Periodic Reporting for period 1 - DES-B-CAT (A Complementary Approach to Aromatic Synthesis by Diels-Alder Reactivity Followed by Desaturative Photoredox, Cobalt and HAT Triple Catalysis.)
Periodo di rendicontazione: 2023-10-01 al 2025-09-30
Sintesi del contesto e degli obiettivi generali del progetto
The main objective of this Marie Curie Fellowship was the development of new chemical reactions for the use of desaturative catalysis and boryl for the synthesis of aromatics with unusual substitution patterns that cannot be explored otherwise employing typical methods for aromatic functionalization. Particulalry, the overarching aim of the project was to demonstrate that photochemically-generated boryl radicals and Co-catalysis could be used as blueprint to by-pass the known issues of aromatic reactivity (SEAr) to access otherwise challenging substitution patterns of polysubstituted aromatics, with especial emphasis for streamlining the functionalization of drug-like molecules and agrochemicals.
As a result of the project we have discovered new processes for aromatic functionalization employing conceptually novel approaches. This has enabled us to the use cobaloxime and photoredox catalysis towards the synthesis of aminated heterocycles via a desaturative approach. We eventually found out that the use of nucleophilic amines in presence of heteroatom-containing piperidones, pyrrolidines, tetrahydrofuranes, and tetrahydrothiophenes could be used to access C3 & C4 aminated heterocycles, which are otherwise difficult to make, via a Co-promoted desaturation approach under visible light. This provided a new solution to long-standing challenges in aromatic and cross-coupling chemistry. Detailed mechanistic studies enabled us to have strong evidence on the dual role of the cobaloxime catalyst both as HAT and SET to complete the desaturation step. Furthermore, during scope exploration, we demonstrated the compatibility of this chemistry with many building blocks of high relevance to both the pharmaceutical and agrochemical sectors.
Subsequently, based on the knowledge that we acquired on amine-borane chemistry, we became interested in the possibility of using light for dearomatization of naphthalenes In this work, we reported the first umpolung approach of the Birch reaction. Mechanistically, the reaction is based on the increased basicity of excited arenes, promoting the break of aromaticity by protonation to form a transient carbocation, which is further trapped with a mild hydride donor (amine-borane). This is in sharp contrast to Birch-like reactivity, where a first SET is needed, enabling an exceptional functional group compatibility with no precedents in the literature. Additionally, we explored the reaction mechanism by making use of transient absorption spectroscopy (TAS), being able to detect the intermediate carbocation species, and testing the mechanistic proposal by DFT calculations. We have harnessed our knowledge on photoprotonation of aromatics for the development of a new method for the hydrogen isotope exchange (HIE) of aromatic C(sp2)ꟷH bonds using HFIP-d1 as the deuterium donor for the deuteration of pharmaceuticals with unusual site-selectivity that is orthogonal to thermal methods.
Finally, we have also exploit the use of amine boranes for alkynylation reactions by using two different approaches. The first one pertains to the photogeneration of nucleophilic boryl radicals employing the cost-effective and highly stable Me3NꟷBH3 adduct. The key of the method consists of using photoexcited ketones (triplet diaryl ketones) to be used as HAT reagents, leading to a boryl radical that is highly reactive as halogen atom transfer (XAT) reagent in presence of alkyl iodides and bromides. The resulting C-centered radicals could be then trapped with SOMOphilic alkynylsulfones, making possible the metal-free Sonogashira-like reaction. The second approach is based on the use of a new boryl radical precursor described by the Leonori group (Me3NꟷBH2CO2H) to promote the formation of alkynyl-boranes by the addition of the nucleophilic boryl radical to the SOMOphilic alkynylsulfone.
As a result of the project we have discovered new processes for aromatic functionalization employing conceptually novel approaches. This has enabled us to the use cobaloxime and photoredox catalysis towards the synthesis of aminated heterocycles via a desaturative approach. We eventually found out that the use of nucleophilic amines in presence of heteroatom-containing piperidones, pyrrolidines, tetrahydrofuranes, and tetrahydrothiophenes could be used to access C3 & C4 aminated heterocycles, which are otherwise difficult to make, via a Co-promoted desaturation approach under visible light. This provided a new solution to long-standing challenges in aromatic and cross-coupling chemistry. Detailed mechanistic studies enabled us to have strong evidence on the dual role of the cobaloxime catalyst both as HAT and SET to complete the desaturation step. Furthermore, during scope exploration, we demonstrated the compatibility of this chemistry with many building blocks of high relevance to both the pharmaceutical and agrochemical sectors.
