The reaction of copper trifluoromethyl sulfide with diaryliodonium salts provides a straightforward pathway for the synthesis of aryl trifluoromethyl thioethers under mild reaction conditions and within short reaction times. High chemoselectivity was achieved by using mesityl as a leaving group. A large range of novel [(het)aryl](mesityl)iodonium salts underwent this reaction under the optimized conditions to give the desired products in moderate to good yields.

An enantioselective addition of thiols and alcohols to aza-ortho-quinone methides, starting from diaryl methanols, was developed. The asymmetric additions occur under mild reaction conditions in the presence of chiral phosphoric acids and furnish the corresponding adducts with excellent yields and enantioselectivities.

In the presence of trialkylaluminum reagents, diverse aryl methyl ethers can be transformed into valuable products by C−O bond-cleaving alkylation, for the first time without the limiting β-hydride elimination. This new nickel-catalyzed dealkoxylative alkylation method enables powerful orthogonal synthetic strategies for the transformation of a variety of naturally occurring and easily accessible anisole derivatives. The directing and/or activating properties of aromatic methoxy groups are utilized first, before they are replaced by alkyl chains in a subsequent coupling process.

The straightforward introduction of the trifluoromethylseleno group into aromatic and heteroaromatic compounds is accomplished by the utilization of readily available aryldiazonium tetrafluoroborates, potassium selenocyanate, and Ruppert–Prakash reagent. The reaction tolerates a wide range of aromatic and heteroaromatic diazonium salts and is also amenable to the synthesis of pentafluoroethyl selenoethers. Furthermore, the methodology can be applied directly starting from anilines.

Eine Aldimin-Anilin- und Aldehyd-Anilin-Kupplung konnte durch eine von sichtbarem Licht vermittelte Photoredoxkatalyse realisiert werden. Die reduktive SET-Umpolung diverser Carbonylderivate ermöglicht die Generierung von intermediären Ketyl- und α-Aminoradikalanionen, die zur Synthese von wertvollen unsymmetrisch substituierten 1,2-Diaminen und Aminoalkoholen genutzt werden.

Diverse Arylmethylether können durch Trialkylaluminiumverbindungen mittels einer Alkylierung unter C-O-Bindungsspaltung in wertvolle Produkte überführt werden, wobei die bislang limitierenden β-Hydrideliminierungen vermieden werden. Basierend auf der Vielfalt natürlich vorhandener oder leicht zugänglicher Anisolderivate ermöglicht die neue Nickel-katalysierte dealkoxylierende Alkylierung orthogonale Synthesestrategien, die zunächst die dirigierenden und/oder aktivierenden Eigenschaften von Methoxysubstituenten an aromatischen Systemen ausnutzen und diese anschließend durch eine Alkylkette ersetzen.

Eine enantioselektive Addition von Thiolen und Alkoholen an Aza-ortho-chinonmethide ausgehend von Diarylmethanolen wurde entwickelt. Die asymmetrischen Additionen verlaufen unter milden Reaktionsbedingungen in Anwesenheit chiraler Phosphorsäuren und ergeben die entsprechenden Addukte mit exzellenten Ausbeuten und Enantioselektivitäten.

Visible-light-mediated photoredox-catalyzed aldimine–aniline and aldehyde–aniline couplings have been realized. The reductive single electron transfer (SET) umpolung of various carbonyl derivatives enabled the generation of intermediary ketyl and α-amino radical anions, which were utilized for the synthesis of unsymmetrically substituted 1,2-diamines and amino alcohols.

Ketyl radical and amino radical anions, valuable reactive intermediates for CC bond-forming reactions, are accessible through a CO/CNR umpolung. However, their utilization in catalysis remains largely underdeveloped owing to the high reduction potential of carbonyl compounds and imines. In the context of photoredox catalysis, tertiary amines are commonly employed as sacrificial co-reducing agents. Herein, an additional role of the amine is proposed, in which it is essential for the organocatalytic substrate activation. The combination of photoredox catalysis and carbonyl/imine activation enables the reductive coupling of aldehydes, ketones, and imines under mild reaction conditions.

An efficient method for the highly enantioselective synthesis of chiral chromanes bearing multiple stereogenic centers was developed. A chiral BINOL-based N-triflylphosphoramide proved to be an effective catalyst for the in situ generation of ortho-quinone methides (o-QMs) and their subsequent cycloaddition reaction with unactivated alkenes provided chromanes with excellent diastereo- and enantioselectivity.

