Publications

Unveiling the impact of the light source and steric factors on [2 + 2] heterocycloaddition reactions

Javier Mateos, Francesco Rigodanza, Paolo Costa, Mirco Natali, Alberto Vega-Peñaloza, Elisa Fresch, Elisabetta Collini, Marcella Bonchio, Andrea Sartorel, and Luca Dell’Amico*

Abstract

Information gained from in-depth mechanistic investigations can be used to control the selectivity of reactions, leading to expansion of the generality of synthetic processes and discovery of new reactivity. Here, we investigate the mechanism of light-driven [2 + 2] heterocycloadditions (Paternò–Büchi reactions) between indoles and ketones to develop insight into these processes. Using ground-state ultraviolet–visible absorption and transient absorption spectroscopy, together with density functional theory calculations, we found that the reactions can proceed via an exciplex or electron–donor–acceptor complex, which are key intermediates in determining the stereoselectivity of the reactions. We used this discovery to control the diastereoselectivity of the reactions, gaining access to previously inaccessible diastereoisomeric variants. When moving from 370 to 456 nm irradiation, the electron–donor–acceptor complex is increasingly favoured, and the diastereomeric ratio (d.r.) of the product moves from >99:<1 to 47:53. In contrast, switching from methyl to ipropyl substitution favours the exciplex intermediate, reversing the d.r. from 89:11 to 16:84. Our study shows how light and steric parameters can be rationally used to control the diastereoselectivity of photoreactions, creating mechanistic pathways to previously inaccessible stereochemical variants.

Nat. Synth. 2022. DOI: 10.1038/s44160-022-00191-5.

Highlighted in News & Views – Nat. Synth., 2022,  DOI: 10.1038/s44160-022-00200-7.

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Giving ketones the green light

Giulio Goti, and Luca Dell’Amico*

Abstract

The α-arylation of ketones is a powerful synthetic strategy for the construction of C–C bonds, but general metal-free methods are scarce. Now, a green-light-mediated photoredox protocol enables this transformation, giving access to a broad range of useful building blocks and value-added biorelevant products.

News & Views invited article – Nat. Synth. 2022, 1, 101–102. DOI: 10.1038/s44160-022-00026-3.

For the original work by Gianetti and co-workers see Nat. Synth., 2022, 1, 147-157. DOI: s44160-021-00021-0.

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The Photochemical Activity of a Halogen-Bonded Complex Enables the Microfluidic Light-Driven Alkylation of Phenols

Sara Cuadros, Cristian Rosso, Giorgia Barison, Paolo Costa, Marcella Bonchio, Maurizio Prato, Giacomo Filippini,* and Luca Dell’Amico*

Abstract

A mild light-driven protocol for the direct alkylation of phenols is reported. The process is driven by the photochemical activity of a halogen-bonded complex formed upon complexation of the in situ generated electron-rich phenolate anion with the α-iodosulfone. The reaction proceeds rapidly (10 min) under microfluidic conditions, delivering a wide variety of ortho-alkylated products (27 examples, up to 97% yield, >20:1 regioselectivity, on a gram scale), including densely functionalized bioactive phenol derivatives.

Org. Lett. 2022, 24, 2961–2966. DOI: 10.1021/acs.orglett.2c00604 – Open access as author choice.

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Unveiling the Synthetic Potential of Substituted Phenols as Fully Recyclable Organophotoredox Catalysts for the Iodosulfonylation of Olefins

Cristian Rosso, Sara Cuadros, Giorgia Barison, Paolo Costa, Marcella Bonchio, Maurizio Prato, Luca Dell’Amico,* Giacomo Filippini*

Abstract

We describe an efficient photocatalytic procedure for the direct iodosulfonylation of terminal olefins 3 with α-iodo phenylsulfones 4. Specifically, the process uses the simple, robust, and fully recyclable phenol derivative 6e as the precatalytic system and occurs with visible-light irradiation (450 nm). Mechanistic investigations proved the key role of the in situ generated photocatalyst, namely phenolate anion 7e, which has shown high catalytic activity and considerable stability toward the operating conditions. Importantly, this photocatalytic transformation provides a wide variety of densely functionalized alkyl iodides 5 (23 examples, up to 95% yield). Finally, the synthetic potential of this photochemical transformation was demonstrated by scaling up the process under microfluidic conditions (up to 0.67 mmol h–1) while accessing a series of relevant product manipulations.

ACS Catal. 2022, 12, 42904295. DOI: 10.1021/acscatal.2c00565 – Open access as author choice.