Subsequently, based on the knowledge that we acquired on amine-borane chemistry, we became interested in the possibility of using light for dearomatization of naphthalenes In this work, we reported the first umpolung approach of the Birch reaction. Mechanistically, the reaction is based on the increased basicity of excited arenes, promoting the break of aromaticity by protonation to form a transient carbocation, which is further trapped with a mild hydride donor (amine-borane). This is in sharp contrast to Birch-like reactivity, where a first SET is needed, enabling an exceptional functional group compatibility with no precedents in the literature. Additionally, we explored the reaction mechanism by making use of transient absorption spectroscopy (TAS), being able to detect the intermediate carbocation species, and testing the mechanistic proposal by DFT calculations. We have harnessed our knowledge on photoprotonation of aromatics for the development of a new method for the hydrogen isotope exchange (HIE) of aromatic C(sp2)ꟷH bonds using HFIP-d1 as the deuterium donor for the deuteration of pharmaceuticals with unusual site-selectivity that is orthogonal to thermal methods.
Finally, we have also exploit the use of amine boranes for alkynylation reactions by using two different approaches. The first one pertains to the photogeneration of nucleophilic boryl radicals employing the cost-effective and highly stable Me3NꟷBH3 adduct. The key of the method consists of using photoexcited ketones (triplet diaryl ketones) to be used as HAT reagents, leading to a boryl radical that is highly reactive as halogen atom transfer (XAT) reagent in presence of alkyl iodides and bromides. The resulting C-centered radicals could be then trapped with SOMOphilic alkynylsulfones, making possible the metal-free Sonogashira-like reaction. The second approach is based on the use of a new boryl radical precursor described by the Leonori group (Me3NꟷBH2CO2H) to promote the formation of alkynyl-boranes by the addition of the nucleophilic boryl radical to the SOMOphilic alkynylsulfone.
Lavoro eseguito dall’inizio del progetto fino alla fine del periodo coperto dalla relazione e principali risultati finora ottenuti
The integration of photoredox catalysis and cobalt catalysis has led to the development of a general and efficient platform for the preparation of amine-substituted heteroaromatics. The use of non-aromatic starting materials bypasses many of the challenges that currently impact the synthesis of these derivatives via either aromatic reactivity or cross-coupling chemistry. The desaturative reactions described in this manuscript occur under mild conditions and can be used for the introduction of complex, densely functionalized amine nucleophiles. The proposed reaction mechanism suggests a dual role for the cobaloxime co-catalyst, that first acts as a H-atom abstractor and then as an oxidant to give the desired heteroaromatic products. Notably, through this desaturation logic, we have developed a general set of reaction conditions that can be used to prepare amine containing heteroaromatics of different nature like electron-poor pyridines and electron-rich pyrroles, furans, thiophenes and pyrazoles. This work wa spublished in Nature Catalysis (DOI:10.1038/s41929-024-01152-1).
Subsequently, based on the knowledge that we acquired on amine-borane chemistry, we became interested in the possibility of using these species for dearomatization of naphthalenes under photochemical activation. In this work, we reported the first umpolung approach of the Birch reaction. Mechanistically, the reaction is based on the increased basicity of excited arenes, promoting the break of aromaticity by protonation to form a transient carbocation, which is further trapped with a mild hydride donor (amine-borane). This is in sharp contrast to Birch-like reactivity, where a first SET is needed, enabling an exceptional functional group compatibility with no precedents in the literature. Additionally, we explored the reaction mechanism by making use of transient absorption spectroscopy (TAS), being able to detect the intermediate carbocation species, and testing the mechanistic proposal by DFT calculations. This work has been published open access: Excited-state protonation & reduction enables the umpolung Birch reduction of naphthalenes. Chem 2025, 11, 102342 (DOI: 10.1016/j.chempr.2024.10.009).
Additionally, we have harnessed our knowledge on photoprotonation of aromatics for the development of a new method for the hydrogen isotope exchange (HIE) of aromatic C(sp2)ꟷH bonds using HFIP-d1 as the deuterium donor. This work draws inspiration from our previous study for the photoBirch reaction, but instead of promoting the dearomatization by trapping of the intermediate carbocation, the method is based on a reversible photodeuteration (2H) in the excited state, followed by reversible exchange with protium (1H). We have applied this strategy to the deuteration of pharmaceuticals with unusual site-selectivity that is orthogonal to thermal methods.
