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# Coordination Chemistry Inspires Molecular Catalysis

Rinaldo Poli, Anne-Marie Caminade

► To cite this version:

Rinaldo Poli, Anne-Marie Caminade. Coordination Chemistry Inspires Molecular Catalysis. Zenodo, 2024, 10.5281/zenodo.10966127. hal-04548441

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Submitted on 16 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

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Distributed under a Creative Commons Attribution 4.0 International License
# Coordination Chemistry Inspires Molecular Catalysis

Rinaldo Poli, Anne-Marie Caminade

► To cite this version:

Rinaldo Poli, Anne-Marie Caminade. Coordination Chemistry Inspires Molecular Catalysis. Zenodo, 2024, 10.5281/zenodo.10966127. hal-04548441

HAL Id: hal-04548441

https://hal.science/hal-04548441v1

Submitted on 16 Apr 2024

HAL is a multi-disciplinary open access
archive for the deposit and dissemination of sci-
entific research documents, whether they are pub-
lished or not. The documents may come from
teaching and research institutions in France or
abroad, or from public or private research centers.

L'archive ouverte pluridisciplinaire HAL, est
destinée au dépôt et à la diffusion de documents
scientifiques de niveau recherche, publiés ou non,
émanant des établissements d'enseignement et de
recherche français ou étrangers, des laboratoires
publics ou privés.

<figure><img src="image_1.png" /></figure>
Rinaldo POLI
Anne-Marie CAMINADE

# Coordination Chemistry Inspires Molecular Catalysis

A book about the journey of 15 early stage researchers

ITN EJD

2020 - 2024

<figure><img src="image_3.png" /></figure>

CIMC

<figure><img src="image_4.png" /></figure>
Rinaldo POLI
Anne-Marie CAMINADE

# Coordination Chemistry Inspires Molecular Catalysis

A book about the journey of 15 early stage researchers

ITN EJD

2020 - 2024

<figure><img src="image_2.png" /></figure>

CIMC

<figure><img src="image_3.png" /></figure>
<figure><img src="image_5.png" /></figure>
<figure><img src="image_4.png" /></figure>
Coordination Chemistry Inspires
Molecular Catalysis
(CCIMC)

**Anne-Marie Caminade, EDITOR**

*Laboratoire de Chimie de Coordination, Toulouse*

**Rinaldo Poli, EDITOR**

*Laboratoire de Chimie de Coordination, Toulouse*

Developed from the Ph.D. Theses of 15 Early-Stage Researchers (ESRs), co-supervised within the framework of an Innovative Training Network (ITN) of the European Joint Doctorate (EJD) type, funded by the European Commission's Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement No 860322)
Coordination Chemistry Inspires
Molecular Catalysis
(CCIMC)

Anne-Marie Caminade, EDITOR

Laboratoire de Chimie de Coordination, Toulouse

Rinaldo Poli, EDITOR

Laboratoire de Chimie de Coordination, Toulouse

Developed from the Ph.D. Theses of 15 Early-Stage Researchers (ESRs), co-supervised within the framework of an Innovative Training Network (ITN) of the European Joint Doctorate (EJD) type, funded by the European Commission's Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement No 860322)
<figure><img src="image_6.png" /></figure>
<figure><img src="image_5.png" /></figure>
# The CCIMC Network

## Beneficiary Institutions

1. Centre National de la Recherche Scientifique - Laboratoire de Chimie de Coordination, Toulouse, France (Coordinator)

2. University of York, York, United Kingdom

3. Universitat Autònoma Barcelona, Bellaterra, Spain

4. Universitatea din Bucuresti, Bucharest, Romania

5. Universitat Rovira i Virgili, Tarragona, Spain

6. Uniwersytet Warszawski, Warsaw, Poland

7. Friedrich-Schiller-Universität, Jena, Germany

8. Universität Leipzig, Leipzig, Germany

9. Danmarks Tekniske Universitet, Lyngby, Denmark

## Partner Institutions

1. Université Paul Sabatier, Toulouse, France

2. Institut National Polytechnique, Toulouse, France

3. IFP Energies Nouvelles, Solaize, France

4. Fundacion Tecnalia Research & Innovation, San Sebastián, Spain

5. Henkel KGaA, Düsseldorf, Germany

6. Johnson Matthey PLC, Reading, United Kingdom

7. Elkem Silicones France SAS, Solaize, France

8. Rhodia Operations, Saint Fons, France

9. BASF SE, Ludwigshafen, Germany

10. Italmatch Chemicals S.p.A., Arese, Italy

## Early Stage Researchers

ESR1 Pawel KRZESINSKI

ESR2 Joris LANGLOIS

ESR3 Irina BOZHINOVSKA

ESR4 Zinnia ARORA

ESR5 Sara BONFANTE

ESR6 Wimonsiri HUADSAI

ESR7 Anastasiia SHERSTIUK

ESR8 Paven KISTEN

ESR9 Chantal J. ABOU-FAYSSAL

ESR10 Joel CEJAS SÁNCHEZ

ESR11 Deepthy KRISHNAN

ESR12 Max MILEWSKI

ESR13 Massimo PETRICONE

ESR14 Aswin CHANDRAN

ESR15 Agustin MORALES
# The CCIMC Network

## Beneficiary Institutions

1. Centre National de la Recherche Scientifique - Laboratoire de Chimie de Coordination, Toulouse, France (Coordinator)

2. University of York, York, United Kingdom

3. Universitat Autònoma Barcelona, Bellaterra, Spain

4. Universitatea din Bucuresti, Bucharest, Romania

5. Universitat Rovira i Virgili, Tarragona, Spain

6. Uniwersytet Warszawski, Warsaw, Poland

7. Friedrich-Schiller-Universität, Jena, Germany

8. Universität Leipzig, Leipzig, Germany

9. Danmarks Tekniske Universitet, Lyngby, Denmark

## Partner Institutions

1. Université Paul Sabatier, Toulouse, France

2. Institut National Polytechnique, Toulouse, France

3. IFP Energies Nouvelles, Solaize, France

4. Fundacion Tecnalia Research & Innovation, San Sebastián, Spain

5. Henkel KGaA, Düsseldorf, Germany

6. Johnson Matthey PLC, Reading, United Kingdom

7. Elkem Silicones France SAS, Solaize, France

8. Rhodia Operations, Saint Fons, France

9. BASF SE, Ludwigshafen, Germany

10. Italmatch Chemicals S.p.A., Arese, Italy

## Early Stage Researchers

ESR1 Pawel KRZESINSKI

ESR2 Joris LANGLOIS

ESR3 Irina BOZHINOVSKA

ESR4 Zinnia ARORA

ESR5 Sara BONFANTE

ESR6 Wimonsiri HUADSAI

ESR7 Anastasiia SHERSTIUK

ESR8 Paven KISTEN

ESR9 Chantal J. ABOU-FAYSSAL

ESR10 Joel CEJAS SÁNCHEZ

ESR11 Deepthy KRISHNAN

ESR12 Max MILEWSKI

ESR13 Massimo PETRICCONE

ESR14 Aswin CHANDRAN

ESR15 Agustin MORALES
<figure><img src="image_7.png" /></figure>

UAB

Universitat Autònoma
de Barcelona

<figure><img src="image_8.png" /></figure>

UNIVERSITY
of York

<figure><img src="image_9.png" /></figure>

UNIVERSITĂT
LEIPZIG

<figure><img src="image_10.png" /></figure>

UNIVERSITAT
ROVIRA I VIRGILI

<figure><img src="image_11.png" /></figure>

<figure><img src="image_12.png" /></figure>

Danmarks
Tekniske
Universitet

<figure><img src="image_13.png" /></figure>

<figure><img src="image_14.png" /></figure>

UNIVERSITATEA DIN
BUCUREŞTI
VIRTUTE ET APICIENIA

<figure><img src="image_15.png" /></figure>

<figure><img src="image_16.png" /></figure>

UNIVERSITÉ
TOULOUSE III

PAUL SABATIER

<figure><img src="image_17.png" /></figure>

Université
de Toulouse

BASF

We create chemistry

tecnal:a

MEMBER OF BASQUE RESEARCH
& TECHNOLOGY ALLIANCE

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

<figure><img src="image_21.png" /></figure>

Johnson Matthey

<figure><img src="image_22.png" /></figure>

Energies
nouvelles

<figure><img src="image_23.png" /></figure>

Elkem
A Bluestar Company
<figure><img src="image_6.png" /></figure>

UAB

Universitat Autònoma
de Barcelona

<figure><img src="image_7.png" /></figure>

UNIVERSITY
of York

<figure><img src="image_8.png" /></figure>

UNIVERSITĂT
LEIPZIG

<figure><img src="image_9.png" /></figure>

UNIVERSITAT
ROVIRA I VIRGILI

<figure><img src="image_10.png" /></figure>

<figure><img src="image_11.png" /></figure>

Danmarks
Tekniske
Universitet

<figure><img src="image_12.png" /></figure>

<figure><img src="image_13.png" /></figure>

UNIVERSITATEA DIN
BUCUREŞTI
VIRTUTE ET APICIENIA

<figure><img src="image_14.png" /></figure>

<figure><img src="image_15.png" /></figure>

UNIVERSITÉ
TOULOUSE III

PAUL SABATIER

<figure><img src="image_16.png" /></figure>

Université
de Toulouse

BASF
We create chemistry

tecnal:a
MEMBER OF BASQUE RESEARCH
& TECHNOLOGY ALLIANCE

<figure><img src="image_17.png" /></figure>

<figure><img src="image_18.png" /></figure>

<figure><img src="image_19.png" /></figure>

<figure><img src="image_20.png" /></figure>

Johnson Matthey

<figure><img src="image_21.png" /></figure>

ifP Energies
nouvelles

<figure><img src="image_22.png" /></figure>

Elkem
A Bluestar Company
# Table of Contents

<table><tbody><tr><td>ESR1.</td><td>N-Heterocyclic Carbene Ligands Designed for Improved Stability and Efficiency of Ruthenium-Based Olefin Metathesis Catalysts</td><td></td></tr><tr><td></td><td>Pawel Krzesinski</td><td>3</td></tr><tr><td>ESR2.</td><td>Towards The Direct Synthesis Of Chiral Amines Via Asymmetric Rhodium Catalyzed Hydroaminomethylation Reactions</td><td></td></tr><tr><td></td><td>Joris Langlois</td><td>21</td></tr><tr><td>ESR3.</td><td>s-Block Metal-Mediated Hydroelementation</td><td></td></tr><tr><td></td><td>Irina Bozhinovska</td><td>41</td></tr><tr><td>ESR4.</td><td>Carbon Nanomaterial Supported Metal Complexes and Nanoparticles for Asymmetric Catalysis</td><td></td></tr><tr><td></td><td>Zinnia Arora</td><td>59</td></tr><tr><td>ESR5.</td><td>Zirconium- and Phosphine-assisted C–F Bond Activation and Functionalisation</td><td></td></tr><tr><td></td><td>Sara Bonfante</td><td>79</td></tr><tr><td>ESR6.</td><td>Activation of Carbon Dioxide with Highly Lewis Acidic Compounds</td><td></td></tr><tr><td></td><td>Wimonsiri Huadsai</td><td>101</td></tr><tr><td>ESR7.</td><td>Photoswitchable phosphines for light-modulated metal catalysts</td><td></td></tr><tr><td></td><td>Anastasiia Sherstik</td><td>119</td></tr><tr><td>ESR8.</td><td>Ir'(η<sup>4</sup>-diene) Precatalyst Activation: Role of the Base</td><td></td></tr><tr><td></td><td>Paven Kisten</td><td>137</td></tr><tr><td>ESR9.</td><td>Metal Nanoparticles Embedded in Ligand- functionalized Water-soluble Core-shell Polymers for Application in Aqueous Biphasic Hydrogenation</td><td></td></tr><tr><td></td><td>Chantal J. Abou-Fayssal</td><td>155</td></tr><tr><td>ESR10.</td><td>Immobilization of Ruthenium Complexes on Supports. Applications in Catalysis</td><td></td></tr><tr><td></td><td>Joel Cejas Sánchez</td><td>181</td></tr><tr><td>ESR11.</td><td>Mono- and Bimetallic Nanoparticles Stabilized by Functionalized Ionic Liquids: Synthesis and Catalytic Applications</td><td></td></tr><tr><td></td><td>Deepthy Krishnan</td><td>201</td></tr><tr><td>ESR12.</td><td>Carboranylphosphines Meet Dendrimers: Electron-deficient Scaffolds for Ligand Design and Application in Catalysis</td><td></td></tr><tr><td></td><td>Max Milewski</td><td>221</td></tr><tr><td>ESR13.</td><td>Specifically Functionalized Dendrimers for Catalysis in Special Media</td><td></td></tr><tr><td></td><td>Massimo Petriccone</td><td>235</td></tr><tr><td>ESR14.</td><td>Coordination of Si–H and Ge–H Bonds to Ruthenium Metal Centres: Structure, Reactivity and Catalytic Applications</td><td></td></tr><tr><td></td><td>Aswin Chandran</td><td>255</td></tr><tr><td>ESR15.</td><td>Single Electron Reduction of NHC-CO<sub>2</sub> and NHC-CO<sub>2</sub>-BR<sub>3</sub> Adducts</td><td></td></tr><tr><td></td><td>Agustin Morales</td><td>273</td></tr></tbody></table>
# Table of Contents

<table><tbody><tr><td>ESR1.</td><td>N-Heterocyclic Carbene Ligands Designed for Improved Stability and Efficiency of Ruthenium-Based Olefin Metathesis Catalysts</td><td></td></tr><tr><td></td><td>Pawel Krzesinski</td><td>3</td></tr><tr><td>ESR2.</td><td>Towards The Direct Synthesis Of Chiral Amines Via Asymmetric Rhodium Catalyzed Hydroaminomethylation Reactions</td><td></td></tr><tr><td></td><td>Joris Langlois</td><td>21</td></tr><tr><td>ESR3.</td><td>s-Block Metal-Mediated Hydroelementation</td><td></td></tr><tr><td></td><td>Irina Bozhinovska</td><td>41</td></tr><tr><td>ESR4.</td><td>Carbon Nanomaterial Supported Metal Complexes and Nanoparticles for Asymmetric Catalysis</td><td></td></tr><tr><td></td><td>Zinnia Arora</td><td>59</td></tr><tr><td>ESR5.</td><td>Zirconium- and Phosphine-assisted C–F Bond Activation and Functionalisation</td><td></td></tr><tr><td></td><td>Sara Bonfante</td><td>79</td></tr><tr><td>ESR6.</td><td>Activation of Carbon Dioxide with Highly Lewis Acidic Compounds</td><td></td></tr><tr><td></td><td>Wimonsiri Huadsai</td><td>101</td></tr><tr><td>ESR7.</td><td>Photoswitchable phosphines for light-modulated metal catalysts</td><td></td></tr><tr><td></td><td>Anastasiia Sherstiu</td><td>119</td></tr><tr><td>ESR8.</td><td>Ir'(η<sup>4</sup>-diene) Precatalyst Activation: Role of the Base</td><td></td></tr><tr><td></td><td>Paven Kisten</td><td>137</td></tr><tr><td>ESR9.</td><td>Metal Nanoparticles Embedded in Ligand- functionalized Water-soluble Core-shell Polymers for Application in Aqueous Biphasic Hydrogenation</td><td></td></tr><tr><td></td><td>Chantal J. Abou-Fayssal</td><td>155</td></tr><tr><td>ESR10.</td><td>Immobilization of Ruthenium Complexes on Supports. Applications in Catalysis</td><td></td></tr><tr><td></td><td>Joel Cejas Sánchez</td><td>181</td></tr><tr><td>ESR11.</td><td>Mono- and Bimetallic Nanoparticles Stabilized by Functionalized Ionic Liquids: Synthesis and Catalytic Applications</td><td></td></tr><tr><td></td><td>Deepthy Krishnan</td><td>201</td></tr><tr><td>ESR12.</td><td>Carboranylphosphines Meet Dendrimers: Electron-deficient Scaffolds for Ligand Design and Application in Catalysis</td><td></td></tr><tr><td></td><td>Max Milewski</td><td>221</td></tr><tr><td>ESR13.</td><td>Specifically Functionalized Dendrimers for Catalysis in Special Media</td><td></td></tr><tr><td></td><td>Massimo Petriccone</td><td>235</td></tr><tr><td>ESR14.</td><td>Coordination of Si–H and Ge–H Bonds to Ruthenium Metal Centres: Structure, Reactivity and Catalytic Applications</td><td></td></tr><tr><td></td><td>Aswin Chandran</td><td>255</td></tr><tr><td>ESR15.</td><td>Single Electron Reduction of NHC-CO<sub>2</sub> and NHC-CO<sub>2</sub>-BR<sub>3</sub> Adducts</td><td></td></tr><tr><td></td><td>Agustin Morales</td><td>273</td></tr></tbody></table>
Preface

This book collates, in fifteen chapters, the extended abstracts of the Ph.D. theses defended by the Early Stage Researchers (ESRs) who participated in the Innovative Training Network (ITN) entitled "Coordination Chemistry Inspires Molecular Catalysis" (CCIMC), which was a Network of the "European Joint Doctorate" (EJD) type. This project was funded by the European Commission's Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement No 860322) and was active between March 1st, 2020 and February 29th, 2024.

The main aim of the CCIMC project was the ESRs' training on the basis of collaborative research projects and of an intense programme of training, comprising theoretical courses, tutorials, workshops, graded research reports, and the active participation of the ESRs in outreach and dissemination activities, as well as organizational efforts. Each ESR carried out his/her research jointly between two groups in two different research institutes (the Beneficiary Institutions) located in two different European countries. In addition, each ESR also received secondment research training in an industrial environment in one of the Partner Institutions (three months in most cases). At the end of their theses, the ESRs received a double or joint Doctorate Diploma on the basis of a bilateral agreement from the two academic institutions.

The research focus of the project was based on the development of catalytic processes, inspired by fundamental work in coordination chemistry. The various activities were classified in four work packages, covering the design and synthesis of innovative ligands, pre-catalyst development, new catalytic reactions and their mechanism, and the implementation of catalytic processes. The innovative ligand work package was particularly focused on N-heterocyclic carbenes (ESRs 1, 10, 15), on chirality (ESRs 2, 4, 8), on photoswitchable (ESR 7) and carborane-functionalized (ESR 12) phosphines, and on the immobilization of existing ligands on innovative supports such as nanostructured carbon materials (ESR 4), precision polymers (ESR 9), ionic liquids (ESR 11) and dendrimers (ESRs 10, 12, 13). Work on the pre-catalyst development comprised the implementation of the new ligands on known platforms for application in hydroaminomethylation (ESR 2), alkene metathesis (ESRs 1, 10), asymmetric (transfer) hydrogenation (ESR 8), and CO2 reduction (ESR 15), the development of new catalytic systems including s-block metal complexes (ESRs 3, 6), metal complexes stabilized by Ge-based ligands (ESR 14) and new or better size- and morphology-controlled metal nanoparticles (ESRs 4, 9, 11), and the implementation of new confinement strategies on supports such as carbon nanotubes and graphene (ESR 4), precision polymers (ESR 9), dendrimers (ESRs 10, 12, 13) and ionic liquids (ESR 11). The work package on new catalytic reactions and mechanisms comprised new bond activation strategies, with the transformation of substrates with C-F bonds (ESR 5), reactions with organocalcium reagents (ESR 6), the organogermanation reaction (ESR 14), and the reductive C-C bond formation from CO2 (ESR 15), as well as experimental and computational studies aimed at improving the Z-selectivity in olefin metathesis (ESR 1), the efficiency of tandem hydroaminomethylation (ESR 2), the stereocontrol in alkene hydroelementation (ESR 3), and at rationalizing the role of strong bases in the hydrogenation of polar substrates (ESR 8). Finally, work on the implementation of catalytic processes comprised the efforts towards achieving higher activities and/or new selectivities in known processes and to extend these to new substrates of industrial interest, all ESRs being involved in this project
# Preface

This book collates, in fifteen chapters, the extended abstracts of the Ph.D. theses defended by the Early Stage Researchers (ESRs) who participated in the Innovative Training Network (ITN) entitled "Coordination Chemistry Inspires Molecular Catalysis" (CCIMC), which was a Network of the "European Joint Doctorate" (EJD) type. This project was funded by the European Commission's Horizon 2020 Research and Innovation Programme (Marie Skłodowska-Curie grant agreement No 860322) and was active between March 1st, 2020 and February 29th, 2024.

The main aim of the CCIMC project was the ESRs' training on the basis of collaborative research projects and of an intense programme of training, comprising theoretical courses, tutorials, workshops, graded research reports, and the active participation of the ESRs in outreach and dissemination activities, as well as organizational efforts. Each ESR carried out his/her research jointly between two groups in two different research institutes (the Beneficiary Institutions) located in two different European countries. In addition, each ESR also received secondment research training in an industrial environment in one of the Partner Institutions (three months in most cases). At the end of their theses, the ESRs received a double or joint Doctorate Diploma on the basis of a bilateral agreement from the two academic institutions.

The research focus of the project was based on the development of catalytic processes, inspired by fundamental work in coordination chemistry. The various activities were classified in four work packages, covering the design and synthesis of innovative ligands, pre-catalyst development, new catalytic reactions and their mechanism, and the implementation of catalytic processes. The innovative ligand work package was particularly focused on N-heterocyclic carbenes (ESRs 1, 10, 15), on chirality (ESRs 2, 4, 8), on photoswitchable (ESR 7) and carborane-functionalized (ESR 12) phosphines, and on the immobilization of existing ligands on innovative supports such as nanostructured carbon materials (ESR 4), precision polymers (ESR 9), ionic liquids (ESR 11) and dendrimers (ESRs 10, 12, 13). Work on the pre-catalyst development comprised the implementation of the new ligands on known platforms for application in hydroaminomethylation (ESR 2), alkene metathesis (ESRs 1, 10), asymmetric (transfer) hydrogenation (ESR 8), and CO₂ reduction (ESR 15), the development of new catalytic systems including s-block metal complexes (ESRs 3, 6), metal complexes stabilized by Ge-based ligands (ESR 14) and new or better size- and morphology-controlled metal nanoparticles (ESRs 4, 9, 11), and the implementation of new confinement strategies on supports such as carbon nanotubes and graphene (ESR 4), precision polymers (ESR 9), dendrimers (ESRs 10, 12, 13) and ionic liquids (ESR 11). The work package on new catalytic reactions and mechanisms comprised new bond activation strategies, with the transformation of substrates with C-F bonds (ESR 5), reactions with organocalcium reagents (ESR 6), the organogermanation reaction (ESR 14), and the reductive C-C bond formation from CO₂ (ESR 15), as well as experimental and computational studies aimed at improving the Z-selectivity in olefin metathesis (ESR 1), the efficiency of tandem hydroaminomethylation (ESR 2), the stereocontrol in alkene hydroelementation (ESR 3), and at rationalizing the role of strong bases in the hydrogenation of polar substrates (ESR 8). Finally, work on the implementation of catalytic processes comprised the efforts towards achieving higher activities and/or new selectivities in known processes and to extend these to new substrates of industrial interest, all ESRs being involved in this project.
objective. The fifteen chapters collected in this book give a brief overview of the main objectives and
results obtained by each student.

We had the privilege and pleasure to coordinate this ITN-EJD, even though our task was not
simple at the beginning: soon after the kickoff meeting, which took place at the beginning or March
2020, the Covid-19 pandemic broke out in Europe, significantly complicating not only the experimental
work in the laboratories but also and especially the planned networking program. All interviews leading
to the recruitment of the 15 ESRs and all networking activities for the first two years (1-week long
events had been planned every 6 months), including the mid-term evaluation by the Project Office of
the European Commission, had to be carried out online. Therefore, the ESRs did not have any
opportunity to spend time together as a group until the pandemic faded away in the Spring of 2022.
In spite of that, and thanks to the good will of the students and their supervisors, the project could be
implemented more or less as initially planned. The fifteen ESRs finally managed to meet and spend
exciting moments together, developing lifelong friendships.