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Properties and Synthetic Performances of Phenylamino Cyanoarenes under One-Photon Excitation Manifolds

Tommaso Bortolato, Mateusz Dyguda, Alberto Vega-Penaloza,* and Luca Dell’Amico*

Abstract

The synthesis of a set of new organic photocatalysts (PCs) with a donor-acceptor carbazolyl dicyanobenzene structure is reported. The PCs developed have fine-tailored redox potentials from -1.62 V (PC•+/PC*) to 1.36 V (PC*/PC•-) and have been accessed through a straightforward two-step synthesis. The potential of these PCs was demonstrated in synthetically relevant photoreactions with mechanistic opposite thermodynamic requirements, previously reported only in the presence of precious Ir-based PCs. Interestingly, the herein reported purely organic PCs outperformed the well-established 4CzIPN organic dye under both types of reaction manifolds.

Synthesis 2022, DOI: 10.1055/a-1776-0929. Invited contribution to the Bürgenstock Conference 2021 issue of Synthesis.

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The Advent and Development of Organophotoredox Catalysis

Tommaso Bortolato, Sara Cuadros, Gianluca Simionato, and Luca Dell’Amico*

Abstract

In the last decade, photoredox catalysis has unlocked unprecedented reactivities in synthetic organic chemistry. Seminal advancements in the field have involved the use of well-studied metal complexes as photoredox catalysts (PCs). More recently, the synthetic community, looking for more sustainable approaches, is moving towards the use of purely organic molecules. Organic PCs are generally cheaper and less toxic, while allowing their rational modification to an increased generality. Furthermore, organic PCs have allowed reactivities that are inaccessible by using the common metal complexes. Likewise in synthetic catalysis, the field of photocatalysis is now experiencing a green evolution moving from metal-catalysis to organocatalysis. In this Feature Article we discuss and critically comment the scientific reasons of this ongoing evolution in the field of photoredox catalysis, showing how and when organic PCs can efficiently replace their metal counterparts.

Chem. Commun. 2022, 58, 1263–1283. DOI: 10.1039/D1CC05850A.

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Radical α-Trifluoromethoxylation of Ketones under Batch and Flow Conditions by Means of Organic Photoredox Catalysis

Thibaut Duhail, Tommaso Bortolato, Javier Mateos, Elsa Anselmi, Benson Jelier, Antonio Togni, Emmanuel Magnier,* Guillaume Dagousset,* and Luca Dell’Amico*

Abstract

The first light-driven method for the α-trifluoromethoxylation of ketones is reported. Enol carbonates react with the N-trifluoromethoxy-4-cyano-pyridinium, using the photoredox-catalyst 4-CzIPN under 456 nm irradiation, affording the α-trifluoromethoxy ketones in up to 50% isolated yield and complete chemoselectivity. As shown by 29 examples, the reaction is general and proceeds very rapidly under batch (1h) and flow conditions (2min). Diverse product manipulations demonstrate the synthetic potential of the disclosed method to accessing elusive trifluoromethoxylated bioactive ingredients.

Org. Lett. 2021, 23, 7088–7093. DOI: 10.1021/acs.orglett.1c02494Open access as author choice

Highlighted in Synfacts 2021, 17, 1294, DOI: 10.1055/s-0041-1737064

Among the most accessed papers in September 2021

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Unlocking the Synthetic Potential of Light-Excited Aryl ketones – Applications in Direct Photochemistry and Photoredox Catalysis

Javier Mateos, Sara Cuadros, Alberto Vega-Peñaloza, and Luca Dell’Amico *

Abstract

In this account article, we summarize the contributions of our group to the field of photochemistry and photocatalysis. Our work deals with the development of novel synthetic methods based on the exploitation of photoexcited aryl ketones. The application of new technologies, such as microfluidic photoreactors (MFPs), have enhanced the synthetic performance and scalability of several photochemical methods i.e. Paternò–Büchi and photoenolization/Diels-Alder processes, while opening the way to unprecedented reactivity. Further, the careful mechanistic analysis of the developed methods has been instrumental to disclosing a new family of powerful organic photocatalyst able to mediate several thermodynamically extreme photoredox processes.

