name of series or title of publication

100 Pages·2012·3.84 MB·English

by  Marcin Kalek

Transition metal-catalysed hydrogen
transfer processes for CC and CN
bond formation
Synthetic studies and mechanistic investigations
Agnieszka Bartoszewicz
© Agnieszka Bartoszewicz, Stockholm 2012

ISBN 978-91-7447-595-1

Printed in Sweden by US-AB, Stockholm 2012
Distributor: Department of Organic Chemistry, Stockholm University
Abstract
This thesis focusses on synthetic studies and mechanistic investigations
of reactions involving hydrogen-transfer processes.
In the first part, the development of an efficient method for the synthesis
of -hydroxy ketones (aldols) and -amino ketones (Mannich products)
from allylic alcohols and aldehydes is described. These reactions use Ru(η5-
C Ph )(CO) Cl as the catalyst. The reaction parameters were optimised in
5 5 2
order to suppress the formation of undesired by-products, such as saturated
ketones, benzyl alcohols, and ,-unsaturated ketones. Neutral and mild
reaction conditions enabled the synthesis of a variety of aldol products in up
to 99% yield, with a good syn/anti ratio. The influence of the
stereoelectronic properties of the catalyst on the reaction outcome was also
studied. Based on the results obtained, a plausible reaction mechanism has
been proposed, involving as the key steps the 1,4-addition of hydride to ,-
unsaturated ketones and the formation of ruthenium (Z)-enolates.
In the second part of this thesis, a ruthenium-catalysed tandem
isomerisation/CH activation reaction is presented. A number of ruthenium
complexes, phosphine ligands, and additives were evaluated in order to
establish the optimal reaction conditions. It was found that the use of a
stable ruthenium catalyst, Ru(PPh ) Cl , together with PtBu and HCO Na
3 3 2 3 2
resulted in an efficient tandem transformation. Using this procedure, a
variety of ortho-alkylated aromatic ketones were obtained in excellent
yields and in short reaction times. Moreover, homoallylic alcohols could
also be used as starting materials for the reaction, which further expands the
substrate scope. Mechanistic investigations into the isomerisation part of the
process were carried out.
The last project described in the thesis deals with the design and
preparation of novel bifunctional iridium complexes containing an N-(2-
hydroxy-isobutyl)-N-Heterocyclic carbene ligand. These complexes were
used as catalysts to alkylate amines using alcohols as latent electrophiles.
The catalytic system developed here was found to be one of the most active
systems reported to date, allowing the reaction to be performed at
temperatures as low as 50 °C for the first time. A broad substrate scope was
examined, including various primary and secondary alcohols. These
alcohols could be efficiently coupled with both primary and secondary
aromatic amines. Combined experimental and theoretical studies into the
reaction mechanism are consistent with a metal-ligand bifunctional activity
of the new catalyst.
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List of Publications
This thesis is based on the following publications, referred to in the text by
their Roman numerals:

I. Synthesis of -Hydroxy Ketones from Allylic Alcohols via
Catalytic Formation of Ruthenium Enolates
Agnieszka Bartoszewicz, Madeleine Livendahl, and Belén
Martín-Matute
Chemistry A European Journal 2008, 14, 10547-10550.

II. Synthesis of Hydroxy and Amino Ketones from
Allylic Alcohols Catalysed by Ru5-Ph C (CO) Cl
5 5 2
Agnieszka Bartoszewicz, Martina M. Jeżowska, Kévin
Laymand, Juri Möbus, and Belén Martín-Matute
European Journal of Inorganic Chemistry 2012, 1517-1530.

III. Building Molecular Complexity via Tandem Ru catalysed
Isomerisation/CH Activation.
Agnieszka Bartoszewicz and Belén Martín-Matute
Organic Letters 2009, 11, 1749-1752.

IV. A Highly Active Bifunctional Iridium Complex with an
Alcohol/Alkoxide-Tethered N-Heterocyclic Carbene for
Alkylation of Amines with Alcohols
Agnieszka Bartoszewicz, Rocío Marcos, Suman Sahoo, A.
Ken Inge, Xiaodong Zou, and Belén Martín-Matute
Chemistry A European Journal 2012, 18, 14510-14519.

Appendix 1. Alkylation of Amines with Alcohols Catalysed by a
Bifunctional Iridium Complex: A Mechanistic
Investigation
Agnieszka Bartoszewicz, Rocío Marcos, Per-Ola Norrby, and
Belén Martín-Matute
Appendix

Reprints were made with kind permission from the publishers.
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Publications not included in this thesis:

A Family of Highly Stable Lanthanide Metal−Organic Frameworks:
Structural Evolution and Catalytic Activity
Mikaela Gustafsson, Agnieszka Bartoszewicz, Belén Martín-Matute,
Junliang Sun, Jekabs Grins, Tony Zhao, Zhongyue Li, Guangshan Zhu,
and Xiaodong Zou
Chemistry of Materials 2010, 22, 3316-3322.