The success of this ITN project would not have been possible without the devoted implication
of our full-time projet managers, first Candice George during the first 9 months and then Alida Lefter
for the remainder of the project time, and beyond. We express our most heartfelt gratitude to these
two outstanding coworkers for having made our Network coordination so smooth, taking off our
shoulder such painful tasks as building and maintaining the web site, establishing the consortium
agreement, leading the negociations to establish the bilateral agreements and the amendments
thereof, writing and uploading the project deliverables, organizing the Network events, and so forth.
Our thanks also go to our academic colleagues and friends, who have supervised the research projects
of the ESRs and have efficiently helped us manage the work packages and scientific tasks of the ITN. In
addition, we wish to acknowledge and thank all the constructive input received from Jan Bäckvall,
Matthias Beller and Giuliano Giambastiani, the three members of our Advisory Board, during our
annual meetings with them.

Our most heartfelt feelings are for the fifteen ESRs. We are proud of what each one of them has
become. We look forward to witnessing their future development and wish them success in their
personal and professional endeavours.

We hope that reading this book will be enyoable and perhaps inspirational for your own research
efforts.

Anne-Marie CAMINADE

CCIMC Deputy Coordinator

Rinaldo POLI

CCIMC Coordinator
objective. The fifteen chapters collected in this book give a brief overview of the main objectives and
results obtained by each student.

We had the privilege and pleasure to coordinate this ITN-EJD, even though our task was not
simple at the beginning: soon after the kickoff meeting, which took place at the beginning or March
2020, the Covid-19 pandemic broke out in Europe, significantly complicating not only the experimental
work in the laboratories but also and especially the planned networking program. All interviews leading
to the recruitment of the 15 ESRs and all networking activities for the first two years (1-week long
events had been planned every 6 months), including the mid-term evaluation by the Project Office of
the European Commission, had to be carried out online. Therefore, the ESRs did not have any
opportunity to spend time together as a group until the pandemic faded away in the Spring of 2022.
In spite of that, and thanks to the good will of the students and their supervisors, the project could be
implemented more or less as initially planned. The fifteen ESRs finally managed to meet and spend
exciting moments together, developing lifelong friendships.

The success of this ITN project would not have been possible without the devoted implication
of our full-time projet managers, first Candice George during the first 9 months and then Alida Lefter
for the remainder of the project time, and beyond. We express our most heartfelt gratitude to these
two outstanding coworkers for having made our Network coordination so smooth, taking off our
shoulder such painful tasks as building and maintaining the web site, establishing the consortium
agreement, leading the negociations to establish the bilateral agreements and the amendments
thereof, writing and uploading the project deliverables, organizing the Network events, and so forth.
Our thanks also go to our academic colleagues and friends, who have supervised the research projects
of the ESRs and have efficiently helped us manage the work packages and scientific tasks of the ITN. In
addition, we wish to acknowledge and thank all the constructive input received from Jan Bäckvall,
Matthias Beller and Giuliano Giambastiani, the three members of our Advisory Board, during our
annual meetings with them.

Our most heartfelt feelings are for the fifteen ESRs. We are proud of what each one of them has
become. We look forward to witnessing their future development and wish them success in their
personal and professional endeavours.

We hope that reading this book will be enyoable and perhaps inspirational for your own research
efforts.

Anne-Marie CAMINADE

CCIMC Deputy Coordinator

Rinaldo POLI

CCIMC Coordinator
Pawel KRZESINSKI

ESR1

**Thesis co-directors**

Dr. Vincent César Laboratoire de Chimie de Coordination, Toulouse, France

Prof. Karol Grela Uniwersytet Warszawski, Warsaw, Poland

**Thesis defense**

Laboratoire de Chimie de Coordination, Toulouse, France, 12 February 2024
Pawel KRZESINSKI

ESR1

**Thesis co-directors**

Dr. Vincent César Laboratoire de Chimie de Coordination, Toulouse, France

Prof. Karol Grela Uniwersytet Warszawski, Warsaw, Poland

**Thesis defense**

Laboratoire de Chimie de Coordination, Toulouse, France, 12 February 2024
<figure><img src="image_24.png" /></figure>
<figure><img src="image_23.png" /></figure>
# N-Heterocyclic Carbene Ligands Designed for Improved Stability and Efficiency of Ruthenium-Based Olefin Metathesis Catalysts

## Introduction

No doubt catalysis is one of the most relevant tools used in the chemical industry, allowing to obtain a myriad of sometimes otherwise inaccessible molecules. Homogeneous catalysis has the advantage of more precise characterization of catalysts and intermediates which makes it more suitable for rational design. Catalyst's auxiliary ligands play a significant role in defining the activity, selectivity and stability of the resulting catalysts [1].

Almost all chemical reactions consist of a series of elementary steps, defined as a direct transformation of reactant molecules into products through a single transition state. Such a sequence of elementary steps is called a reaction mechanism and when it describes forms of catalyst, it is referred to as a catalytic cycle. A precatalyst is a stable compound that is used to generate the active catalyst in situ by a sort of activation process. An off-loop species is defined as a complex in equilibrium with a catalytic intermediate but itself not involved in the catalytic cycle. Finally, when the formation of an off-loop species is irreversible, catalyst deactivation takes place and the formed compound is called a dead or deactivated catalyst [2].

N-heterocyclic carbenes (NHCs) are neutral divalent carbon species having six valence electrons and at least one adjacent nitrogen atom. Nitrogen atoms are at the same time σ-electron-withdrawing and π-electron-donating. As a result, NHCs are singlet carbenes. One of the most significant advantages of NHCs is their relatively facile synthetic modularity which allows tuning of the ligand steric and electronic properties [3]. The overall electron-donating ability of the NHC ligands can be quantified by recording the average stretching frequency of the carbonyl ligands in complexes of nickel, rhodium and iridium [4]. The σ-donating properties can be assessed by measuring the ¹J(C–H) coupling constant between the carbon and the hydrogen atoms on the pre-carbenic position in the azolium precursors [5]. Furthermore, π-accepting abilities of the NHCs can be independently determined by recording the chemical shift of ⁷⁷Se nuclei in corresponding seleno adducts [6].

Olefin metathesis (OM) is a carbon skeleton redistribution around an unsaturated carbon–carbon double bond by its scission and regeneration. The reaction is catalyzed by a transition metal complex. Considering ruthenium-based OM catalyst, the impact made by NHC ligands on this domain was arguably the greatest of all when compared with other transition metal catalysis. In 2005 Chauvin, Grubbs and Schrock were honored with The Nobel Prize in Chemistry for the development of the metathesis method in organic synthesis. Despite the incredible progress made in the discipline, there are still many hurdles to overcome, such as reaction stereoselectivity or the formation of tetrasubstituted carbon–carbon double bonds.

## Objectives of the thesis

The work described here aimed at NHC ligand design to give more stable, durable and thus more efficient OM catalysts. Two strategies were investigated to enhance the stability of corresponding NHC OM catalysts.

The first strategy builds on the solution presented by Grubbs and coworkers for a Z-selective OM catalyst bearing a chelating LX-type NHC ligand (Ru21, Scheme 1) [7]. The biggest weakness of those complexes derives from the presence of a ruthenium-alkyl bond which makes them prone to
# N-Heterocyclic Carbene Ligands Designed for Improved Stability and Efficiency of Ruthenium-Based Olefin Metathesis Catalysts

## Introduction

No doubt catalysis is one of the most relevant tools used in the chemical industry, allowing to obtain a myriad of sometimes otherwise inaccessible molecules. Homogeneous catalysis has the advantage of more precise characterization of catalysts and intermediates which makes it more suitable for rational design. Catalyst's auxiliary ligands play a significant role in defining the activity, selectivity and stability of the resulting catalysts [1].

Almost all chemical reactions consist of a series of elementary steps, defined as a direct transformation of reactant molecules into products through a single transition state. Such a sequence of elementary steps is called a reaction mechanism and when it describes forms of catalyst, it is referred to as a catalytic cycle. A precatalyst is a stable compound that is used to generate the active catalyst in situ by a sort of activation process. An off-loop species is defined as a complex in equilibrium with a catalytic intermediate but itself not involved in the catalytic cycle. Finally, when the formation of an off-loop species is irreversible, catalyst deactivation takes place and the formed compound is called a dead or deactivated catalyst [2].

N-heterocyclic carbenes (NHCs) are neutral divalent carbon species having six valence electrons and at least one adjacent nitrogen atom. Nitrogen atoms are at the same time σ-electron-withdrawing and π-electron-donating. As a result, NHCs are singlet carbenes. One of the most significant advantages of NHCs is their relatively facile synthetic modularity which allows tuning of the ligand steric and electronic properties [3]. The overall electron-donating ability of the NHC ligands can be quantified by recording the average stretching frequency of the carbonyl ligands in complexes of nickel, rhodium and iridium [4]. The σ-donating properties can be assessed by measuring the ¹J(C–H) coupling constant between the carbon and the hydrogen atoms on the pre-carbenic position in the azolium precursors [5]. Furthermore, π-accepting abilities of the NHCs can be independently determined by recording the chemical shift of ⁷⁷Se nuclei in corresponding seleno adducts [6].

Olefin metathesis (OM) is a carbon skeleton redistribution around an unsaturated carbon–carbon double bond by its scission and regeneration. The reaction is catalyzed by a transition metal complex. Considering ruthenium-based OM catalyst, the impact made by NHC ligands on this domain was arguably the greatest of all when compared with other transition metal catalysis. In 2005 Chauvin, Grubbs and Schrock were honored with The Nobel Prize in Chemistry for the development of the metathesis method in organic synthesis. Despite the incredible progress made in the discipline, there are still many hurdles to overcome, such as reaction stereoselectivity or the formation of tetrasubstituted carbon–carbon double bonds.

## Objectives of the thesis

The work described here aimed at NHC ligand design to give more stable, durable and thus more efficient OM catalysts. Two strategies were investigated to enhance the stability of corresponding NHC OM catalysts.

The first strategy builds on the solution presented by Grubbs and coworkers for a Z-selective OM catalyst bearing a chelating LX-type NHC ligand (Ru21, Scheme 1) [7]. The biggest weakness of those complexes derives from the presence of a ruthenium-alkyl bond which makes them prone to
undergo decomposition pathways involving alkylidene ligand insertion into ruthenium-alkyl bond [8,9]. This work aimed at obtaining an OM catalyst bearing chelating NHC with a more stable ruthenium-carbon(sp³) bond. We envisaged that changing the adamantyl group to a more stabilized carbon ligand would result in a more durable catalyst. With those objectives in mind, we investigated the synthesis of bidentate NHC ligands comprising either a barbituric heterocycle (axis A) or *N*-heterocyclic olefin (NHO) moiety (axis B).

The imidazopyridinylidene NHC containing a barbituric heterocycle was chosen since it has proven a versatile platform for $d^6$ [Ru(II), Mn(I)] or $d^8$ [Pd(II), Rh(I), Ir(I), Au(III)] transition-metal centers, giving access to stable metal complexes [10]. However, the NHC-NHO ligand architecture is a completely novel approach and thus also interesting from the basic science perspective than application. Furthermore, the domain of NHO ligands is much less explored than the NHC field and examples of well-defined metal NHO complexes remain rather rare in literature [11].

<figure><img src="image_25.png" /><figcaption>**Scheme 1.** The concept for a robust Z-selective OM catalyst.</figcaption></figure>

The second strategy aimed at robust and efficient catalysts for the formation of tetrasubstituted carbon-carbon double bonds (Scheme 2). The commonly utilized approach is based on specialized ruthenium catalysts with sterically reduced NHC ligands, able to accommodate more crowded olefinic substrates during the catalytic steps (e.g. **Ru-67**) [12]. Yet, although highly active, these complexes are rather unstable, mainly due to intramolecular C-H activation at the ortho position of an *N*-aryl group of the NHC ligand, leading to catalyst deactivation [13]. Considering that the deleterious C-H activation process requires the rotation of the *N*-aryl arm of the NHC ligand, we reasoned that the introduction of a second decker of aromatic groups in benzimidazolylidene-based *N*-phenyl NHC ligands would improve the stability and efficiency of the corresponding catalyst, while their activity in the challenging metathesis of sterically crowded bonds would be maintained. We also wanted to explore whether $\pi-\pi$ stacking interactions would contribute to blocking the rotation. For those purposes, attempted was the installation of phenyl groups into the backbone since the synthesis should be relatively feasible (**Ru-68**), but also pentafluorophenyl groups since it should result in stronger $\pi-\pi$ interactions (**Ru-69**).
undergo decomposition pathways involving alkylidene ligand insertion into ruthenium-alkyl bond [8,9]. This work aimed at obtaining an OM catalyst bearing chelating NHC with a more stable ruthenium-carbon(sp³) bond. We envisaged that changing the adamantyl group to a more stabilized carbon ligand would result in a more durable catalyst. With those objectives in mind, we investigated the synthesis of bidentate NHC ligands comprising either a barbituric heterocycle (axis A) or *N*-heterocyclic olefin (NHO) moiety (axis B).

The imidazopyridinylidene NHC containing a barbituric heterocycle was chosen since it has proven a versatile platform for $d^6$ [Ru(II), Mn(I)] or $d^8$ [Pd(II), Rh(I), Ir(I), Au(III)] transition-metal centers, giving access to stable metal complexes [10]. However, the NHC-NHO ligand architecture is a completely novel approach and thus also interesting from the basic science perspective than application. Furthermore, the domain of NHO ligands is much less explored than the NHC field and examples of well-defined metal NHO complexes remain rather rare in literature [11].

<figure><img src="image_24.png" /><figcaption>**Scheme 1.** The concept for a robust Z-selective OM catalyst.</figcaption></figure>

The second strategy aimed at robust and efficient catalysts for the formation of tetrasubstituted carbon-carbon double bonds (Scheme 2). The commonly utilized approach is based on specialized ruthenium catalysts with sterically reduced NHC ligands, able to accommodate more crowded olefinic substrates during the catalytic steps (e.g. **Ru-67**) [12]. Yet, although highly active, these complexes are rather unstable, mainly due to intramolecular C-H activation at the ortho position of an *N*-aryl group of the NHC ligand, leading to catalyst deactivation [13]. Considering that the deleterious C-H activation process requires the rotation of the *N*-aryl arm of the NHC ligand, we reasoned that the introduction of a second decker of aromatic groups in benzimidazolylidene-based *N*-phenyl NHC ligands would improve the stability and efficiency of the corresponding catalyst, while their activity in the challenging metathesis of sterically crowded bonds would be maintained. We also wanted to explore whether $\pi-\pi$ stacking interactions would contribute to blocking the rotation. For those purposes, attempted was the installation of phenyl groups into the backbone since the synthesis should be relatively feasible (**Ru-68**), but also pentafluorophenyl groups since it should result in stronger $\pi-\pi$ interactions (**Ru-69**).
<figure><img src="image_26.png" /><figcaption>**Scheme 2.** The concept for robust OM catalyst for the formation of tetrasubstituted carbon-carbon double bonds.</figcaption></figure>

The last part of the work describes a potential application of the obtained catalytic systems in the synthesis of bio-based polyesters and polyamides (Scheme 3). To demonstrate the applicability of this study, a technical grade methyl oleate (28) was used as the starting material for the self-cross metathesis step. Such material derives from broadly available sunflower or rapeseed oil and contains a substantial amount (20 wt%) of methyl linoleate (94), which is the most abundant polyunsaturated fatty acid methyl ester (FAME). The resulting dimethyl octadec-9-enedioate (29) was used in a subsequent polycondensation reaction to obtain polymeric materials. In this research, we used commercially available catalysts and catalysts developed in the latter part.

<figure><img src="image_27.png" /><figcaption>**Scheme 3.** A) Proposed process of the synthesis of biobased polyesters and polyamides by self-CM of technical grade methyl oleate (28) and subsequent polycondensation reaction. B) Catalysts used in the study.</figcaption></figure>

## Ruthenium complexes supported by a chelating NHC ligand comprising a barbituric heterocycle

In this project complex **Ru-54** was studied as a metal precursor since its methallyl ligands could serve as an internal base to deprotonate the imidazopyridinium precursor **31** to form a ruthenium-NHC complex. The reaction of complex **Ru-54** with two equivalents of precursor **31** led to the formation of the stable complex **Ru-56** in 30 % isolated yield (Scheme 4). Indeed, the methallyl moiety of **Ru-54** served as an internal base to deprotonate the imidazopiridinium position of **31** and form a desired ruthenium-NHC complex. However, the reaction did not stop after the first protonolysis step and the second methallyl group was spent on the cyclometallation of the *ortho*-methyl group of the mesityl N-substituent. Surprisingly, rather than retain the cyclooctadiene (COD) ligand the metal center was stabilized by the coordination of a second molecule of imidazopyridinium precursor **31**. Interestingly, the coordination sphere was stabilized by the η³ coordination mode of the carbon-carbon-oxygen part of the malonate giving the 18e⁻ complex **Ru-56**.

In the next step, we attempted to cleave the ruthenium-mesityl bond with the use of pivalic acid. Indeed, the reaction gave the complex **Ru-57** with free N-mesityl group, however, the coordination mode of barbituric heterocycle changed to η¹. Interestingly, when PPh₃ was added along
<figure><img src="image_25.png" /><figcaption>**Scheme 2.** The concept for robust OM catalyst for the formation of tetrasubstituted carbon-carbon double bonds.</figcaption></figure>

The last part of the work describes a potential application of the obtained catalytic systems in the synthesis of bio-based polyesters and polyamides (Scheme 3). To demonstrate the applicability of this study, a technical grade methyl oleate (28) was used as the starting material for the self-cross metathesis step. Such material derives from broadly available sunflower or rapeseed oil and contains a substantial amount (20 wt%) of methyl linoleate (94), which is the most abundant polyunsaturated fatty acid methyl ester (FAME). The resulting dimethyl octadec-9-enedioate (29) was used in a subsequent polycondensation reaction to obtain polymeric materials. In this research, we used commercially available catalysts and catalysts developed in the latter part.

<figure><img src="image_26.png" /><figcaption>**Scheme 3.** A) Proposed process of the synthesis of biobased polyesters and polyamides by self-CM of technical grade methyl oleate (28) and subsequent polycondensation reaction. B) Catalysts used in the study.</figcaption></figure>

## Ruthenium complexes supported by a chelating NHC ligand comprising a barbituric heterocycle

In this project complex **Ru-54** was studied as a metal precursor since its methallyl ligands could serve as an internal base to deprotonate the imidazopyridinium precursor **31** to form a ruthenium-NHC complex. The reaction of complex **Ru-54** with two equivalents of precursor **31** led to the formation of the stable complex **Ru-56** in 30 % isolated yield (Scheme 4). Indeed, the methallyl moiety of **Ru-54** served as an internal base to deprotonate the imidazopiridinium position of **31** and form a desired ruthenium-NHC complex. However, the reaction did not stop after the first protonolysis step and the second methallyl group was spent on the cyclometallation of the *ortho*-methyl group of the mesityl N-substituent. Surprisingly, rather than retain the cyclooctadiene (COD) ligand the metal center was stabilized by the coordination of a second molecule of imidazopyridinium precursor **31**. Interestingly, the coordination sphere was stabilized by the η³ coordination mode of the carbon-carbon-oxygen part of the malonate giving the 18e⁻ complex **Ru-56**.

In the next step, we attempted to cleave the ruthenium-mesityl bond with the use of pivalic acid. Indeed, the reaction gave the complex **Ru-57** with free N-mesityl group, however, the coordination mode of barbituric heterocycle changed to η¹. Interestingly, when PPh₃ was added along
with pivalic acid, this resulted in complex **Ru-58** with η³ coordinated barbituric heterocycle. Furthermore, the steric bulk imposed by the barbituric heterocycle resulted in a *cis*-coordinated PPh₃ ligand with respect to the NHC.

At last, we attempted the installation of the pyridine ligand in the hope of having a labile functionality suitable for the introduction of an alkylidene ligand. Indeed, the reaction of **Ru-57** with dry pyridine gave the complex **Ru-59** with two pyridine ligands coordinated, however, the crystal structure of **Ru-59** revealed a molecule of water coordinated as well. Since a dry substrate was used for this reaction, most probably the water was introduced during the working up of the reaction. All four new complexes were characterized using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffractometry (XRD).

<figure><img src="image_28.png" /><figcaption>**Scheme 4.** Synthesis of ruthenium complexes **Ru-56**-**Ru-59** bearing the chelating NHC ligand. Reaction conditions: a) 2 equiv. of **31**, 1 equiv. of **Ru-54**, THF, 90 °C, 2 h; b) 2.2 equiv. $^tBuCO_2H$, THF, 80 °C, 15 h; c) 1.2 equiv. PPh₃, 1.2 equiv. $^tBuCO_2H$, DCE, 80 °C, 6 h; d) dry pyridine (excess), 80 °C, 2 h.</figcaption></figure>

With the small library of ruthenium complexes bearing the targeted NHC ligand, the installation of an alkylidene ligand was attempted. First, the reaction of complexes **Ru-57**-**Ru-59** with diazomethane derivative **34** was tried, however, no reactivity was observed with the starting complexes remaining unchanged (Scheme 5A). Even the very promising pyridine derivative **Ru-59** exhibited no reactivity with **34**. Next, we attempted a reaction with propargyl alcohol **18** at 80 °C. This time a reactivity of the starting complexes was observed, however, no product could be isolated and characterized because a complex mixture of unidentified species was formed. At last, we turned our attention to phenylacetylene (Scheme 5B) as an alkylidene precursor. Quite similar reactivity pattern was observed to the reaction with **18** in the sense that a mixture of products was formed. However, this time it was possible to isolate the major product **Ru-60** from the reaction of **Ru-57** with phenylacetylene. Indeed, **Ru-60** contained an alkylidene functionality in its structure, however, an unexpected tetramerization of phenylacetylene occurred to form a cyclopentadienyl unit whose η⁵ coordination replaced the pivalic anion giving the piano stool complex **Ru-60** whose structure was confirmed by XRD.
with pivalic acid, this resulted in complex **Ru-58** with η³ coordinated barbituric heterocycle. Furthermore, the steric bulk imposed by the barbituric heterocycle resulted in a *cis*-coordinated PPh₃ ligand with respect to the NHC.

At last, we attempted the installation of the pyridine ligand in the hope of having a labile functionality suitable for the introduction of an alkylidene ligand. Indeed, the reaction of **Ru-57** with dry pyridine gave the complex **Ru-59** with two pyridine ligands coordinated, however, the crystal structure of **Ru-59** revealed a molecule of water coordinated as well. Since a dry substrate was used for this reaction, most probably the water was introduced during the working up of the reaction. All four new complexes were characterized using nuclear magnetic resonance (NMR) spectroscopy and X-ray diffractometry (XRD).

<figure><img src="image_27.png" /><figcaption>**Scheme 4.** Synthesis of ruthenium complexes **Ru-56**-**Ru-59** bearing the chelating NHC ligand. Reaction conditions: a) 2 equiv. of **31**, 1 equiv. of **Ru-54**, THF, 90 °C, 2 h; b) 2.2 equiv. $^tBuCO_2H$, THF, 80 °C, 15 h; c) 1.2 equiv. PPh₃, 1.2 equiv. $^tBuCO_2H$, DCE, 80 °C, 6 h; d) dry pyridine (excess), 80 °C, 2 h.</figcaption></figure>

With the small library of ruthenium complexes bearing the targeted NHC ligand, the installation of an alkylidene ligand was attempted. First, the reaction of complexes **Ru-57-Ru-59** with diazomethane derivative **34** was tried, however, no reactivity was observed with the starting complexes remaining unchanged (Scheme 5A). Even the very promising pyridine derivative **Ru-59** exhibited no reactivity with **34**. Next, we attempted a reaction with propargyl alcohol **18** at 80 °C. This time a reactivity of the starting complexes was observed, however, no product could be isolated and characterized because a complex mixture of unidentified species was formed. At last, we turned our attention to phenylacetylene (Scheme 5B) as an alkylidene precursor. Quite similar reactivity pattern was observed to the reaction with **18** in the sense that a mixture of products was formed. However, this time it was possible to isolate the major product **Ru-60** from the reaction of **Ru-57** with phenylacetylene. Indeed, **Ru-60** contained an alkylidene functionality in its structure, however, an unexpected tetramerization of phenylacetylene occurred to form a cyclopentadienyl unit whose η⁵ coordination replaced the pivalic anion giving the piano stool complex **Ru-60** whose structure was confirmed by XRD.
<figure><img src="image_29.png" /><figcaption>**Scheme 5.** A) Attempts of reaction of complexes **Ru-57-Ru-59** with either diazomethane derivative **34** or propargyl alcohol derivative **18**. B) Reaction of complex **Ru-57** with phenylacetylene.</figcaption></figure>

In summary, several ruthenium complexes bearing the targeted chelating NHC-barbiturate ligand were successfully synthesized. Depending on the nature of the other ligands present in the structure it was found that the barbiturate-derived NHC can flexibly accommodate between η¹ coordination mode *via* malonate carbon and η³ *via* carbon-carbon-oxygen part of the malonate in order to stabilize the coordination sphere. Furthermore, the NHC-barbiturate ligand can even adopt a tetradentate coordination mode when the benzylic position of the *N*-mesityl NHC's substituent is cyclometalated (structure **Ru-56**).