The first asymmetric metal-catalyzed Nazarov cyclization of N-heterocycles has been developed. The use of a chiral catalyst allows the enantioselective electrocyclization of N-heterocycles under mild conditions and the corresponding products are obtained in good yields with excellent enantio- and diastereoselectivity. The reaction mechanism and the absolute configuration of the obtained products are explained by means of computational studies.

A combination of ruthenium and photoredox catalysis allowed the ortho olefination of phenols. Using visible light, the direct CH functionalization of o-(2-pyridyl)phenols occurred, and diverse phenol ethers were obtained in good yields. The regeneration of the ruthenium catalyst was accomplished by a photoredox-catalyzed oxidative process.

Ein effizientes Verfahren für die enantioselektive Synthese von chiralen Chromanen mit mehreren Stereozentren wurde entwickelt. Ein chirales Binol-basiertes N-Triflylphosphoramid erwies sich dabei als effektiver Katalysator für die In-situ-Generierung von ortho-Chinonmethiden (o-QMs) und deren nachfolgende Cycloaddition mit nichtaktivierten Alkenen. Diese führte hoch diastereo- und enantioselektiv zu Chromanen.

Eine Kombination von Ruthenium- und Photoredoxkatalysatoren ermöglicht die ortho-Olefinierung von Phenolen. Mithilfe von sichtbarem Licht kann die direkte C-H-Funktionalisierung von o-(2-Pyridyl)phenolen erfolgen, wobei diverse Phenolether in guten Ausbeuten erhalten werden. Die Regenerierung des Rutheniumkatalysators erfolgt durch einen photoredoxkatalysierten oxidativen Prozess.

A catalytic (E)- to (Z)-isomerization of olefins using a photoredox catalyst under mild reaction conditions is presented. A variety of (Z)-alkenes can be prepared in the presence of visible light. A new reaction system allows an easy and efficient scale-up, as well as a continuous flow process in which the photocatalyst is immobilized in an ionic liquid and continuously recycled by simple phase separation.

Aza-ortho-quinone methides allow the straightforward asymmetric synthesis of natural-product-inspired indole scaffolds possessing a quaternary stereocenter. Our approach provides access to diverse communesin and spiroindoline derivatives with high enantioselectivity under mild reaction conditions. Predictable substitution patterns are found to be the key to our regiodivergent protocols.

Aza-ortho-Chinonmethide ermöglichen eine effiziente asymmetrische Synthese Naturstoff-inspirierter Indolgerüste mit quartärem Stereozentrum. Mit diesem Ansatz konnten diverse Communesin- und Spiroindolin-Gerüste unter milden Reaktionsbedingungen mit hohen Enantioselektivitäten erzeugt werden, wobei Regiodivergenz durch Variation des Substitutionsmusters erzielt werden kann.

Die erste asymmetrische metallkatalysierte Nazarov-Cyclisierung von N-Heterocyclen wurde entwickelt. Die Verwendung eines chiralen Katalysators ermöglicht die enantioselektive Elektrocyclisierung unter milden Bedingungen, wobei die Produkte in guten Ausbeuten und mit exzellenten Selektivitäten erhalten werden. Mittels Dichtefunktionalrechnungen werden der Reaktionsmechanismus und die absolute Konfiguration der erhaltenen Produkte erklärt.

Ketylradikale und Aminoradikalanionen sind interessante reaktive Intermediate für C-C-Kupplungen. Dennoch ist die Verwendung dieser reaktiven Intermediate in der Katalyse nur spärlich beschrieben. Grund hierfür sind die thermodynamisch ungünstigen Verhältnisse einer Carbonyl- oder Imin-Umpolung mittels der Redoxkatalysatoren. Im Rahmen des reduktiven Löschzyklus in der Photoredoxkatalyse kommen gewöhnlich tertiäre Amine als Coreduktionsmittel zum Einsatz, die keine weitere nennenswerte Funktion erfüllen. Wir zeigen hier, dass dem Amin eine duale Rolle zukommen kann und für eine organokatalytische Präaktivierung der Substrate entscheidend ist. Die Kombination von Photoredoxkatalyse und Carbonyl/Imin-Aktivierung ermöglichte uns erstmals die reduktive Kupplung von Benzaldehyden, Ketonen und Iminen unter milden Bedingungen.