A Facile Synthesis of -Fluoroketones Catalysed by [Cp*IrCl ]
2 2
Nanna Ahlsten, Agnieszka Bartoszewicz, Santosh Agrawal, and Belén
Martín-Matute
Synthesis, 2011, 2600-2608.

Microporous Aluminoborates with 18- and 24-Octahedral-Atom
Channels: Structural and Catalytic Properties
Tao Yang, Agnieszka Bartoszewicz, Jing Ju, Junliang Sun, Zheng Liu,
Xiaodong Zou; Yingxia Wang, Guobao Li, Fuhui Liao, Belén Martín-
Matute, and Jianhua Lin
Angewandte Chemie International Edition 2011, 50, 12555-12558.

Ruthenium Complexation in an Aluminium Metal-Organic
Framework and its Application in Alcohol Oxidation Catalysis
Fabian Carson, Santosh Agrawal, Mikaela Gustafsson, Agnieszka
Bartoszewicz, Francisca Moraga, Xiaodong Zou, Belén Martín-Matute
Chemistry A European Journal 2012,
DOI: 10.1002/chem.201200885

Allylic Alcohols as Synthetic Enoalte Equivalents: Isomerisation and
Tandem Reactions Catalysed by Transition Metal Complexes
Nanna Ahlsten, Agnieszka Bartoszewicz, and Belén Martín-Matute
Dalton Transactions 2012, 41, 1660-1670. (review)

Enantioselective Synthesis of Alcohols and Amines via Iridium-
Catalyzed Hydrogenation, Transfer Hydrogenation and Related
processes
Agnieszka Bartoszewicz, Nanna Ahlsten, and Belén Martín-Matute
Under revision. (review)

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Contents
Abstract ............................................................................... iii
List of Publications .................................................................. v
Contents ............................................................................. vii
Abbreviations ........................................................................ ix
Chapter 1 Introduction ............................................................ 1
1.1 Multi-component synthesis ....................................................... 1
1.2 Borrowing hydrogen strategy .................................................... 2
1.3 Bifunctional catalysis ............................................................... 3
1.4 Isomerisation of allylic alcohols to ketones ................................. 5
1.4.1 The isomerisation mechanisms ........................................... 6
1.5 Tandem isomerisation/enolate intermediate trapping ................... 8
1.6 Transition-metal-catalysed C(sp2)–H cleavage ........................... 12
1.7 The Murai reaction .................................................................. 13
1.8 Alkylation of amines with alcohols ............................................ 15
1.9 N-Heterocyclic carbenes as ligands for transition metal catalysts .. 16
1.10 Objectives of the thesis ......................................................... 17
Chapter 2 Efficient synthesis of -hydroxy ketones and -amino
ketones from allylic alcohols by catalytic formation of ruthenium
enolates. (Paper I and II) ...................................................... 19
2.1 Introduction .......................................................................... 19
2.2 Catalyst screening and optimisation of reaction conditions ........... 20
2.3 Synthesis of -hydroxy ketones – scope and limitations .............. 21
2.4 Synthesis of -amino ketones – scope and limitations ................. 25
2.5 Mechanistic investigations ....................................................... 29
2.5.1 Kinetics of the reaction ..................................................... 29
2.5.2 Additional stoichiometric mechanistic investigations ............. 32
2.5.2 Reaction mechanism ........................................................ 37
2.6 Conclusions ........................................................................... 40
Chepter 3 Building molecular complexity through tandem
ruthenium catalysed isomerisation/ CH activation/CC coupling
reaction. (Paper III) .............................................................. 41
3.1 Introduction .......................................................................... 41
3.2 Optimisation of the reaction conditions...................................... 42
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3.3 Scope of the reaction .............................................................. 45
3.4 Mechanistic investigations ....................................................... 47
3.5 Summary .............................................................................. 49
Chapter 4 A bifunctional iridium complex with an alcohol/alkoxide-
tethered N-Heterocyclic carbene ligand for alkylation of amines
with alcohols  synthetic and mechanistic studies (Paper IV and
Appendix 1). ........................................................................ 51
4.1 Introduction .......................................................................... 51
4.2 Ligand design and synthesis of the complexes ........................... 52
4.3 Catalytic activity .................................................................... 55
4.4 Substrate scope ..................................................................... 58
4.5 Mechanistic investigations ....................................................... 61
4.5.1 Experimental studies ........................................................ 61
4.5.2 Theoretical studies ........................................................... 65
4.7 Conclusions ........................................................................... 73
Concluding Remarks ............................................................. 75
Appendix 1 Alkylation of amines with alcohols catalysed by a
bifunctional iridium complex: a mechanistic investigation .......... 77
Experimental details ..................................................................... 77
Computational details ................................................................... 78
Acknowledgements ............................................................... 79
References .......................................................................... 81

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Abbreviations
The abbreviations and acronyms used are in agreemement with the standards
of the subject. 1i

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