Periodic Reporting for period 1 - SUPER (Synthetic Utilization of Photoredox-generated Electrophilic Radicals)
Période du rapport: 2018-04-01 au 2020-03-31
The greatest strength of the radical reactions lies in the possibility of executing them late in a synthetic route when the substrates usually have broad and dense functionalization. A downside of these reactions is that they commonly require the utilization of superstochiometric amounts of toxic organotin compounds. In fact, almost a decade ago, tin-free radical reactions were proclaimed by the ACS’s roundtable on green chemistry as one of the key areas of improvement in the synthesis of pharmaceuticals. With the advent of photoredox catalysis, tin-free opportunities of radical reactions emerged. This is reflected in the number of publications demonstrating that abundant low-energy visible-light together with an appropriate photoredox catalyst, can substitute organotin compounds and effectively mediate radical reactions. For organic chemists, it is of vital importance to explore and develop novel, less toxic and more user-friendly syntheses. It is crucial to realize that if a chemical process is useful throughout the academic and industrial sectors, it produces significant amounts of toxic waste, which is most of the time incinerated. In the proposed research, we aimed to develop a practical and scalable radical synthesis of small heterocycles, that would be free of organotin compounds. We envisioned a formal [3+2] cycloaddition of azahomoallyl radicals and olefins. A critical aspect would be the generation of a heteroatom-centered radical, which could potentially undergo two different elemental processes – addition or abstraction of hydrogen. While both of these reactions take place during the radical reactions, a theoretical framework that would allow chemists to predict when each step is favored is still missing. We aimed to explore if the electrophilicity of nitrogen-centered radical effects the preference of addition and abstraction of hydrogen.
The majority of work done in this project was laboratory work, with synthesis, isolation, and characterization of novel compounds as the most common tasks. Additional aspects included electrochemical and photochemical measurements and theoretical quantum chemistry calculations.
Early in the project, we identified alkoxy indanones as a class of compounds that displayed the physical and chemical properties we were seeking. Upon photochemical activation, they were generating reactive hydrogen-abstracting reactive species; they were non-hygroscopic solids and based on the literature review, we assume that they were non -toxic solids. The reactivity of the alkoxyiodanone was explored and a manuscript is currently in preparation. The hydrogen-abstracting capacity was critical in our attempts to generate the key azahomoallyl radicals. Furthermore, the oxidative quenching of the photocatalyst was also essential because the process that we envisioned required oxidation as the radical terminating step. Despite extensive optimization, we were not able to identify suitable conditions, that would allow us to attach the hypervalent iodine moiety to the aziridines, which were our substrates.
Given that this was relatively early in the project, we explore other compounds, which were depicted in the proposal. However, none of the literature-reported compounds displayed the desired chemical properties. After extensive screening, we identified aziridinylmethyl iodides as the ideal synthetic precursors. The majority of these products could be prepared by modification of reported procedures.
Furthermore, they provided access to a variety of substitution patterns that could modulate the electrophilicity of the target azahomoallyl radicals.
Consequently, we synthesized a library of compounds substituted with groups that could influence the electrophilicity (CN, Br, CH3, OMe, alkyl and polycyclic aromatics). Next, in line with the proposed research, we calculated the electronic parameters of all accessible azahomoallyl radicals and explored their reactivity in the proposed [3+2] cycloaddition. However, we did not observe any structure-reactivity relationship between the electrophilicity of the azahomoallyl radical and its potential to either abstract a hydrogen or to add to an olefin. Most likely, the initial formation of the C-N bond is not rate-limiting, as we initially assumed. Thus, we could not develop the map of the reactivity and we were forced to pivot. We decided to explore the mechanism of the proposed [3+2] cycloaddition of azahomoallyl radicals and olefins in terms of scope, photochemistry and electrochemistry. We discovered that the reaction works well with electron-rich and somewhat strained olefins and can provide polycyclic pyrrolidines with three contiguous stereogenic centers which are relevant compounds in the pharmaceutical research. This discovery was disseminated in the form of a poster at the Gordon research conference on Organic Reactions and Processes at Stonehill College, Easton, United States.
Through electrochemical and photochemical experiments, we established that the reported [3+2] operates via an energy transfer mechanism. The mechanistic research has been published in the European Journal of Organic Chemistry, with open access. Furthermore, the study has been selected for an oral presentation on meeting on the 4th International Symposium on Green Chemistry, which was supposed to be held in Rennes, France, but due to Coronavirus restriction, this meeting was postponed to autumn 2020.
