 101(0.5mol%),
alcohol (1.2 equiv.)
O
Ph
Entry
+
NH 2
HO
R
Alcohol
OH
1
Yield
Entry
96%
6
87%
OH
95%
OH
N
H
Alcohol
R
Isolated yield
OH
S
97%
119
OH
7
S
115
3
Ph
Cs2CO 3 (0.2 equiv.), 120 oC,
toluene, 12 hours
114
2
O
8
98%
120
63%a
OH
O
N
116
4
87%
OH
N
121
OH
9
O
117
72%a
122
OH
5
N
90%
118
10
OH
70%a
123
a) 1.0mol% Catalyst and 0.5 equiv. of Cs2CO 3 were used and reaction time was 12 hours.
Further studies of the substrate scope included different benzamide derivatives with various alcohols (Table 17). The substituents on the phenyl ring
(Table 17, entries 1-5) with benzyl alcohol and long chain alcohols were
evaluated with good results. The para-methyl benzamide 124 coupled with
benzyl alcohol 98 provided a 93% yield, but the yield dropped to 78% for
the bromo-substrate 125. The meta-methoxy substrate 126 was obtained in
96% yield of the alkylated product with benzyl alcohol (Table 17, entry 3)
and the ortho-methyl gave 84% yield (Table 17, entry 4). The para-methyl
benzamide 124 (Table 17, entries 5) was tested with long chain alcohols 123,
giving 77% yield in the presence of 1.0 mol% catalyst. Heterocyclic amides
(Table 17, entries 6-10), also displayed good activity with high isolated
yields of alkylated products. Over 90% yields were obtained for benzyl alcohol with the pyridine and thiophene amides (Table 17, entries 6-8). Moderate results (Table 17, entries 9 and 10) were observed for compound 130
with a thiophene alcohol and an aliphatic alcohol, where isolated yields were
73% and 52%, respectively.
41
Table 17. N-Alkylation of the aryl amides with alcohols
Ir-Cat. 101(0.5mol%),
alcohol (1.2 equiv.)
O
Ar
Entry
NH 2
+
HO
Amide
R
O
Cs2CO 3 (0.2 equiv.), 120 oC,
toluene, 12 hours
Alcohol
Isolated yield
Entry
93%
6
R
Isolated yield
Alcohol
O
Ph
NH 2
124
OH
Ph
NH 2
N
98
OH
128
O
97%
98
O
NH 2
2
N
H
Amide
O
1
Ar
Ph
OH
78%
7
Ph
NH 2
OH
94%
N
Br
125
98
129
98
O
O
NH 2
3
Ph
OH
96%
8
Ph
NH 2
OH
96%
S
OMe
126
98
130
O
98
O
4
Ph
NH 2
OH
84%
9
OH
NH 2
127
98
130
O
5
73%
S
S
131
O
OH
NH 2
77%a
10
52%a
NH 2
OH
S
124
123
130
123
a) 1.0mol% Catalyst and 0.5 equiv. of Cs2CO 3 were used and reaction time was 12 hours.
Next, several aliphatic amides were taken into consideration (Table 18).
Generally, in the presence of benzyl alcohol (Table 18, entries 1 and 3),
good yields (86% and 93%) of the aliphatic amide products were observed,
whereas the catalytic efficiency was decreased for the thiophene and alkyl
alcohols (Table 18, entries 2 and 4), with only 37% and 26% yields.
Table 18. N-Alkylation of aliphatic amides with alcohols
Ir-Cat. 101(0.5mol%),
alcohol (1.2 equiv.)
O
Alkyl
NH 2
Entry
+
HO
R
O
equiv.), 120 oC,
Cs2CO 3 (0.2
toluene, 12 hours
Amide
Alcohol
Alkyl
N
H
R
Isolated yield
O
1
NH 2
132
Ph
OH
98
86%
OH
131
37%
OH
98
93%
OH
123
26%a
O
2
132
S
NH 2
133
Ph
NH 2
133
NH 2
O
3
O
4
a) 1.0mol% Catalyst and 0.5 equiv. of Cs2CO 3 were used and reaction time was 12 hours.
42
Recently, we also found that complex 101 provided high catalytic activity
for the N-alkylation of sulfonamides as well as amides (Scheme 14). Sulfonamides 134 and 135 could both be alkylated with benzyl alcohol 98 in 98%
and 95% isolated yields, respectively.
O
R
O
S
NH 2
+
HO
134, R= o-Tol
135, R= Me
Ph
98
Ir-Cat. 101(0.5mol%),
alcohol (1.2 equiv.)
equiv.), 120 oC,
Cs2CO 3 (0.2
toluene, 12 hours
O
R
O
S
N
Ph
H
134a, R= o-Tol, 98% yield
135a, R= Me, 95% yield
Scheme 14. N-Alkylation of sulfonamides with benzyl alcohol
5.3 Conclusion
The carbene iridium complexes were found to be a highly active catalyst for
both the methylation of ketones using methanol as well as N-alkylation of
amides with alcohols. In the presence of 1.0 mol% of catalyst 60, the methylation of ketones provided over 90% isolated yields in 24 hours. Good
chemoselectivity was dependent on the catalyst structure and the base being
used. By far, catalyst 60 together with cesium carbonate was the best combination, which provided a clean methylation reaction. The mechanistic study
revealed that the reaction followed the hydrogen auto-transfer pathway with
an aldol reaction as the key-step for the new C-C bond formation. The homogeneous nature of the catalyst system has been proved by the mercury
poisoning experiment and a kinetic study revealed a pre-activation of iridium
complex 60. Modification of the NHC-iridium complexes to iridium complex 101 provided an efficient catalyst for the N-alkylation of amides with
alcohols. The substrate scope was explored and covers a wide range of amides including aromatic, heterocyclic and aliphatic amides with various
combinations of alcohols. Iridium catalyst 101 was found to be highly reactive for the N-alkylation of the sulfonamides with alcohols as well.