This review provides an overview of recent developments in the area of continuous flow process optimization by employing self-optimizing reactor systems. Although only few reactor concepts have been realized to date, impressive progress has been made, which now allows fully automated reaction optimization without the need of human interactions.

A new and safe method for the synthesis of N-(trifluoromethylthio)phthalimide, a convenient and shelf-stable reagent for the direct trifluoromethylthiolation, has been developed. N-(Trifluoromethylthio)phthalimide can be used as an electrophilic source of F₃CS⁺ and reacts readily with boronic acids and alkynes under copper catalysis. The utility of CF₃S-containing molecules as biologically active agents, the mild reaction conditions employed, and the high tolerance of functional groups demonstrate the potential of this new methodology to be widely applied in organic synthesis as well as industrial pharmaceutical and agrochemical research and development.

Eine kombinierte Palladium- und Photoredox-katalysierte C-H-Olefinierung ermöglicht die Synthese von Indolen. Mithilfe von sichtbarem Licht gelingt die direkte C-H-Aktivierung von aromatischen Enaminen, wobei eine Vielzahl von Indolderivaten in guten Ausbeuten unter milden Reaktionsbedingungen zugänglich wird.

Catalytic fluorolactonisations of aromatic carboxylic acids have been developed. The reactions proceed under mild conditions using the commercially available reagent Selectfluor. A weak phase transfer of the reagent mediated by Na₂CO₃ allows the reaction to be conducted in non-polar solvents. Furthermore, by the use of a catalytic amount of (DHQ)₂PHAL (hydroquinine 1,4-phthalazinediyl diether), the first asymmetric fluorolactonisation has been achieved. The corresponding isobenzofuran core can be found in many biologically active molecules.

The enantioselective synthesis of α- and γ-tocopherol (the most biologically active members of vitamin E family) and analogues has been accomplished employing a new enantioselective gold catalyzed intramolecular allylic alkylation reaction followed by an olefin cross-metathesis as key steps. The methodology proved to be applicable to different olefins highlighting its potential for the synthesis of diverse libraries.

A new and safe method for the synthesis of N-(trifluoromethylthio)phthalimide, a convenient and shelf-stable reagent for the direct trifluoromethylthiolation, has been developed. N-(Trifluoromethylthio)phthalimide can be used as an electrophilic source of F₃CS⁺ and reacts readily with boronic acids and alkynes under copper catalysis. The utility of CF₃S-containing molecules as biologically active agents, the mild reaction conditions employed, and the high tolerance of functional groups demonstrate the potential of this new methodology to be widely applied in organic synthesis as well as industrial pharmaceutical and agrochemical research and development.

A protocol for the highly enantioselective synthesis of 9-substituted tetrahydroxanthenones by means of asymmetric Brønsted acid catalysis has been developed. A chiral binol-based N-triflyphosphoramide was found to promote the in situ generation of ortho-quinone methides and their subsequent reaction with 1,3-cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio- and diastereoselective Brønsted acid catalyzed desymmetrization of 5-monosubstituted 1,3-dicarbonyl substrates with ortho-quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.

A combined palladium- and photoredox-catalyzed CH olefination enables the synthesis of indoles. By using visible light, the direct CH activation of aromatic enamines can be achieved and a variety of indole derivatives can be obtained in good yields under mild reaction conditions.

Direct, oxidative metal-catalyzed CH functionalizations of arenes are important in synthetic organic chemistry. Often, (over-)stoichoimetric amounts of organic or inorganic oxidants have to be used in these reactions. The combination of rhodium and photoredox catalysis with visible light allows the direct CH olefination of arenes. Small amounts (1 mol %) of a photoredox catalyst resulted in the efficient CH functionalization of a broad range of substrates under mild conditions.

A protocol for the highly enantioselective synthesis of 9-substituted tetrahydroxanthenones by means of asymmetric Brønsted acid catalysis has been developed. A chiral binol-based N-triflyphosphoramide was found to promote the in situ generation of ortho-quinone methides and their subsequent reaction with 1,3-cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio- and diastereoselective Brønsted acid catalyzed desymmetrization of 5-monosubstituted 1,3-dicarbonyl substrates with ortho-quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.