Early in the project, we identified alkoxy indanones as a class of compounds that displayed the physical and chemical properties we were seeking. Upon photochemical activation, they were generating reactive hydrogen-abstracting reactive species; they were non-hygroscopic solids and based on the literature review, we assume that they were non -toxic solids. The reactivity of the alkoxyiodanone was explored and a manuscript is currently in preparation. The hydrogen-abstracting capacity was critical in our attempts to generate the key azahomoallyl radicals. Furthermore, the oxidative quenching of the photocatalyst was also essential because the process that we envisioned required oxidation as the radical terminating step. Despite extensive optimization, we were not able to identify suitable conditions, that would allow us to attach the hypervalent iodine moiety to the aziridines, which were our substrates.
Given that this was relatively early in the project, we explore other compounds, which were depicted in the proposal. However, none of the literature-reported compounds displayed the desired chemical properties. After extensive screening, we identified aziridinylmethyl iodides as the ideal synthetic precursors. The majority of these products could be prepared by modification of reported procedures.
Furthermore, they provided access to a variety of substitution patterns that could modulate the electrophilicity of the target azahomoallyl radicals.
Consequently, we synthesized a library of compounds substituted with groups that could influence the electrophilicity (CN, Br, CH3, OMe, alkyl and polycyclic aromatics). Next, in line with the proposed research, we calculated the electronic parameters of all accessible azahomoallyl radicals and explored their reactivity in the proposed [3+2] cycloaddition. However, we did not observe any structure-reactivity relationship between the electrophilicity of the azahomoallyl radical and its potential to either abstract a hydrogen or to add to an olefin. Most likely, the initial formation of the C-N bond is not rate-limiting, as we initially assumed. Thus, we could not develop the map of the reactivity and we were forced to pivot. We decided to explore the mechanism of the proposed [3+2] cycloaddition of azahomoallyl radicals and olefins in terms of scope, photochemistry and electrochemistry. We discovered that the reaction works well with electron-rich and somewhat strained olefins and can provide polycyclic pyrrolidines with three contiguous stereogenic centers which are relevant compounds in the pharmaceutical research. This discovery was disseminated in the form of a poster at the Gordon research conference on Organic Reactions and Processes at Stonehill College, Easton, United States.
Through electrochemical and photochemical experiments, we established that the reported [3+2] operates via an energy transfer mechanism. The mechanistic research has been published in the European Journal of Organic Chemistry, with open access. Furthermore, the study has been selected for an oral presentation on meeting on the 4th International Symposium on Green Chemistry, which was supposed to be held in Rennes, France, but due to Coronavirus restriction, this meeting was postponed to autumn 2020.
There are several discoveries in the project that expanded the current state of the art. First of all, we have developed a non-toxic the synthesis of tetrahydrofuranes using alkoxy radicals. Currently, the state-of-the-art relies on superstochiometric amounts of lead acetate (Pb(OAc)4), which is toxic. In our conditions, we were able to circumvent this need by the employment of hypervalent iodine compounds. Furthermore, we identified conditions that allow the preparation of alkoxyiodanones in more atom-economic conditions. The current literature procedures require the alcohol utilized used as the solvent, but we were able to reduce it to only stoichiometric amounts, which provides advantages for applications, where the alcohol is precious. These cases include natural products and potential late-stage pharmaceutical and agrochemical intermediates.
Furthermore, the synthesis of tetrahydrofuranes can be, in some cases, expanded to the synthesis of highly medicinally prevalent chromanes. Despite not being able to deliver the reactivity map, the research on the [3+2] cycloaddition also presents progress beyond the state-of-the-art. We have proven, that the reaction operates by energy-transfer, which is a less prevalent activation mode in photoredox catalysis. Furthermore, scientists currently assume that the energy of photoexcited species must be higher than the bond dissociation energy of the homolyzed bond. We also demonstrated that this approximation does not always hold and has to be treated as an approximation and not as a rigorous principle.
We believe that the funded research will be beneficial for expert chemists in the pharmaceutical industry and also academics. We aim to inspire and encourage chemists, who are working with radical chemistry to explore opportunities provided by photoredox catalysis. The wider socio-economic impact will be greener organic synthesis, less toxic waste produced and more renewables on organic synthesis. In other words – a more sustainable chemical synthesis.
Furthermore, the synthesis of tetrahydrofuranes can be, in some cases, expanded to the synthesis of highly medicinally prevalent chromanes. Despite not being able to deliver the reactivity map, the research on the [3+2] cycloaddition also presents progress beyond the state-of-the-art. We have proven, that the reaction operates by energy-transfer, which is a less prevalent activation mode in photoredox catalysis. Furthermore, scientists currently assume that the energy of photoexcited species must be higher than the bond dissociation energy of the homolyzed bond. We also demonstrated that this approximation does not always hold and has to be treated as an approximation and not as a rigorous principle.
We believe that the funded research will be beneficial for expert chemists in the pharmaceutical industry and also academics. We aim to inspire and encourage chemists, who are working with radical chemistry to explore opportunities provided by photoredox catalysis. The wider socio-economic impact will be greener organic synthesis, less toxic waste produced and more renewables on organic synthesis. In other words – a more sustainable chemical synthesis.