43
6. Chiral Bidentate NHC, Phosphine-Iridium
Complexes and their Catalytic Activities in
Hydrogenation Reactions (Paper VI)
In the previous chapter, a class of novel NHC, phosphine-iridium complexes
has demonstrated their high catalytic activity for hydrogen transfer reactions.
They provided an efficient and relatively mild synthetic route for the methylation of the ketones and N-alkylation of amides with alcohols. The Nheterocyclic carbene has been the subject of intense research regarding their
preparation50 and applications51. Due to the good δ-donating properties of the
carbenic carbons they often form efficient binding to transition metals52 and
NHCs have now become a popular ligand class for transition metal catalysts,
in many cases competitive with phosphine ligands. One of the major breakthroughs of using NHCs as ligands in transition metal catalyzed reactions
(Figure 15) was their application in the Grubbs 2nd generation ruthenium
catalysts for the metathesis reaction, which resulted in a great improvement
of catalytic activity by replacing a PCy3 from the bi-phosphine ruthenium
catalyst with NHC.53
PCy 3
Cl Ru
Cl
PCy 3Ph
136
1st generation of Grubbs Catalyst
N Mes
Mes N
Cl Ru
Cl
Ph
PCy 3
137
2nd generation of Grubbs Catalyst
Figure 15. Grubbs metathesis catalysts
The strong stabilization properties in the NHC-metal complexes have resulted in a number of efficient catalysts for the reduction of carbonyls, imines
and olefins.51c For example (Figure 16), Nolan54 has described a highly efficient monodentate NHC iridium catalyst (Figure 16a), which led to the complete reduction of ketones and imines in 30 minutes. Also, the Cp∗ Ir complex having two monodentate NHC ligands (Figure 16b) has emerged as a
very active precatalyst for transfer hydrogenation in the presence of base.55
44
NHC-iridium catalyts for transfer hydrogenation (a and b)
a)
R N
N R
Ir
PF 6
b)
N
BF 4
N
Py
Ir
N
Cl
N
NHC-iridium and ruthenium catalyts for hydrogenation (c and d)
c)
d)
n
N
R
N
N
R BF 4
N
R1
Ir
with [Ru(2-Me-allyl) 2(COD)]
N
O
R2
n=0, 1
Figure 16. Examples of carbene catalysts for hydrogenation
The application of NHC-metal catalysts was also reported in asymmetric
hydrogenation, prominently for the hydrogenation of olefins. Successful
examples with high enantioselectivity include the in situ generated monodentate ruthenium complexes with C2-symmetric NHC ligands (Figure 16c)
reported by Glorius and the chiral bidentate oxazoline - NHC-iridium catalysts developed by Burgess (Figure 16d). When compared with the high
catalytic activity of the NHC–metal complexes in the hydrogenation of ketones and imines, there are few articles reporting high enantioselectivities in
asymmetric versions of the reaction.
6.1 A Class of Novel Bidentate
Phosphine-Iridium Complexes.
Chiral
NHC,
A number of novel chiral NHC-phosphine iridium complexes were prepared
as outlined in Scheme 15. The details for the syntheses, isolation and characterization are described in the Supporting Information of the corresponding
paper. Amino alcohols 139, which were either commercially available or
simply obtained by earlier reported synthetic procedures, were protected
with a Boc group and then oxidized using Swern oxidation to the corresponding aldehyde 140 in good isolated yields. The reductive amination with
an optically pure amino phosphine58 provided product 141 in yields of up to
94%.
45
R2
R1
NH
OH
R2
R2
1) Boc 2O
R1
2) (COCl) 2, DMSO,
DIPEA
N
O
Boc
139
R3
3) NaBH(OAc) 3
∗
138
R2
R3
N
5) NH 4BF 4, CH(OEt) 3
6) NaBArF
N
∗
40-94% yield
R2
R1
HN
Boc
Ph 2P
141
Ph 2P
80-95% yield in
two steps
4) TFA
N
R3
H 2N
140
R1
BArF
∗
7) t-BuONa,
[Ir(COD)Cl] 2
R1
N
Ph 2P
Ir
142
25-45% yield in
three steps
R 3 BArF
N
∗
P
Ph Ph
143
38-59% yield
Scheme 15. Synthesis of chiral carbene iridium complexes 143
Diamine phosphine 141 underwent deprotection by treatment with TFA (trifluoroacetic acid) and was then cyclized in the presence of NH4BF4 and triethyl orthoformate. Anion exchange with NaBArF gave the imidazoline derivatives 142. Finally, reaction with [Ir(COD)Cl]2 and sodium tert-butoxide
furnished the iridium complexes 143-A – 143-K.
N
BArF
N
Ir
BArF
N
P
Ph Ph
Bn N
N
Ir
Ir
P
Ph Ph
BArF
N
N
Ir
P
Ph Ph
143-B
143-A
BArF
Bn N
P
Ph Ph
143-D
143-C
Bn
BArF
Bn N
N
Ir
N
P
Ph Ph
N
Ir
143 -E
Bn N
P
Ph Ph
143 -F
Bn N
N
Ir
N
Ir
P
Ph Ph
143 -I
Ph
N
N
Ir
P
Ph Ph
143 -J
Ph
N
Ir
Figure 17. Chiral bidentate NHC, P-iridium complexes.
46
BArF
N
P
Ph Ph
143 -K
P
Ph Ph
143 -H
143 -G
BArF
BArF
N
Ir
P
Ph Ph
Bn
Bn N
BArF
BArF
BArF
The iridium complexes thus obtained were purified by column chromatography and pure NHC, phosphine iridium complexes 143 (Figure 17) were
isolated in 38% to 59% yields. These complexes remained quite stable under
air as well as room temperature for at least one month without decomposition or significant loss of catalytic reactivity.
6.2 Evaluation of Chiral NHC-P Iridium Complexes
6.2.1 Hydrogenation of alkenes
Several iridium carbene-phosphine complexes were tested in the hydrogenation of unfunctionalized olefins 15 and 144. As shown in Table 19, the hydrogenations of trans-methylstilbene 15 were extremely slow in all cases
with less than 10% completion being observed in 12 hours.