This paper has been recently accepted in Angewandte Chemie, and it will be published as open access on a due time: Excited-State Basicity Diverts the Site-Selectivity of Photochemical Aromatic Deuteration: Application to the Late-Stage Labelling of Pharmaceuticals. Angew. Chem. Int. Ed. 2025, accepted.
Finally, although we could not implement the use of boryl radicals as HAT reagents for desaturation chemistry, we have recently exploit them in alkynylation reactions by using two different approaches. The first one pertains to the photogeneration of nucleophilic boryl radicals employing the cost-effective and highly stable Me3NꟷBH3 adduct. The key of the method consists of using photoexcited ketones (triplet diaryl ketones) to be used as HAT reagents, leading to a Me3NꟷBH2● boryl radical that is highly reactive as halogen atom transfer (XAT) reagent in presence of alkyl iodides and bromides. The resulting C-centered radicals could be then trapped with SOMOphilic alkynylsulfones, making possible the metal-free Sonogashira-like reaction. The second approach is based on the use of a new boryl radical precursor described by the Leonori group (Me3NꟷBH2CO2H) to promote the formation of alkynyl-boranes by the addition of the nucleophilic boryl radical to the SOMOphilic alkynylsulfone. These two works highlight the knowledge obtained on boryl radical chemistry since the beginning of the project to solve persistent problems in organic chemistry through innovative transformations.
These works have been published, respectively, as open access in the following journals:
a) Boryl Radical- Mediated Halogen-Atom Transfer (XAT) Enables the Sonogashira-Like Alkynylation of Alkyl Halides. Chem. Sci. 2024, 15, 19113-19118. DOI: 10.1039/D4SC06516F.
b) A photocatalytic C(sp)ꟷB bond formation employing SOMOphilic alkynyl sulfones and nucleophilic boryl radicals. Synthesis, 2025, accepted article. DOI: 10.1055/a-2464-8904.
Subsequently, based on the knowledge that we acquired on amine-borane chemistry, we became interested in the possibility of using these species for dearomatization of naphthalenes under photochemical activation. In this work, we reported the first umpolung approach of the Birch reaction. Mechanistically, the reaction is based on the increased basicity of excited arenes, promoting the break of aromaticity by protonation to form a transient carbocation, which is further trapped with a mild hydride donor (amine-borane). This is in sharp contrast to Birch-like reactivity, where a first SET is needed, enabling an exceptional functional group compatibility with no precedents in the literature. Additionally, we explored the reaction mechanism by making use of transient absorption spectroscopy (TAS), being able to detect the intermediate carbocation species, and testing the mechanistic proposal by DFT calculations. This work has been published open access: Excited-state protonation & reduction enables the umpolung Birch reduction of naphthalenes. Chem 2025, 11, 102342 (DOI: 10.1016/j.chempr.2024.10.009).
Additionally, we have harnessed our knowledge on photoprotonation of aromatics for the development of a new method for the hydrogen isotope exchange (HIE) of aromatic C(sp2)ꟷH bonds using HFIP-d1 as the deuterium donor. This work draws inspiration from our previous study for the photoBirch reaction, but instead of promoting the dearomatization by trapping of the intermediate carbocation, the method is based on a reversible photodeuteration (2H) in the excited state, followed by reversible exchange with protium (1H). We have applied this strategy to the deuteration of pharmaceuticals with unusual site-selectivity that is orthogonal to thermal methods.
This paper has been recently accepted in Angewandte Chemie, and it will be published as open access on a due time: Excited-State Basicity Diverts the Site-Selectivity of Photochemical Aromatic Deuteration: Application to the Late-Stage Labelling of Pharmaceuticals. Angew. Chem. Int. Ed. 2025, accepted.
Finally, although we could not implement the use of boryl radicals as HAT reagents for desaturation chemistry, we have recently exploit them in alkynylation reactions by using two different approaches. The first one pertains to the photogeneration of nucleophilic boryl radicals employing the cost-effective and highly stable Me3NꟷBH3 adduct. The key of the method consists of using photoexcited ketones (triplet diaryl ketones) to be used as HAT reagents, leading to a Me3NꟷBH2● boryl radical that is highly reactive as halogen atom transfer (XAT) reagent in presence of alkyl iodides and bromides. The resulting C-centered radicals could be then trapped with SOMOphilic alkynylsulfones, making possible the metal-free Sonogashira-like reaction. The second approach is based on the use of a new boryl radical precursor described by the Leonori group (Me3NꟷBH2CO2H) to promote the formation of alkynyl-boranes by the addition of the nucleophilic boryl radical to the SOMOphilic alkynylsulfone. These two works highlight the knowledge obtained on boryl radical chemistry since the beginning of the project to solve persistent problems in organic chemistry through innovative transformations.