Direkte oxidative metallkatalysierte C-H-Funktionalisierungen von Arenen haben sich in den letzten Jahren zu einem wichtigen Gebiet der organischen Synthesechemie entwickelt. Häufig werden in diesen Reaktionen (über)stöchiometrische Mengen an organischen oder anorganischen Oxidantien verwendet. Die Kombination von Rhodiumkatalyse und Photoredoxkatalyse mit sichtbarem Licht ermöglichte nun die direkte katalytische C-H-Olefinierung von Arenen. Geringe Mengen (1 Mol-%) des Photoredoxkatalysators und milde Reaktionsbedingungen erlauben eine effiziente C-H-Funktionalisierung mit guter Substratbreite.

The chemoselective trifluoromethylthiolation of nitrogen nucleophiles and thiols using N-(trifluoromethylthio)phthalimide under mild, metal-free conditions is described. A series of trifluoromethanesulfenamides and unsymmetrical disulfides is prepared from the corresponding aliphatic and aromatic amines and thiols in good yields. The reactions are operationally simple and tolerate a wide variety of functional groups. Trifluoromethanesulfenamides and disulfides belong to interesting classes of organic molecules which possess remarkable properties for medicinal and agrochemical applications.

A direct process for the trifluoromethylthiolation of allylic and benzylic alcohols under mild conditions has been developed. A wide range of free alcohols underwent nucleophilic substitution in the presence of stable CuSCF₃ and BF₃⋅Et₂O to give the corresponding products in good to excellent yields.

Der direkte Austausch aromatischer Methoxygruppen mit einem aktivierten Kohlenstoffatom würde neue Wege für gezielte und diversitätsorientierte Synthesen bahnen. Wir zeigen hier, dass solche Reaktionen in einem Schritt mit einem difunktionellen Nukleophil und einem C_Ar-OMe-bindungsspaltenden Katalysator ablaufen können. Die gebildeten Produkte sind stabil, α-CH-aktiv und für diverse weitere Modifikationen geeignet.

The direct replacement of aromatic methoxy groups with activated carbon nucleophiles would give rise to novel synthetic pathways for targeted and diversity-oriented syntheses. We demonstrate here that this transformation can be achieved in a one-step reaction involving a bifunctional organolithium nucleophile in combination with a C_ArOMe bond-cleaving nickel catalyst. The resulting products are stable, α-CH active, and suitable for various further modifications.

The proline-catalyzed addition of various aliphatic aldehydes to sterically hindered 2-aryl-substituted 3H-indol-3-ones affords 2,2-disubstituted 2,3-dihydro-1H-indol-3-one derivatives with excellent enantioselectivities. In addition, the synthesis of a chiral derivative, (S)-2-(2-bromophenyl)-2,3-dihydro-2-(2-hydroxyethyl)-1H-indol-3-one, which can be used as an intermediate for the preparation of the natural product hinckdentine A was accomplished with a high level of enantioselectivity.

A Brønsted acid-catalyzed asymmetric Nazarov cyclization of acyclic α-alkoxy dienones has been developed. The reaction offers access to chiral cyclopentenones in a highly enantioselective manner. The reaction is complementary to our previously reported Brønsted acid-catalyzed electrocyclization reactions, which provided differently substituted optically active cyclopentenones with a fused tetrahydropyrane ring in good yields and with excellent enantioselectivities.

A multicatalytic system consisting of tetrapropylammonium perruthenate/N-methylmorpholine N-oxide (TPAP/NMO) as oxidant, and diarylprolinol TMS-ether as chiral amine catalyst, has been developed and applied in the efficient construction of valuable chiral molecules. The one-pot domino reactions elaborated in the present study are based on the in situ generation of α,β-unsaturated aldehydes from allylic alcohols and their subsequent use in various asymmetric transformations (e.g., cyclopropanation, Michael addition, Michael addition/acetalization). TPAP as a substrate-selective redox catalyst is well tolerated by the amine catalyst and the domino reactions proceed in good yields and high enantioselectivities. The compatibility of metal and organocatalysis presented herein widens the scope of asymmetric iminium catalysis.

The diarylprolinol TMS ether catalyzed enantioselective addition–acetalization cascade reaction of 1,3-diketones with α,β-unsaturated aldehydes provides access to biologically active hydroxychromenone derivatives. These chromenones can be converted into the corresponding lactones, oxadecalinones, and benzopyranes in good yields without loss of enantiomeric excess. The usefulness of this newly developed methodology was demonstrated in the synthesis of the core structure of a Δ⁹-tetrahydrocannabinol analog.