It was possible to install an alkylidene ligand to a ruthenium complex bearing the chelating NHC-barbiturate ligand, however, an unexpected tetramerization of phenylacetylene occurred leading to the formation of a cyclopentadienyl co-ligand (complex **Ru-60**). Possibly isolation of complex **Ru-60** results from a preferred formation of ruthenium dicarbene species rather than the expected vinylidene complex.

## NHC-NHO ligand architecture

This project was started by the synthesis of the NHC-NHO ligand precursor **48** bearing an NHC and NHO pre-functionalities connected *via* two $CH_2$ units (Scheme 6). From dimethylimidazolium iodide (**45**) the corresponding dimethylimidazolylidiene NHC was formed by the deprotonation with lithium hexamethyldisilazide (LiHMDS) which next in a nucleophilic substitution reaction with 1,3-dibromopropane (**46**) and subsequent Finkelstein reaction gave the expected compound **47**. At last, ligand precursor **48** was obtained in the nucleophilic substitution reaction of **47** and *N*-mesitylimidazoline. The structure of **48** was confirmed by XRD.

With the NHC-NHO ligand precursor **48** in hand, the synthesis of the corresponding NHC-ruthenium OM catalyst (**Ru-66**, Scheme 7A) was attempted. However, no displacement of the $PCy_3$ ligand from complex **Ru-9** by the postulated *in situ* generated NHC ligand derived from **48** was observed. We decided to shift at this point from the attempts to synthesize the corresponding ruthenium NHC catalysts and focus on a general study of the novel NHC-NHO ligand architecture.
<figure><img src="image_28.png" /><figcaption>**Scheme 5.** A) Attempts of reaction of complexes **Ru-57-Ru-59** with either diazomethane derivative **34** or propargyl alcohol derivative **18**. B) Reaction of complex **Ru-57** with phenylacetylene.</figcaption></figure>

In summary, several ruthenium complexes bearing the targeted chelating NHC-barbiturate ligand were successfully synthesized. Depending on the nature of the other ligands present in the structure it was found that the barbiturate-derived NHC can flexibly accommodate between η¹ coordination mode *via* malonate carbon and η³ *via* carbon-carbon-oxygen part of the malonate in order to stabilize the coordination sphere. Furthermore, the NHC-barbiturate ligand can even adopt a tetradentate coordination mode when the benzylic position of the *N*-mesityl NHC's substituent is cyclometalated (structure **Ru-56**).

It was possible to install an alkylidene ligand to a ruthenium complex bearing the chelating NHC-barbiturate ligand, however, an unexpected tetramerization of phenylacetylene occurred leading to the formation of a cyclopentadienyl co-ligand (complex **Ru-60**). Possibly isolation of complex **Ru-60** results from a preferred formation of ruthenium dicarbene species rather than the expected vinylidene complex.

## NHC-NHO ligand architecture

This project was started by the synthesis of the NHC-NHO ligand precursor **48** bearing an NHC and NHO pre-functionalities connected *via* two $CH_2$ units (Scheme 6). From dimethylimidazolium iodide (**45**) the corresponding dimethylimidazolylidiene NHC was formed by the deprotonation with lithium hexamethyldisilazide (LiHMDS) which next in a nucleophilic substitution reaction with 1,3-dibromopropane (**46**) and subsequent Finkelstein reaction gave the expected compound **47**. At last, ligand precursor **48** was obtained in the nucleophilic substitution reaction of **47** and *N*-mesitylimidazoline. The structure of **48** was confirmed by XRD.

With the NHC-NHO ligand precursor **48** in hand, the synthesis of the corresponding NHC-ruthenium OM catalyst (**Ru-66**, Scheme 7A) was attempted. However, no displacement of the $PCy_3$ ligand from complex **Ru-9** by the postulated *in situ* generated NHC ligand derived from **48** was observed. We decided to shift at this point from the attempts to synthesize the corresponding ruthenium NHC catalysts and focus on a general study of the novel NHC-NHO ligand architecture.
<figure><img src="image_30.png" /><figcaption>**Scheme 6.** The synthesis of the second NHC-NHO ligand precursor **48** and its XRD structure (ellipsoids are drawn at 50% probability, hydrogens were omitted for clarity); reaction conditions: d) 1.05 equiv. of LiHMDS, THF, rt, 80 min.; e) 20 equiv. of **46**, -80 °C to rt, overnight. f) 5 equiv. of NaI, acetone, rt, overnight; g) 1.3 equiv. of **40**, MeCN, 90 °C, overnight; h) 3.4 equiv. of AgCl, water, rt, 30 min.; i) 5.6 equiv. of KPF<sub>6</sub>, DCM, 40 °C, 7 days.</figcaption></figure>

To better understand why the complex **Ru-66** was not formed, reactivity studies of the NHC-NHO were performed. We found that once the imidazolinium position of **48** is deprotonated the formed NHC **51** can undergo two competing reactions (Scheme 7B). **51** can either form the desired complex with the electrophile (**52**), however, the imidozolinylidene ring can open due to the presence of traces of water, which gives *N*-formylated product **50**. It became clear at this point why the synthesis of the ruthenium-NHC complex **Ru-66** failed. The energy barrier of PCy<sub>3</sub> replacement with an NHC in the structure of **Ru-9** is usually relatively high as heating is required. Consequently, the formation of the side product **50** is preferred instead.

<figure><img src="image_31.png" /><figcaption>**Scheme 7.** A) The attempted synthesis of **Ru-66**. B) Proposed explanation for the observed reactivity of carbene **51**.</figcaption></figure>

Learning the general reactivity pattern of our ligand, we set off to synthesize a metal complex bearing the targeted ligand coordinated in a monodentate mode through NHC and next attempt the coordination of the NHO moiety. We hypothesized that a dimeric structure of metal precursor might be reactive enough to give a metal-NHC complex in a good yield. Rhodium(I) metal center was chosen as the corresponding NHC complex should be air-stable, isolatable by column chromatography (CC) and after installation of CO ligands allow for measuring the ligand's electronic properties. Indeed, utilizing dimeric rhodium precursor **Rh-1** proved to be a good strategy and gave the rhodium-NHC complex **Rh-2** isolated by CC in 73 % yield (Scheme 8A). The structure of **Rh-2** was confirmed by XRD (Scheme 8B).

In the next step, deprotonation of the α-imidazolium position was attempted in the hope of forming the corresponding NHO complex. When the reaction was performed in THF, although complex
<figure><img src="image_29.png" /><figcaption>**Scheme 6.** The synthesis of the second NHC-NHO ligand precursor **48** and its XRD structure (ellipsoids are drawn at 50% probability, hydrogens were omitted for clarity); reaction conditions: d) 1.05 equiv. of LiHMDS, THF, rt, 80 min.; e) 20 equiv. of **46**, -80 °C to rt, overnight. f) 5 equiv. of NaI, acetone, rt, overnight; g) 1.3 equiv. of **40**, MeCN, 90 °C, overnight; h) 3.4 equiv. of AgCl, water, rt, 30 min.; i) 5.6 equiv. of KPF<sub>6</sub>, DCM, 40 °C, 7 days.</figcaption></figure>

To better understand why the complex **Ru-66** was not formed, reactivity studies of the NHC-NHO were performed. We found that once the imidazolinium position of **48** is deprotonated the formed NHC **51** can undergo two competing reactions (Scheme 7B). **51** can either form the desired complex with the electrophile (**52**), however, the imidozolinylidene ring can open due to the presence of traces of water, which gives *N*-formylated product **50**. It became clear at this point why the synthesis of the ruthenium-NHC complex **Ru-66** failed. The energy barrier of PCy<sub>3</sub> replacement with an NHC in the structure of **Ru-9** is usually relatively high as heating is required. Consequently, the formation of the side product **50** is preferred instead.

<figure><img src="image_30.png" /><figcaption>**Scheme 7.** A) The attempted synthesis of **Ru-66**. B) Proposed explanation for the observed reactivity of carbene **51**.</figcaption></figure>

Learning the general reactivity pattern of our ligand, we set off to synthesize a metal complex bearing the targeted ligand coordinated in a monodentate mode through NHC and next attempt the coordination of the NHO moiety. We hypothesized that a dimeric structure of metal precursor might be reactive enough to give a metal-NHC complex in a good yield. Rhodium(I) metal center was chosen as the corresponding NHC complex should be air-stable, isolatable by column chromatography (CC) and after installation of CO ligands allow for measuring the ligand's electronic properties. Indeed, utilizing dimeric rhodium precursor **Rh-1** proved to be a good strategy and gave the rhodium-NHC complex **Rh-2** isolated by CC in 73 % yield (Scheme 8A). The structure of **Rh-2** was confirmed by XRD (Scheme 8B).

In the next step, deprotonation of the α-imidazolium position was attempted in the hope of forming the corresponding NHO complex. When the reaction was performed in THF, although complex
**Rh-2** reactivity was observed, no rhodium-NHC-NHO complex **Rh-3** could be isolated. Most probably an alkoxy ligand replaced chloride, although for unclear reasons the desired product **Rh-3** was not formed. Interestingly, when the same reaction was attempted in acetonitrile isolated was complex **Rh-4** bearing acetonitrile deprotonated ligand which replaced the chloride. Although rather unstable in air or in solution, complex **Rh-4** was characterized by NMR and XRD. To the best of our knowledge, no cyanomethyl rhodium complex has been reported so far.

<figure><img src="image_32.png" /><figcaption>**Scheme 8.** A) Synthesis of rhodium-NHC complex **Rh-2**, rhodium-NHC-cyanomethyl complex **Rh-4** and attempts to synthesize the rhodium-NHC-NHO complex **Rh-3**; reaction conditions: a) 0.5 equiv. of **48**, 1.1 equiv. $K_2CO_3$, acetone (HPLC), 60 °C, overnight; b) 1.1 equiv. $KO_bBu$, THF, rt; c) 1.1 equiv. $KO_bBu$, acetonitrile, rt, 4 h. B) XRD crystal structures of **Rh-2** and **Rh-4**, ellipsoids are drawn at 50 % probability, hydrogens were omitted for clarity.</figcaption></figure>

With the met obstacles in the cyclometallation of a rhodium complex, we next turn our attention to palladium metal in the hope that it will be possible to obtain a palladium-NHC-NHO complex. Similarly to the case of **Rh-1**, utilizing a dimeric palladium precursor **Pd-1** gave the desired palladium-NHC complex **Pd-2** in a good yield of 71 % (Scheme 9). Furthermore, deprotonation of α-imidazolium position in **Pd-2** gave the expected cyclometalated palladium-NHC-NHO complex **Pd-3** in 64 % yield. Diastereomers of **Pd-3** were formed in dr of 60:40. The structure of **Pd-3** was confirmed with XRD.

In summary, an NHC-NHO ligand precursor **48** was successfully obtained, however, the formation of the corresponding ruthenium-NHC complex was precluded due to an unexpected ring opening of the formed imidazolinylidene heterocycle. The reactivity of the novel class NHC-NHO ligand was explored in the coordination chemistry of rhodium(I) and palladium(II) metal centers, ultimately leading to the synthesis of the first NHC-NHO complex based on palladium. Furthermore, the first rhodium-cyanomethyl complex supported with the NHC ligand was obtained.
**Rh-2** reactivity was observed, no rhodium-NHC-NHO complex **Rh-3** could be isolated. Most probably an alkoxy ligand replaced chloride, although for unclear reasons the desired product **Rh-3** was not formed. Interestingly, when the same reaction was attempted in acetonitrile isolated was complex **Rh-4** bearing acetonitrile deprotonated ligand which replaced the chloride. Although rather unstable in air or in solution, complex **Rh-4** was characterized by NMR and XRD. To the best of our knowledge, no cyanomethyl rhodium complex has been reported so far.

<figure><img src="image_31.png" /><figcaption>**Scheme 8.** A) Synthesis of rhodium-NHC complex **Rh-2**, rhodium-NHC-cyanomethyl complex **Rh-4** and attempts to synthesize the rhodium-NHC-NHO complex **Rh-3**; reaction conditions: a) 0.5 equiv. of **48**, 1.1 equiv. $K_2CO_3$, acetone (HPLC), 60 °C, overnight; b) 1.1 equiv. $KO_bBu$, THF, rt; c) 1.1 equiv. $KO_bBu$, acetonitrile, rt, 4 h. B) XRD crystal structures of **Rh-2** and **Rh-4**, ellipsoids are drawn at 50 % probability, hydrogens were omitted for clarity.</figcaption></figure>

With the met obstacles in the cyclometallation of a rhodium complex, we next turn our attention to palladium metal in the hope that it will be possible to obtain a palladium-NHC-NHO complex. Similarly to the case of **Rh-1**, utilizing a dimeric palladium precursor **Pd-1** gave the desired palladium-NHC complex **Pd-2** in a good yield of 71 % (Scheme 9). Furthermore, deprotonation of α-imidazolium position in **Pd-2** gave the expected cyclometalated palladium-NHC-NHO complex **Pd-3** in 64 % yield. Diastereomers of **Pd-3** were formed in dr of 60:40. The structure of **Pd-3** was confirmed with XRD.

In summary, an NHC-NHO ligand precursor **48** was successfully obtained, however, the formation of the corresponding ruthenium-NHC complex was precluded due to an unexpected ring opening of the formed imidazolinylidene heterocycle. The reactivity of the novel class NHC-NHO ligand was explored in the coordination chemistry of rhodium(I) and palladium(II) metal centers, ultimately leading to the synthesis of the first NHC-NHO complex based on palladium. Furthermore, the first rhodium-cyanomethyl complex supported with the NHC ligand was obtained.
<figure><img src="image_33.png" /><figcaption>**Scheme 9.** Synthesis of the palladium-NHC-NHO complex **Pd-3** and its XRD crystal structure (ellipsoids are drawn at 30% probability, hydrogens were omitted for clarity).</figcaption></figure>

### NHC ligands bearing parallelly-stacked aromatics for efficient OM catalysts in tetrasubstituted C-C double bond formation

Commercially available 4,7-dibromo-2,1,3-benzothiadiazole (62) was chosen as a precursor for both phenyl and pentafluorophenyl substituted benzimidazolium salts 67 and 71 (Scheme 10). Suzuki coupling allowed for the installation of phenyl groups in the backbone motif giving functionalized benzothiadiazole 63 in 73 % yield and subsequent reductive sulfur extrusion gave access to the o-phenylenediamine derivative 64 in 99 % yield. Next, the bicyclic benzimidazole skeleton was obtained using standard cyclization protocol with triethyl orthoformate, affording 65 in quantitative yield. Products 63, 64 and 65 were obtained on a gram scale without any purification steps by CC. In the final step, the desired benzimidazolium salt 67 was obtained using copper-catalyzed arylation with diphenyliodonium tetrafluoroborate. Although examples of N-R substituted imidazoles arylations to corresponding imidazolium salts can be found in the literature, as well as arylations from NH imidazoles to corresponding N-aryl imidazoles, worth highlighting is that such direct arylation of NH imidazole to imidazolium salt has never been reported in the literature. This protocol gave a mixture of the desired N,N'-diphenylbenzimidazolium salt 67 (36 % isolated yield) and neutral N-phenylbenzimidazole 66 (58 % isolated yield) which were separated using CC. The succeeding arylation of isolated 66 gave salt 67 in 77 % yield, therefore the two subsequent arylation reactions led to an overall yield of 81 % in compound 67.

Synthesis of pentafluorophenyl substituted derivative 71 presented more synthetic challenges. A Kumada-Corriu coupling was successfully employed to graft pentafluorophenyl groups into the benzothiadiazole motif giving 68 in 76 % yield. The subsequent reductive sulfur extrusion step gave the o-phenylenediamine derivative 69 in 72 % yield. Unlike the synthesis of salt 67, the N-phenyl groups were first installed through a Buchwald-Hartwig amination, giving compound 70 in 21 % isolated yield. In a final step, the benzimidazolium salt 71 was obtained with quantitative yield using a modified cyclization protocol using triethyl orthoformate in the presence of HBF₄·Et₂O.

The corresponding Hoveyda-Grubbs complexes were obtained by displacement of the PCy₃ ligand in **Ru-9** ruthenium precursor by the free NHCs generated using KOC(CF₃)CH₃ as a base (Scheme 11A). Complex **Ru-69** was isolated using column chromatography, whereas complex **Ru-68** was purified by simple crystallization from a tetrahydrofuran-pentane mixture. Both complexes (brown-orange solids) are stable for months when stored in a protective atmosphere. It is noteworthy that upon
<figure><img src="image_32.png" /><figcaption>**Scheme 9.** Synthesis of the palladium-NHC-NHO complex **Pd-3** and its XRD crystal structure (ellipsoids are drawn at 30% probability, hydrogens were omitted for clarity).</figcaption></figure>

### NHC ligands bearing parallelly-stacked aromatics for efficient OM catalysts in tetrasubstituted C-C double bond formation

Commercially available 4,7-dibromo-2,1,3-benzothiadiazole (62) was chosen as a precursor for both phenyl and pentafluorophenyl substituted benzimidazolium salts 67 and 71 (Scheme 10). Suzuki coupling allowed for the installation of phenyl groups in the backbone motif giving functionalized benzothiadiazole 63 in 73 % yield and subsequent reductive sulfur extrusion gave access to the o-phenylenediamine derivative 64 in 99 % yield. Next, the bicyclic benzimidazole skeleton was obtained using standard cyclization protocol with triethyl orthoformate, affording 65 in quantitative yield. Products 63, 64 and 65 were obtained on a gram scale without any purification steps by CC. In the final step, the desired benzimidazolium salt 67 was obtained using copper-catalyzed arylation with diphenyliodonium tetrafluoroborate. Although examples of N-R substituted imidazoles arylations to corresponding imidazolium salts can be found in the literature, as well as arylations from NH imidazoles to corresponding N-aryl imidazoles, worth highlighting is that such direct arylation of NH imidazole to imidazolium salt has never been reported in the literature. This protocol gave a mixture of the desired N,N'-diphenylbenzimidazolium salt 67 (36 % isolated yield) and neutral N-phenylbenzimidazole 66 (58 % isolated yield) which were separated using CC. The succeeding arylation of isolated 66 gave salt 67 in 77 % yield, therefore the two subsequent arylation reactions led to an overall yield of 81 % in compound 67.

Synthesis of pentafluorophenyl substituted derivative 71 presented more synthetic challenges. A Kumada-Corriu coupling was successfully employed to graft pentafluorophenyl groups into the benzothiadiazole motif giving 68 in 76 % yield. The subsequent reductive sulfur extrusion step gave the o-phenylenediamine derivative 69 in 72 % yield. Unlike the synthesis of salt 67, the N-phenyl groups were first installed through a Buchwald-Hartwig amination, giving compound 70 in 21 % isolated yield. In a final step, the benzimidazolium salt 71 was obtained with quantitative yield using a modified cyclization protocol using triethyl orthoformate in the presence of HBF₄·Et₂O.

The corresponding Hoveyda-Grubbs complexes were obtained by displacement of the PCy₃ ligand in **Ru-9** ruthenium precursor by the free NHCs generated using KOC(CF₃)CH₃ as a base (Scheme 11A). Complex **Ru-69** was isolated using column chromatography, whereas complex **Ru-68** was purified by simple crystallization from a tetrahydrofuran-pentane mixture. Both complexes (brown-orange solids) are stable for months when stored in a protective atmosphere. It is noteworthy that upon
synthesis of known **Ru-67** we noticed its fragility when column chromatography was performed with regular solvents. Even with carefully degassed dry solvents, complex **Ru-67** was obtained in 19 % yield only, which is considerably lower than in the case of **Ru-68** and **Ru-69**, 72 % and 43 % respectively. The molecular structures of complexes **Ru-68** and **Ru-69** were confirmed by XRD experiments on single crystals grown by layering DCM complex solutions of **Ru-68** and **Ru-69** with pentane, respectively (Scheme 11B).

<figure><img src="image_34.png" /><figcaption>**Scheme 10.** Synthesis of benzimidazolium salts 67 and 71; reaction conditions: a) 2.1 equiv. of PhB(OH)₂, 4 equiv. of K₂CO₃, 0.8 mol% Pd(PPh₃)₄, toluene/water 2.5 : 1 v/v, reflux, overnight; b) 9 equiv. of NaBH₄, 6 mol% CoCl₂×6H₂O, EtOH/THF 3:1 v/v, reflux, 3 h; c) (EtO)₃CH (excess), 6 equiv. of HClaq, reflux, overnight; d) 2 x 2 equiv. of Ph₂IBF₄, 2 × 5 mol% Cu(OAc)₂×H₂O, DMF, 100 °C, 24 h, then 48 h; e) 2 equiv. of Ph₂IBF₄, 7.5 mol% Cu(OAc)₂×H₂O, DMF, 100 °C, overnight; f) 3 equiv. of BrMgC₆F₅, 10 mol% Pd(PPh₃)₃, THF, 70 °C, overnight; g) 3 equiv. of NaBH₄, 7 mol% CoCl₂×6H₂O, EtOH/THF 3:1 v/v, 50 °C, 1 min. 30 sec.; h) PhBr (excess), 2.5 mol% Pd₂(dba)₃, 7.5 mol% PtBu₃, 1.5 equiv. of KHMDS, 160 °C, 30 min.; i) (EtO)₃CH (excess), 1 equiv. of HBF₄·Et₂O, 60 °C, 30 min.</figcaption></figure>

<figure><img src="image_35.png" /><figcaption>**Scheme 11.** A) Synthesis of **Ru-67**, **Ru-68** and **Ru-69**; reaction conditions: a) 1.75 equiv. of **77** or **67**, 1.75 equiv. KOC(CF₃)₂CH₃, benzene, rt, 30 min. then 1 equiv. **Ru-9**, 60 °C, 1 h; b) 1.75 equiv. of **71**, 2 equiv. of KOC(CF₃)₂CH₃, benzene, rt, 15 min. then 1 equiv. of **Ru-9**, 60 °C, 30 min. B) XRD structure of **Ru-68** and **Ru-69**, ellipsoids are drawn at 50% probability.</figcaption></figure>
synthesis of known **Ru-67** we noticed its fragility when column chromatography was performed with regular solvents. Even with carefully degassed dry solvents, complex **Ru-67** was obtained in 19 % yield only, which is considerably lower than in the case of **Ru-68** and **Ru-69**, 72 % and 43 % respectively. The molecular structures of complexes **Ru-68** and **Ru-69** were confirmed by XRD experiments on single crystals grown by layering DCM complex solutions of **Ru-68** and **Ru-69** with pentane, respectively (Scheme 11B).