Table 19. Hydrogenation of unfunctionalized olefins 15 and 144
Ph
R1
R2
Ir-Cat.(0.5 mol%)
0.1 M substrate in CH2Cl2
H 2 (50bar), r.t., 12 h
15, R1 = Ph, R 2= Me
144, R1 = H, R 2= i-Pr
Ir
BArF
BArF
Bn N
N
R2
15a, R1 = Ph, R 2= Me
144a, R1 = H, R 2= i-Pr
BArF
N
Ph
R1
N
Ir
P
Ph Ph
143-B
Bn N
N
Ir
P
Ph Ph
143-C
For 15, conv. 4%, ee For 144, conv. 10%, ee 34%
Bn
For 15, conv. 5%, ee For 144, conv. 9%, ee 34%
P
Ph Ph
143-D
For 15, conv. 9%, ee For 144, conv. 45%, ee 15%
Bn
BArF
BArF
Bn N
N
N
BArF
Bn N
N
N
Ph
Ir
Ir
P
Ph Ph
143 -H
For 15, conv. 4%, ee For 144, conv. 8%, ee 25%
Ir
P
Ph Ph
143 -I
For 15, conv. 6%, ee For 144, conv. 40%, ee 15%
P
Ph Ph
143 -K
For 15, conv. 3%, ee For 144, conv. 32%, ee 7%
47
The reactivity was higher when the less hindered terminal alkene 144 was
used, with conversions up to 45% in 12 hours (Table 19, 143-D). However,
the enantioselectivity was not satisfactory, giving 25% ee (Table 19, 143-H)
at most.
6.2.2.
Hydrogenation of ketones and imines
Next, the complexes were examined as catalysts in the hydrogenation of
ketones. Commonly, transition metal catalyzed reduction of ketones proceeds in the presence of base or acid and additives that serve to activate the
pre-catalyst. In our case, the iridium complex 143-D showed very poor activity for ketone reduction at room temperature in the presence of additives
such as tert-butoxide and formic acid (Table 20, entries 1 and 2), which gave
less than 10% conversions. However, by increasing the temperature to 80oC,
the reactions were completed in both basic and acidic conditions (Table 20,
entries 3 and 4). Nevertheless, it was found that these conditions nullified
any enantioselectivity. Using either of the two additives at 80oC resulted in
full conversion and phenylethanol 87a was obtained in the racemic form.
The formation of racemic products could possibly be explained by the fact
that basic or acidic conditions facilitate racemization of the optically enriched product.
Table 20. Investigation of hydrogenation conditions
O
143-D (1.0mol%),
i-PrOH.
OH
Ph
Entry
87a
Reaction condition
BArF
N
Ir
Ph
87
Bn N
P
Ph Ph
143-D
Result
1
t-BuOK (5mol%), r.t., 12 hours
conv. < 10%
2
HCOOH (20mol%), r.t., 12 hours
conv. < 10%
3
4
t-BuOK
(5mol%),80 oC,
HCOOH (20mol%),
12 hours
80oC,
12 hours
conv. 99%, ee 0%
conv. 99%, ee 0%
Historically, there are very few reports that describe asymmetric reduction of
ketones without basic or acidic additives.59-65 For example, cationic iridium
complexes chelating with chiral diphosphine ligands were able to catalyze
the hydrogenation of ketones under hydrogen pressure.65 It required quite
high hydrogen pressure (over 50bar) as well as high temperature (60oC) to
48
proceed. Despite the harsh reaction conditions that were necessary to maintain a high catalytic activity, this neutral reaction condition could be a possible route for hydrogenations of base or acid sensitive substrates.
Surprisingly, it emerged that carbene complex 143-D, (Scheme 16) was able
to form an active hydrogenation catalyst in the absence of additives such as
acid or base. Initially, in order to investigate only the impact of hydrogen
gas, a reaction was attempted (Scheme 16) using the same solvent and temperature, but instead of base, 3 bar of hydrogen gas was applied. Encouragingly, when the reaction was preformed under 3 bar of hydrogen gas, the
reaction gave full conversion and more importantly, the enantioselectivity of
the hydrogenation was revived. It gave 70% ee with full conversion in a very
short time (30 minutes).
O
143-D (1.0mol%),
i-PrOH, 80oC, H 2 (3bar), 30min.
Bn N
OH
Ph
Ir
Ph
87
BArF
N
(S)-87a
P
Ph Ph
143-D
Conv. 99%
ee 70%
Scheme 16. Hydrogenation of the ketone 87 under hydrogen pressure
This preliminary result initiated a study of the carbene catalysts for hydrogenation of ketones under neutral base/acid-free condition. First, the effect
of temperature and pressure on the catalyst was studied. Table 21 summarizes the results from evaluation of the reactions, hydrogen pressure and temperature dependence.
Table 21. The reaction’s temperature and pressure dependenciesa
O
143-D (1.0mol%),
i-PrOH, r.t., H 2, 30min.
Ph
OH
Bn N
Ir
Ph
87
(S)-87a
BArF
N
P
Ph Ph
143-D
Entry
Temperature
H2
conversion
ee
1
2
3
4
5
6
7
8
80oC
60oC
40oC
R.T (20 oC)
10 oC
R.T (20 oC)
R.T (20 oC)
R.T (20 oC)
3bar
3bar
3bar
3bar
3bar
1bar
0.5bar
balloon
99%
99%
99%
98%
97%
98%
98%
98%
70%
75%
96%
96%
96%
96%
96%
96%
a) 0.1mmol of the substrate, 1.0mol% of the 143-D and 2.0ml of i-PrOH.
49
The efficiency of the catalyst endured a wide range of temperatures and
pressures. The temperature was decreased from 80oC to 20oC with significant enhancement of the enantioselectivity (Table 21, entries 1 to 4). At
60oC, the ee increased by 5% and reached 75% (Table 21, entry 2), while at
room temperature, 96% ee was achieved (Table 21, entry 4). Further decrease of the temperature to 10oC resulted in slightly lower conversion, but
the ee value did not go up. The pressure could be decreased to as low as 0.5
bar without any loss of catalytic efficiency (Table 21, entry 7). Surprisingly,
even a balloon pressure of hydrogen was sufficient to retain the catalyst’s
high reactivity at room temperature. (Table 21, entry 8).