These works have been published, respectively, as open access in the following journals:
a) Boryl Radical- Mediated Halogen-Atom Transfer (XAT) Enables the Sonogashira-Like Alkynylation of Alkyl Halides. Chem. Sci. 2024, 15, 19113-19118. DOI: 10.1039/D4SC06516F.
b) A photocatalytic C(sp)ꟷB bond formation employing SOMOphilic alkynyl sulfones and nucleophilic boryl radicals. Synthesis, 2025, accepted article. DOI: 10.1055/a-2464-8904.
Progressi oltre lo stato dell’arte e potenziale impatto previsto (incluso l’impatto socioeconomico e le implicazioni sociali più ampie del progetto fino ad ora)
Impact on the Researcher Career. This MSCA Fellowship has had a very positive impact on my personal and scientific development:
• Supervision skills: During this time, I had the opportunity to supervise several young researchers at both PhD (Dr. Henry Caldora, Ms. Mailen Alonso & Ms. Yuri Katayama) and MSc level (Mr. Luka Obradovic & Nick Heiming) that were working on related projects. These collaborations were very successful and some of them were also joined authors in the publications.
• Presentation skills: During the regular group meeting presentations I managed to significantly improved my presentation skills, learning how to explain difficult concepts in short amount of time while also emphasizing the key results. Additionally, I had the opportunity to organize and direct problem sessions within the Leonori group, where I have increased my skills on mentoring and teaching, something that is crucial for my future position as an academic.
• Scientific writing skills: During the Fellowship I had the opportunity to prepare first draft of all the papers. These drafts were critically assessed by Prof. Leonori that explained me how to improve them to make sure the narrative was succinct but scholarly rigorous. Since I am planning to launch an academic career, these skills will be very important to me when I will be able to publish my first independent papers. Additionally, I have gained experience in writing research grants supervised by Prof. Leonori.
• Establish a personal network: Some of the work I conducted as part of this Fellowship was also run in collaboration with different chemical companies at the international level. This includes: (1) Collaboration with Minakem (France): I have collaborated with Dr. Clément Jacob and Dr. Pierre G. Echeverria to study the potential scalability of a new process based on the photochemical Birch-type reduction of naphthalenes. I was responsible to design the reaction conditions and guide the team on the potential for scaling-up the process based on regular meetings. This collaboration has resulted in the publication of the project with these industrial partners in Chem (DOI: 10.1016/j.chempr.2024.10.009). (2) Collaboration with Sanofi (Germany): I have an active collaboration with Dr. Volker Derdau (Head Isotope Chemistry at Sanofi, Senior Distinguished Scientist). Our collaboration consists of the application of a new method for deuteration of pharmaceuticals that I developed during my postdoctoral stay to be employed at the industrial level. Additionally, I have regular meetings with Dr. Derdau and his team to guide them on how to set-up the experiments with the aim of applying this concept for tritiation. This is an ongoing collaboration for which we have already submitted the corresponding manuscript in collaboration with Sanofi. (3) Collaboration with AstraZeneca (UK): I have collaborated with Dr. Oliver Turner (Senior research scientist) on the synthesis of aminated pyridines. Dr. Turner’s team is very interested in the methodology that I developed, and we had several meetings to discuss and applied this chemistry to MedChem programs, resulting in the publication of the method in Nature Catalysis (DOI: 10.1038/s41929-024-01152-1) in collaboration with AstraZeneca.
Furthermore, I have increased my personal network with different academics around the world as a result of multiple meetings with invited speakers withing the seminar program at the Institute of Organic Chemistry (RWTH Aachen).
Impact on the Scientific Field. The projects developed in the Fellowship have had a very positive impact on the field, as the level of the resulting publications demonstrate. First, the ability to use desaturative catalysis to access aminated heteroaromatics, regardless of their electronic nature, implies a highly innovative solution to a timely problem with no general solution in the literature. Second, the application of photoprotonation of aromatics to the Birch-like reactivity and HIE, provides two new methodologies with unprecedented chemo- and site-selectivity, respectively, for which previous methods simply did not give a solution. Finally, the use of boryl radicals for alkynylation reactions enables a new disconnection approach toward these entities.