Synlett . 2022, DOI: 10.1055/a-1403-4613Contribution to the EuCheMS Organic Division Young Investigator Workshop of Synlett

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A Rational Approach to Organo‐Photocatalysis. Novel Designs and Structure‐Property‐Relationships

Alberto Vega-Peñaloza, Javier Mateos, Xavier Companyó, Margarita Escudero-Casao, and Luca Dell’Amico *

Abstract

Organic photocatalysts (PCs) are emerging as viable and more sustainable tools with respect to metal complexes. Recently, the field of organo‐photocatalysis has experienced an explosion in terms of applications, redesign of well‐established systems and identification of novel scaffolds. A rational approach to the structural modification of the different PCs is key to accessing unprecedented reactivity, while improving their catalytic performances. We herein discuss the concepts underpinning the scaffold modifications of some of the most recently used PCs, analysing how specific structural changes alter their physicochemical and redox properties.

Angew. Chem. Int. Ed.,  2021, 133, 1096-1111. DOI: 10.1002/ange.202006416

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Microfluidic Visible-Light Paternò-Büchi Reaction of Oxindole Enol Ethers

Pietro Franceschi, Javier Mateos, Alberto Vega-Peñaloza,* and Luca Dell’Amico *

Abstract

A novel microfluidic visible-light process for the functionalisation of oxindoles is reported. The chemistry is based on the reactivity of the corresponding enol ethers, which participate in a site-, regio- and diastereoselective [2+2] heterocycloaddition (Paternò–Büchi) process. The mild reaction conditions, the use of available ketones, together with the high generality (23 examples) and robustness (up to gram scale) make of this process a useful synthetic platform for the construction of structurally strained heterocycles.

Eur. J. Org. Chem.,  2020, 6718-6722. DOI: 10.1002/ejoc.202001057Invited contribution to the YourJOC Talents collection 2020

Highlighted in ChemistryView: Microfluidic, Light-Driven Process for Oxindole Functionalization

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Visible-Light Paternò-Büchi Dearomatisation Process Towards the Construction of Oxeto-Indolinic Polycycles

Javier Mateos, Alberto Vega-Peñaloza, Pietro Franceschi, Francesco Rigodanza, Xavier Companyó,* Philip Andreetta, Giorgio Pelosi, Marcella Bonchio, and Luca Dell’Amico *

Abstract

A variety of highly functionalised N-containing polycycles (35 examples) are synthetised from simple indoles and aromatic ketones through a mild visible-light Paternò-Büchi process. Tetrahydrooxeto[2,3-b]indole scaffolds, with up to three contiguous all-substituted stereocenters, are generated in high yield (up to >98%) and excellent site- regio- and diastereocontrol (>20:1). The use of visible light (405 or 465 nm) ensures enhanced performances by switching off undesired photodimerisation side reactions. The reaction can be easely implemented under a microfluidic photoreactor with improved productivity (up to up to 0.176 mmol·h-1) and generality. Mechanistic investigations revealed that two alternative reaction mechanisms can account for the excellent regio- and diasterecontrol observed.

Chem. Sci.  2020, 11, 6532-6538. DOI: 10.1039/D0SC01569E

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Naphthochromenones: Organic Bimodal Photocatalysts Engaging in Both Oxidative and Reductive Quenching Processes

Javier Mateos, Francesco Rigodanza, Alberto Vega, Andrea Sartorel, Mirco Natali, Tommaso Bortolato, Giorgio Pelosi, Xavier Companyó, Marcella Bonchio, Luca Dell’Amico*

Abstract

12 different naphthochromenone photocatalysts (PCs) have been synthesized at gram–scale, combining absorption features across the UV–Vis spectrum, up to 440 nm with an extremely wide redox window (up to 3.22 eV) that is accessible using simple visible light irradiation sources (CFL or LED). Their excited state redox potentials, PC*/PC ●– = up to 1.65 V and PC ●+ /PC* up to –1.77 V vs SCE, are such that these novel PCs can engage in both oxidative and reductive quenching mechanisms with strong thermodynamic requirements . Converging absorption/emission spectroscopy and cyclic voltammetry we delineate robust structure–properties relationships, that are further supported by time–dependent density functional theory (TD–DFT) calculations. The potential of these bimodal PCs has been benchmarked in thermodynamically challenging photocatalytic processes, were strong oxidative (> 1.46 V) and strong reductive power (< –1.96 V) is required. Further advantages are given by their simple recovery and reuse – up to four times, without any significant loss in their photocatalytic performances. The ability of efficiently catalysing mechanistically opposite oxidative/reductive photoreactions is a unique feature for organic photocatalysts. This new class of molecules represents a decisive advancement towards generality, sustainability and cost efficiency in photoredox catalysis.