An asymmetric organocatalyzed reaction sequence involving a Michael addition of various 1,3-dicarbonyl compounds to α,β-unsaturated aldehydes with subsequent diastereoselective Pictet–Spengler cyclization has been developed. The substrate scope was found to be general and optically active indoloquinolizidines were isolated as single diastereomers in high yields with high to excellent enantioselectivites. In addition to tryptamine, the reaction has also been successfully applied to other nucleophiles including o-aminobenzylamine and anthranilamide giving rise to pyridoquinauolines and quinazolinones.

A new enantioselective Brønsted acid-catalyzed Friedel–Crafts reaction of indole with cyclic imines has been develeoped. This organocatalytic reaction provides for the first time optically active indolindolinone derivatives in high yields and with excellent enantioselectivities (up to 91% ee) under mild reaction conditions.

Recently, chiral highly acidic Brønsted acids have emerged as powerful catalysts for enantioselective CC and CX bond-forming reactions. Their strong acidity renders them valuable tools for the activation of imines, carbonyl compounds, and other weakly basic substrates. As a result, new perspectives are opened and highly stereoselective transformations based on the concept of chiral contact-ion-pair catalysis can be realized. This Minireview gives an overview of the design and application of these new organocatalysts and presents recent results in this rapidly growing field.

Chirale, hoch acide Brønsted-Säuren haben sich als metallfreie Katalysatoren in der organischen Synthese etabliert und konnten mittlerweile in einer Vielzahl enantioselektiver C-C- und C-X-Bindungsknüpfungen eingesetzt werden. Die hohe Acidität dieser neuen Katalysatoren macht sie zu nützlichen Hilfsmitteln für die Aktivierung verschiedener Imine, Carbonyle und weiterer schwach basischer Substrate. Durch die Bildung chiraler Kontaktionenpaare ergeben sich völlig neue Aktivierungsmöglichkeiten für die asymmetrische Katalyse. Dieser Kurzaufsatz gibt einen Überblick über das rationale Design dieser neuen Organokatalysatoren und beschreibt verschiedenste, kürzlich erschienene Anwendungen.

A simple and efficient continuous-flow hydroarylation of arenes and heteroarenes using various styrenes in conjunction with a heterogeneous catalyst has been developed. Additionally, this method has been successfully extended to the hydroalkylation of styrenes by employing 1,3-dicarbonyl compounds as the nucleophile. Multigram quantities of diarylmethanes have been prepared using this new flow method.

The first catalytic enantioselective synthesis of benzodiazepinones employing an efficient hydrogenation protocol has been developed. The corresponding products are obtained in good yields, with excellent enantioselectivities and broad functional group tolerance. In addition, a one-pot procedure involving in situ generation of benzodiazepin-2-ones followed by asymmetric reduction is presented.

A new methodology for the immobilization of chiral Brønsted acids has been developed. The resulting heterogeneous organocatalysts have been employed in multiple consecutive catalysis cycles in the asymmetric organocatalytic transfer hydrogenation. The new catalyst system can not only be easily recovered from the reaction mixture in a tea-bag approach but it can also be easily reused in several catalytic cycles without loss of reactivity and selectivity.

Asymmetric catalysis is a key feature of modern synthetic organic chemistry. Traditionally, different combinations of ligands and metals are used to perform highly enantioselective reactions. Since the renaissance of organocatalysis in the early 2000s, tremendous improvement in the field of metal-free catalysis has been achieved. Recently, the combination of transition metals and organocatalysts has allowed the development of new protocols enabling transformations that could not previously be realized. This article aims to present the latest contributions in the field of combined chiral Brønsted acid and metal catalyzed reactions, highlighting the advantages of these catalytic systems as well as describing the uncertainties regarding the molecular structure of the catalytically active species and the reaction mechanisms.

Recently, 1,1′-bi-2-naphthol (BINOL)-based N-triflylphosphoramides emerged as a new class of potent Brønsted acid catalysts. In this paper we describe the efficient synthesis of various BINOL-based N-triflylphosphoramides and their calcium salts. Furthermore, X-ray crystal structure analysis combined with energy-dispersive X-ray spectroscopy (EDX) measurements confirmed that the synthesised chiral N-triflylphosphoramides are highly acidic metal-free catalysts.