<figure><img src="image_33.png" /><figcaption>**Scheme 10.** Synthesis of benzimidazolium salts 67 and 71; reaction conditions: a) 2.1 equiv. of PhB(OH)2, 4 equiv. of K2CO3, 0.8 mol% Pd(PPh3)4, toluene/water 2.5 : 1 v/v, reflux, overnight; b) 9 equiv. of NaBH4, 6 mol% CoCl2×6H2O, EtOH/THF 3:1 v/v, reflux, 3 h; c) (EtO)3CH (excess), 6 equiv. of HClaq, reflux, overnight; d) 2 x 2 equiv. of Ph2IBF4, 2 × 5 mol% Cu(OAc)2×H2O, DMF, 100 °C, 24 h, then 48 h; e) 2 equiv. of Ph2IBF4, 7.5 mol% Cu(OAc)2×H2O, DMF, 100 °C, overnight; f) 3 equiv. of BrMgC6F5, 10 mol% Pd(PPh3)3, THF, 70 °C, overnight; g) 3 equiv. of NaBH4, 7.5 mol% CoCl2×6H2O, EtOH/THF 3:1 v/v, 50 °C, 1 min. 30 sec.; h) PhBr (excess), 2.5 mol% Pd2(dba)3, 7.5 mol% PtBu3, 1.5 equiv. of KHMDS, 160 °C, 30 min.; i) (EtO)3CH (excess), 1 equiv. of HBF4·Et2O, 60 °C, 30 min.</figcaption></figure>

<figure><img src="image_34.png" /><figcaption>**Scheme 11.** A) Synthesis of **Ru-67**, **Ru-68** and **Ru-69**; reaction conditions: a) 1.75 equiv. of 77 or 67, 1.75 equiv. KOC(CF3)2CH3, benzene, rt, 30 min. then 1 equiv. **Ru-9**, 60 °C, 1 h; b) 1.75 equiv. of 71, 2 equiv. of KOC(CF3)2CH3, benzene, rt, 15 min. then 1 equiv. of **Ru-9**, 60 °C, 30 min. B) XRD structure of **Ru-68** and **Ru-69**, ellipsoids are drawn at 50% probability.</figcaption></figure>
The stability of the two newly obtained biplane-type NHC ruthenium complexes **Ru-68** and **Ru-69** was then quantitatively monitored and compared with the benchmark **Ru-67**. Since NHC ligand remains coordinated to the metal center throughout the entire catalytic cycle, the differences in complexes' stability should directly translate to the stability of actual propagating species, thus conveying their effectiveness in catalysis. Gratifyingly, **Ru-68** and **Ru-69** remained perfectly unchanged for approximately three weeks in solution at ambient temperature, while **Ru-67** slowly degraded to around 50% of the initial amount (Figure 1A, left). This fact confirmed our previous observation that upon isolation the top-covered complexes **Ru-68** and **Ru-69** are considerably more stable than **Ru-67**. Furthermore, the differences in stability were even more pronounced at higher temperature (Figure 1A, right), where **Ru-67** disappeared completely after about 27 hours while **Ru-68** and **Ru-69** were still detectable even after more than 100 hours in solution at 80 °C. Furthermore, the elevated temperature allowed to distinguish **Ru-68** from **Ru-69** in terms of stability and **Ru-69** proved to be the more stable pre-catalyst, which we assign to the beneficial impact of the π-π interactions between *N*-phenyl groups and pentafluorophenyl backbone motifs.

To unambiguously confirm the nature of the catalyst deactivation pathway, we attempted to isolate the degradation product of **Ru-67**. The previous report featuring isolation and characterization of the decomposition product from BIPh ruthenium OM catalyst describes only its $PCy_3$ derivative. After steering **Ru-68** in dichloromethane at 40 °C for one week, the expected, tethered $\eta^6$-arene-NHC ruthenium complex **Ru-70** was isolated (Figure 1B), whose formation should proceed through the activation of an ortho C-H bond of one *N*-phenyl group followed by insertion into the alkylidene. The molecular structure of complex **Ru-70** was confirmed by XRD experiments on single crystals grown by layering dichloromethane complex solution with pentane.

<figure><img src="image_36.png" /><figcaption>**Figure 1.** A) Stability tests in solution at ambient and elevated temperature. Measured by NMR (1,3,5-trimethoxybenzene added as reference). Lines are visual aid only. Conditions: (left) $CD_2Cl_2$ at 22 °C, under argon; (right) $C_6D_6$ at 80 °C, under argon. B) study of the decomposition of the complex **Ru-67** into the complex **Ru-70** and XRD structure of complex **Ru-70** (ellipsoids are drawn at 50% probability).</figcaption></figure>
The stability of the two newly obtained biplane-type NHC ruthenium complexes **Ru-68** and **Ru-69** was then quantitatively monitored and compared with the benchmark **Ru-67**. Since NHC ligand remains coordinated to the metal center throughout the entire catalytic cycle, the differences in complexes' stability should directly translate to the stability of actual propagating species, thus conveying their effectiveness in catalysis. Gratifyingly, **Ru-68** and **Ru-69** remained perfectly unchanged for approximately three weeks in solution at ambient temperature, while **Ru-67** slowly degraded to around 50% of the initial amount (Figure 1A, left). This fact confirmed our previous observation that upon isolation the top-covered complexes **Ru-68** and **Ru-69** are considerably more stable than **Ru-67**. Furthermore, the differences in stability were even more pronounced at higher temperature (Figure 1A, right), where **Ru-67** disappeared completely after about 27 hours while **Ru-68** and **Ru-69** were still detectable even after more than 100 hours in solution at 80 °C. Furthermore, the elevated temperature allowed to distinguish **Ru-68** from **Ru-69** in terms of stability and **Ru-69** proved to be the more stable pre-catalyst, which we assign to the beneficial impact of the π-π interactions between N-phenyl groups and pentafluorophenyl backbone motifs.

To unambiguously confirm the nature of the catalyst deactivation pathway, we attempted to isolate the degradation product of **Ru-67**. The previous report featuring isolation and characterization of the decomposition product from BIPh ruthenium OM catalyst describes only its $PCy_3$ derivative. After steering **Ru-68** in dichloromethane at 40 °C for one week, the expected, tethered η<sup>6</sup>-arene-NHC ruthenium complex **Ru-70** was isolated (Figure 1B), whose formation should proceed through the activation of an ortho C-H bond of one N-phenyl group followed by insertion into the alkylidene. The molecular structure of complex **Ru-70** was confirmed by XRD experiments on single crystals grown by layering dichloromethane complex solution with pentane.

<figure><img src="image_35.png" /><figcaption>**Figure 1.** A) Stability tests in solution at ambient and elevated temperature. Measured by NMR (1,3,5-trimethoxybenzene added as reference). Lines are visual aid only. Conditions: (left) $CD_2Cl_2$ at 22 °C, under argon; (right) $C_6D_6$ at 80 °C, under argon. B) study of the decomposition of the complex **Ru-67** into the complex **Ru-70** and XRD structure of complex **Ru-70** (ellipsoids are drawn at 50% probability).</figcaption></figure>
The catalytic performance of the new, “stacked” complexes was compared with the known benchmark **Ru-67** using a set of model reactions. Firstly, we checked their activity in RCM with tetrasubstituted carbon-carbon double bond formation. For that purpose diethyl 2,2-di(2-methylallyl)malonate (**78a**) was chosen as the model substrate and the time-conversion plots of its RCM reaction were constructed with 0.2 mol% of each catalyst, in toluene, at 80 °C (Figure 2). All complexes exhibited high activity, affording considerable conversions within the first 30 minutes, however, the reaction catalyzed by **Ru-67** reached its limits at a significantly lower conversion than the one recorded with **Ru-68** and **Ru-69**. This can be attributed to a more stable 14 e⁻ catalytic species formed from the latter pre-catalysts versus those generated from **Ru-67**. Interestingly, although **Ru-68** gave higher conversions than **Ru-69** within the first hour of the reaction, after this point the trend reversed leading to 96 % conversion with **Ru-69** versus 91 % with **Ru-68** after 5 hours (and 72 % for the benchmark **Ru-67**).

<figure><img src="image_37.png" /><figcaption>**Figure 2.** Time-conversion curves in RCM of diene **78a**. Conditions: catalyst 0.2 mol%, toluene, 80 °C under argon. Measured by GC with 1,3,5-trimethoxybenzene added as internal standard. Lines are visual aid only.</figcaption></figure>

To further examine the differences in catalyst productivity, the previously described reaction of **78a** was reattempted at two times lower catalyst loading of 0.1 mol% (Scheme 12). The trend observed earlier was maintained and **Ru-67** gave a rather poor conversion for such reaction (50 %), whereas **Ru-68** and **Ru-69** gave much higher conversions of 81 % and 92 % respectively. The three BIPh-type catalysts were further tested in five more challenging RCM reactions featuring tetrasubstituted double carbon-carbon bond formation. Similar was the case of the formation of the six-membered ring (malonate **79b**) and five-membered tosylamide **81b**, where **Ru-68** and **Ru-69** gave up to 32 percentage points (%p) higher substrate conversions compared to **Ru-67**. The fluorinated complex **Ru-69** slightly but noticeably outperformed **Ru-68** in those two latter reactions. The superiority of the new catalysts **Ru-68** and **Ru-68** was even more pronounced in the more challenging formation of a less thermodynamically favored seven-membered ring (compounds **80b** and **82b**). In these latter cases, a higher catalyst loading of 2 mol% with malonate **80a** and 1 mol% with tosylamide **82b** was required to
The catalytic performance of the new, “stacked” complexes was compared with the known benchmark **Ru-67** using a set of model reactions. Firstly, we checked their activity in RCM with tetrasubstituted carbon-carbon double bond formation. For that purpose diethyl 2,2-di(2-methylallyl)malonate (**78a**) was chosen as the model substrate and the time-conversion plots of its RCM reaction were constructed with 0.2 mol% of each catalyst, in toluene, at 80 °C (Figure 2). All complexes exhibited high activity, affording considerable conversions within the first 30 minutes, however, the reaction catalyzed by **Ru-67** reached its limits at a significantly lower conversion than the one recorded with **Ru-68** and **Ru-69**. This can be attributed to a more stable 14 e⁻ catalytic species formed from the latter pre-catalysts versus those generated from **Ru-67**. Interestingly, although **Ru-68** gave higher conversions than **Ru-69** within the first hour of the reaction, after this point the trend reversed leading to 96 % conversion with **Ru-69** versus 91 % with **Ru-68** after 5 hours (and 72 % for the benchmark **Ru-67**).

<figure><img src="image_36.png" /><figcaption>**Figure 2.** Time-conversion curves in RCM of diene **78a**. Conditions: catalyst 0.2 mol%, toluene, 80 °C under argon. Measured by GC with 1,3,5-trimethoxybenzene added as internal standard. Lines are visual aid only.</figcaption></figure>

To further examine the differences in catalyst productivity, the previously described reaction of **78a** was reattempted at two times lower catalyst loading of 0.1 mol% (Scheme 12). The trend observed earlier was maintained and **Ru-67** gave a rather poor conversion for such reaction (50 %), whereas **Ru-68** and **Ru-69** gave much higher conversions of 81 % and 92 % respectively. The three BIPh-type catalysts were further tested in five more challenging RCM reactions featuring tetrasubstituted double carbon-carbon bond formation. Similar was the case of the formation of the six-membered ring (malonate **79b**) and five-membered tosylamide **81b**, where **Ru-68** and **Ru-69** gave up to 32 percentage points (%p) higher substrate conversions compared to **Ru-67**. The fluorinated complex **Ru-69** slightly but noticeably outperformed **Ru-68** in those two latter reactions. The superiority of the new catalysts **Ru-68** and **Ru-68** was even more pronounced in the more challenging formation of a less thermodynamically favored seven-membered ring (compounds **80b** and **82b**). In these latter cases, a higher catalyst loading of 2 mol% with malonate **80a** and 1 mol% with tosylamide **82b** was required to
reach suitable conversions, however, such loading is still considered low in the context of the challenging formation of carbon-carbon tetrasubstituted bonds. Noteworthy, **Ru-68** and **Ru-69** gave conversions 4 to 8 times higher than **Ru-67** and again **Ru-69** was slightly better than **Ru-68** which overall correlates with the observed trend in stability tests.

<figure><img src="image_38.png" /><figcaption>**Scheme 12.** Scope and limitation study of catalysts **Ru-67**, **Ru-68** and **Ru-69** in RCM of challenging substrates. %p – percentage point difference from **Ru-67**.</figcaption></figure>

To further evaluate the scope and limitations of catalysts **Ru-68** and **Ru-69**, several challenging CM reactions were investigated (Scheme 13). First, we studied the reaction between ethyl chrysanthemate (85) and Z-1,4-diacetoxy-2-butene (86). Catalysts **Ru-68** and **Ru-69** gave similar conversions of 85, 69 % and 73 % respectively, giving product 87 selectively, whereas known **Ru-67** provided only 26 % of conversion. Next, the functionalization of the geminal carbon-carbon double bond of 4-methylene-1-tosylpiperidine (88) with either 86 or amylene (90) was probed. In the case of reaction with 86, the use of **Ru-68** and **Ru-69** allowed for conversions up to 18 %p higher compared to benchmark **Ru-67**, leading to 76 % conversion for **Ru-69**.

Noteworthy, in the example of CM of 88 with amylene, the double-decker NHC catalysts **Ru-68** and **Ru-69** gave almost quantitative conversions of 88, 93 % and 91 % respectively, which was 5 times higher than in the case of **Ru-67** reaching only 18 %. Last but not least, the highly challenging 1,5-enyne metathesis of substrate 92 to obtain crowded and strained cyclobutene derivative 93 was attempted. An additional difficulty arising in this reaction is that its selectivity can be compromised by a competing self-CM side reaction and by degradation of the resulting highly strained product. We were pleased to find that catalysts **Ru-68** and **Ru-69** gave good yields of 59 % and 53 % respectively, which was around 10 times higher than with **Ru-67** forming only traces of product which amounted to a 6 % yield.
reach suitable conversions, however, such loading is still considered low in the context of the challenging formation of carbon-carbon tetrasubstituted bonds. Noteworthy, **Ru-68** and **Ru-69** gave conversions 4 to 8 times higher than **Ru-67** and again **Ru-69** was slightly better than **Ru-68** which overall correlates with the observed trend in stability tests.

<figure><img src="image_37.png" /><figcaption>**Scheme 12.** Scope and limitation study of catalysts **Ru-67**, **Ru-68** and **Ru-69** in RCM of challenging substrates. %p – percentage point difference from **Ru-67**.</figcaption></figure>

To further evaluate the scope and limitations of catalysts **Ru-68** and **Ru-69**, several challenging CM reactions were investigated (Scheme 13). First, we studied the reaction between ethyl chrysanthemate (85) and Z-1,4-diacetoxy-2-butene (86). Catalysts **Ru-68** and **Ru-69** gave similar conversions of 85, 69 % and 73 % respectively, giving product 87 selectively, whereas known **Ru-67** provided only 26 % of conversion. Next, the functionalization of the geminal carbon-carbon double bond of 4-methylene-1-tosylpiperidine (88) with either 86 or amylene (90) was probed. In the case of reaction with 86, the use of **Ru-68** and **Ru-69** allowed for conversions up to 18 %p higher compared to benchmark **Ru-67**, leading to 76 % conversion for **Ru-69**.

Noteworthy, in the example of CM of 88 with amylene, the double-decker NHC catalysts **Ru-68** and **Ru-69** gave almost quantitative conversions of 88, 93 % and 91 % respectively, which was 5 times higher than in the case of **Ru-67** reaching only 18 %. Last but not least, the highly challenging 1,5-enyne metathesis of substrate 92 to obtain crowded and strained cyclobutene derivative 93 was attempted. An additional difficulty arising in this reaction is that its selectivity can be compromised by a competing self-CM side reaction and by degradation of the resulting highly strained product. We were pleased to find that catalysts **Ru-68** and **Ru-69** gave good yields of 59 % and 53 % respectively, which was around 10 times higher than with **Ru-67** forming only traces of product which amounted to a 6 % yield.
<figure><img src="image_39.png" /><figcaption>**Scheme 13.** Scope and limitation study of catalysts **Ru-67**, **Ru-68** and **Ru-69** in CM and cycloisomerization of challenging substrates. <sup>a</sup> Reaction conducted in perfluorotoluene. %p – percentage point difference from **Ru-67**.</figcaption></figure>

In summary, we developed the two new biplane-type NHC ligands based on a benzimidazolylidene core, whose lower wings are set as *N*-phenyl rings to reduce their steric hindrance on the first coordination sphere and whose upper wings are phenyl or pentafluorophenyl rings, respectively. The corresponding second-generation Grubbs-Hoveyda complexes **Ru-68** and **Ru-69** were generated. Importantly, both complexes **Ru-68** and **Ru-69** were shown to be significantly more stable than the known BIPh-supported complex **Ru-67**. Moreover, the observed increased stability of the ruthenium precursors **Ru-68** and **Ru-69** was also translated to the active species and enabled their implementation as highly efficient, stable pre-catalysts in challenging olefin metathesis reactions for the formation of tri- and tetra-substituted carbon-carbon double bonds.

## CM of technical grade methyl oleate for the synthesis of bio-based polyesters and polyamides

We started off with the self-CM of **28(Z)** after its prior simple distillation from activated alumina to decrease the content of catalyst poisons. 100 ppm of **Ru-10** allowed to reach equilibrium in 3 h (50 °C, no solvent, Table 1, entry 1). Even though the reaction mixture contained a variety of products including several internal alkenes and monoesters (**28(E/Z)**, **30**, **95**, **96**, **97**), we were pleased to find that the equilibrium mixture contained predominantly **29** as a diester species. Upon decreasing the catalyst loading, we noticed that monoester **95** was also present in the reaction mixture and that the relation was inversely proportional (Table 1, entries 1-3). This suggests that at loadings lower than 100 ppm of **Ru-10** the reaction equilibrium is not reached. We wanted to avoid any monofunctional species such as **28**, **95**, or **96** in the isolated product since they would lead to a lower molecular mass of the resulting polyester, as monoesters would terminate a polymer chain. From gas chromatography, we
<figure><img src="image_38.png" /><figcaption>**Scheme 13.** Scope and limitation study of catalysts **Ru-67**, **Ru-68** and **Ru-69** in CM and cycloisomerization of challenging substrates. <sup>a</sup> Reaction conducted in perfluorotoluene. %p – percentage point difference from **Ru-67**.</figcaption></figure>

In summary, we developed the two new biplane-type NHC ligands based on a benzimidazolylidene core, whose lower wings are set as *N*-phenyl rings to reduce their steric hindrance on the first coordination sphere and whose upper wings are phenyl or pentafluorophenyl rings, respectively. The corresponding second-generation Grubbs-Hoveyda complexes **Ru-68** and **Ru-69** were generated. Importantly, both complexes **Ru-68** and **Ru-69** were shown to be significantly more stable than the known BIPh-supported complex **Ru-67**. Moreover, the observed increased stability of the ruthenium precursors **Ru-68** and **Ru-69** was also translated to the active species and enabled their implementation as highly efficient, stable pre-catalysts in challenging olefin metathesis reactions for the formation of tri- and tetra-substituted carbon-carbon double bonds.

## CM of technical grade methyl oleate for the synthesis of bio-based polyesters and polyamides

We started off with the self-CM of **28(Z)** after its prior simple distillation from activated alumina to decrease the content of catalyst poisons. 100 ppm of **Ru-10** allowed to reach equilibrium in 3 h (50 °C, no solvent, Table 1, entry 1). Even though the reaction mixture contained a variety of products including several internal alkenes and monoesters (**28(E/Z)**, **30**, **95**, **96**, **97**), we were pleased to find that the equilibrium mixture contained predominantly **29** as a diester species. Upon decreasing the catalyst loading, we noticed that monoester **95** was also present in the reaction mixture and that the relation was inversely proportional (Table 1, entries 1-3). This suggests that at loadings lower than 100 ppm of **Ru-10** the reaction equilibrium is not reached. We wanted to avoid any monofunctional species such as **28**, **95**, or **96** in the isolated product since they would lead to a lower molecular mass of the resulting polyester, as monoesters would terminate a polymer chain. From gas chromatography, we
deduced that boiling temperatures of **95** and **29** would be very similar, which would make the purification of **29** challenging. Hence, we decided to focus on minimizing the formation of **95** as the primary objective of catalyst screening, rather than maximizing catalyst efficiency.

<figure><img src="image_40.png" /><figcaption>**Scheme 14.** Self-CM of methyl oleate (28) with 20 wt% of methyl linoleate (94) and the observed products.</figcaption></figure>

All of the complexes gave reasonably similar conversions of substrates **28(Z)** and **94** around 95 %, except for **Ru-69** giving a lower 91 %. Catalysts **Ru-10**, **Ru-18**, **Ru-17** and **Ru-71** gave a ratio of **29** to **95** above 90:10, with **Ru-10** and **Ru-71** exceeding 95:5. **Ru-68** and **Ru-69** yielded much higher amounts of **95**, which can be attributed to their higher fragility due to lower steric protection of the NHCs. **Ru-10** gave a slightly higher yield of **29** than catalyst **Ru-71** (54 % versus 49 % respectively, the maximal yield being approximately 50 % resulting from the reaction equilibrium) and therefore it was chosen to continue with the development.

<table><caption>**Table 1.** Results of catalyst screening.</caption><thead><tr><th>Entry</th><th>Catalyst</th><th>Loading [ppm]</th><th>Conversion of 28(Z) + 94 [%]</th><th>Yield of 29 [%]</th><th>29 to 95 wt. ratio</th><th>E to Z ratio of 29</th></tr></thead><tbody><tr><td>1</td><td></td><td>100</td><td>95</td><td>54</td><td>96:4</td><td>84:16</td></tr><tr><td>2</td><td>Ru-10</td><td>50</td><td>94</td><td>51</td><td>89:11</td><td>82:18</td></tr><tr><td>3</td><td></td><td>25</td><td>80</td><td>26</td><td>63:37</td><td>78:22</td></tr><tr><td>4</td><td>Ru-18</td><td></td><td>94</td><td>45</td><td>90:10</td><td>82:18</td></tr><tr><td>5</td><td>Ru-17</td><td></td><td>94</td><td>54</td><td>92:8</td><td>82:18</td></tr><tr><td>6</td><td>Ru-71</td><td>100</td><td>95</td><td>49</td><td>96:4</td><td>82:18</td></tr><tr><td>7</td><td>Ru-68</td><td></td><td>94</td><td>50</td><td>82:18</td><td>82:18</td></tr><tr><td>8</td><td>Ru-69</td><td></td><td>91</td><td>42</td><td>70:30</td><td>80:20</td></tr></tbody></table>

Reaction conditions: no solvent, 50 °C, 3 h.

With the selected catalyst, self-CM of methyl oleate was conducted with 300 g of substrate. After the reaction, product **29** was isolated by fractional distillation and subsequently purified by crystallization from methanol at -30 °C. Interestingly, this protocol gave pure **29** containing almost only E isomer (E/Z ratio of 97:3) in 36 % yield.

Having monomer **29** in hand, we attempted the melt polycondensation reaction with different co-monomers (Scheme 15). Titanium *n*-butoxide was used as the catalyst for this reaction. This
deduced that boiling temperatures of **95** and **29** would be very similar, which would make the purification of **29** challenging. Hence, we decided to focus on minimizing the formation of **95** as the primary objective of catalyst screening, rather than maximizing catalyst efficiency.

<figure><img src="image_39.png" /><figcaption>**Scheme 14.** Self-CM of methyl oleate (28) with 20 wt% of methyl linoleate (94) and the observed products.</figcaption></figure>

All of the complexes gave reasonably similar conversions of substrates **28(Z)** and **94** around 95 %, except for **Ru-69** giving a lower 91 %. Catalysts **Ru-10**, **Ru-18**, **Ru-17** and **Ru-71** gave a ratio of **29** to **95** above 90:10, with **Ru-10** and **Ru-71** exceeding 95:5. **Ru-68** and **Ru-69** yielded much higher amounts of **95**, which can be attributed to their higher fragility due to lower steric protection of the NHCs. **Ru-10** gave a slightly higher yield of **29** than catalyst **Ru-71** (54 % versus 49 % respectively, the maximal yield being approximately 50 % resulting from the reaction equilibrium) and therefore it was chosen to continue with the development.

<table><caption>**Table 1.** Results of catalyst screening.</caption><thead><tr><th>Entry</th><th>Catalyst</th><th>Loading [ppm]</th><th>Conversion of 28(Z) + 94 [%]</th><th>Yield of 29 [%]</th><th>29 to 95 wt. ratio</th><th>E to Z ratio of 29</th></tr></thead><tbody><tr><td>1</td><td></td><td>100</td><td>95</td><td>54</td><td>96:4</td><td>84:16</td></tr><tr><td>2</td><td>Ru-10</td><td>50</td><td>94</td><td>51</td><td>89:11</td><td>82:18</td></tr><tr><td>3</td><td></td><td>25</td><td>80</td><td>26</td><td>63:37</td><td>78:22</td></tr><tr><td>4</td><td>Ru-18</td><td></td><td>94</td><td>45</td><td>90:10</td><td>82:18</td></tr><tr><td>5</td><td>Ru-17</td><td></td><td>94</td><td>54</td><td>92:8</td><td>82:18</td></tr><tr><td>6</td><td>Ru-71</td><td>100</td><td>95</td><td>49</td><td>96:4</td><td>82:18</td></tr><tr><td>7</td><td>Ru-68</td><td></td><td>94</td><td>50</td><td>82:18</td><td>82:18</td></tr><tr><td>8</td><td>Ru-69</td><td></td><td>91</td><td>42</td><td>70:30</td><td>80:20</td></tr></tbody></table>

Reaction conditions: no solvent, 50 °C, 3 h.