Next, the evaluation of the solvent commenced using acetophenone 87 as the
substrate together with complex 143-C (Table 22). Huge differences in the
reactivity and enantioselectivity were observed depending on the solvent
used.
Table 22. Hydrogenation of acetophenone 87 in various solventsa
O
143-C (1.0mol%),
r.t., H 2 (20bar)
Ph
Ph
87
Bn N
OH
(S)-87a
+ Ph
O
Ph
87b
BArF
N
Ir
P
Ph Ph
143-C
Solvent
Reaction time
Conv.
ee
1
DCM
2 hours
99%
87%
2
Toluene
4 hours
41%
53%
Entry
3
Et 2O
4 hours
6%
-
4
DMSO
4 hours
-
-
5
DMF
4 hours
-
-
6
i-PrOH
1 hour
99%(98%)a
91%(91%)a
a) 1 bar of the hydrogen pressure was used, and the reaction time was 30min.
Full conversion and moderate ee (Table 22, entry 1) was obtained in 2 hours,
when DCM was used as the solvent, while toluene (Table 22, entry 2) resulted in a conversion of 41% and an ee of 53%. In addition, approximately 20%
of ether 87b was formed in both DCM and toluene. Only 6% conversion was
detected using diethyl ether as solvent and both DMSO and DMF seemed to
completely inhibit the hydrogenation reaction (Table 22, entries 4 and 5). On
the other hand, the use of i-PrOH as solvent significantly improved both
conversion and ee (Table 22, entries 6). Full conversion and 91% of ee was
obtained in i-PrOH in 1 hour without any by-product 87b being formed at 20
bar hydrogen pressure. As mentioned before, hydrogen pressure could be
further decreased to 1 bar without any obvious loss of either reactivity or
50
enantioselectivity. Even at this low pressure the reaction reached completion
in 30 minutes.
The catalyst screening was carried out using 1.0 mol% iridium catalyst under
1 bar hydrogen pressure for 30 minutes (Table 23). Most of the catalysts
obtained full conversion in 30 minutes. The iridium complex 143-A gave
98% conversion with 92% ee. The increased bulkiness from the i-propyl
group in 143-B did not affect the conversions; however, it showed a great
impact on the ee. Changing the methyl group on the ligand into an i-propyl
group decreased the ee from 92% to 57%. Benzyl derivative 143-C gave
similar results to that of complex 143-A with hydrogenation complete in 30
minutes with 91% ee. Changing the substituent on the stereogenic center of
the ligand also had a large effect on the enantioselectivity. An ethyl group
(Table 23, 143-D) raised the ee to 96%. However, further modification of
143-C with i-propyl group (Table 23, 143-E) did not improve the enantioselectivity further.
Table 23. Catalyst screening for hydrogenation of acetophenone 87
Ir-cat. (1.0mol%), H 2 (1bar),
i-PrOH, R.T. (20 oC), 30min
O
OH
Ph
Ph
87
N
BArF
N
Ir
87a
BArF
N
P
Ph Ph
Ir
N
P
Ph Ph
Ir
conv. 98%, ee 91% (S)
Ir
conv. 99%, ee 94% (S)
143-D
conv. 98%, ee 96% (S)
N
P
Ph Ph
143 -F
conv. 98%, ee 91% (R)
P
Ph Ph
BArF
Bn N
P
Ph Ph
143 -E
Ir
BArF
N
N
143-C
conv. 98%, ee 57% (S)
BArF
N
BArF
Bn N
P
Ph Ph
143-B
conv. 98%, ee 92% (S)
Ir
BArF
N
Ir
P
Ph Ph
143-A
Bn N
Bn N
N
143 -G
conv. 99%, ee 66% (S)
Bn
Bn
Bn N
BArF
N
Ir
P
Ph Ph
143 -H
conv. 80%, ee 82% (R)
Bn N
Ir
BArF
BArF
N
Ph
P
Ph Ph
143 -I
conv. 34%, ee 69% (S)
N
N
Ir
Ph
P
Ph Ph
143 -J
conv. 71%, ee 86% (R)
N
N
Ir
BArF
P
Ph Ph
143 -K
conv. 73%, ee 0%
51
The results from 143-A and 143-C revealed that the methyl and benzyl
group on the imidazole led to similar conversions, but methyl 143-A gave
slightly better enantioselectivity. Also, 143-C and 143-D, that differed only
by a small change on the stereogenic center, led to a 5% ee difference. Thus,
it seemed that the combination of a methyl group on the nitrogen and an
ethyl group on the stereogenic center might result in a more selective catalyst. Hence, the iridium complex 143-F was prepared. Acetophenone 87 was
fully hydrogenated when catalyzed by 143-F in 30 minutes with 94% ee,
which did show that there was an improvement by replacing the methyl on
143-A with ethyl. However the combined effect of changing the substituent
on the nitrogen (Table 23, from 143-D to 143-F) was not achieved. Significant loss of enantioselectivity was observed for 143-G, where the chirality of
the ligand was generated from a more rigid cyclic structure.
Further modification of the ligand skeleton by adding a second stereogenic
center provided two pairs of diastereoisomeric iridium complexes 143-H/I
and 143-J/K. The iridium catalyst 143-H gave 80% conversion and 82% ee,
while 34% conversion and 69% ee were obtained from diastereoisomer 143I. Obviously, the addition of the extra stereogenic center in the catalyst resulted in a large change of ee as well as reactivity. The ee values decreased
from 91% for 143-C to 82% and 69% for 143-H and 143-I. Also the conversions went down to 80% and 34% respectively. However, the absolute configuration of the product appeared to be controlled by the configuration of
the substituent on the nitrogen atom instead of the configuration on the heterocyclic component. (R)-87a was formed by 143-H, while enantiomer (S)87a was the major product by 143-I. The two diastereoisomers 143-J and
143-K had almost similar reactivity but large differences in the enantioselectivity. The conversions remained virtually unchanged when 143-J and 143K were used, and was 71% and 73%, respectively. However, the ee dropped
dramatically from 86% for 143-J to 0% for 143-K. These results revealed
that the enantioselectivity relies on the combination of stereogenic centres on
both sides of the N-heterocyclic carbene.
