Timothy Noel

• Professor (Assistant) at Eindhoven University of Technology

image [3023745‐16‐3] C 11 H 11 F 3 N 2 O 4 S (MW 324.27) InChI = 1S/C11H11F3N2O4S/c1‐2‐20‐10(17)7‐15‐16‐21(18,19)9‐5‐3‐8(4‐6‐9)11(12,13)14/h3‐7,16H,2H2,1H3/b15‐7+ InChIKey = MNJLWXRKQQLOSO‐VIZOYTHASA‐N (C1 homologation carboxylic acid, radical addition) Physical Data: white solid, mp: 150 °C (decomposition). Solubility: methanol, ethanol, tetrahyd...

We report a metallaphotocatalytic strategy for the selective methylation of (hetero)aryl bromides via nickel-catalyzed cross-coupling with bis(trimethylaluminum)-1,4-diazabicyclo[2.2.2]octane (DABAl-Me₃), as a commercially available, air-stable, and non-pyrophoric aluminum-based reagent. The method enables a fast, robust, and scalable methylation p...

Cyclopropanes are valuable motifs in organic synthesis, widely featured in pharmaceuticals and functional materials. Herein, we report an efficient electrochemical methodology for the cyclopropanation of alkenes, leveraging a nickel‐catalyzed process in continuous‐flow. The developed protocol demonstrates broad substrate scope, accommodating both e...

Cyclopropanes are valuable motifs in organic synthesis, widely featured in pharmaceuticals and functional materials. Herein, we report an efficient electrochemical methodology for the cyclopropanation of alkenes, leveraging a nickel‐catalyzed process in continuous‐flow. The developed protocol demonstrates broad substrate scope, accommodating both e...

Secondary amines are vital functional groups in pharmaceuticals, agrochemicals, and natural products, necessitating efficient synthetic methods. Traditional approaches, including N-monoalkylation and reductive amination, suffer from limitations such as poor chemoselectivity and complexity. Herein, we present a streamlined deoxygenative photochemica...

Electrophotocatalysis (EPC) is emerging as a powerful tool in organic synthesis, offering unique redox transformations without the need for sacrificial oxidants or reductants. Building on this activation mode, we have developed an electrophotocatalytic method for the direct amidation of aldehydes, utilizing electricity as the sole oxidant and light...

Photochemical transformations have garnered renewed interest over the past decade for their ability to enable unique reactions under mild conditions. However, scaling up such processes, particularly in multiphase systems (e.g., gas–liquid), remains challenging. Previously, we demonstrated the potential of the photochemical rotor-stator spinning dis...

Light interacts with gas bubbles in various ways, potentially leading to photon losses in gas-liquid photochemical applications. Given that light is a valuable 'reagent', understanding these losses is crucial for...

The rising popularity of bioconjugate therapeutics has led to growing interest in late-stage functionalization (LSF) of peptide scaffolds. α,β-Unsaturated amino acids like dehydroalanine (Dha) derivatives have emerged as particularly useful structures, as the electron-deficient olefin moiety can engage in late-stage functionalization reactions, lik...

Continuous-flow methodologies offer promising avenues for sustainable processing due to their precise process control, scalability, and efficient heat and mass transfer. The small dimensions of continuous-flow reactors render them highly suitable for light-assisted reactions, as can be encountered in carbon dioxide hydrogenations. In this study, we...

The homologous series of gaseous C1‐4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C−H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of com...

Light interacts with gas bubbles in various ways, potentially leading to photon losses in gas-liquid photochemical applications. Given that light is a costly 'reagent', understanding these losses is crucial for optimizing reactor efficiency. In this study, we address the challenge of quantifying these interactions by implementing a method that sepa...

The trifluoromethyl group (CF 3 ) is a key functionality in pharmaceutical and agrochemical development, greatly enhancing the efficacy and properties of resulting compounds. However, attaching the CF 3 group to heteroatoms such as sulfur, oxygen, and nitrogen poses challenges because of the lack of general synthetic methods and reliance on bespoke...

The homologous series of gaseous C1‐4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C–H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of com...

Photoinduced halogen-atom transfer (XAT) has rapidly emerged as a programmable approach to generate carbon-centered radical intermediates, mainly relying on silyl and α-aminoalkyl radicals as halogen abstractors. More recently, ligated boryl radicals have also been proposed as effective halogen abstractors under visible-light irradiation. In this s...

The development of robust and reliable methods for the construction of C(sp²)−C(sp³) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocata...

The development of robust and reliable methods for the construction of C(sp ² )−C(sp ³ ) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photo...

