Metal-free photocatalytic cross-electrophile coupling enables C1 homologation and alkylation of carboxylic acids with aldehydes

Authors are grateful to have received generous funding from the European Union H2020 research and innovation program under the Marie S. Curie Grant Agreement (PhotoReAct, No 956324, S.B., M.L., A.L., G.M., E.Z.C., T.N.; CHAIR, No 860762, A.P., M.J., T.N.)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 Eosin Y as an organophotocatalyst under visible light irradiation. This approach serves as a versatile, metal-free C(sp3)−C(sp3) cross-coupling platform. We demonstrate its synthetic value as a safer, broadly applicable C1 homologation of carboxylic acids, offering an alternative to the traditional Arndt-Eistert reaction. Additionally, our method provides direct access to cyclic and acyclic β-arylethylamines using diverse aldehyde-derived sulfonyl hydrazones. Notably, the methodology proves to be compatible with the late-stage functionalization of peptides on solid-phase, streamlining the modification of intricate peptides without the need for exhaustive de-novo synthesis.Peer reviewe

Sintesi formale organocatalitica enantioselettiva del composto bioattivo AG-041R

Nonostante il diffuso impiego di esteri azodicarbossilici in reazioni di a-amminazione asimmetrica (aAA) su substrati carbonilici, la successiva elaborazione del prodotto idrazinico nella corrispondente ammina primaria può risultare problematico. Questo è particolarmente vero quando come reagenti amminanti sono impiegati gli esteri azodicarbossilici di tipo etilico, iso-propilico e benzilico: infatti, a causa di condizioni di deprotezione e fissione del legame N-N troppo drastiche, e perciò poco chemoselettive, l’applicabilità di tali agenti elettrofili all’azoto nella preparazione di composti polifunzionali bio-attivi risulta fortemente limitata. Per questo motivo nella presente Tesi è stato esplorato l’uso del bis-(2,2,2-tricloroetile)-azodicarbossilato (13), come agente elettrofilo in reazioni organocatalizzate di aAA su sistemi carbonilici a struttura 2-ossindolica. In dettaglio, i substrati 14, 88 selezionati in questo studio contenevano una catena carbossimetilica -CH2CO2R (R = Et o tBu) in posizione C-3, in modo da ottenere prodotti amminati di potenziale interesse per lo sviluppo di una nuova via sintetica enantioselettiva verso il composto bio-attivo AG-041R (45). In un primo stadio è stato condotto un lavoro di ottimizzazione della reazione di aAA con 13 degli esteri 14 e 88, esplorando a tale scopo differenti condizioni sperimentali (solvente, temperatura, catalizzatore, concentrazione). In questo modo sono state raggiunte buone stereoselettività sia nella formazione del prodotto amminato etilico 15 (77-80% ee, resa > 80%), che per quello tert-butilico 89 (77% ee, 92% resa), che migliorano significativamente i risultati riportati in precedenza da questo laboratorio. In seguito, il derivato 15 è stato convertito nella corrispondente ammina primaria 29 nelle blande condizioni riducenti di Leblanc-Fitzsimmons. Anche in questo caso è stato effettuato uno specifico lavoro di ottimizzazione, allo scopo di isolare il composto desiderato in forma pura e con rese utili dal punto di vista sintetico (>80%). Infine sono state condotte alcune prove di trasformazione di 29 in intermedi noti per la sintesi di AG-041R. In questo ambito è stato valutato anche il comportamento alla ricristallizzazione dell’urea 87, trovando condizioni per il forte arricchimento enantiomerico (97% ee) di tale precursore di letteratura del composto bio-attivo di interesse

A Scalable Continuous Photochemical Process for the Generation of Aminopropylsulfones

An efficient continuous photochemical process is presented that delivers a series of novel γ-aminopropylsulfones via a tetrabutylammonium decatungstate (TBADT) catalysed HAT-process. Crucial to this success is the exploitation of a new high-power LED emitting at 365 nm that was found to be superior to an alternative medium-pressure Hg lamp. The resulting flow process enabled the scale-up of this transformation reaching throughputs of 20 mmol h−1 at substrate concentrations up to 500 mM. Additionally, the substrate scope of this transformation was evaluated demonstrating the straightforward incorporation of different amine substituents as well as alkyl appendages next to the sulfone moiety. It is anticipated that this methodology will allow for further exploitations of these underrepresented γ-aminopropylsulfone scaffolds in the future.European Commission - European Regional Development FundScience Foundation IrelandUniversity College Dubli