With the selected catalyst, self-CM of methyl oleate was conducted with 300 g of substrate. After the reaction, product **29** was isolated by fractional distillation and subsequently purified by crystallization from methanol at -30 °C. Interestingly, this protocol gave pure **29** containing almost only E isomer (E/Z ratio of 97:3) in 36 % yield.

Having monomer **29** in hand, we attempted the melt polycondensation reaction with different co-monomers (Scheme 15). Titanium *n*-butoxide was used as the catalyst for this reaction. This
resulted in a red-brown solid insoluble in all the most common solvents including trifluoroacetic acid. This stood in contradiction to the findings reported by Warwel et al, where authors claimed to characterize the same polyesters using gel permeation chromatography (GPC), although no experimental data was provided thereof [14]. To confirm the formation of macromolecules, the reaction was stopped at an earlier stage and the formed oligomers (soluble in conventional organic solvents) were characterized by NMR spectroscopy.

The obtained oligomers and polymers were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The obtained polyesters have relatively low melting temperatures between 9 and 42 °C (Table 2, entries 1 – 7), which is characteristic of linear aliphatic polyesters. Significantly higher was the melting temperature for polyamide (152 °C, Table 2, entry 8), which is due to the formation of hydrogen bonds in comparison to polyesters. Heats of fusion varied from 25 to 73 J/g. Aliphatic polyesters exhibited degradation temperatures around 400 °C, however, the polyester containing 1,4-cyclohexanediol block unit showed an increased degradation temperature of 446 °C due to the higher rigidity of the polymer that such a monomer provides.

<figure><img src="image_41.png" /><figcaption>**Scheme 15.** Polycondensation reaction to obtain polyesters and polyamides from diester 29.</figcaption></figure>

<table><caption>**Table 2.** Polymerization of monomer 29 and characterization of obtained polyesters and polyamides.</caption><thead><tr><th>Entry</th><th>Polyester</th><th>Vacuum time</th><th>Yield</th><th>DP<sup>a</sup></th><th>M<sub>n</sub> (g/mol)<sup>a</sup></th><th>T<sub>m</sub> (°C)<sup>b</sup></th><th>ΔH (J/g)<sup>b</sup></th><th>T<sub>d</sub> (°C)<sup>c</sup></th><th>mass loss<sup>c</sup></th></tr></thead><tbody><tr><td>1</td><td>[29]</td><td>30 min.</td><td>51 %</td><td>1.7</td><td>592</td><td>42</td><td>64</td><td>403</td><td>97 %</td></tr><tr><td>2</td><td>[29]<sub>DP</sub></td><td>19 h</td><td>52 %</td><td>n.d.</td><td>n.d.</td><td>14</td><td>25</td><td>413</td><td>96 %</td></tr><tr><td>3</td><td>[29]<sub>DP</sub></td><td>225 min.</td><td>76 %</td><td>6.6</td><td>2238</td><td>34</td><td>72</td><td>395</td><td>98 %</td></tr><tr><td>4</td><td>[29]<sub>DP</sub></td><td>21 h</td><td>81 %</td><td>n.d.</td><td>n.d.</td><td>11</td><td>55</td><td>398</td><td>97 %</td></tr><tr><td>5</td><td>[29]<sub>DP</sub></td><td>180 min.</td><td>74 %</td><td>7.5</td><td>2539</td><td>38</td><td>73</td><td>397</td><td>98 %</td></tr><tr><td>6</td><td>[29]<sub>DP</sub></td><td>21 h</td><td>88 %</td><td>n.d.</td><td>n.d.</td><td>10</td><td>60</td><td>398</td><td>96 %</td></tr><tr><td>7</td><td>[29]<sub>DF</sub></td><td>19 h</td><td>24 %</td><td>n.d.</td><td>n.d.</td><td>9</td><td>35</td><td>446<sup>d</sup></td><td>78 %<sup>d</sup></td></tr><tr><td>9</td><td>[29]<sub>DP</sub></td><td>19 h</td><td>51 %</td><td>n.d.</td><td>n.d.</td><td>152</td><td>55</td><td>443</td><td>82 %</td></tr></tbody></table>

Reaction conditions: Ti(O<sup>n</sup>Bu)<sub>4</sub> 1 mol%, no solvent, 140 min. melt time with temperature increase from 150 to 200 °C. <sup>a</sup> – degree of polymerization (DP) and number average molecular weight (M<sub>n</sub>) were calculated from <sup>1</sup>H NMR by end group analysis. <sup>b</sup> – determined by DSC. <sup>c</sup> – T<sub>d</sub> (decomposition temperature) and mass loss of the samples were determined by TGA. <sup>d</sup> – evident mass loss of 50 % was observed at temperature 353 °C. n.d. – not determined due to polymer insolubility.
resulted in a red-brown solid insoluble in all the most common solvents including trifluoroacetic acid. This stood in contradiction to the findings reported by Warwel et al, where authors claimed to characterize the same polyesters using gel permeation chromatography (GPC), although no experimental data was provided thereof [14]. To confirm the formation of macromolecules, the reaction was stopped at an earlier stage and the formed oligomers (soluble in conventional organic solvents) were characterized by NMR spectroscopy.

The obtained oligomers and polymers were characterized by differential scanning calorimetry (DSC) and thermogravimetric analysis (TGA). The obtained polyesters have relatively low melting temperatures between 9 and 42 °C (Table 2, entries 1 – 7), which is characteristic of linear aliphatic polyesters. Significantly higher was the melting temperature for polyamide (152 °C, Table 2, entry 8), which is due to the formation of hydrogen bonds in comparison to polyesters. Heats of fusion varied from 25 to 73 J/g. Aliphatic polyesters exhibited degradation temperatures around 400 °C, however, the polyester containing 1,4-cyclohexanediol block unit showed an increased degradation temperature of 446 °C due to the higher rigidity of the polymer that such a monomer provides.

<figure><img src="image_40.png" /><figcaption>**Scheme 15.** Polycondensation reaction to obtain polyesters and polyamides from diester 29.</figcaption></figure>

<table><caption>**Table 2.** Polymerization of monomer 29 and characterization of obtained polyesters and polyamides.</caption><thead><tr><th>Entry</th><th>Polyester</th><th>Vacuum time</th><th>Yield</th><th>DP<sup>a</sup></th><th>M<sub>n</sub> (g/mol)<sup>a</sup></th><th>T<sub>m</sub> (°C)<sup>b</sup></th><th>ΔH (J/g)<sup>b</sup></th><th>T<sub>d</sub> (°C)<sup>c</sup></th><th>mass loss<sup>c</sup></th></tr></thead><tbody><tr><td>1</td><td>[29]</td><td>30 min.</td><td>51 %</td><td>1.7</td><td>592</td><td>42</td><td>64</td><td>403</td><td>97 %</td></tr><tr><td>2</td><td>[29]<sub>DP</sub></td><td>19 h</td><td>52 %</td><td>n.d.</td><td>n.d.</td><td>14</td><td>25</td><td>413</td><td>96 %</td></tr><tr><td>3</td><td>[29]<sub>DP</sub></td><td>225 min.</td><td>76 %</td><td>6.6</td><td>2238</td><td>34</td><td>72</td><td>395</td><td>98 %</td></tr><tr><td>4</td><td>[29]<sub>DP</sub></td><td>21 h</td><td>81 %</td><td>n.d.</td><td>n.d.</td><td>11</td><td>55</td><td>398</td><td>97 %</td></tr><tr><td>5</td><td>[29]<sub>DP</sub></td><td>180 min.</td><td>74 %</td><td>7.5</td><td>2539</td><td>38</td><td>73</td><td>397</td><td>98 %</td></tr><tr><td>6</td><td>[29]<sub>DP</sub></td><td>21 h</td><td>88 %</td><td>n.d.</td><td>n.d.</td><td>10</td><td>60</td><td>398</td><td>96 %</td></tr><tr><td>7</td><td>[29]<sub>DF</sub></td><td>19 h</td><td>24 %</td><td>n.d.</td><td>n.d.</td><td>9</td><td>35</td><td>446<sup>d</sup></td><td>78 %<sup>d</sup></td></tr><tr><td>9</td><td>[29]<sub>DP</sub></td><td>19 h</td><td>51 %</td><td>n.d.</td><td>n.d.</td><td>152</td><td>55</td><td>443</td><td>82 %</td></tr></tbody></table>

Reaction conditions: Ti(O<sup>n</sup>Bu)<sub>4</sub> 1 mol%, no solvent, 140 min. melt time with temperature increase from 150 to 200 °C. <sup>a</sup> – degree of polymerization (DP) and number average molecular weight (M<sub>n</sub>) were calculated from <sup>1</sup>H NMR by end group analysis. <sup>b</sup> – determined by DSC. <sup>c</sup> – T<sub>d</sub> (decomposition temperature) and mass loss of the samples were determined by TGA. <sup>d</sup> – evident mass loss of 50 % was observed at temperature 353 °C. n.d. – not determined due to polymer insolubility.
In summary, a novel process of obtaining functional polymer materials from technical grade methyl oleate was developed. Self-CM of methyl oleate (28) in the presence of substantial amounts of methyl linoleate (94) was investigated and the reaction was optimized to obtain dimethyl octadec-9-enedioate (29) with high selectivity and yield. Subsequent polycondensation with a co-monomer (diol or diamine) resulted in the formation of polymeric materials which were characterized using TGA and DSC.

## References

[1] B. Cornils, W. Herrmann A., M. Beller, R. Paciello (Editors), *Applied Homogeneous Catalysis with Organometallic Compounds*, Wiley-VCH: Weinheim, Germany, **2017**. ISBN: 9783527651733. DOI: 10.1002/9783527651733.

[2] R. Poli, *Comm. Inorg. Chem.* **2009**, *30*, 177–228. DOI: 10.1080/02603590903423942.

[3] L. Benhamou, E. Chardon, G. Lavigne, S. Bellemin-Laponnaz, V. César, *Chem. Rev.* **2011**, *111*, 2705–2733. DOI: 10.1021/cr100328e.

[4] T. Dröge, F. Glorius, *Angew. Chem. Int. Ed.* **2010**, *49*, 6940–6952. DOI: 10.1002/anie.201001865.

[5] K. Verlinden, H. Buhl, W. Frank, C. Ganter, *Eur. J. Inorg. Chem.* **2015**, *2015*, 2416–2425. DOI: 10.1002/ejic.201500174.

[6] A. Liske, K. Verlinden, H. Buhl, K. Schaper, C. Ganter, *Organometallics* **2013**, *32*, 5269–5272. DOI: 10.1021/om400858y.

[7] K. Endo, R. H. Grubbs, *J. Am. Chem. Soc.* **2011**, *133*, 8525–8527. DOI: 10.1021/ja202818v.

[8] M. B. Herbert, Y. Lan, B. K. Keitz, P. Liu, K. Endo, M. W. Day, K. N. Houk, R. H. Grubbs, *J. Am. Chem. Soc.* **2012**, *134*, 7861–7866. DOI: 10.1021/ja301108m.

[9] K. Gajda, A. Sytniczuk, L. Vendier, B. Trzaskowski, N. Lugan, A. Kajetanowicz, S. Bastin, K. Grela, V. César, *Eur. J. Inorg. Chem.* **2023**, *26*, e202300169. DOI: 10.1002/ejic.202300169.

[10] I. Benaissa, K. Gajda, L. Vendier, N. Lugan, A. Kajetanowicz, K. Grela, V. Michelet, V. César, S. Bastin, *Organometallics* **2021**, *40*, 3223–3234. DOI: 10.1021/acs.organomet.1c00458.

[11] M. M. D. Roy, E. Rivard, *Acc. Chem. Res.* **2017**, *50*, 2017–2025. DOI: 10.1021/acs.accounts.7b00264.

[12] N. Mukherjee, S. Planer, K. Grela, *Org. Chem. Front.* **2018**, *5*, 494–516. DOI: 10.1039/C7QO00800G.

[13] S. H. Hong, A. Chlenov, M. W. Day, R. H. Grubbs, *Angew. Chem. Int. Ed.* **2007**, *46*, 5148–5151. DOI: 10.1002/anie.200701234.

[14] S. Warwel, F. Brüse, C. Demes, M. Kunz, M. R. gen Klaas, *Chemosphere* **2001**, *43*, 39–48. DOI: 10.1016/s0045-6535(00)00322-2.
In summary, a novel process of obtaining functional polymer materials from technical grade methyl oleate was developed. Self-CM of methyl oleate (28) in the presence of substantial amounts of methyl linoleate (94) was investigated and the reaction was optimized to obtain dimethyl octadec-9-enedioate (29) with high selectivity and yield. Subsequent polycondensation with a co-monomer (diol or diamine) resulted in the formation of polymeric materials which were characterized using TGA and DSC.

## References

[1] B. Cornils, W. Herrmann A., M. Beller, R. Paciello (Editors), *Applied Homogeneous Catalysis with Organometallic Compounds*, Wiley-VCH: Weinheim, Germany, **2017**. ISBN: 9783527651733. DOI: 10.1002/9783527651733.

[2] R. Poli, *Comm. Inorg. Chem.* **2009**, *30*, 177–228. DOI: 10.1080/02603590903423942.

[3] L. Benhamou, E. Chardon, G. Lavigne, S. Bellemin-Laponnaz, V. César, *Chem. Rev.* **2011**, *111*, 2705–2733. DOI: 10.1021/cr100328e.

[4] T. Dröge, F. Glorius, *Angew. Chem. Int. Ed.* **2010**, *49*, 6940–6952. DOI: 10.1002/anie.201001865.

[5] K. Verlinden, H. Buhl, W. Frank, C. Ganter, *Eur. J. Inorg. Chem.* **2015**, *2015*, 2416–2425. DOI: 10.1002/ejic.201500174.

[6] A. Liske, K. Verlinden, H. Buhl, K. Schaper, C. Ganter, *Organometallics* **2013**, *32*, 5269–5272. DOI: 10.1021/om400858y.

[7] K. Endo, R. H. Grubbs, *J. Am. Chem. Soc.* **2011**, *133*, 8525–8527. DOI: 10.1021/ja202818v.

[8] M. B. Herbert, Y. Lan, B. K. Keitz, P. Liu, K. Endo, M. W. Day, K. N. Houk, R. H. Grubbs, *J. Am. Chem. Soc.* **2012**, *134*, 7861–7866. DOI: 10.1021/ja301108m.

[9] K. Gajda, A. Sytniczuk, L. Vendier, B. Trzaskowski, N. Lugan, A. Kajetanowicz, S. Bastin, K. Grela, V. César, *Eur. J. Inorg. Chem.* **2023**, *26*, e202300169. DOI: 10.1002/ejic.202300169.

[10] I. Benaissa, K. Gajda, L. Vendier, N. Lugan, A. Kajetanowicz, K. Grela, V. Michelet, V. César, S. Bastin, *Organometallics* **2021**, *40*, 3223–3234. DOI: 10.1021/acs.organomet.1c00458.

[11] M. M. D. Roy, E. Rivard, *Acc. Chem. Res.* **2017**, *50*, 2017–2025. DOI: 10.1021/acs.accounts.7b00264.

[12] N. Mukherjee, S. Planer, K. Grela, *Org. Chem. Front.* **2018**, *5*, 494–516. DOI: 10.1039/C7QO00800G.

[13] S. H. Hong, A. Chlenov, M. W. Day, R. H. Grubbs, *Angew. Chem. Int. Ed.* **2007**, *46*, 5148–5151. DOI: 10.1002/anie.200701234.

[14] S. Warwel, F. Brüse, C. Demes, M. Kunz, M. R. gen Klaas, *Chemosphere* **2001**, *43*, 39–48. DOI: 10.1016/S0045-6535(00)00322-2.
Joris LANGLOIS

ESR2

**Thesis co-directors**

Prof. Cyril Godard Universitata Rovira i Virgili, Tarragona, Spain

Prof. Martine Urrutigoity Laboratoire de Chimie de Coordination, Toulouse, France

**Thesis defense**

Department of Chemistry, University Rovira i Virgili, 15 December 2023
Joris LANGLOIS

ESR2

**Thesis co-directors**

Prof. Cyril Godard Universitata Rovira i Virgili, Tarragona, Spain

Prof. Martine Urrutigoity Laboratoire de Chimie de Coordination, Toulouse, France

**Thesis defense**

Department of Chemistry, University Rovira i Virgili, 15 December 2023
<figure><img src="image_42.png" /></figure>
<figure><img src="image_41.png" /></figure>
# Towards The Direct Synthesis Of Chiral Amines Via Asymmetric Rhodium Catalyzed Hydroaminomethylation Reactions

## Introduction

The use of carbon monoxide as C1 building block via metal-catalyzed carbonylation processes has revealed an efficient tool for the functionalization of organic molecules; moreover, the atom-economic nature of this type of reaction has increased the interest of both academia and industry [1]. Among the metals that catalyze carbonylation reactions, rhodium was largely studied due to its intrinsic properties that provide high activity and selectivity for this type of reaction [2]. Rhodium catalyzed hydroformylation constitutes an attractive strategy for the synthesis of aldehydes from readily available starting materials such as alkenes in a high atom economy process [3]. The reaction consists in the addition of “synthesis gas” (syngas), a mixture of CO and $H_2$, to olefins in the presence of a catalyst. A formyl group and hydrogen are added through the π system of the alkene for the formation of aldehydes. Currently, several million tons of oxo-products are manufactured per year, mainly through the hydroformylation of propene 1.1. The products iso-butyraldehyde 1.2 and n-butanal 1.3 are important intermediates to synthesize esters, acrylates, and 2-ethylhexanol (Scheme 1) [4].

<figure><img src="image_43.png" /><figcaption>**Scheme 1.** Hydroformylation of propene.</figcaption></figure>

From an organic point of view, aldehydes are products of interest due to their potential in terms of subsequent functionalization, that can lead to the formation of new carbon-carbon and carbon-heteroatom bonds [5]. However, despite the clear potential of asymmetric hydroformylation for the synthesis of chiral aldehydes, the application of this process at a large scale has not yet been completed. Aldehydes are generally not isolated as final products since the products of interest are usually derivatives. In this context, tandem processes with hydroformylation as the initial step constitute an interesting strategy. Indeed, the possibility to carry out several catalytic transformations in “one-pot” is even more attractive from an environmental and efficiency point of view. In this context, tandem catalytic processes are described as sequential catalytic transformations of the substrate through two, or even more, mechanistic pathways (Scheme 2) [6].

When hydroformylation is the first step of such processes, alcohols can be prepared by *in situ* reduction of the aldehyde using the hydrogen pressure present in the medium [7]. In the presence of a carbonyl compound such as an aldehyde and an organocatalyst, aldol reactions take place to expand the structure of the molecule [8]. It is also possible to create new C-C bonds if the aldehyde reacts with a phosphorus ylide via a Wittig reaction [9]. On the other hand, aldehydes can act as electrophiles and react with a nucleophile present in the media. If the nucleophile is an alcohol, hemiacetals or acetals can be created [10]. In the presence of a primary or secondary amine, imines and enamines can be easily prepared [11]. When these imines or enamines are hydrogenated to produce the corresponding amine, the reaction is called hydroaminomethylation (HAM).
# Towards The Direct Synthesis Of Chiral Amines Via Asymmetric Rhodium Catalyzed Hydroaminomethylation Reactions

## Introduction

The use of carbon monoxide as C1 building block via metal-catalyzed carbonylation processes has revealed an efficient tool for the functionalization of organic molecules; moreover, the atom-economic nature of this type of reaction has increased the interest of both academia and industry [1]. Among the metals that catalyze carbonylation reactions, rhodium was largely studied due to its intrinsic properties that provide high activity and selectivity for this type of reaction [2]. Rhodium catalyzed hydroformylation constitutes an attractive strategy for the synthesis of aldehydes from readily available starting materials such as alkenes in a high atom economy process [3]. The reaction consists in the addition of “synthesis gas” (syngas), a mixture of CO and $H_2$, to olefins in the presence of a catalyst. A formyl group and hydrogen are added through the $\pi$ system of the alkene for the formation of aldehydes. Currently, several million tons of oxo-products are manufactured per year, mainly through the hydroformylation of propene 1.1. The products iso-butyraldehyde 1.2 and n-butanal 1.3 are important intermediates to synthesize esters, acrylates, and 2-ethylhexanol (Scheme 1) [4].

<figure><img src="image_42.png" /><figcaption>**Scheme 1.** Hydroformylation of propene.</figcaption></figure>

From an organic point of view, aldehydes are products of interest due to their potential in terms of subsequent functionalization, that can lead to the formation of new carbon-carbon and carbon-heteroatom bonds [5]. However, despite the clear potential of asymmetric hydroformylation for the synthesis of chiral aldehydes, the application of this process at a large scale has not yet been completed. Aldehydes are generally not isolated as final products since the products of interest are usually derivatives. In this context, tandem processes with hydroformylation as the initial step constitute an interesting strategy. Indeed, the possibility to carry out several catalytic transformations in “one-pot” is even more attractive from an environmental and efficiency point of view. In this context, tandem catalytic processes are described as sequential catalytic transformations of the substrate through two, or even more, mechanistic pathways (Scheme 2) [6].

When hydroformylation is the first step of such processes, alcohols can be prepared by *in situ* reduction of the aldehyde using the hydrogen pressure present in the medium [7]. In the presence of a carbonyl compound such as an aldehyde and an organocatalyst, aldol reactions take place to expand the structure of the molecule [8]. It is also possible to create new C-C bonds if the aldehyde reacts with a phosphorus ylide via a Wittig reaction [9]. On the other hand, aldehydes can act as electrophiles and react with a nucleophile present in the media. If the nucleophile is an alcohol, hemiacetals or acetals can be created [10]. In the presence of a primary or secondary amine, imines and enamines can be easily prepared [11]. When these imines or enamines are hydrogenated to produce the corresponding amine, the reaction is called hydroaminomethylation (HAM).
$$ \text{Hydroformylation/hydrogenation reaction} \\ \chemfig{*6(=-=-(-R(=[2]O)-[7]R(=[1]O)-[2]OH)-=-)} \xrightarrow{\text{Rh cat.}} \chemfig{*6(=-=-(-R(=[2]O)-[7]R(=[1]O)-[2]OH)-=-)} $$

$$ \text{Hydroformylation/Aldol reaction} \\ \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]O)-=-)} + \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]O)-=-)} \xrightarrow{\text{Rh cat.}} \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]O)-=-)} $$

$$ \text{Hydroformylation/Wittig olefination} \\ \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]O)-=-)} + \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]O)-=-)} \xrightarrow{\text{PPh}_3} \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]O)-=-)} $$

$$ \text{Hydroformylation/Acetylation} \\ \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]OH)-=-)} \xrightarrow{\text{Rh cat.}} \chemfig{*6(=-=-(-R(=[2]O)-[7]R(=[1]O)-[2]OR_2)-=-)} $$

$$ \text{Hydroaminovinylation reaction} \\ \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]N'-H)-=-)} \xrightarrow{\text{Rh cat.}} \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]N'-H)-=-)} $$

$$ \text{Hydroaminomethylation reaction} \\ \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]N'-H)-=-)} \xrightarrow{\text{Rh cat.}} \chemfig{*6(=-=-(-R_1(=[2]O)-[7]R_2(=[1]O)-[2]N'-H)-=-)} $$

<caption>**Scheme 2.** Examples of hydroformylation tandem processes.</caption>

In this chapter, advances in the field of asymmetric hydroaminomethylation of alkenes is described. A part will also be devoted to the hydroformylation which is the first step of this tandem reaction. After a brief introduction of these reactions, the mechanisms of the processes will be detailed, and the most relevant catalytic results will be described according to the alkenes substrates. The efficient and selective synthesis of amines using readily available and abundant precursors is a long-standing goal of chemical research since they are powerful building blocks for the synthesis of pharmaceuticals, peptides, alkaloids and agrochemical, dyes, and monomers for polymerization [12].