Angew. Chem. Int. Ed. 2020, 59, 1302-1312. DOI: 10.1002/anie.201912455

Profiling the Privileges of Pyrrolidine-Based Catalysts in Asymmetric Synthesis: From Polar to Light-Driven Radical Chemistry

Alberto Vega-Peñaloza, Suva Paria, Marcella Bonchio, Luca Dell’Amico*, Xavier Companyó*

Abstract

Asymmetric catalysis is a rapidly evolving field in synthetic chemistry. This is due to the growing needs of stereoselective synthetic routes to access enantiopure natural products and bioactive molecules. An efficient approach involves the use of readily available and robust catalysts, while ensuring high yields and stereocontrol. In this scenario, the pyrrolidine-based catalyst has played a dominant role over the past decades. Interestingly, simple scaffold modifications result in dramatic physicochemical and reactivity changes. These features have facilitated the generation of different catalyst variants for the development of highly diversified asymmetric transformations. In this Perspective, we analyze the structural evolution of the pyrrolidine-based catalyst, moving from polar to light-induced radical processes. We discuss the concepts underpinning the most relevant scaffold modifications while defining structure–reactivity relationships. The present work will encourage a rational scaffold design toward unprecedented reactivity pathways and improved catalytic performances.

ACS Catal. 2019, 9, 6058-6072. DOI: 10.1021/acscatal.9b01556

Acetaldehyde Silyl Enol Ethers in Enantioselective Mukaiyama Aldol Reactions: Enzyme-Like Organocatalysis in Action

Luca Dell’Amico*, Franca Zanardi*

Abstract

Touched for the very first time! It is herein highlighted how acetaldehyde silyl enol ethers undergo enantioselective Mukaiyama aldol reaction with aliphatic and aromatic aldehydes. The chemistry relies on the use of the highly efficient and substrate‐selective imidodiphosphorimidate catalyst, which displays some of the features of enzymatic catalysis.

Angew. Chem. Int. Ed. 2019, 58, 3264-3266. DOI:  10.1002/anie.201812964

Microfluidic light-driven synthesis of tetracyclic molecular architectures

Javier Mateos, Nicholas Meneghini, Marcella Bonchio, Nadia Marino, Tommaso Carofiglio, Xavier Companyó* and Luca Dell’Amico*

Abstract

Herein we report an effective synthetic method for the direct assembly of highly functionalized tetracyclic pharmacophoric cores. Coumarins and chromones undergo diastereoselective [4 + 2] cycloaddition reactions with light-generated photoenol intermediates. The reactions occur by aid of a microfluidic photoreactor (MFP) in high yield (up to >98%) and virtually complete diastereocontrol (>20:1 dr). The method is easily scaled-up to a parallel setup, furnishing 948 mg of product over a 14 h reaction time. Finally, a series of manipulations of the tetracyclic scaffold obtained gave access to valuable precursors of biologically active molecules.

Beilstein J. Org. Chem. 2018,14, 2418–2424. DOI :10.3762/bjoc.14.219 

Transition Metal‐Free CO2 Fixation into New Carbon–Carbon Bonds

Alessio Cherubini‐Celli, Javier Mateos, Marcella Bonchio*, Luca Dell’Amico*, Xavier Companyó*

Abstract

CO2 is the ultimate renewable carbon source on Earth and the essential C1 building block for carbohydrate biosynthesis in photosynthetic organisms. Modern synthetic chemistry is facing the key challenge of developing fundamental transformations, such as C−C bond formation, in a sustainable and efficient manner from renewable sources. In this Minireview, the most significant methods recently reported for CO2 fixation under transition metal‐free conditions are summarized, organized into three different chapters according to the nature of the chemical transformation that forges the new C−C bond. The focus is on the mechanistic aspects of the different CO2 activation modes, with specific attention to those systems that operate under catalytic conditions.

ChemSusChem 2018,11, 3056–3070. DOI : 10.1002/cssc.201801063

A microfluidic photoreactor enables 2-methylbenzophenone light-driven reactions with superior performance

Javier Mateos, Alessio Cherubini-Celli, Tommaso Carofiglio, Marcella Bonchio, Nadia Marino, Xavier Companyó* and Luca Dell’Amico*

Abstract

Light-driven reactions of 2-methylbenzophenones (2-MBPs) occur with improved yields (up to >98%) and reaction rates (up to 0.240 mmol h−1) by using a tailored microfluidic photoreactor (MFP). For the first time, coumarins were converted into 4-benzylated chromanones in high yields (50–93%) and diastereoselectivity (up to >20 : 1 dr), thus by-passing their photo-dimerisation end-reaction

Chem. Commun., 2018, 54, 6820-6823 . DOI: 10.1039/C8CC01373J