Since it was surprising that the bidentate NHC,P-iridium catalyst required
very mild conditions for the asymmetric hydrogenation of a ketone, a more
detailed investigation was performed to understand this catalyst system. The
time-dependent experiment for the early stage of the reaction was carried out
with iridium complexes 143-B, 143-D and 143-H (Figure 18). During the
first 20 minutes of the reaction, catalyst 143-D gave 19% conversion within
1 minute and 45% conversion within 5 minutes. The reaction reached completion at 16 minutes. No significant change in the ee was detected over the
entire reaction time. 143-B displayed lower reaction rates. Only 3% conversion was observed after 1 minute, and then it increased smoothly to 16% at 5
minutes, at which point the reaction accelerated. In the next 10 minutes,
approximately 80% of the ketone was consumed and the conversion was
52
94% at 16 minutes. At 20 minutes, the reaction was almost complete with
97% of conversion.
143-B
143-D
143-H
Figure 18. Time-dependent study
Hydrogenation was much slower when using catalyst 143-H. The yield was
less than 1% in 2 minutes and only 3% at 5 minutes. The conversion began
to increase from the 5th minute, where the curve climbed up to 15% at 9
minutes. Thereafter, the conversion increased to approximately 20% every 5
minutes and reached 56% in 20 minutes. More attention was given to the
first 3 minutes of the reaction, where during this time, the iridium catalyst
143-B and 143-D gave 7% and 24% conversion, while only 1% conversion
was obtained for 143-H. This difference in conversion, especially for 143-H
implied that there could be a big difference in the pre-activation process
depending on the ligand structure. This will have an important impact on the
total reaction rate.
Next, pre-activating the catalysts by hydrogen gas before the addition of
ketone 87 was attempted and resulted in a significant difference at 5 minutes
(Table 24). The ee values remained unchanged, but conversions increased
dramatically. Under the standard conditions, ketone 87 was hydrogenated to
16%, 45% and 3% completion by 143-B, 143-D and 143-H. However, when
the iridium complexes were exposed under hydrogen gas in i-PrOH for 15
minutes before adding the substrates, the final result changed to 65%, 89%,
and 26% completion by 143-B, 143-D and 143-H.
53
Table 24. Hydrogenation of ketone 87 using pre-activated catalyst
Ir-Cat. (1.0mol%),
i-PrOH, r.t.
O
Ph
OH
Ph
87
87a
Iridium complexes
Reaction condition
Conv.
ee
1
143-B
pre-activated a
65%
57%
2
143-B
standard conditionb
16%
57%
3
143-D
pre-activated a
89%
96%
4
143-D
standard conditionb
45%
96%
5
143-H
pre-activated a
26%
82%
6
143-H
standard conditionb
3%
Entry
-
a) The complexes were pre-activated under the H 2 for 15 minutes, then acetophenone 87
was added. The reaction mixture was stirred under H 2 for 5 minutes.
b) The complexes were mixed with acetophenone 87 and stirred under H 2 for 5 minutes.
Furthermore, in a separate experiment where 10 mol% of iridium complex
143-C was used with 1.0 equiv. of acetophenone 87, formation of over 80%
of cyclooctane from the available COD ligand in the iridium complex was
detected. To this reaction mixture, another 1 equiv. of 87 was added and it
still reached complete hydrogenation with 95.5% ee. This observation, together with the results shown in Table 24, is a strong indication of a preactivation process in the reaction that involves hydrogenation of the COD
ligand. In order to observe the signal of cyclooctane from 1H NMR, 1.0
equiv. of the 143-D and 2.0 equiv. of the 87 with 5.0 equiv. of i-PrOH were
mixed in d8-THF. The mixture was stirred under balloon hydrogen gas for 1
hour. From the 1H NMR, 95% of the expected cyclooctane was detected. To
this resulting reaction mixture, 100 equiv. of acetophenone in i-PrOH was
added and hydrogenated with 79% conversion, which is further evidence for
the elimination of the COD during the catalyst’s pre-activating period.
O
a)
Ph
87
O
b)
Ph
87
143-D (1.0mol%), d 8 i-PrOD
H 2 (balloon)
98% conversion,
96% ee.
OH/D
H
Ph
Ph
OH/D
H
87b 52%
Scheme 17. Deuterium experiments of the hydrogenation
54
Ph
OH/D
D
87c 55%
87b 45%
143-D (1.0mol%), i-PrOH
D 2 (balloon)
98% conversion,
96% ee.
+
+
Ph
OH/D
D
87c 48%
In the deuterium experiment (Scheme 17), d8 i-propanol was used as solvent
and produced a mixture of deuterated products in 45% and 55% yield. A
similar ratio of deuterated products was obtained in i-PrOH when deuterium
gas was applied instead of hydrogen. This H/D scrambling indicates that the
hydrogen gas is not only required for activating the pre-catalyst but also
participates in the whole catalytic cycle, and the catalyst accepts the hydrides
both from hydrogen gas and i-PrOH.
The iridium catalyst 143-D was examined with a range of ketones (Table
25). The catalyst retained its efficiency with para-substituted acetophenones.
The para-halogenated acetophenones (Table 25, 145-147) reacted with high
conversions and with good ee. The bromo- and chloro- substrates were hydrogenated to alcohols completely in 30 minutes with 94% and 95% ee, respectively. The hydrogenation of the fluoro- substrates 147 also provided
good enantioselectivity with 94% ee and 94% conversion. The methyl 148
and trifluoromethyl substrates 149 were hydrogenated with high conversions
and 94% ee. The catalyst was also efficient for the hydrogenation of several
meta-substituted acetophenones (Table 25, 150-153). Over a period of 30
minutes, the hydrogenations achieved over 90% ee. A decrease in the ee
value was observed for ortho-methyl acetophenone 154 in which the reaction was complete in 30 minutes with 87% ee. High reactivity of catalyst
143-D was maintained for the two naphtyl-ketones 155 and 156. The reactions went to nearly completion in 30 minutes with 90% and 84% ee, respectively.