Chiral amine moieties are present in ca. 40% of pharmaceutical products. The introduction of these chiral units is therefore of high importance and usually performed through multistep processes [13,14]. As enantiomerically pure amines are required in large quantities in the pharmaceutical and agrochemical industry, the development of efficient methodologies for their preparation is of great significance and highly desirable. In the context of green chemistry, research on organometallic catalysis is still progressing to access and produce optically pure chiral amines. The main enantioselective metal-catalyzed reactions for the synthesis of chiral amines are reductive amination, hydroamination, hydroaminoalkylation and hydroaminomethylation (Scheme 3) [15].

<figure><img src="image_44.png" /><figcaption>**Scheme 3.** Transition metal catalyzed processes to access chiral amines.</figcaption></figure>

A thorough study was performed by Kalck and co-workers on the asymmetric hydroaminomethylation of styrene with piperidine, using a variety of chiral diphosphine ligands which
$$ \text{Hydroformylation/hydrogenation reaction} \\ \chemfig{*6(=-=-(-R(=[2]O)-[7]R(=[1]O)-[2]OH)-=-=)} \xrightarrow{\text{Rh cat.}} \chemfig{*6(=-=-(-R(=[2]O)-[7]R(=[1]O)-[2]OH)-=-=)} $$

$$ \text{Hydroformylation/Aldol reaction} \\ \text{R}_1 \overset{\text{Rh cat.}}{\rightleftharpoons} \text{R}_2 + \text{O} \\ \text{R}_1 \overset{\text{Rh cat.}}{\rightleftharpoons} \underset{\text{N}-\text{H}}{\text{C}} \text{CO}_2\text{H} $$

$$ \text{Hydroformylation/Wittig olefination} \\ \text{R}_1 \overset{\text{PPh}_3}{\rightleftharpoons} \text{R}_2 + \text{R}_1 \overset{\text{Rh cat.}}{\rightleftharpoons} \text{R}_2 $$

$$ \text{Hydroformylation/Acetylation} \\ \chemfig{*6(=-=-(-R(=[2]O)-[7]R(=[1]O)-[2]OR_2)-=-=)} \xrightarrow{\text{Rh cat.}} \chemfig{*6(=-=-(-R(=[2]O)-[7]R(=[1]O)-[2]OH)-=-=)} $$

$$ \text{Hydroaminovinylation reaction} \\ \text{R}_1 \overset{\text{Rh cat.}}{\rightleftharpoons} \underset{\text{N}-\text{H}}{\text{C}} \text{CO}_2 \text{R}_2 + \text{R}_1 \overset{\text{N}-\text{R}_2}{\rightleftharpoons} \text{C} \text{R}_2 $$

$$ \text{Hydroaminomethylation reaction} \\ \text{R}_1 \overset{\text{Rh cat.}}{\rightleftharpoons} \underset{\text{N}-\text{H}}{\text{C}} \text{CO}_2 \text{R}_2 + \text{R}_1 \overset{\text{N}-\text{R}_2}{\rightleftharpoons} \text{C} \text{R}_2 $$

<caption>**Scheme 2.** Examples of hydroformylation tandem processes.</caption>

In this chapter, advances in the field of asymmetric hydroaminomethylation of alkenes is described. A part will also be devoted to the hydroformylation which is the first step of this tandem reaction. After a brief introduction of these reactions, the mechanisms of the processes will be detailed, and the most relevant catalytic results will be described according to the alkenes substrates. The efficient and selective synthesis of amines using readily available and abundant precursors is a long-standing goal of chemical research since they are powerful building blocks for the synthesis of pharmaceuticals, peptides, alkaloids and agrochemical, dyes, and monomers for polymerization [12].

Chiral amine moieties are present in ca. 40% of pharmaceutical products. The introduction of these chiral units is therefore of high importance and usually performed through multistep processes [13,14]. As enantiomerically pure amines are required in large quantities in the pharmaceutical and agrochemical industry, the development of efficient methodologies for their preparation is of great significance and highly desirable. In the context of green chemistry, research on organometallic catalysis is still progressing to access and produce optically pure chiral amines. The main enantioselective metal-catalyzed reactions for the synthesis of chiral amines are reductive amination, hydroamination, hydroaminoalkylation and hydroaminomethylation (Scheme 3) [15].

$$ \text{Reductive amination} \\ \chemfig{*6(=-=-(-O-R1-R2-[:90])-=)} \xrightarrow{\text{[cat]}} \chemfig{*6(=-=-(-R3-[:90]N-[:150]R4-[:270])-=)} \text{+} \text{H}_2\text{O} $$

$$ \text{Hydroamination} \\ \chemfig{*6(=-=-(-R-[:90])-=)} \xrightarrow{\text{[cat]}} \chemfig{*6(=-=-(-R-[:90]N-[:150]R-[:270])-=)} $$

$$ \text{Hydroaminoalkylation} \\ \text{R}_1 \overset{\text{[cat]}}{\rightleftharpoons} \underset{\substack{\text{branched isomer} \\ \text{linear isomer}}}{\text{C}} \text{N}-\text{H} \text{C} \text{H} $$

$$ \text{Hydroaminomethylation} \\ \text{R}_1 \overset{\text{Rh cat.}}{\rightleftharpoons} \underset{\substack{\text{branched isomer} \\ \text{linear isomer}}}{\text{C}} \text{H}_2\text{CO} \text{R}_2 + \text{R}_1 \overset{\text{N}-\text{R}_2}{\rightleftharpoons} \text{C} \text{R}_2 $$

<caption>**Scheme 3.** Transition metal catalyzed processes to access chiral amines.</caption>

A thorough study was performed by Kalck and co-workers on the asymmetric hydroaminomethylation of styrene with piperidine, using a variety of chiral diphosphine ligands which
had been previously reported as very efficient in both asymmetric hydroformylation and hydrogenation reactions (Scheme 4) [16]. The study also included ¹H and ³¹P NMR investigations as well as DFT calculations.

<figure><img src="image_45.png" /><figcaption>**Scheme 4.** Rh-catalyzed hydroaminomethylation of styrene using chiral diphosphine ligands.</figcaption></figure>

It was observed that the hydroformylation and the condensation proceeded rapidly, whilst the hydrogenation step was rate determining. In this reaction, the enantioselectivity should be induced in the hydrogenation step, since the chiral information obtained in the hydroformylation step is lost after condensation of the amine with the chiral aldehyde to form the corresponding enamine.

High to full conversions were obtained, and good chemo- and regioselectivity towards the branched intermediates were also attained, even if only diphospholane ligand **L17** provided the amine with high selectivity (Scheme 4). However, in all cases, no enantiomeric excess was obtained.

As detected by NMR spectroscopy, upon condensation of the amine, both (E)- and (Z)-enamines are produced. This is a crucial fact as the asymmetric hydrogenation of these enamines will lead to the opposite enantiomers, namely the (S) or (R)-products, respectively. DFT calculations established that the hydrogenation of both enamines is very close in energy (-12,2 vs -12,8 kcal/mol), therefore supporting why no enantiomeric excess could be obtained.

Godard and his group studied the asymmetric HAM of different α-substituted acrylamides using a series of amines with the $[Rh(acac)(CO)₂]/(S_{αx}, S_{αx})$-**L25** (R= Cy) catalytic system. The latter turned out to be active to directly yield chiral γ-aminobutyric acid (GABA) derivatives, with good to high yields (59-70%) and high enantioselectivities (70-86%) (Scheme 5).

In this thesis, we focused on the asymmetric HAM of 1,1-disubstituted alkenes with a chiral center obtained via asymmetric hydroformylation, as well as on the intramolecular version of 2-propenyl aniline derivatives whose chiral center is obtained by hydrogenation.
had been previously reported as very efficient in both asymmetric hydroformylation and hydrogenation reactions (Scheme 4) [16]. The study also included ¹H and ³¹P NMR investigations as well as DFT calculations.

<figure><img src="image_43.png" /><figcaption>**Scheme 4.** Rh-catalyzed hydroaminomethylation of styrene using chiral diphosphine ligands.</figcaption></figure>

It was observed that the hydroformylation and the condensation proceeded rapidly, whilst the hydrogenation step was rate determining. In this reaction, the enantioselectivity should be induced in the hydrogenation step, since the chiral information obtained in the hydroformylation step is lost after condensation of the amine with the chiral aldehyde to form the corresponding enamine.

High to full conversions were obtained, and good chemo- and regioselectivity towards the branched intermediates were also attained, even if only diphospholane ligand **L17** provided the amine with high selectivity (Scheme 4). However, in all cases, no enantiomeric excess was obtained.

As detected by NMR spectroscopy, upon condensation of the amine, both (E)- and (Z)-enamines are produced. This is a crucial fact as the asymmetric hydrogenation of these enamines will lead to the opposite enantiomers, namely the (S) or (R)-products, respectively. DFT calculations established that the hydrogenation of both enamines is very close in energy (-12,2 vs -12,8 kcal/mol), therefore supporting why no enantiomeric excess could be obtained.

Godard and his group studied the asymmetric HAM of different α-substituted acrylamides using a series of amines with the $[Rh(acac)(CO)₂]/(S_{αx}, S_{αx})$-**L25** (R= Cy) catalytic system. The latter turned out to be active to directly yield chiral γ-aminobutyric acid (GABA) derivatives, with good to high yields (59-70%) and high enantioselectivities (70-86%) (Scheme 5).

In this thesis, we focused on the asymmetric HAM of 1,1-disubstituted alkenes with a chiral center obtained via asymmetric hydroformylation, as well as on the intramolecular version of 2-propenyl aniline derivatives whose chiral center is obtained by hydrogenation.
<figure><img src="image_46.png" /><figcaption>**Scheme 5.** Rh-catalyzed asymmetric hydroaminomethylation of α-substituted acrylamides with various amines.</figcaption></figure>

<figure><img src="image_47.png" /><figcaption>**Scheme 6.** Asymmetric induction in HAM.</figcaption></figure>

## Objectives

**Objective 1:** Study the asymmetric hydroaminomethylation of 1,1-disubstituted alkenes.

**Objective 2:** Synthesis of 2-cyclopropylmethacrylamide derivatives and their reactivity in hydroformylation and hydroaminomethylation.

**Objective 3:** Development of heterogenized catalysts for the asymmetric hydroformylation and hydroaminomethylation of 1,1-disubstituted alkenes.

**Objective 4:** Intramolecular asymmetric hydroaminomethylation of monosubstituted alkenes.

**Objective 5:** Scale-up of a sugar-based phosphite phosphoramidite ligand.

## Rhodium catalyzed asymmetric hydroaminomethylation of 1,1-diarylethenes towards Tolterodine and its derivatives

Following the strategy developed by our group for the production of chiral amines via the asymmetric hydroaminomethylation of 1,1-disubstituted alkenes forming chiral 1,1-disubstituted propylamines, the work presented in this chapter aimed at the synthesis of molecules of biological interest such as chiral 3,3'-diarylpropylamines. More precisely, the study presented here deals with
<figure><img src="image_44.png" /><figcaption>**Scheme 5.** Rh-catalyzed asymmetric hydroaminomethylation of α-substituted acrylamides with various amines.</figcaption></figure>

<figure><img src="image_45.png" /><figcaption>**Scheme 6.** Asymmetric induction in HAM.</figcaption></figure>

## Objectives

**Objective 1:** Study the asymmetric hydroaminomethylation of 1,1-disubstituted alkenes.

**Objective 2:** Synthesis of 2-cyclopropylmethacrylamide derivatives and their reactivity in hydroformylation and hydroaminomethylation.

**Objective 3:** Development of heterogenized catalysts for the asymmetric hydroformylation and hydroaminomethylation of 1,1-disubstituted alkenes.

**Objective 4:** Intramolecular asymmetric hydroaminomethylation of monosubstituted alkenes.

**Objective 5:** Scale-up of a sugar-based phosphite phosphoramidite ligand.

## Rhodium catalyzed asymmetric hydroaminomethylation of 1,1-diarylethenes towards Tolterodine and its derivatives

Following the strategy developed by our group for the production of chiral amines via the asymmetric hydroaminomethylation of 1,1-disubstituted alkenes forming chiral 1,1-disubstituted propylamines, the work presented in this chapter aimed at the synthesis of molecules of biological interest such as chiral 3,3'-diarylpropylamines. More precisely, the study presented here deals with
the asymmetric hydroaminomethylation of 1,1-diarylethene for the production of Tolterodine derivatives (Scheme 7).

<figure><img src="image_48.png" /><figcaption>**Scheme 7.** Retrosynthetic analysis of Tolterodine 3.1 via hydroaminomethylation.</figcaption></figure>

Tolterodine stands as a notable pharmaceutical compound within the realm of medicinal chemistry, categorized as an antimuscarinic drug that has garnered considerable attention for its remarkable efficacy in treating overactive bladder (OAB) and its associated urinary symptoms [17]. The annual bulk production of this active pharmaceutical ingredient (API) reaches approximately 0.5 tons in industrialized countries worldwide. In 2020, it ranked as the 271st most frequently prescribed medication in the United States, with over 1 million prescriptions dispensed [18]. The initial approach for synthesizing Tolterodine was detailed in a patent by Kabi Pharmacia AB in 1998 (Scheme 2) [19]. This route includes 8 consecutive synthetic steps and an overall yield <13%. The synthesis also employed non-environmentally friendly chemicals including pyridine, phosphorus tribromide, and dichloromethane.

<figure><img src="image_49.png" /><figcaption>**Scheme 8.** Synthesis of Tolterodine 3.1 patented by Kabi Pharmacia AB.</figcaption></figure>

The work described in the following section represents the first Rh-catalyzed asymmetric hydroformylation and hydroaminomethylation of 1,1-diarylethene, leading to Tolterodine and derivatives.

1,1-diarylethenes were synthesized using a modified reported procedure [20]. Regioselective hydroarylation was performed using phenols **3.18** (1.5 equiv.) and phenylacetylenes **3.19** (1 equiv.) in the presence of an alumina-sulfuric acid heterogeneous catalyst at 160°C using microwave heating. The microwave assisted synthesis described constitutes a fast and effective manner of accessing these substrates using readily available products, in 30 to 60% yield after purification by column chromatography (Scheme 9).
the asymmetric hydroaminomethylation of 1,1-diarylethene for the production of Tolterodine derivatives (Scheme 7).

<figure><img src="image_46.png" /><figcaption>**Scheme 7.** Retrosynthetic analysis of Tolterodine 3.1 via hydroaminomethylation.</figcaption></figure>

Tolterodine stands as a notable pharmaceutical compound within the realm of medicinal chemistry, categorized as an antimuscarinic drug that has garnered considerable attention for its remarkable efficacy in treating overactive bladder (OAB) and its associated urinary symptoms [17]. The annual bulk production of this active pharmaceutical ingredient (API) reaches approximately 0.5 tons in industrialized countries worldwide. In 2020, it ranked as the 271st most frequently prescribed medication in the United States, with over 1 million prescriptions dispensed [18]. The initial approach for synthesizing Tolterodine was detailed in a patent by Kabi Pharmacia AB in 1998 (Scheme 2) [19]. This route includes 8 consecutive synthetic steps and an overall yield <13%. The synthesis also employed non-environmentally friendly chemicals including pyridine, phosphorus tribromide, and dichloromethane.

<figure><img src="image_47.png" /><figcaption>**Scheme 8.** Synthesis of Tolterodine 3.1 patented by Kabi Pharmacia AB.</figcaption></figure>

The work described in the following section represents the first Rh-catalyzed asymmetric hydroformylation and hydroaminomethylation of 1,1-diarylethene, leading to Tolterodine and derivatives.

1,1-diarylethenes were synthesized using a modified reported procedure [20]. Regioselective hydroarylation was performed using phenols **3.18** (1.5 equiv.) and phenylacetylenes **3.19** (1 equiv.) in the presence of an alumina-sulfuric acid heterogeneous catalyst at 160°C using microwave heating. The microwave assisted synthesis described constitutes a fast and effective manner of accessing these substrates using readily available products, in 30 to 60% yield after purification by column chromatography (Scheme 9).
<figure><img src="image_50.png" /><figcaption>**Scheme 9.** Synthesis of 1,1-diarylethenes via microwave assisted catalysis.</figcaption></figure>

At this stage, the scope of 1,1-diarylethene substrates that can be used in the Rh-catalyzed asymmetric hydroaminomethylation reactions was evaluated using ligand L14e (Figure 1). In all cases, high conversions were obtained (Table 1) with ca. 50% chemoselectivity and ee's ranging from 14 to 36%. No clear conclusions could be drawn from the influence of the substrate substituents.

<figure><img src="image_51.png" /><figcaption>**Figure 1.** Best ligands used for HF and HAM of substrates 3.2a-3.2g.</figcaption></figure>

Next, we were interested in studying the asymmetric hydroformylation of substrates **3.2a-g** leading to the chromanols **3.8a-g** using the ligand **L14e**.

After the catalytic tests, the products **3.8** were isolated and oxidized into the chromanones **3.6** for determination of the enantiomeric excesses. The results are described in Table 2.

High conversions were obtained for all substrates (87-99%) with excellent chemoselectivity to the chromanol products (ca. 90%). In this reaction, the highest ee's (44 and 37%, entries 4 and 7 respectively) were obtained when a *tert*-butyl group was present in *para* position of one of the aryl substituents of the substrates. It is noteworthy that slightly higher chemo- and enantioselectivities were obtained in this hydroformylation reaction when compared to the results obtained in hydroaminomethylation. This again indicated that the presence of amine in the medium negatively affected the catalytic process.
<figure><img src="image_48.png" /><figcaption>**Scheme 9.** Synthesis of 1,1-diarylethenes via microwave assisted catalysis.</figcaption></figure>

At this stage, the scope of 1,1-diarylethene substrates that can be used in the Rh-catalyzed asymmetric hydroaminomethylation reactions was evaluated using ligand **L14e** (Figure 1). In all cases, high conversions were obtained (Table 1) with ca. 50% chemoselectivity and ee's ranging from 14 to 36%. No clear conclusions could be drawn from the influence of the substrate substituents.

<figure><img src="image_49.png" /><figcaption>**Figure 1.** Best ligands used for HF and HAM of substrates **3.2a-3.2g**.</figcaption></figure>

Next, we were interested in studying the asymmetric hydroformylation of substrates **3.2a-g** leading to the chromanols **3.8a-g** using the ligand **L14e**.

After the catalytic tests, the products **3.8** were isolated and oxidized into the chromanones **3.6** for determination of the enantiomeric excesses. The results are described in Table 2.

High conversions were obtained for all substrates (87-99%) with excellent chemoselectivity to the chromanol products (ca. 90%). In this reaction, the highest ee's (44 and 37%, entries 4 and 7 respectively) were obtained when a *tert*-butyl group was present in *para* position of one of the aryl substituents of the substrates. It is noteworthy that slightly higher chemo- and enantioselectivities were obtained in this hydroformylation reaction when compared to the results obtained in hydroaminomethylation. This again indicated that the presence of amine in the medium negatively affected the catalytic process.
<figure><img src="image_52.png" /><figcaption>**Table 1.** Asymmetric Rh-catalyzed hydroaminomethylation of **3.2a-g** to the chiral amines **3.1a-g** using **L14e**.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Substrate</th><th>Conv (%)</th><th>% 3.1 [yield]*</th><th>% ee (3.1)</th><th>% 3.8</th><th>%3.14</th></tr></thead><tbody><tr><td>1</td><td>3.2a</td><td>90</td><td>48 [42]</td><td>36</td><td>42</td><td>10</td></tr><tr><td>2</td><td>3.2b</td><td>85</td><td>46 [32]</td><td>32</td><td>41</td><td>13</td></tr><tr><td>3</td><td>3.2c</td><td>93</td><td>46 [39]</td><td>33</td><td>45</td><td>9</td></tr><tr><td>4</td><td>3.2d</td><td>84</td><td>44 [30]</td><td>17</td><td>38</td><td>18</td></tr><tr><td>5</td><td>3.2e</td><td>90</td><td>44 [36]</td><td>14</td><td>46</td><td>10</td></tr><tr><td>6</td><td>3.2f</td><td>97</td><td>51 [47]</td><td>27</td><td>40</td><td>9</td></tr><tr><td>7</td><td>3.2g</td><td>86</td><td>43 [34]</td><td>25</td><td>43</td><td>15</td></tr></tbody></table>

<figure><img src="image_53.png" /><figcaption>**Table 2.** Asymmetric Rh-catalyzed hydroformylation of **3.2a-g** to the chiral chromanols **3.8a-g** using **L14e**.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Substrate</th><th>Conv. (%)</th><th>% 3.8 [yield]*</th><th>ee 3.6 (%)</th><th>% 3.14</th></tr></thead><tbody><tr><td>1</td><td>3.2a</td><td>97</td><td>90 [78]</td><td>21</td><td>10</td></tr><tr><td>2</td><td>3.2b</td><td>87</td><td>88 [81]</td><td>22</td><td>12</td></tr><tr><td>3</td><td>3.2c</td><td>96</td><td>95 [90]</td><td>35</td><td>5</td></tr><tr><td>4</td><td>3.2d</td><td>96</td><td>88 [45]</td><td>44</td><td>12</td></tr><tr><td>5</td><td>3.2e</td><td>99</td><td>91 [61]</td><td>14</td><td>9</td></tr><tr><td>6</td><td>3.2f</td><td>99</td><td>94 [49]</td><td>28</td><td>6</td></tr><tr><td>7</td><td>3.2g</td><td>98</td><td>94 [68]</td><td>37</td><td>6</td></tr></tbody></table>

<footnote><sup>a</sup> Reaction conditions: **1a** (0.12 mmol), **Rh** = [Rh(acac)(CO)<sub>2</sub>] (1 mol%), **L14e** (1.2 mol%), **P** = 30 bar (H<sub>2</sub>/CO, 1:2), MeTHF (0.2 mL), **T** = 125 °C, **t** = 38 h, 400 r.p.m. % ee of **3.1a** determined by chiral HPLC. * isolated yield.</footnote>

<footnote><sup>a</sup> Reaction conditions: **1a** (0.12 mmol), **Rh** = [Rh(acac)(CO)<sub>2</sub>] (1 mol%), **L14e** (1.2 mol%), **P** = 30 bar (H<sub>2</sub>/CO, 1:2), MeTHF (0.2 mL), **T** = 125 °C, **t** = 38 h, 400 r.p.m. % ee of **3.1a** determined by chiral HPLC. * isolated yield.</footnote>
<figure><img src="image_50.png" /><figcaption>**Table 1.** Asymmetric Rh-catalyzed hydroaminomethylation of **3.2a-g** to the chiral amines **3.1a-g** using **L14e**.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Substrate</th><th>Conv (%)</th><th>% 3.1 [yield]*</th><th>% ee (3.1)</th><th>% 3.8</th><th>%3.14</th></tr></thead><tbody><tr><td>1</td><td>3.2a</td><td>90</td><td>48 [42]</td><td>36</td><td>42</td><td>10</td></tr><tr><td>2</td><td>3.2b</td><td>85</td><td>46 [32]</td><td>32</td><td>41</td><td>13</td></tr><tr><td>3</td><td>3.2c</td><td>93</td><td>46 [39]</td><td>33</td><td>45</td><td>9</td></tr><tr><td>4</td><td>3.2d</td><td>84</td><td>44 [30]</td><td>17</td><td>38</td><td>18</td></tr><tr><td>5</td><td>3.2e</td><td>90</td><td>44 [36]</td><td>14</td><td>46</td><td>10</td></tr><tr><td>6</td><td>3.2f</td><td>97</td><td>51 [47]</td><td>27</td><td>40</td><td>9</td></tr><tr><td>7</td><td>3.2g</td><td>86</td><td>43 [34]</td><td>25</td><td>43</td><td>15</td></tr></tbody></table>

<figure><img src="image_51.png" /><figcaption>**Table 2.** Asymmetric Rh-catalyzed hydroformylation of **3.2a-g** to the chiral chromanols **3.8a-g** using **L14e**.</figcaption></figure>

<table><thead><tr><th>Entry</th><th>Substrate</th><th>Conv. (%)</th><th>% 3.8 [yield]*</th><th>ee 3.6 (%)</th><th>% 3.14</th></tr></thead><tbody><tr><td>1</td><td>3.2a</td><td>97</td><td>90 [78]</td><td>21</td><td>10</td></tr><tr><td>2</td><td>3.2b</td><td>87</td><td>88 [81]</td><td>22</td><td>12</td></tr><tr><td>3</td><td>3.2c</td><td>96</td><td>95 [90]</td><td>35</td><td>5</td></tr><tr><td>4</td><td>3.2d</td><td>96</td><td>88 [45]</td><td>44</td><td>12</td></tr><tr><td>5</td><td>3.2e</td><td>99</td><td>91 [61]</td><td>14</td><td>9</td></tr><tr><td>6</td><td>3.2f</td><td>99</td><td>94 [49]</td><td>28</td><td>6</td></tr><tr><td>7</td><td>3.2g</td><td>98</td><td>94 [68]</td><td>37</td><td>6</td></tr></tbody></table>

<footnote><sup>a</sup> Reaction conditions: **1a** (0.12 mmol), **Rh** = [Rh(acac)(CO)<sub>2</sub>] (1 mol%), **L14e** (1.2 mol%), **P** = 30 bar (H<sub>2</sub>/CO, 1:2), MeTHF (0.2 mL), **T** = 125 °C, **t** = 38 h, 400 r.p.m. % ee of **3.1a** determined by chiral HPLC. * isolated yield.</footnote>

<footnote><sup>a</sup> Reaction conditions: **1a** (0.12 mmol), **Rh** = [Rh(acac)(CO)<sub>2</sub>] (1 mol%), **L14e** (1.2 mol%), **P** = 30 bar (H<sub>2</sub>/CO, 1:2), MeTHF (0.2 mL), **T** = 125 °C, **t** = 38 h, 400 r.p.m. % ee of **3.1a** determined by chiral HPLC. * isolated yield.</footnote>
Rh-catalyzed hydroaminomethylation of 1,1-cyclopropylmethacrylamides.