Synthetic Applications of Photocatalyzed Halogen-Radical Mediated Hydrogen Atom Transfer for C−H Bond Functionalization

 Photocatalysis is a method of choice for the generation of reactive intermediates under mild conditions. This Review collects the recent examples exploiting this manifold to generate highly aggressive halogen radicals to activate C(sp3)−H bonds via Hydrogen Atom Transfer (HAT) for synthetic purposes. Available strategies to influence site-selectivity of the hydrogen atom transfer step have also been discussed. </p

Synthetic Applications of Photocatalyzed Halogen-Radical Mediated Hydrogen Atom Transfer for C−H Bond Functionalization

 Photocatalysis is a method of choice for the generation of reactive intermediates under mild conditions. This Review collects the recent examples exploiting this manifold to generate highly aggressive halogen radicals to activate C(sp3)−H bonds via Hydrogen Atom Transfer (HAT) for synthetic purposes. Available strategies to influence site-selectivity of the hydrogen atom transfer step have also been discussed. </p

Synthetic Applications of Photocatalyzed Halogen-Radical Mediated Hydrogen Atom Transfer for C−H Bond Functionalization

 Photocatalysis is a method of choice for the generation of reactive intermediates under mild conditions. This Review collects the recent examples exploiting this manifold to generate highly aggressive halogen radicals to activate C(sp3)−H bonds via Hydrogen Atom Transfer (HAT) for synthetic purposes. Available strategies to influence site-selectivity of the hydrogen atom transfer step have also been discussed. </p

Catalytic enantioselective alpha-amination of 2-oxindoles and a new route to the bio-active compound AG-041R

AG-041R is a chiral, enantiopure 2-oxindole urea derivative provided with a remarkable bio-activity that ranges from anti-ulcer, to condrogenic and anti-proliferative. Following the introduction by our group of a convenient protocol for the organocatalytic, asymmetric alpha-amination (AaA) of N-unprotected 3-alkyl-2-oxindoles with bis(trichloroethyl)¬azodicarboxylate (BTCEAD), we report herein a novel route to AG-041R, which takes advantage of the prompt elaboration of chiral hydrazine derivatives masked as trichloroethyl carbamates. In addition to the optimization of the AA step and the subsequent elaboration of the resulting aminated product, the possibility to enhance the enantiomeric purity of suitable intermediates, by selective crystallization of the racemate, will be briefly discussed

Photocatalytic Deoxygenative Alkylation of C(sp3)−H Bonds Using Sulfonylhydrazones

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 subsequent fragmentation of the obtained alkylated hydrazide. This mild and metal-free protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products and is tolerant of a variety of functional groups. The application of this chemistry further provides a preparatively useful route to various medicinally-relevant compounds, such as homobenzylic ethers, aryl ethyl amines, β-amino acids and other moieties which are commonly encountered in approved pharmaceuticals, agrochemicals and natural products

Modular allylation of C(sp3)−H bonds by combining decatungstate photocatalysis and HWE olefination in flow

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 to accomplish this goal, including a photocatalytic Hydrogen Atom Transfer and an ensuing Horner-Wadsworth-Emmons reaction. This practical protocol enables the modular and scalable allylation of valuable building blocks and medicinally relevant molecules

Photocatalytic Alkylation of C(sp3)−H Bonds Using Sulfonylhydrazones

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 transferand a subsequent fragmentation of the obtained alkylated hydrazide. This mild and metal-free protocol was employed to prepare a wide array of alkyl-alkyl cross-coupled products and is tolerant of a variety of functional groups. The application of this chemistry further provides a preparatively useful route to various medicinally-relevant compounds, such as homobenzylic ethers, aryl ethyl amines, β-amino acids and other moieties which are commonly encounteredin approved pharmaceuticals, agrochemicals and natural product