Changing the alkyl substituents on the ketone resulted in larger changes in
the enantioselectivity and reactivity as well. A decrease of the ee was clearly
revealed by changing the steric hindrances from 157 to 159. Ethylphenyl
ketone 157 was still hydrogenated completely with high ee, while the ee
dropped to 83% when a longer carbon chain was introduced (Table 25, 158)
and it slowed down the reaction to 55% completion. Moderate reactivity was
obtained from tert-butyl phenyl ketone 159, however, a dramatic loss in
enantioselectivity was observed and gave only 50% ee. Another substrate
160 was completely converted to the corresponding alcohol 160a with moderate ee (82%). The chloro- and bromo- substrates 161 and 162, which were
expected to be the problematic substrates under strong basic reaction conditions, were successfully reduced using the base-free conditions. Both hydrogenations resulted in 76% and 84% ee. The reaction mixture was very clean
without any by-products being observed. Also, substrate 91 gave full conversion with 80% ee. The catalyst was completely unreactive for the reduction of substrates 163 and 90 with functional groups –OH and –CN. Benzoylacetate 164 could not be hydrogenated under this reaction condition.
Further efforts such as increasing the temperature and hydrogen pressure,
and prolonging the reaction times failed to improve the hydrogenation results for these three substrates.
55
Table 25. Investigation of the substrate scopea
O
R1
R2
143-D (1.0mol%), H 2 (1bar), i-PrOH
r.t., (20 oC), 30min.
O
R
R1
R2
Conv.
ee
87a
145a
146a
147a
148a
149a
150a
151a
152a
153a
154a
99%
99%
99%
94%
94%
99%
99%
99%
97%
97%
99%
96%
94%
95%
94%
94%
94%
96%
96%
90%
90%
87%
155a
98%
90%
156
156a
99%
84%
157
158
159
160
161
162
91
163
90
164
157a
158a
159a
160a
161a
162a
91b
163a
90b
164a
99%
55%
88%
99%
99%
99%
99%
-
94%
83%
50%
82%
76%
84%
80%
-
Product
Substrate
R= H
R=p-Br
R=p-Cl
R=p-F
R=p-Me
R=p-CF3
R=m-Cl
R=m-CF 3
R=m-Me
R=m-NO2
R=o-Me
OH
87
145
146
147
148
149
150
151
152
153
154
OH
R
OH
O
155
OH
O
O
R
R= Ethyl
R= n-Butyl
R= t-Butyl
R= (CH 2)2Ph
R= CH2Cl
R= CH2Br
R= CH2OPh
R= CH2OH
R= CH2CN
R= CH2CO2Et
OH
R
a) 0.1mmol of the substrate, 1.0mol% of the 143-D and 2.0ml of i-PrOH were used.
The NHC-iridium catalysts were also tested for hydrogenation of imines
(Table 26). Imine 165 was hydrogenated in the presence of 1.0 mol% catalyst under 1 bar hydrogen pressure. When compared to the results from the
ketones, the imine reductions were slow and the enantioselectivity was not
as good as those obtained for the hydrogenation of ketones. Catalysts 143-C
and 143-D were able to provide high catalytic activity for imine 165, but
only moderate enantioselectivity. The hydrogenations were nearly complete
in 30 minutes with 81% ee for both 143-C and 143-D. The best enantioselectivity was for 143-J, which gave 88%, however, only 15% of the starting
material was converted into product. It appears that the stereogenic centers
from both sides of the carbene nitrogen atoms played a crucial role on the
enantioselectivity.
56
Table 26. Asymmetric hydrogenation of imine 165 with carbene iridium catalysts
N
Ir-cat. (1.0mol%), H 2 (1bar),
i-PrOH, r.t. (20 oC), 30min.
Ph
HN
Ph
Ph
165
N
Ir
165a
BArF
N
BArF
N
P
Ph Ph
N
Ir
conv. 12%, ee 19% (S)
N
P
Ph Ph
BArF
N
Ir
Bn
N
P
Ph Ph
143 -G
conv. 70%, ee 76% (R)
Bn
Bn N
BArF
N
Ir
Bn N
P
Ph Ph
143 -H
conv. 87%, ee 79% (S)
Ir
BArF
BArF
N
Ph
P
Ph Ph
143 -I
conv. 26% , ee 30% (R)
143-D
conv. 99% , ee 81% (R)
BArF
Bn N
Ir
conv. 24%., ee 31% (R)
P
Ph Ph
143-C
143 -F
conv. 42%, racemic
N
Ir
conv. 98% , ee 81% (R)
P
Ph Ph
143 -E
BArF
Bn N
P
Ph Ph
143-B
N
Ir
BArF
N
Ir
BArF
Bn N
Bn N
P
Ph Ph
143-A
conv. 50% , ee 47% (R)
Ph
N
N
Ir
Ph
P
Ph Ph
143 -J
conv. 15%, ee 88% (S)
N
N
Ir
BArF
P
Ph Ph
143 -K
conv. 2%, ee -
a) 0.1mmol of the substrate, 1.0mol% of the 143-D and 2.0ml of i-PrOH were used.
Another interesting observation was that the same catalyst resulted in different absolute configurations of the products from hydrogenation of ketones
and imines (Scheme 18). For example, ketone 87 was hydrogenated using
catalyst 143-D to form the alcohol with (S)-configuration in 96% ee, however, the opposite absolute configuration was observed when 143-D catalyzed
the hydrogenation of imine 164 (R conf, 96% ee). For ketone 87 and imine
165, the prochiral carbons were both polarized by electronegative atoms
(oxygen and nitrogen), and the substituent pairs on the two prochiral carbons
were identical (phenyl and methyl groups). For the ketone, the steric difference between the phenyl and methyl groups governed the enantioselectivity
of the hydrogenation. For imine hydrogenation, the enantioselectivity was
determined by the substituent on nitrogen atom as well as the substituents on
the prochiral carbons.