The possibility to access chiral GABA and derivatives through a direct approach is of major interest. As such, the asymmetric HAM of the cyclopropyl acrylamide **4.2** with the spirocyclic amine **4.3** could yield **4.1** based on the retrosynthetic route described in Scheme 10.

<figure><img src="image_54.png" /><figcaption>**Scheme 10.** Retrosynthetic analysis for the production of CCR2 antagonist **4.1** via HAM.</figcaption></figure>

A drawback of this strategy involved the presence of a vinylcyclopropyl moiety in the starting material, which could undergo undesired side reactions. Vinylcyclopropanes (VCPs) have found extensive applications in transition-metal-catalyzed cycloaddition reactions due to the presence of an olefin group that guides the transition-metal towards the selective cleavage of C–C bonds [21]. VCPs were reported in reactions with Ru, Ni, Pd, Ir, Co, Fe and Rh based metal catalysts. Among them, Rh was one of the most studied as it was active in both C–C bond cleavage of activated and non-activated VCPs in either inter- or intramolecular processes. In the next section, only Rh-based C–C bond cleavage is described.

<figure><img src="image_55.png" /><figcaption>**Scheme 11.** Reactivity of VCPs with Rh.</figcaption></figure>

Cyclopropyl acetylene **4.13** and different amines were tested as substrates in the Pd-catalyzed hydroaminocarbonylation reaction based on previous reports involving different alkynes [22]. The substrates were reacted with carbon monoxide gas in the presence of Pd(OAc)₂ as the metal precursor and 1,3-bis(diphenylphosphino)propane (dppp) **L1** as ligand. For the synthesis of α-cyclopropyl acrylamide **4.27**, ammonium carbonate was used as the amine source and the reaction was run for 6h (Scheme 12) [23].

Various new 1,1-disubstituted alkenes containing either primary, secondary or tertiary amide moieties were synthesized using this protocol. The primary amide **4.27** was synthesized in 38% yield and the four secondary amides **4.2**, **4.23**, **4.24** and **4.25** were synthesized in moderate to good yields (47 to 62%). The tertiary amide **4.26** was obtained in 47% yield.

Hydroformylation of secondary 2-cyclopropylacrylamides with **L3** provided new dihydro-pyridinone products which were isolated and fully characterized. Moreover, reduction of the catalytic crude revealed that the hydroformylation product **4.45** was also formed as the main linear aldehyde.

Notably, dppf provided a linear aldehyde, **4.45**, in 69% as observed by the triplet pattern of the aldehyde signal in ¹H NMR. The formation of products **4.41** and **4.45** could be explained through the mechanism displayed in Scheme 14. The formation of the cyclic dihydropyridinone **4.41** and the aldehyde **4.45** product indicated that C–C bond activation of cyclopropanes had taken place, as previously observed in the presence of Rh(I) catalysts. The possible mechanism described in Scheme
Rh-catalyzed hydroaminomethylation of 1,1-cyclopropylmethacrylamides.

The possibility to access chiral GABA and derivatives through a direct approach is of major interest. As such, the asymmetric HAM of the cyclopropyl acrylamide **4.2** with the spirocyclic amine **4.3** could yield **4.1** based on the retrosynthetic route described in Scheme 10.

<figure><img src="image_52.png" /><figcaption>**Scheme 10.** Retrosynthetic analysis for the production of CCR2 antagonist **4.1** via HAM.</figcaption></figure>

A drawback of this strategy involved the presence of a vinylcyclopropyl moiety in the starting material, which could undergo undesired side reactions. Vinylcyclopropanes (VCPs) have found extensive applications in transition-metal-catalyzed cycloaddition reactions due to the presence of an olefin group that guides the transition-metal towards the selective cleavage of C–C bonds [21]. VCPs were reported in reactions with Ru, Ni, Pd, Ir, Co, Fe and Rh based metal catalysts. Among them, Rh was one of the most studied as it was active in both C–C bond cleavage of activated and non-activated VCPs in either inter- or intramolecular processes. In the next section, only Rh-based C–C bond cleavage is described.

<figure><img src="image_53.png" /><figcaption>**Scheme 11.** Reactivity of VCPs with Rh.</figcaption></figure>

Cyclopropyl acetylene **4.13** and different amines were tested as substrates in the Pd-catalyzed hydroaminocarbonylation reaction based on previous reports involving different alkynes [22]. The substrates were reacted with carbon monoxide gas in the presence of Pd(OAc)₂ as the metal precursor and 1,3-bis(diphenylphosphino)propane (dppp) **L1** as ligand. For the synthesis of α-cyclopropyl acrylamide **4.27**, ammonium carbonate was used as the amine source and the reaction was run for 6h (Scheme 12) [23].

Various new 1,1-disubstituted alkenes containing either primary, secondary or tertiary amide moieties were synthesized using this protocol. The primary amide **4.27** was synthesized in 38% yield and the four secondary amides **4.2**, **4.23**, **4.24** and **4.25** were synthesized in moderate to good yields (47 to 62%). The tertiary amide **4.26** was obtained in 47% yield.

Hydroformylation of secondary 2-cyclopropylacrylamides with **L3** provided new dihydro-pyridinone products which were isolated and fully characterized. Moreover, reduction of the catalytic crude revealed that the hydroformylation product **4.45** was also formed as the main linear aldehyde.

Notably, dppf provided a linear aldehyde, **4.45**, in 69% as observed by the triplet pattern of the aldehyde signal in ¹H NMR. The formation of products **4.41** and **4.45** could be explained through the mechanism displayed in Scheme 14. The formation of the cyclic dihydropyridinone **4.41** and the aldehyde **4.45** product indicated that C–C bond activation of cyclopropanes had taken place, as previously observed in the presence of Rh(I) catalysts. The possible mechanism described in Scheme
14 relies on the oxidative addition of Rh(I) into VCPs described in Scheme 11 [24]. As the catalysis is performed under syngas pressure, a rhodium hydride species is present in the system.

<figure><img src="image_56.png" /><figcaption>**Scheme 12.** Synthesis of 1,1-disubstituted alkenes via hydroaminocarbonylation.</figcaption></figure>

<figure><img src="image_57.png" /><figcaption>**Scheme 13.** Hydroformylation of 4.42 and 4.43 using ligand L3.</figcaption></figure>

<figure><img src="image_58.png" /><figcaption>**Scheme 14.** Possible mechanism for the formation of dihydropyridinone 4.41 and aldehyde 4.50.</figcaption></figure>
14 relies on the oxidative addition of Rh(I) into VCPs described in Scheme 11 [24]. As the catalysis is performed under syngas pressure, a rhodium hydride species is present in the system.

<figure><img src="image_54.png" /><figcaption>**Scheme 12.** Synthesis of 1,1-disubstituted alkenes via hydroaminocarbonylation.</figcaption></figure>

<figure><img src="image_55.png" /><figcaption>**Scheme 13.** Hydroformylation of 4.42 and 4.43 using ligand L3.</figcaption></figure>

<figure><img src="image_56.png" /><figcaption>**Scheme 14.** Possible mechanism for the formation of dihydropyridinone 4.41 and aldehyde 4.50.</figcaption></figure>
The reactivity of N-benzyl-2-cyclopropylacrylamide **4.23** was tested in hydroaminomethylation using Rh(acac)(CO)₂ as rhodium precursor, **L10** as ligand, and with 1 equivalent of piperidine. The reaction was carried out at 1 mmol scale under 20 bar of syngas for 16 h at 90 °C.

<figure><img src="image_59.png" /><figcaption>**Scheme 15.** Reactivity of **4.23** under hydroaminomethylation conditions with piperidine.</figcaption></figure>

The substrate was converted in 70% in mainly two products, **4.54** (44%) and **4.55** (48%). Surprisingly, the expected condensation of the amine on the resulting aldehyde **4.45** obtained previously in the hydroformylation of **4.23** with Rh/L10 catalytic system was not detected. However, opening of the VCP occurred yielding the new product **4.54**. The second surprise was the formation of the cyclopropyl containing hydroamination product **4.55**. This unexpected result would suggest that a fast hydroamination would occur before the opening of the VCP.

Rhodium catalyzed asymmetric hydroaminomethylation towards continuous flow.

Currently, over 90% of all industrial chemicals are produced through catalytic processes [25]. Hence, an important challenge in modern chemistry is the discovery of catalytic systems that combine the merits of both homogeneous (selectivity) and heterogeneous (recycling) catalysis. Numerous techniques were devised to retrieve and reuse homogeneous catalysts, as well as to efficiently separate the catalyst from the products. Among these methods, one of the prevailing approaches involves anchoring homogeneous catalysts onto solid supports, resulting in the so-called "heterogenized catalysts". These heterogenized systems can be produced through various approaches (Figure 2) [26].

<figure><img src="image_60.png" /><figcaption>**Figure 2.** Main approaches for the immobilization of homogeneous catalysts onto solid supports.</figcaption></figure>

In this work, we focused on the non-covalent immobilization of homogeneous catalysts for their application in hydroformylation and hydroaminomethylation reactions. Graphitic materials have attracted significant interest as potential supports for anchoring homogeneous catalysts through π-π
The reactivity of N-benzyl-2-cyclopropylacrylamide **4.23** was tested in hydroaminomethylation using Rh(acac)(CO)₂ as rhodium precursor, **L10** as ligand, and with 1 equivalent of piperidine. The reaction was carried out at 1 mmol scale under 20 bar of syngas for 16 h at 90 °C.

<figure><img src="image_57.png" /><figcaption>**Scheme 15.** Reactivity of **4.23** under hydroaminomethylation conditions with piperidine.</figcaption></figure>

The substrate was converted in 70% in mainly two products, **4.54** (44%) and **4.55** (48%). Surprisingly, the expected condensation of the amine on the resulting aldehyde **4.45** obtained previously in the hydroformylation of **4.23** with Rh/L10 catalytic system was not detected. However, opening of the VCP occurred yielding the new product **4.54**. The second surprise was the formation of the cyclopropyl containing hydroamination product **4.55**. This unexpected result would suggest that a fast hydroamination would occur before the opening of the VCP.

Rhodium catalyzed asymmetric hydroaminomethylation towards continuous flow.

Currently, over 90% of all industrial chemicals are produced through catalytic processes [25]. Hence, an important challenge in modern chemistry is the discovery of catalytic systems that combine the merits of both homogeneous (selectivity) and heterogeneous (recycling) catalysis. Numerous techniques were devised to retrieve and reuse homogeneous catalysts, as well as to efficiently separate the catalyst from the products. Among these methods, one of the prevailing approaches involves anchoring homogeneous catalysts onto solid supports, resulting in the so-called "heterogenized catalysts". These heterogenized systems can be produced through various approaches (Figure 2) [26].

<figure><img src="image_58.png" /><figcaption>**Figure 2.** Main approaches for the immobilization of homogeneous catalysts onto solid supports.</figcaption></figure>

In this work, we focused on the non-covalent immobilization of homogeneous catalysts for their application in hydroformylation and hydroaminomethylation reactions. Graphitic materials have attracted significant interest as potential supports for anchoring homogeneous catalysts through π-π
interactions. These interactions provide a stable foundation for the anchoring metal complexes and refer to non-covalent connections that arise between the electron densities of stacked aromatic systems. While benzene traditionally serves as the prototype for aromatic interactions, recent investigations have unveiled that larger aromatic systems, such as pyrene and coronene, provide even more resilient π-π stacking bonds with CNTs [27]. Good results were reported in the Rh-catalyzed hydroaminomethylation reaction under flow conditions. However, the asymmetric version of this process was not reported to date.

Hence, here, our objective was the preparation of heterogenized chiral Rh catalysts for their application in the asymmetric hydroaminomethylation of acrylamides under batch and flow conditions. The design of the catalysts was based on a previous report from our group that described the efficient hydroaminomethylation of these substrates into chiral amines under homogeneous conditions [28]. These catalysts would be supported onto carbon support via π-π interaction by introduction of a pyrene moiety in the backbone of the phosphite-phosphoramidite ligands (Figure 3). In the following sections, the results obtained to reach this objective will be described.

<figure><img src="image_61.png" /><figcaption>**Figure 3.** Aimed catalysts for the asymmetric HAM of acrylamides in continuous flow.</figcaption></figure>

Using the same strategy as described for the synthesis of **5.5**, the amine moiety was introduced first in the xylose backbone followed by the incorporation of the pyrene. For this purpose, the tosyl **5.7** was reacted with sodium azide in dimethylformamide at 90 °C. The azide intermediate **5.16** was reduced with triphenylphosphine in a mixture of water and tetrahydrofuran at room temperature, yielding the water-soluble amino alcohol **5.17** in 64% yield over the two steps, after recrystallization in diethyl ether (Scheme 16).

<figure><img src="image_62.png" /><figcaption>**Scheme 16.** Synthesis of the amino-alcohol **5.17** from the tosyl **5.7**.</figcaption></figure>

In parallel, 1-pyrenebutyric acid **5.8** was reduced by $LiAlH_4$ in THF at room temperature for 16 h to 1-pyrenebutanol **5.18** in quantitative yield. The 1-pyrenebutanol **5.18** was further oxidized using pyridinium chlorochromate (PCC) in dichloromethane to the 1-pyrenebutanal **5.19** in 80% yield (Scheme 17).
interactions. These interactions provide a stable foundation for the anchoring metal complexes and refer to non-covalent connections that arise between the electron densities of stacked aromatic systems. While benzene traditionally serves as the prototype for aromatic interactions, recent investigations have unveiled that larger aromatic systems, such as pyrene and coronene, provide even more resilient π-π stacking bonds with CNTs [27]. Good results were reported in the Rh-catalyzed hydroaminomethylation reaction under flow conditions. However, the asymmetric version of this process was not reported to date.

Hence, here, our objective was the preparation of heterogenized chiral Rh catalysts for their application in the asymmetric hydroaminomethylation of acrylamides under batch and flow conditions. The design of the catalysts was based on a previous report from our group that described the efficient hydroaminomethylation of these substrates into chiral amines under homogeneous conditions [28]. These catalysts would be supported onto carbon support via π-π interaction by introduction of a pyrene moiety in the backbone of the phosphite-phosphoramidite ligands (Figure 3). In the following sections, the results obtained to reach this objective will be described.

<figure><img src="image_59.png" /><figcaption>**Figure 3.** Aimed catalysts for the asymmetric HAM of acrylamides in continuous flow.</figcaption></figure>

Using the same strategy as described for the synthesis of **5.5**, the amine moiety was introduced first in the xylose backbone followed by the incorporation of the pyrene. For this purpose, the tosyl **5.7** was reacted with sodium azide in dimethylformamide at 90 °C. The azide intermediate **5.16** was reduced with triphenylphosphine in a mixture of water and tetrahydrofuran at room temperature, yielding the water-soluble amino alcohol **5.17** in 64% yield over the two steps, after recrystallization in diethyl ether (Scheme 16).

<figure><img src="image_60.png" /><figcaption>**Scheme 16.** Synthesis of the amino-alcohol **5.17** from the tosyl **5.7**.</figcaption></figure>

In parallel, 1-pyrenebutyric acid **5.8** was reduced by $LiAlH_4$ in THF at room temperature for 16 h to 1-pyrenebutanol **5.18** in quantitative yield. The 1-pyrenebutanol **5.18** was further oxidized using pyridinium chlorochromate (PCC) in dichloromethane to the 1-pyrenebutanal **5.19** in 80% yield (Scheme 17).
<figure><img src="image_63.png" /><figcaption>**Scheme 17.** Reduction and oxidation sequence of 1-pyrenebutyric acid 5.8 to 1-pyrenebutanal 5.19.</figcaption></figure>

The amino-alcohol **5.17** and the aldehyde **5.19** partners were reacted in reductive amination to form the hemiaminal intermediate **5.20** in 90% yield. Surprisingly, neither sodium borohydride or sodium cyanoborohydride could open the 6 members ring intermediate **5.20**.

<figure><img src="image_64.png" /><figcaption>**Scheme 18.** Synthesis of pyrene-tagged amino alcohol linear backbone 5.12.</figcaption></figure>

However, when $LiAlH_4$ was used in THF, the chiral pyrene-tagged amino alcohol linear backbone **5.12** was obtained in 89% yield (Scheme 18). Overall, this product was obtained in 41% yield from the tosyl intermediate **5.7** and the commercially available pyrene carboxylic acid **5.8**.

The amino-alcohol backbone **5.12** was reacted at rt for 2 h with the (S)-binolchlorophosphite formed *in situ* from phosphorus trichloride and (S)-BINOL (Scheme 19). The reaction time was critical since impurities that couldn't be separated by chromatography were detected by <sup>31</sup>P NMR when the reaction time was increased. The new phosphite phosphoramidite pyrene tagged ligand **5.11** was obtained in a 33% yield after column chromatography.

<figure><img src="image_65.png" /><figcaption>**Scheme 19.** Synthesis of phosphite phosphoramidite ligand 5.11.</figcaption></figure>

The phosphite phosphoramidite ligand **5.11** was reacted in stoichiometric amount with $[Rh(COD)_2]BF_4$ in dichloromethane at 0°C and stirred at room temperature for 1 h (Scheme 20). The cationic complex **5.10** was immobilized on multiwall carbon nanotubes (MWCNT), reduced graphene oxide (rGO) and carbon beads (CB) and the corresponding Rh loadings are described in Table 3. The
<figure><img src="image_61.png" /><figcaption>**Scheme 17.** Reduction and oxidation sequence of 1-pyrenebutyric acid 5.8 to 1-pyrenebutanal 5.19.</figcaption></figure>

The amino-alcohol **5.17** and the aldehyde **5.19** partners were reacted in reductive amination to form the hemiaminal intermediate **5.20** in 90% yield. Surprisingly, neither sodium borohydride or sodium cyanoborohydride could open the 6 members ring intermediate **5.20**.

<figure><img src="image_62.png" /><figcaption>**Scheme 18.** Synthesis of pyrene-tagged amino alcohol linear backbone 5.12.</figcaption></figure>

However, when $LiAlH_4$ was used in THF, the chiral pyrene-tagged amino alcohol linear backbone **5.12** was obtained in 89% yield (Scheme 18). Overall, this product was obtained in 41% yield from the tosyl intermediate **5.7** and the commercially available pyrene carboxylic acid **5.8**.

The amino-alcohol backbone **5.12** was reacted at rt for 2 h with the (S)-binolchlorophosphite formed *in situ* from phosphorus trichloride and (S)-BINOL (Scheme 19). The reaction time was critical since impurities that couldn't be separated by chromatography were detected by <sup>31</sup>P NMR when the reaction time was increased. The new phosphite phosphoramidite pyrene tagged ligand **5.11** was obtained in a 33% yield after column chromatography.

<figure><img src="image_63.png" /><figcaption>**Scheme 19.** Synthesis of phosphite phosphoramidite ligand 5.11.</figcaption></figure>

The phosphite phosphoramidite ligand **5.11** was reacted in stoichiometric amount with $[Rh(COD)_2]BF_4$ in dichloromethane at 0°C and stirred at room temperature for 1 h (Scheme 20). The cationic complex **5.10** was immobilized on multiwall carbon nanotubes (MWCNT), reduced graphene oxide (rGO) and carbon beads (CB) and the corresponding Rh loadings are described in Table 3. The
highest rhodium loading was on **5.10@MWCNT** with 1.61 wt% followed by **5.10@CB** with 1.44 wt% and finally **5.10@rGO** with 1.10 wt%.

<figure><img src="image_66.png" /><figcaption>**Scheme 20.** Expected structure of the product **5.3** from the complexation of **5.11** with $[Rh(COD)_{2}]BF_{4}$.</figcaption></figure>

<table><caption>**Table 3.** Immobilization of **5.10** on carbon materials.</caption><thead><tr><td>Catalyst</td><td>Rh loading wt%</td></tr></thead><tbody><tr><td>5.10@MWCNT</td><td>1.61</td></tr><tr><td>5.10@rGO</td><td>1.10</td></tr><tr><td>5.10@CB</td><td>1.44</td></tr></tbody></table>

The successfully immobilized catalysts were then tested in asymmetric hydroformylation of acrylamide derivatives. The activity of the [Rh/5.11] catalytic system was tested in homogeneous hydroformylation and hydroaminomethylation of **5.22**. The asymmetric hydroformylation of **5.22** (Scheme 21) resulted in an excellent 80% ee of **5.23**. The asymmetric hydroaminomethylation (Scheme 22) resulted in a good 67% ee of **5.27**. These results indicated that the introduction of the pyrene moiety in the ligand did not significantly affect the catalytic outcome of the reaction.

<figure><img src="image_67.png" /><figcaption>**Scheme 21.** Homogeneous asymmetric hydroformylation of **5.22** with the catalytic system [Rh/5.11].</figcaption></figure>

<figure><img src="image_68.png" /><figcaption>**Scheme 22.** Homogeneous asymmetric hydroaminomethylation of **5.22** with the catalytic system [Rh/5.11].</figcaption></figure>

The immobilized catalysts were tested in batch hydroformylation in view of a continuous flow application. The catalysts presented a low activity, but the catalyst **5.10@MWCNT** provided a conversion of 30% at 110°C with a selectivity towards the linear aldehyde of 31% and a good enantioselectivity of 61%.
highest rhodium loading was on **5.10@MWCNT** with 1.61 wt% followed by **5.10@CB** with 1.44 wt% and finally **5.10@rGO** with 1.10 wt%.

<figure><img src="image_64.png" /><figcaption>**Scheme 20.** Expected structure of the product **5.3** from the complexation of **5.11** with $[Rh(COD)_{2}]BF_{4}$.</figcaption></figure>

<table><caption>**Table 3.** Immobilization of **5.10** on carbon materials.</caption><thead><tr><td>Catalyst</td><td>Rh loading wt%</td></tr></thead><tbody><tr><td>5.10@MWCNT</td><td>1.61</td></tr><tr><td>5.10@rGO</td><td>1.10</td></tr><tr><td>5.10@CB</td><td>1.44</td></tr></tbody></table>

The successfully immobilized catalysts were then tested in asymmetric hydroformylation of acrylamide derivatives. The activity of the [Rh/5.11] catalytic system was tested in homogeneous hydroformylation and hydroaminomethylation of **5.22**. The asymmetric hydroformylation of **5.22** (Scheme 21) resulted in an excellent 80% ee of **5.23**. The asymmetric hydroaminomethylation (Scheme 22) resulted in a good 67% ee of **5.27**. These results indicated that the introduction of the pyrene moiety in the ligand did not significantly affect the catalytic outcome of the reaction.