Therefore, these projects have been very well perceived by both the academic and industrial audience as these reactions are generally performed using expensive, toxic and geo-politically at-risk palladium complexes. Since the publication of our work, we have received many enquiries by scientists working in the major pharmaceutical companies worldwide seeking to adopt their methodology in their discovery programs. As a proof of that is that in most of them we have established collaborations with different companies of high reputation (AstraZeneca, Minakem & Sanofi). Furthermore, our work has been recently highlighted in different research platforms (see, for example: Synfacts 2025, 21, 186; Org. Process Res. Dev. 2024, 28, 2367).
• Supervision skills: During this time, I had the opportunity to supervise several young researchers at both PhD (Dr. Henry Caldora, Ms. Mailen Alonso & Ms. Yuri Katayama) and MSc level (Mr. Luka Obradovic & Nick Heiming) that were working on related projects. These collaborations were very successful and some of them were also joined authors in the publications.
• Presentation skills: During the regular group meeting presentations I managed to significantly improved my presentation skills, learning how to explain difficult concepts in short amount of time while also emphasizing the key results. Additionally, I had the opportunity to organize and direct problem sessions within the Leonori group, where I have increased my skills on mentoring and teaching, something that is crucial for my future position as an academic.
• Scientific writing skills: During the Fellowship I had the opportunity to prepare first draft of all the papers. These drafts were critically assessed by Prof. Leonori that explained me how to improve them to make sure the narrative was succinct but scholarly rigorous. Since I am planning to launch an academic career, these skills will be very important to me when I will be able to publish my first independent papers. Additionally, I have gained experience in writing research grants supervised by Prof. Leonori.
• Establish a personal network: Some of the work I conducted as part of this Fellowship was also run in collaboration with different chemical companies at the international level. This includes: (1) Collaboration with Minakem (France): I have collaborated with Dr. Clément Jacob and Dr. Pierre G. Echeverria to study the potential scalability of a new process based on the photochemical Birch-type reduction of naphthalenes. I was responsible to design the reaction conditions and guide the team on the potential for scaling-up the process based on regular meetings. This collaboration has resulted in the publication of the project with these industrial partners in Chem (DOI: 10.1016/j.chempr.2024.10.009). (2) Collaboration with Sanofi (Germany): I have an active collaboration with Dr. Volker Derdau (Head Isotope Chemistry at Sanofi, Senior Distinguished Scientist). Our collaboration consists of the application of a new method for deuteration of pharmaceuticals that I developed during my postdoctoral stay to be employed at the industrial level. Additionally, I have regular meetings with Dr. Derdau and his team to guide them on how to set-up the experiments with the aim of applying this concept for tritiation. This is an ongoing collaboration for which we have already submitted the corresponding manuscript in collaboration with Sanofi. (3) Collaboration with AstraZeneca (UK): I have collaborated with Dr. Oliver Turner (Senior research scientist) on the synthesis of aminated pyridines. Dr. Turner’s team is very interested in the methodology that I developed, and we had several meetings to discuss and applied this chemistry to MedChem programs, resulting in the publication of the method in Nature Catalysis (DOI: 10.1038/s41929-024-01152-1) in collaboration with AstraZeneca.
Furthermore, I have increased my personal network with different academics around the world as a result of multiple meetings with invited speakers withing the seminar program at the Institute of Organic Chemistry (RWTH Aachen).
Impact on the Scientific Field. The projects developed in the Fellowship have had a very positive impact on the field, as the level of the resulting publications demonstrate. First, the ability to use desaturative catalysis to access aminated heteroaromatics, regardless of their electronic nature, implies a highly innovative solution to a timely problem with no general solution in the literature. Second, the application of photoprotonation of aromatics to the Birch-like reactivity and HIE, provides two new methodologies with unprecedented chemo- and site-selectivity, respectively, for which previous methods simply did not give a solution. Finally, the use of boryl radicals for alkynylation reactions enables a new disconnection approach toward these entities.
Therefore, these projects have been very well perceived by both the academic and industrial audience as these reactions are generally performed using expensive, toxic and geo-politically at-risk palladium complexes. Since the publication of our work, we have received many enquiries by scientists working in the major pharmaceutical companies worldwide seeking to adopt their methodology in their discovery programs. As a proof of that is that in most of them we have established collaborations with different companies of high reputation (AstraZeneca, Minakem & Sanofi). Furthermore, our work has been recently highlighted in different research platforms (see, for example: Synfacts 2025, 21, 186; Org. Process Res. Dev. 2024, 28, 2367).