57
O
143-D (1.0mol%), H 2 (1bar),
i-PrOH, r.t. (20 oC), 30min.
Ph
OH
Ph
87
(S)-87a
Conv. 99%, ee 96%
Bn N
Ir
N
Ph
143-D (1.0mol%), H 2 (1bar),
i-PrOH, r.t. (20 oC), 30min.
HN
Ph
BArF
N
P
Ph Ph
143-D
Ph
Ph
165
(R)-165a
Conv. 99%, ee 81%
Scheme 18. Comparison of absolute configurations of hydrogenation products from
ketone 87 and imine 165.
Since these were preliminary results for the hydrogenation of imines, more
experimental data is required to draw any mechanistic hypotheses. The results could possibly be improved by optimizing the conditions and also by
employing substrates having substituents besides phenyl on the nitrogen
atom.
6.3 Conclusion
A novel library of chiral NHC, phosphine iridium complexes was prepared
and investigated for catalytic activity in the hydrogenation of the olefins,
ketones and imines. Poor reactivity was obtained when the catalysts were
used for the hydrogenation of an unfunctionalized olefin. Less than 10%
conversions were obtained for trans-methylstilbene. The reactivity was improved when less hindered terminal olefins were applied as substrates. However, neither the catalyst reactivity nor the enantioselectivity were comparable to the previously developed N,P-iridium catalyst system. Conversely,
these chiral carbene iridium complexes were found to be extremely active
catalysts for the hydrogenation of ketones. The hydrogenation of the ketone
was complete in 30 minutes using 1.0 mol% metal catalyst with up to 96%
ee. The reaction took place under very mild conditions. High conversion was
obtained at 1 bar of hydrogen pressure at room temperature without any
basic or acidic additives. From a kinetic study and a pre-activation experiment, it was found that the COD was reduced and eliminated in order to
generate the active catalyst species and the time for the pre-activation depended greatly on the ligand structure. This carbene iridium catalyst system
also showed good reactivity and moderate enantioselectivity for the hydrogenation of imines. However more experiments are required for optimization
of the reaction conditions.
58
7. Concluding Remarks and Outlook
This thesis describes the development of new bidentate iridium complexes
and their applications in asymmetric hydrogenation and hydrogen transfer
reactions.
The first part focuses mainly on the extension of the N,P-iridium catalyst
library that has been developed in the Andersson group and the synthesis of
chiral molecules using iridium catalyzed asymmetric hydrogenation. Pyridine based N,P-iridium complexes were synthesized and showed good reactivity and enantioselectivity for the asymmetric hydrogenation of olefins
with non- and weakly-coordinating substituents. The well-developed iridium
catalysts provided an approach to obtain the chiral esters from the conjugated esters and lactones via the asymmetric hydrogenation with good enantioselectivity.
The second part consists of the development of new NHC,P-iridium catalysts
for hydrogenation and hydrogen transfer reactions. High catalytic activity
and selectivity was obtained in hydrogen transfer reactions. The catalysts
were successfully used for the formation of C-C and C-N bond via a multistep hydrogen auto-transfer process. Furthermore, the chiral NHC,P-iridium
complexes were found to be highly reactive as a catalyst for hydrogenation
of the ketones under mild and base-free conditions. Hydrogen balloon pressure was sufficient to permit the hydrogenation to completion. No other base
or acid additives were necessary and high conversions and ee values were
obtained using 1.0 mol% catalyst and 30 minutes reaction time.
More experiments are required in order to unveil the reaction mechanism
and explain the enantioselectivity. From the preliminary mechanistic study,
it was found that the carbene complexes easily eliminated the COD even
under low pressures of hydrogen and thus the activated iridium hydride species were able to survive without loss of activity. These results should be an
encouragement for subsequent studies on the application of these activated
iridium species in the iridium catalyzed asymmetric C-C bond formation
through the hydrogen transfer process.
59
Contribution List
I.
Iridium Catalysts with Chiral Bicyclic Pyridine-Phosphane
Ligands for the Asymmetric Hydrogenation of Olefins.
Synthesis of the catalysts and their evaluations.
Major writing of the manuscript and preparing the supporting information.
II.
Highly Enantioselective Iridium Catalyzed Hydrogenation of
α, β-Unsaturated Esters.
Synthesis of α-substituted conjugated esters and their iridium catalyzed asymmetric hydrogenations.
Participation in the preparation of the manuscript and supporting
information.
III. Chiral Hetero- and Carbocyclic Compounds from the Asymmetric Hydrogenation of Cyclic Alkenes.
Synthesis of conjugated lactones and ketones as well as the catalyst
screening.
Participation in the preparation of the supporting information.
IV.
C-C Coupling of Ketones with Methanol Catalyzed by a NHeterocyclic Carbene-Phosphine Iridium Complex.
The catalyst screening and optimization of the reaction conditions,
and also a major part of the investigation of the substrate scope.
Major writing of the manuscript.
V.
C-N Coupling of Amides with Alcohols Catalyzed by NHeterocyclic Carbene-Phosphine Iridium Complexes.
Preparation and the optimization of the iridium catalysts.
Participation in the preparation of the manuscript.
60
VI.
Highly Active Cationic NHC, Phosphine Iridium Catalysts for
Base Free Asymmetric Hydrogenation of Ketones.
Major contribution on the synthesis of catalysts, investigation of
the reaction conditions, experiments for the mechanistic study and
partly participation in the study of substrate scope.
Major writing of the manuscript.
61
Acknowledgments
I would like to express my sincere gratitude to the following people:
Professor Pher G. Andersson, for accepting me as a PhD student in his group
and introducing me to this fantastic research area. His good advice on the
projects always encouraged me to persevere to an answer. I would also like
to thank him for giving me a great degree of freedom with the research.