Herein, we report an approach for generating thionyl fluoride (SOF2) from the commodity chemicals thionyl chloride (SOCl2) and potassium fluoride (KF). The methodology relies on a microfluidic device that can efficiently produce and dose this toxic gaseous reagent under extremely mild and safe conditions. Subsequently, the in situ-generated thionyl...

Photocatalysis for small-molecule activation has advanced considerably over the past decade, yet its scale-up remains challenging in part due to photon attenuation effects. One promising solution lies in combining high photonic intensities with continuous-flow reactor technology, requiring careful understanding of photon transport for successful im...

Sulfur-containing scaffolds originating from small alkyl fragments play a crucial role in various pharmaceuticals, agrochemicals, and materials. Nonetheless, their synthesis using conventional methods presents significant challenges. In this study, we introduce a practical and efficient approach that harnesses hydrogen atom transfer photocatalysis...

In recent years, there has been a growing demand for drug design approaches that incorporate a higher number of sp³-hybridized carbons, necessitating the development of innovative cross-coupling strategies to reliably introduce aliphatic fragments. Here, we present a powerful approach for the light-mediated B-alkyl Suzuki−Miyaura cross-coupling bet...

The trifluoromethyl group (CF3) is a key moiety in pharmaceutical and agrochemical development, greatly enhancing the efficacy and properties of resulting compounds. However, attaching the CF3 group to heteroatoms such as sulfur, oxygen, and nitrogen poses significant challenges due to the lack of general synthetic methods and reliance on bespoke r...

The homologous series of gaseous C1-4 alkanes represents one of the most abundant sources of short alkyl fragments. However, their application in synthetic organic chemistry is exceedingly rare due to the challenging C–H bond cleavage, which typically demands high temperatures and pressures, thereby limiting their utility in the construction of com...

Continuous-flow methodologies offer promising avenues for sustainable processing due to their precise process control, scalability, and efficient heat and mass transfer. The small dimensions of continuous-flow reactors render them highly suitable for light-assisted reactions, as can be encountered in carbon dioxide hydrogenations. In this study, we...

Unnatural amino acids, and their synthesis by the late‐stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. Historically, the LSF of biomolecules has predominantly utilized traditional synthetic methodologies that exploit nucleophilic residues, such as cysteine, lysine or tyrosine. Herein, we pr...

The development of robust and reliable methods for the construction of C(sp2)–C(sp3) bonds is vital for accessing an increased array of structurally diverse scaffolds in drug discovery and development campaigns. While significant advances towards this goal have been achieved using metallaphotoredox chemistry, many of these methods utilise photocata...

Unnatural amino acids, and their synthesis via the late‐stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. Historically, the LSF of biomolecules has predominantly utilized traditional synthetic methodologies that exploit nucleophilic residues, such as cysteine, lysine or tyrosine. In this stud...

In contemporary drug discovery, enhancing the sp³-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters with aldehyde sulfonyl hydrazones, employing Eosi...

Unnatural amino acids, and their synthesis via the late-stage functionalization (LSF) of peptides, play a crucial role in areas such as drug design and discovery. Historically, the LSF of biomolecules has predominantly utilized traditional synthetic methodologies that exploit nucleophilic residues, such as cysteine, lysine or tyrosine. In this stud...

Herein, we report an approach for generating thionyl fluoride (SOF2) from the commodity chemicals thionyl chloride (SOCl2) and potassium fluoride (KF). The methodology relies on a microfluidic device that can efficiently produce and dose this toxic, gaseous reagent under extremely mild and safe conditions. Subsequently, the in situ generated thiony...

Sulfur-containing scaffolds originating from small alkyl fragments play a crucial role in various pharmaceuticals, agrochemicals, and materials. Nonetheless, their synthesis using conventional methods presents significant challenges. In this study, we introduce a practical and efficient approach that harnesses hydrogen atom transfer photocatalysis...

The optimization, intensification, and scale-up of photochemical processes constitute a particular challenge in a manufacturing environment geared primarily toward thermal chemistry. In this work, we present a versatile flow-based robotic platform to address these challenges through the integration of readily available hardware and custom software....

A two-step protocol for the modular synthesis of β ² - and α-quaternary β 2,2 -amino acid derivatives is reported. The key steps are a photocatalytic hydroalkylation reaction, followed by an oxidative functionalisation to...

Photocatalysis for small molecule activation has seen significant advancements over the past decade, yet its scale-up remains a challenge due to photon attenuation effects. A promising solution lies in harnessing high photonic intensities paired with continuous-flow reactor technology. However, a deep grasp of photon transport is essential, typical...