<figure><img src="image_65.png" /><figcaption>**Scheme 21.** Homogeneous asymmetric hydroformylation of **5.22** with the catalytic system [Rh/5.11].</figcaption></figure>

<figure><img src="image_66.png" /><figcaption>**Scheme 22.** Homogeneous asymmetric hydroaminomethylation of **5.22** with the catalytic system [Rh/5.11].</figcaption></figure>

The immobilized catalysts were tested in batch hydroformylation in view of a continuous flow application. The catalysts presented a low activity, but the catalyst **5.10@MWCNT** provided a conversion of 30% at 110°C with a selectivity towards the linear aldehyde of 31% and a good enantioselectivity of 61%.
Rhodium catalyzed intramolecular asymmetric hydroaminomethylation of alkenes.

Through intramolecular HAM, compounds such as indoline, tetrahydroisoquinoline or benzazepine derivatives, privileged scaffolds which exhibit interesting and important pharmacological activities, can be accessed in a one step process [29]. As presented in scheme 6, pathway B, the hydroaminomethylation of monosubstituted alkenes undergoes racemization during the condensation step between the aldehyde formed during the HF step and the amine reagent, and as such, the enantioselectivity must be induced during the hydrogenation of the imine/enamine to produce a chiral amine. In contrast with the intermolecular HAM [30], only one enamine isomer can be formed, making more efficient the asymmetric hydrogenation (Scheme 23).

<figure><img src="image_69.png" /><figcaption>**Scheme 23.** Intramolecular HAM of different substrates.</figcaption></figure>

Substrates **6.33**, **6.34**, **6.39**, **6.42** were successfully synthesized according to reported procedure and tested in intramolecular hydroaminomethylation. As a general trend, the hydrogenation of the enamine intermediate is the limiting factor for the reaction to proceed and might require high pressure and temperature.

<figure><img src="image_70.png" /><figcaption>**Figure 4.** Substrates **6.33**, **6.34**, **6.39**, **6.42** used in intramolecular HAM.</figcaption></figure>

Increasing the size of the enamine ring formed from 5 to 7-membered ring resulted in a more efficient hydrogenation under HAM conditions. However, no asymmetric hydroaminomethylation could be tested due to the lack of time.

Secondment at Italmatch Chemicals: scale-up of a ligand synthesis based on D-xylose

The lab scale-up was realized in three steps with an overall yield of 26%. The first step was the synthesis of the selective monoprotected ketal **7.17** (Scheme 24). D-xylose **7.15** was reacted with concentrated sulfuric acid in acetone for 1 h at room temperature. Then, the selective
Rhodium catalyzed intramolecular asymmetric hydroaminomethylation of alkenes.

Through intramolecular HAM, compounds such as indoline, tetrahydroisoquinoline or benzazepine derivatives, privileged scaffolds which exhibit interesting and important pharmacological activities, can be accessed in a one step process [29]. As presented in scheme 6, pathway B, the hydroaminomethylation of monosubstituted alkenes undergoes racemization during the condensation step between the aldehyde formed during the HF step and the amine reagent, and as such, the enantioselectivity must be induced during the hydrogenation of the imine/enamine to produce a chiral amine. In contrast with the intermolecular HAM [30], only one enamine isomer can be formed, making more efficient the asymmetric hydrogenation (Scheme 23).

<figure><img src="image_67.png" /><figcaption>**Scheme 23.** Intramolecular HAM of different substrates.</figcaption></figure>

Substrates **6.33**, **6.34**, **6.39**, **6.42** were successfully synthesized according to reported procedure and tested in intramolecular hydroaminomethylation. As a general trend, the hydrogenation of the enamine intermediate is the limiting factor for the reaction to proceed and might require high pressure and temperature.

<figure><img src="image_68.png" /><figcaption>**Figure 4.** Substrates **6.33**, **6.34**, **6.39**, **6.42** used in intramolecular HAM.</figcaption></figure>

Increasing the size of the enamine ring formed from 5 to 7-membered ring resulted in a more efficient hydrogenation under HAM conditions. However, no asymmetric hydroaminomethylation could be tested due to the lack of time.

Secondment at Italmatch Chemicals: scale-up of a ligand synthesis based on D-xylose

The lab scale-up was realized in three steps with an overall yield of 26%. The first step was the synthesis of the selective monoprotected ketal **7.17** (Scheme 24). D-xylose **7.15** was reacted with concentrated sulfuric acid in acetone for 1 h at room temperature. Then, the selective
monodeprotection of the ketal was realized *in situ* by adding potassium carbonate and stirred for 3 h. Then, K₂CO₃ was added until neutral pH was reached, yielding **7.17** in 90% after work-up and evaporation of the aqueous phase.

<figure><img src="image_71.png" /><figcaption>**Scheme 24.** Synthesis of the diol 7.17 in one step.</figcaption></figure>

Activation of the primary alcohol was achieved with a slightly modified procedure. The diol **7.17** was reacted with 4-toluenesulfonyl chloride in triethylamine and tetrahydrofuran at room temperature for 16 h (Scheme 25). The product **7.18** was obtained in a similar 57% yield after precipitation in cold diethyl ether. The system NEt₃/THF was preferred to the pyridine/DCM system due to safety hazard and waste management.

<figure><img src="image_72.png" /><figcaption>**Scheme 25.** Synthesis of tosylated product 7.18.</figcaption></figure>

Finally, the amino alcohol **7.19a** was synthesized by reacting **7.18** with an excess of cyclohexylamine (4 equiv.) in 1-butanol at 110°C for 3 h 30 (Scheme 26). The product was obtained in 50% yield after acid base work up. Changing isopropanol to 1-butanol drastically reduced the reaction time as further heating was possible. The final aqueous treatment avoided the purification by column chromatography.

<figure><img src="image_73.png" /><figcaption>**Scheme 26.** Synthesis of the amino alcohol 7.19a.</figcaption></figure>

Then, an optimization of the continuous flow synthesis of chlorophosphite **7.30** was performed using syringe pumps. It was carried out with acetonitrile and a base. Samples were rapidly analyzed by ³¹P NMR to evaluate the conversion and selectivity. The optimal conditions included the use of diol solution with NMI (0.2 equiv.) in acetonitrile (1 M) and PCl₃ in acetonitrile (1 M) for 1 min at room temperature.

<figure><img src="image_74.png" /><figcaption>**Figure 5.** Flow synthesis of chlorophosphite 7.30.</figcaption></figure>
monodeprotection of the ketal was realized *in situ* by adding potassium carbonate and stirred for 3 h. Then, K₂CO₃ was added until neutral pH was reached, yielding **7.17** in 90% after work-up and evaporation of the aqueous phase.

<figure><img src="image_69.png" /></figure>

7.15

<figure><img src="image_70.png" /></figure>

<figure><img src="image_71.png" /></figure>

7.17

<caption>**Scheme 24.** Synthesis of the diol 7.17 in one step.</caption>

Activation of the primary alcohol was achieved with a slightly modified procedure. The diol **7.17** was reacted with 4-toluenesulfonyl chloride in triethylamine and tetrahydrofuran at room temperature for 16 h (Scheme 25). The product **7.18** was obtained in a similar 57% yield after precipitation in cold diethyl ether. The system NEt₃/THF was preferred to the pyridine/DCM system due to safety hazard and waste management.

<figure><img src="image_72.png" /></figure>

7.17

<figure><img src="image_73.png" /></figure>

<figure><img src="image_74.png" /></figure>

<figure><img src="image_75.png" /></figure>

7.18

<caption>**Scheme 25.** Synthesis of tosylated product 7.18.</caption>

Finally, the amino alcohol **7.19a** was synthesized by reacting **7.18** with an excess of cyclohexylamine (4 equiv.) in 1-butanol at 110°C for 3 h 30 (Scheme 26). The product was obtained in 50% yield after acid base work up. Changing isopropanol to 1-butanol drastically reduced the reaction time as further heating was possible. The final aqueous treatment avoided the purification by column chromatography.

<figure><img src="image_76.png" /></figure>

7.18

<figure><img src="image_77.png" /></figure>

<figure><img src="image_78.png" /></figure>

7.19a

<caption>**Scheme 26.** Synthesis of the amino alcohol 7.19a.</caption>

Then, an optimization of the continuous flow synthesis of chlorophosphite **7.30** was performed using syringe pumps. It was carried out with acetonitrile and a base. Samples were rapidly analyzed by ³¹P NMR to evaluate the conversion and selectivity. The optimal conditions included the use of diol solution with NMI (0.2 equiv.) in acetonitrile (1 M) and PCl₃ in acetonitrile (1 M) for 1 min at room temperature.

<figure><img src="image_79.png" /></figure>

7.29

<figure><img src="image_80.png" /></figure>

<figure><img src="image_81.png" /></figure>

7.30

<figure><img src="image_82.png" /></figure>

7.31

<figure><img src="image_83.png" /></figure>

7.32

<caption>**Figure 5.** Flow synthesis of chlorophosphite 7.30.</caption>
**General conclusions.**

This manuscript details research work on various chemical reactions, including the homogeneous asymmetric hydroaminomethylation of specific compounds, the synthesis of chiral catalysts for this reaction, and the evaluation of reactivity of various compounds in hydroformylation and hydroaminomethylation reactions.

The first part described the results of asymmetric hydroformylation and hydroaminomethylation of 1,1-diarylethenes. It outlines the direct synthesis of Tolterodine and its derivatives via asymmetric hydroaminomethylation of these compounds, along with experimental conditions and yields obtained.

The second part focused on the synthesis of different compounds and their reactivity in rhodium-catalyzed reactions. The hydroformylation and hydroaminomethylation reactions of these compounds are studied, with observations on the reactivity of cyclopropylmethacrylamide and the formation of derivative products.

The third part addressed the development of heterogeneous catalysts for hydroformylation and hydroaminomethylation reactions. Pyrene-tagged ligands were synthesized and tested as immobilized catalysts, showing promising results despite relatively low activity.

The fourth part explored into the reactivity of ortho-substituted styrene derivatives in rhodium-catalyzed intramolecular hydroaminomethylation. The results indicate that the reaction is limited by the hydrogenation of the enamine intermediate.

Finally, the last part presented the results obtained during a stay at Italmatch Chemicals, highlighting the synthesis of different compounds and the scaling up of the synthesis of certain intermediates.

**References**

[1] M. Beller (Editor), *Catalytic Carbonylation Reactions*, Top. Organomet. Chem., **2006**, *18*, 1-283.
DOI: 10.1007/b105253.

[2] C. Claver (Editor), *Rhodium Catalysis*, Top. Organomet. Chem., **2018**, *61*, 1-288. DOI:
[10.1007/978-3-319-66665-5](https://doi.org/10.1007/978-3-319-66665-5).

[3] (a) B. Breit, *Aldehydes: synthesis by hydroformylation of alkenes*, in *Science of synthesis*, Thieme: Stuttgart, Germany, **2007**, Vol. 25, pp 277-282. DOI: 10.1055/sos-SD-025-00196. (b) R. Franke, D. Selent, A. Börner, *Chem. Rev.* **2012**, *112*, 5675-5732. DOI: [10.1021/cr3001803](https://doi.org/10.1021/cr3001803).

[4] (a) B. Cornils, W. A. Herrmann (Editors), *Applied Homogeneous Catalysis with Organometallic Compounds*, Vol. 1, Wiley-VCH: Weinheim, Germany, **2002**. DOI: [10.1002/9783527618231](https://doi.org/10.1002/9783527618231). (b) K. Weissermel, H.-J. Arpe, *Industrial Organic Chemistry*, Wiley-VCH: Weinheim, Germany, **2008**. DOI: [10.1002/9783527619191](https://doi.org/10.1002/9783527619191).

[5] (a) B. M. Trost, *Science* **1991**, *254*, 1471-1477. DOI: [10.1126/science.1962206](https://doi.org/10.1126/science.1962206). (b) B. Breit, *Acc. Chem. Res.* **2003**, *36*, 264-275. DOI: [10.1021/ar0200596](https://doi.org/10.1021/ar0200596).

[6] (a) D. E. Fogg, E. N. dos Santos, *Coord. Chem. Rev.* **2004**, *248*, 2365-2379. DOI:
[10.1016/j.ccr.2004.05.012](https://doi.org/10.1016/j.ccr.2004.05.012). (b) J. C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, *Chem. Rev.*
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[7] P. Eilbracht, L. Bärfacker, C. Buss, C. Hollmann, B. E. Kitsos-Rzychon, C. L. Kranemann, T. Rische, R. Roggenbuck, A. Schmidt, *Chem. Rev.* **1999**, *99*, 3329-3366. DOI: [10.1021/cr970413r](https://doi.org/10.1021/cr970413r).
**General conclusions.**

This manuscript details research work on various chemical reactions, including the homogeneous asymmetric hydroaminomethylation of specific compounds, the synthesis of chiral catalysts for this reaction, and the evaluation of reactivity of various compounds in hydroformylation and hydroaminomethylation reactions.

The first part described the results of asymmetric hydroformylation and hydroaminomethylation of 1,1-diarylethenes. It outlines the direct synthesis of Tolterodine and its derivatives via asymmetric hydroaminomethylation of these compounds, along with experimental conditions and yields obtained.

The second part focused on the synthesis of different compounds and their reactivity in rhodium-catalyzed reactions. The hydroformylation and hydroaminomethylation reactions of these compounds are studied, with observations on the reactivity of cyclopropylmethacrylamide and the formation of derivative products.

The third part addressed the development of heterogeneous catalysts for hydroformylation and hydroaminomethylation reactions. Pyrene-tagged ligands were synthesized and tested as immobilized catalysts, showing promising results despite relatively low activity.

The fourth part explored into the reactivity of ortho-substituted styrene derivatives in rhodium-catalyzed intramolecular hydroaminomethylation. The results indicate that the reaction is limited by the hydrogenation of the enamine intermediate.

Finally, the last part presented the results obtained during a stay at Italmatch Chemicals, highlighting the synthesis of different compounds and the scaling up of the synthesis of certain intermediates.

**References**

[1] M. Beller (Editor), *Catalytic Carbonylation Reactions*, Top. Organomet. Chem., **2006**, *18*, 1-283.
DOI: 10.1007/b105253.

[2] C. Claver (Editor), *Rhodium Catalysis*, Top. Organomet. Chem., **2018**, *61*, 1-288. DOI:
[10.1007/978-3-319-66665-5](https://doi.org/10.1007/978-3-319-66665-5).

[3] (a) B. Breit, *Aldehydes: synthesis by hydroformylation of alkenes*, in *Science of synthesis*, Thieme: Stuttgart, Germany, **2007**, Vol. 25, pp 277-282. DOI: 10.1055/sos-SD-025-00196. (b) R. Franke, D. Selent, A. Börner, *Chem. Rev.* **2012**, *112*, 5675-5732. DOI: [10.1021/cr3001803](https://doi.org/10.1021/cr3001803).

[4] (a) B. Cornils, W. A. Herrmann (Editors), *Applied Homogeneous Catalysis with Organometallic Compounds*, Vol. 1, Wiley-VCH: Weinheim, Germany, **2002**. DOI: [10.1002/9783527618231](https://doi.org/10.1002/9783527618231). (b) K. Weissermel, H.-J. Arpe, *Industrial Organic Chemistry*, Wiley-VCH: Weinheim, Germany, **2008**. DOI: [10.1002/9783527619191](https://doi.org/10.1002/9783527619191).

[5] (a) B. M. Trost, *Science* **1991**, *254*, 1471-1477. DOI: [10.1126/science.1962206](https://doi.org/10.1126/science.1962206). (b) B. Breit, *Acc. Chem. Res.* **2003**, *36*, 264-275. DOI: [10.1021/ar0200596](https://doi.org/10.1021/ar0200596).

[6] (a) D. E. Fogg, E. N. dos Santos, *Coord. Chem. Rev.* **2004**, *248*, 2365-2379. DOI:
[10.1016/j.ccr.2004.05.012](https://doi.org/10.1016/j.ccr.2004.05.012). (b) J. C. Wasilke, S. J. Obrey, R. T. Baker, G. C. Bazan, *Chem. Rev.*
**2005**, *105*, 1001-1020. DOI: [10.1021/cr020018n](https://doi.org/10.1021/cr020018n).

[7] P. Eilbracht, L. Bärfacker, C. Buss, C. Hollmann, B. E. Kitsos-Rzychon, C. L. Kranemann, T. Rische, R. Roggenbuck, A. Schmidt, *Chem. Rev.* **1999**, *99*, 3329-3366. DOI: [10.1021/cr970413r](https://doi.org/10.1021/cr970413r).
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[13] D. Ghislieri, N. J. Turner, *Top. Catal.* **2014**, *57*, 284–300. DOI: 10.1007/s11244-013-0184-1.

[14] T. C. Nugent (Editor), *Chiral amines synthesis: methods, developments and applications*. Wiley-VCH: Weinheim, **2010**. DOI: 10.1002/9783527629541.

[15] A. Cunillera, C. Godard, C. Claver, M. Urrutigoïty, P. Kalck, *Transition metal catalyzed chiral amines synthesis in Methodologies in amine synthesis: challenges and applications*, A. Ricci, L. Bernardi (Editors), Wiley-VCH: Weinheim, **2021**, p. 155–186. DOI: 10.1002/9783527826186.ch5.

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[9] (a) B. Breit, S. K. Zahn, *Angew. Chem. Int. Ed.* **1999**, *38*, 969–971. DOI: 10.1002/(SICI)1521-3773(19990401)38:7<969::AID-ANIE969>3.0.CO;2-4.
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[10] O. Diebolt, C. Cruzeuil, C. Müller, D. Vogt, *Adv. Synth. Catal.* **2012**, *354*, 670–677. DOI: 10.1002/adsc.201100707.

[11] (a) M. Ahmed, R. P. J. Bronger, R. Jackstell, P. C. J. Kamer, P. W. N. M. van Leeuwen, M. Beller, *Chem. Eur. J.* **2006**, *12*, 8979–8988. DOI: 10.1002/chem.200600702.
(b) A. Moballigh, S. A. Majeed, J. Ralf, B. Matthias, *Angew. Chem. Int. Ed.* **2003**, *42*, 5615–5619. DOI: 10.1002/anie.200352320.

[12] J. W. Blunt, B. R. Copp, R. A. Keyzers, M. H. G. Munro, M. R. Prinsep, *Nat. Prod. Rep.* **2012**, *29*, 144–222. DOI: 10.1039/C5NP00156K.

[13] D. Ghislieri, N. J. Turner, *Top. Catal.* **2014**, *57*, 284–300. DOI: 10.1007/s11244-013-0184-1.

[14] T. C. Nugent (Editor), *Chiral amines synthesis: methods, developments and applications*. Wiley-VCH: Weinheim, **2010**. DOI: 10.1002/9783527629541.

[15] A. Cunillera, C. Godard, C. Claver, M. Urrutigoïty, P. Kalck, *Transition metal catalyzed chiral amines synthesis in Methodologies in amine synthesis: challenges and applications*, A. Ricci, L. Bernardi (Editors), Wiley-VCH: Weinheim, **2021**, p. 155–186. DOI: 10.1002/9783527826186.ch5.

[16] D. Crozet, C. E. Kefalidis, M. Urrutigoïty, L. Maron, P. Kalck, *ACS Catal.* **2014**, *4*, 435–447. DOI: 10.1021/cs400906b.

[17] L. Nilvebrant, B. Hallen, G. Larsson, *Life Sci.* **1997**, *60*, 1129–1136. DOI: 10.1016/S0024-3205(97)00057-X.

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[19] N. A. Joensson, B. A. Sparf, L. Mikiver, P. Moses, L. Nilvebrant, G. Glas, *EP 325571*, **1998**.

[20] A. Pramanik, A. Ghatak, S. Khan, S. Bhar, *Tetrahedron Lett.* **2019**, *60*, 1091–1095. DOI: 10.1016/j.tetlet.2019.03.006.

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[25] J. N. Armor, *Catal. Today* **2011**, *163*, 3–9. DOI: 10.1016/j.cattod.2009.11.019.

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(b) A. Corma, H. Garcia, *Top. Catal.* **2008**, *48*, 8–31. DOI: 10.1007/s11244-008-9056-5.

[27] F. Tournus, S. Latil, M. I. Heggie, J. C. Charlier, *Phys. Rev. B* **2005**, *72*, 1–5. DOI: 10.1103/PhysRevB.72.075431.

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(b) A. Ansari, S. Satalkar, V. Patil, A. S. Shete, S. Kaur, A. Gupta, S.
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Irina BOZHINOVSKA

ESR3

**Thesis co-directors**

Prof. Agustí Lledós

Universitat Autònoma de Barcelona, Bellaterra, Spain

Prof. Matthias Westerhausen

Friedrich-Schiller-Universität, Jena, Germany

**Thesis defense**

Universitat Autònoma de Barcelona, Bellaterra, June 2024 (scheduled)
Irina BOZHINOVSKA

ESR3

**Thesis co-directors**

Prof. Agustí Lledós

Universitat Autònoma de Barcelona, Bellaterra, Spain

Prof. Matthias Westerhausen

Friedrich-Schiller-Universität, Jena, Germany

**Thesis defense**

Universitat Autònoma de Barcelona, Bellaterra, June 2024 (scheduled)
<figure><img src="image_75.png" /></figure>
<figure><img src="image_84.png" /></figure>
# s-Block Metal-Mediated Hydroelementation

## Introduction

The addition of P(III) and P (V) compounds across alkynes or diynes is an example of formation of new P-C bonds in an atom-economic way [1-4]. However, this addition necessitates catalysts to overcome electrostatic and kinetic barriers [3,5-7]. As a method to this approach, we propose the use of alkali metal-based catalysts, which are ideal candidates for this task due to their non-toxicity, global abundance, and environmentally benign properties [8,9]. Nonetheless, the outcome of these reactions strongly depends on the nature of the alkali metal and the bulkiness of P-bound substituents [10,11]. It should be noted that there is no fundamental understanding of electronic and steric control for these reactions, particularly in terms of predictive experimental and theoretical capability, because these metals lack directing d-orbitals.

With the aim of forming stereo- and regioselectively P-C bonds via alkali-metal catalyzed reactions, this work focuses on a combined approach involving experimental and theoretical methods to determine the mechanistic steps by which these reactions ensue, to identify and underline the decisive factors which govern the stereo- and regio-selectivity and to ascertain which alkali metal is the most suited one. The combination of these two methods also enables us to understand why these reactions do not happen with several combinations of alkali cation and phosphine substituents. This project was initially divided into two parts: i) alkali metal mediated hydrophosphorylation (Pudovik reaction) of alkynes and diynes and ii) alkali metal catalyzed hydrophosphination of diynes. We set to achieve this goal by using M-HMDS (metal bis(trimethylsilyl)amides; M = Li, Na, and K) as precatalysts for the formation of new P-C bonds. For both projects we employed the same precatalyst and the same loading as to establish a homogenous protocol. We chose bis(trimethylsilyl)amide complexes as our precatalysts as they are commonly available, easy to synthesize from inexpensive starting materials, highly soluble in common organic solvents, and cheap. To elucidate the experimental outcome of the reactions, we have performed DFT calculations to achieve an understanding of the results from a theoretical standpoint.

Additionally, we also explored the oxidation of hetero cyclopentadienes with an incorporated phosphorus atom (product from the alkali metal-catalyzed hydrophosphination of diynes) and the subsequent dimerization of the oxidized product into a [2+2] adduct under visible light irradiation. In this part of the project, we aimed to evaluate the properties, which promoted the formation of oxide and the subsequent formation of the [2+2] adduct, in terms of HOMO-LUMO gap and the energy barriers facilitating the photoinduced cycloaddition. This additional project also combined DFT and experimental techniques.

## Alkali metal mediated Pudovik reaction

*Pudovik reaction Part I: alkali metal-mediated addition of di(organyl)phosphine oxides across phenylacetylene.*

In the initial stages of the project, we decided to elucidate the energy profile for the alkali metal mediated Pudovik reaction onto phenylacetylene (Scheme 1). For this section, we took the experimental data obtained by Westerhausen *et al.* [8].