The past and present members of the PGA group:
Alexander Paptchikhine, for being my fantastic neighbour in the lab and
helping on many projects. Your efficiency on many projects inspired me a
lot. J. Johan Verendel, for professional assistance with the instruments and
chemistry as well. Your great jokes and fun activities outside the lab were
welcome. Most importantly, your well-written thesis and review provided
me with tremendous help. Jiaqi Li, who was always busy and excited about
reactions. Thank you for the enlightening discussions on chemistry and life.
Also, for the fun times outside the lab. Taigang Zhou, a nice guy to hang out
with. The wonderful Friday night dinners and drinks at your apartment won’t
be forgotten. Byron Peters, an awesome person, not only as a chemist but
also a good friend. You helped me a lot, both in and out of the lab with many
issues. Your talent and extensive knowledge of chemistry always encouraged me to improve myself. Of course, the drinks and cigars times together
were absolutely wonderful too. Alban Cadu (Dr. Alban!!), for your superior
jokes, talks and movies recommendations. Also, the fun times at the Irish
pub and let’s Gangnam style anytime! Thishana Singh, for your beautiful
friendly smile and continuous help in and outside the office even when you
are in South Africa. Thank you for reading this thesis and the helpful suggestions. Thank you also for the ferry trips, group dinners, BBQs and keeping
the group sane. The vuvuzela you gave me will definitely travel with me and
not contribute to the good achievement in music ☺. Janjira Rujirawanich
(Nan), you are kind, neat and tidy. Also, thank you for the good advice on
Thai food and all your efforts to establish good order in the lab. My Indian
friends- Vijay Singh Parihar, for our collaboration on projects; Puspesh Kumar Upadhyay, who always persuaded me to quit smoking and failed. Kaori
Itto, for her pleasant introduction to Japanese culture; Simone Diomedi, for
sharing the same great passion on both Italian football and chemistry.
62
Jianguo Liu, who keeps busy with chemistry and baby care but with happiness. My best wishes for the rest of your PhD study and cheer up! Wangchuk
Rabten, a fine and funny gentleman. I really appreciate all your efforts on the
maintenance of the GCMS. Also, the good times we spent outside the lab.
You are the reason that I now know the beautiful country Bhutan. Sutthichat
Kerdphon (Kim), a good colleague whom I enjoyed working together with
on many projects. Also, an enjoyable person who I had fun times with outside the lab. It’s too bad that we never have a chance to go to Thailand together. Suppachai Krajangsri (Boy), I appreciate your hard work and considerable contribution on the project and hope this experience helps you in
your PhD study. Cristiana Margarita, a lady with passion in the lab. Buona
fortuna con la chimica e continuare a giocare a pallavolo! And Michael G.,
Dominic B. and Julie K. for introducing a new and interesting chemistry to
me.
Many thanks to the friends in Uppsala:
Maxim G. and his beautiful wife Aleksandra D.; Hao H., Ruisheng X., JiaFei P., Huan M., Xiao H., Jie Y., Supaporn S. and Xiaojiao S. Fengjia Z.,
Xingwu Z., Xijia L. for the good friendship. Lei Y. Bing S., Hu Q. and
Shanshan Z., who gave me much support in my first two years in Sweden.
Dr. Joseph S., a good researcher and teacher, who helped me improve my
knowledge of organic reactions with his excellent lectures.
Profound appreciation to the people at Stockholm University:
Deep gratitude to all the friends and colleagues in the Department of Organic
Chemistry for an unforgettable time spent here. I enjoyed the guest lectures,
seminars, presentations and discussions at the SDM. It has been good spending time with you.
Professor Kálmán Szabó, for agreeing to be my co-supervisor and providing
the perfect definition for organometallic chemistry.
Professor Jan-E. Bäckvall, for his interest and good advice on the carbene,
iridium catalyzed hydrogenation of ketones.
Dr. Abraham Mendoza, for his discussions and considerate suggestions
about my future plans in academic research.
Many thanks to Alban Cadu and Dr. Thishana Singh for their great contribution on the proofreading and suggestions for this thesis.
Finally a special thank you to my parents and my wife, Ling Jin who have
always been there and supported me in everything.
63
Summary in Swedish
En katalysator är en förening som underlättar och accellererar en kemisk
reaktion utan att själv förbrukas av densamma. Eftersom den inte ingår i
reaktionsprodukten är det oftast möjligt att bara använda en liten mängd
katalysator för att påskynda en reaktion i stor skala. Katalysatorn kan också
användas för att påverka och öka en reaktions selektivitet så att bara en av
flera möjliga produkter bildas. Studier och utveckling av nya, selektiva katalysatorer är av centralt intresse, både inom grundforskning och i industrin.
Denna avhandling beskriver utvecklingen av nya iridium-baserade katalysatorer för asymmetriska hydrogeneringar och väte överföringsreaktioner. Tre
typer av iridium katalysatorer har utvecklats och använts för selektiv framställning av olika typer av föreningar.
Kapitel 2-4 beskriver framställningen av en ny typ av kväve-fosfor-iridium
komplex samt deras användning som katalysatorer i asymmetriska hydrogeneringar. Katalysatorerna hade ett brett användningsområde och kunde
användas på flera nya substrat med hög selektivitet och goda utbyten.
Kapitel 5 avhandlar utvecklingen av en ny typ av karben fosfin iridium
komplex och dess användning som katalysator i reaktioner som bildar nya
kol-kol samt kol-kväve bindningar. Katalysatorerna kunde användas på ett
stort antal olika startmaterial, de hade hög aktivitet och kunde användas under milda betingelser.
Kapitel 6 beskriver framställningen av kirala karben fosfor iridium komplex
och deras användning som katalysatorer i stereoselektiv reduktion av ketoner
till alkoholer. Den katalyserade reaktionen äger rum under neutrala och
milda betingelser samt producerar alkoholer i hög selektivitet. Genom att
studera reaktionens mekanism kunde katalysatorerna förbättras ytterligare
vilket resulterade i kortare reaktionstider.
64
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