In both batch and continuous-flow reactor technology, reproducibility can be challenging for photochemical processes due to setup variability. One major contributor to this issue is the lack of standardized reactor...

Utilizing electrons directly offers significant potential for advancing organic synthesis by facilitating novel reactivity and enhancing selectivity under mild conditions.

The use of reactive gaseous reagents for the production of active pharmaceutical ingredients (APIs) remains a scientific challenge due to safety and efficiency limitations. The implementation of continuous‐flow reactors has resulted in rapid development of gas‐handling technology because of several advantages such as increased interfacial area, imp...

The urgent need to reduce the carbon dioxide level in the atmosphere and keep the effects of climate change manageable has brought the concept of carbon capture and utilization to the forefront of scientific research. Amongst the promising pathways for this conversion, sunlight‐powered photothermal processes, synergistically using both thermal and...

The use of reactive gaseous reagents for the production of active pharmaceutical ingredients (APIs) remains a scientific challenge due to safety and efficiency limitations. The implementation of continuous‐flow reactors has resulted in rapid development of gas‐handling technology because of several advantages such as increased interfacial area, imp...

A vicinal diamine motif can be found in numerous natural compounds and pharmaceuticals, making it an important synthetic target. Herein, we report a telescoped synthesis of vicinal diamines under continuous flow conditions. This approach involves the electrochemical aziridination of alkenes with primary amines, followed by the strain-release driven...

Electrophotocatalytic transformations are garnering attention in organic synthesis, particularly for accessing reactive intermediates under mild conditions. Moving these methodologies to continuous‐flow systems, or flow ElectroPhotoCatalysis ( f ‐EPC), showcases potential for scalable processes due to enhanced irradiation, increased electrode surfa...

In contemporary drug discovery, enhancing the sp3-hybridized character of molecular structures is paramount, necessitating innovative synthetic methods. Herein, we introduce a deoxygenative cross-electrophile coupling technique that pairs easily accessible carboxylic acid-derived redox-active esters (RAEs) with aldehyde sulfonyl hydrazones, employi...

b-Amino acids are privileged scaffolds present in numerous bioactive compounds, as well as versatile synthons in organic chemistry. b2- or b3-amino acids can be readily synthesised, however, access to b2,2-analogues is limited by challenges associated with building the quaternary centre. Herein, we report a two-step protocol for the modular synthes...

A practical electrochemical method for synthesizing aryliminophosphoranes from widely available nitro(hetero)arenes in a continuous‐flow system is presented. The utilization of flow technology offers several advantages to our approach, including the elimination of the need for a supporting electrolyte and enhanced scalability. Our method demonstrat...

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C−H functionalization at sp³‐hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C−H bonds known in Nature, requiring extreme activation conditions that are not tolerant t...

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C−H functionalization at sp ³ ‐hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C−H bonds known in Nature, requiring extreme activation conditions that are not tolerant...

The optimization, intensification, and scaling up of chemical processes are essential and time-consuming aspects of contemporary chemical manufacturing, necessitating expertise and precision due to their intricate and sensitive nature. However, these process development problems are often carried out independently and consecutively, which can exace...

SuFEx click chemistry has established itself as a formidable tool to rapidly and effectively link chemical structures. Despite tremendous advancements in the field in recent years, the installment of the crucial -SO2F handle still requires the use of purposely designed, expensive, and non-atom economical reagents. However, the use of the most obvio...

In recent years, the "Escape-from-Flatland" trend has prompted the synthetic community to develop a set of cross-coupling strategies to introduce sp3-carbon-based fragments in organic compounds. This study presents a novel nickel-catalyzed electrochemical methodology for reductive cross-electrophile coupling. The method enables C(sp2)-C(sp3) linkag...

Flow chemistry has unlocked a world of possibilities for the synthetic community, but the idea that it is a mysterious "black box" needs to go. In this review, we show that several of the benefits of microreactor technology can be exploited to push the boundaries in organic synthesis and to unleash unique reactivity and selectivity. By "lifting the...

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C–H functionalization at sp ³ -hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C–H bonds known in Nature, requiring extreme activation conditions that are not tolerant...

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C-H functionalization at sp3-hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C-H bonds known in Nature, requiring extreme activation conditions that are not tolerant t...

Herein, we present a comprehensive study on the use of N-heterocyclic carbene (NHC)-ligated boryl radicals to enable C(sp3)-C(sp3) bond formation under visible-light irradiation via Halogen-Atom Transfer (XAT). The methodology relies on the use of an acridinium dye to generate the boron-centered radicals from the corresponding NHC-ligated boranes v...

The ability to construct C(sp³)−C(sp³) bonds from easily accessible reagents is a crucial, yet challenging endeavor for synthetic organic chemists. Herein, we report the realization of such a cross‐coupling reaction, which combines N‐sulfonyl hydrazones and C(sp³)−H donors through a diarylketone‐enabled photocatalytic hydrogen atom transfer and a s...

The ability to construct C(sp3)–C(sp3) bonds from easily accessible reagents is a crucial, yet challenging endeavor for synthetic organic chemists. Herein, we report the realization of such a cross‐coupling reaction, which combines N‐sulfonyl hydrazones and C(sp3)–H donors through a diarylketone‐enabled photocatalytic hydrogen atom transfer and a s...

Photocatalytic hydrogen atom transfer (HAT) processes have been the object of numerous studies showcasing the potential of the homogeneous photocatalyst tetrabutylammonium decatungstate (TBADT) for the functionalization of C(sp³)–H bonds. However, to translate these studies into large-scale industrial processes, careful considerations of catalyst l...

The efficient C-4 selective modification of pyridines is a major challenge for the synthetic community. Current strategies are plagued with at least one drawback regarding functional group-tolerant electronic activation of the heteroarene, mild generation of the required alkyl radicals, regioselectivity, safety and/or scalability. Herein, we descri...

The ability to construct C(sp3)–C(sp3) bonds from easily accessible reagents is a crucial, yet challenging endeavor for synthetic organic chemists. Herein, we report the realization of such a cross-coupling reaction, which combines N-sulfonyl hydrazones and C(sp3)–H donors through a diarylketone-enabled photocatalytic Hydrogen Atom Transfer and a s...

A strategy for both cross-electrophile coupling and 1,2-dicarbofunctionalization of olefins has been developed. Carbon-centered radicals are generated from alkyl bromides by merging benzophenone hydrogen atom transfer (HAT) photocatalysis and silyl radical-induced halogen atom transfer (XAT) and are subsequently intercepted by a nickel catalyst to...

In the realm of radical chemistry, halogen-atom transfer (XAT) is emerging as a powerful activation strategy in synthetic endeavors to engage otherwise recalcitrant organic halides. Although toxic tin radicals have been in the spotlight as halo-gen abstractors for decades, the era of photocatalysis has brought to light more sustainable options. Her...

The sun is the most sustainable source of photons on the earth but is rarely used in photochemical transformations due its relatively low and variable intensity, broad wavelength range, and lack of focus. Luminescent solar concentrator-based photomicroreactors (LSC-PMs) can be an answer to all these issues, but widespread adoption is plagued by cha...

Photocatalytic hydrogen atom transfer (HAT) processes have been the object of numerous studies showcasing the potential of the homogeneous photocatalyst tetrabutylammonium decatungstate (TBADT) for the functionalization of C(sp3)-H bonds. However, to translate these studies into large-scale industrial processes, careful considerations of catalyst...

The opportunity to activate C(sp³)−H bonds via homolytic cleavage by means of halogen radicals has long been disregarded in synthetic endeavors due to the unpredictable selectivity. Nowadays, photocatalysis has established itself as a method of choice for the generation of such reactive intermediates under mild conditions. This Minireview collects...

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, furnishing a rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)-H bonds. Our sequence features the merger of two distinct ste...

The Front Cover demonstrates that electrochemistry in continuous flow is so convenient and reliable that even kids could do it. Electrochemical hydroxylation of sensitive electron‐rich arenes was achieved by the implementation of a flow setup. Our goal is to motivate organic chemists, who tend to be quite conservative, to apply the modern technique...

Photocatalysis has recently given impetus to the use of ligated boryl radicals (LBRs) in synthesis, thanks to the mild conditions required for their generation based on the use of visible light. LBRs are B-centered radicals wherein the boron atom is coordinated with a suitable Lewis base (e.g., amine, phosphine, or N-heterocyclic carbene [NHC]) and...

Many chemical reactions contain heterogeneous reagents, products, byproducts, or catalysts, making their transposition from batch to continuous-flow processing challenging. Herein, we report the use of a photochemical rotor–stator spinning disk reactor (pRS-SDR) that can handle and scale solid-containing photochemical reaction conditions in flow. I...

Electrochemical conversion of biomass-derived 5-hydroxymethyl-furfural (HMF) to 2,5-furandicarboxylic acid (FDCA), the building block of bio-based plastics, is an attractive process that leverages renewable electrons and carbon resources. The process offers the potential to increase energy and cost efficiency by combining mild reaction conditions w...

Carbon–nitrogen bonds are ubiquitous in biologically active compounds, prompting synthetic chemists to design various methodologies for their preparation. Arguably, the ideal synthetic approach is to be able to directly convert omnipresent C–H bonds in organic molecules, enabling even late-stage functionalization of complex organic scaffolds. While...

Sunlight strikes our planet every day with more energy than we consume in an entire year. Therefore, many researchers have explored ways to efficiently harvest and use sunlight energy for the activation of organic molecules. However, implementation of this energy source in the large-scale production of fine chemicals has been mostly neglected. The...

Photochemistry using inexhaustible solar energy is an eco‐friendly way to produce fine chemicals outside the typical laboratory or chemical plant environment. However, variations in solar irradiation conditions and the need for an external energy source to power electronic components limits the accessibility of this approach. In this work, a chemic...

The late-stage introduction of allyl groups provides an opportunity to synthetic organic chemists for subsequent diversification, providing rapid access to new chemical space. Here, we report the development of a modular synthetic sequence for the allylation of strong aliphatic C(sp3)–H bonds. Our sequence features the merger of two distinct steps...

The functionalization of aryl C(sp²)−H bonds is a useful strategy for the late‐stage modification of biologically active molecules, especially for the regioselective introduction of azole heterocycles to prepare medicinally‐relevant compounds. Herein, we describe a practical photocatalytic transformation using a mesoporous carbon nitride (mpg‐CNx)...

The electrochemical synthesis of aryl azoles was performed for the first time in a microflow reactor. The reaction relies on the anodic oxidation of the arene partners making these substrates susceptible for C–H functionalization with azoles, thus requiring no homogeneous transition-metal-based catalysts. The synthetic protocol benefits from the im...

Photoinduced chemical transformations have received in recent years a tremendous amount of attention, providing a plethora of opportunities to synthetic organic chemists. However, performing a photochemical transformation can be quite a challenge because of various issues related to the delivery of photons. These challenges have barred the widespre...

A comprehensive understanding of the underlying phenomena (coupled fluid flow, charge transfer, mass transfer and chemical reaction) is fundamental for a proper design, analysis and scale-out of chemical reactors when carrying out multiphase electro-organic transformations. In this study, we have explored the novel combination of organic electroche...

Photocatalytic hydrogen atom transfer is a very powerful strategy for the regioselective C(sp³)–H functionalization of organic molecules. Herein, we report on the unprecedented combination of decatungstate hydrogen atom transfer photocatalysis with the oxidative radical–polar crossover concept to access the direct net‐oxidative C(sp³)–H heteroaryla...

The handling of solid reagents, catalysts and by-products is a daunting challenge in continuous-flow micro- and milli-reactors. Suspensions tend to settle over time leading to irrevocable clogging of the reaction channels. Herein, we describe our efforts to develop an ultrasonic milli-reactor which can handle such challenging solid-containing trans...

The combination of decatungstate photocatalysis with oxidative radical–polar crossover is reported. This strategy enables the C(sp³)–H heteroarylation under mild conditions with excellent functional group tolerance. It was also adopted to enable late-stage functionalization of valuable compounds. Microflow technology reduced reaction times and boos...

Katritzky salts have emerged as effective alkyl radical sources upon metal-or photocatalysis. These are typically prepared from the corresponding triarylpyrylium ions, in turn an important class of photocatalysts for small molecules synthesis and photopolymerization. Here, a flow method for the rapid synthesis of both pyrylium and Katrizky salts in...

Continuous-flow microreactor technology has been embraced by researchers in academia and industry due to its excellent transport properties and the increased safety and control over challenging chemical transformations. Despite its popularity, scaling the benefits associated with the microenvironment has proven to be a daunting challenge. This revi...

Aziridines are useful synthetic building blocks, widely employed for the preparation of various nitrogen-containing derivatives. As the current methods require the use of prefunctionalized amines, the development of a synthetic strategy toward aziridines that can establish the union of alkenes and amines would be of great synthetic value. Herein, w...

By embedding flow technology in the early phases of academic education, students are exposed to both the theoretical and practical aspects of this modern and widely-used technology. Herein, two laboratory flow experiments are described which have been carried out by first year undergraduate students at Eindhoven University of Technology. The experi...

Liquid‐phase adsorption has hardly been established in micro‐flow, although this constitutes an industrially vital method for product separation. A micro‐flow UV‐photo isomerization process converts cis‐cyclooctene partly into trans‐cyclooctene, leaving an isomeric mixture. Trans‐cyclooctene adsorption and thus separation was achieved in a fixed‐be...