Isothioureas have become a cornerstone of modern Lewis base organocatalysis being involved in a plethora of applications ranging from large scale syntheses to enantioselective reactions to immobilised catalysts. To date, most catalyst structure–activity studies have considered variation of the stereodirecting functionality or chalcogen atom within the catalyst framework. Systematic exploration of substituent electronic effects has been broadly neglected. Herein, the effect of incorporating a range of electron‐donating and electron‐withdrawing substituents at the 7‐, 8‐, and 9‐positions of the benzannulated part of the HyperBTM scaffold, as well as extended π‐systems, is explored. The rate of acylation of a model achiral tertiary alcohol is used to benchmark catalyst reactivity, while catalyst selectivity is evaluated by comparing the effectiveness of secondary and tertiary alcohol acylative kinetic resolutions. The reaction of the developed catalysts with benzhydrylium ions was used to determine their nucleophilicity and Lewis basicity. Comparison of the catalysts indicated that highest reactivity and selectivity was generally observed with the incorporation of electron‐donating substituents at the aromatic part of the HyperBTM skeleton, which also correlated with higher nucleophilicity and Lewis basicity.

The electrophilic reactivities of para-quinone methides (pQMs) with functional groups (FG) at the exocyclic polarized carbon-carbon double bond were determined by photometrically monitoring the kinetics of their reactions with carbanions in dimethyl sulfoxide (DMSO) at 20 °C. The experimental second-order rate constants k2 were evaluated by the Mayr-Patz equation, that is, the linear free energy relationship lg k2 = sN(N + E), which was leveraged to determine the electrophilicity descriptors E of the pQMs. These electrophilicity parameters E were subsequently used to successfully predict the scope of the pQM reactions with C-, H-, N-, O-, and S-centered nucleophiles. Moreover, the electrophilicity parameters E correlate linearly with a linear combination of quantum-chemically calculated methyl anion affinities (MAAs) and buried volumes (%Vbur). While MAA values mainly reflect the thermodynamic driving force of the carbon-carbon bond formation, %Vbur values take account of the variable steric effects of substituents at the electrophilic δ-position of the pQMs. Knowledge of MAA and %Vbur thus enables chemists to tailor novel pQMs with predictable reactivity properties.

Isochalcogenoureas (IChU) embedded in bi- or tricyclic ring systems have proven to be versatile Lewis base/nucleophilic catalysts that activate a wide range of electrophilic substrates for organocatalytic transformations. Ring size, variation of substituents, and the choice of the chalcogen atom affect the efficiency of IChU catalysis in a complex way. To gain a systematic insight into the key parameters that influence reactivity, 14 IChUs covering the fundamental motifs of these structural variations were selected and analyzed by a combination of kinetic, thermodynamic, and quantum-chemical methods. Two previously unknown tricyclic isotellurourea catalysts were synthesized to facilitate a comparison of all naturally abundant chalcogens (O, S, Se, and Te) in the IChU structure. Furthermore, their reactivity on the Mayr nucleophilicity scale as well as their Brønsted and Lewis basicities were determined in polar organic solvents under standardized conditions. Catalyst performance was assessed in two alcohol acylation reactions and in allenoate activation. The low electronegativity of tellurium gave rise to superior nucleophilicity and Lewis basicity of the isotelluroureas when compared to O-, S-, or Se-containing IChUs. Embedding tellurium in IChU structures thus provides a novel handle to influence and fine-tune the effectiveness of IChU organocatalysis.

Mesoionic polarization allows access to electron-rich olefins that have found application as organocatalysts, ligands, or nucleophiles. Herein, we report the synthesis and characterization of a series of 3-methylpyridinium-derived mesoionic olefins (py-mNHOs). We used a DFT-supported design concept, which showed that the introduction of aryl groups in the 1-, 2-, 4-, and 6-positions of the heterocyclic core allowed the kinetic stabilization of the novel mesoionic compounds. Tolman electronic parameters indicate that py-mNHOs are remarkably strong σ-donor ligands toward transition metals and main group Lewis acids. Additionally, they are among the strongest nucleophiles on the Mayr reactivity scale. In reactions of py-mNHOs with electron-poor π-systems, a gradual transition from the formation of zwitterionic adducts via stepwise to concerted 1,3-dipolar cycloadditions was observed experimentally and analyzed by quantum-chemical calculations.

Imidazolidine-4-thiones (ITOs) are cyclic, secondary amines that were considered as potential prebiotic organocatalysts for light-driven alpha-alkylations of aldehydes by bromoacetonitrile (BAN). Recent studies showed that the initially supplied ITOs represent the pre-catalyst because they undergo S-alkylation with BAN to give 4-(alkylthio)-3-imidazolines (TIMs). Given that the same reagent mix that undergoes light-driven alpha-alkylations is also effective in the dark, we synthesized ten ITO- or TIM-derived enamines of aldehydes and characterized their nucleophilic reactivities by kinetic studies in acetonitrile. The experimental second-order rate constants k2 for reactions of enamines with benzhydrylium ions (reference electrophiles) were evaluated by the Mayr-Patz equation, lg k2(20 degrees C)=sN(N+E). The determined nucleophilicities N (and sN) reveal the reactivity profiles of these enamines under prebiotically relevant conditions as well as their potential for use in organocatalytic synthesis. Enamine activation is a key method to enhance the reactivity of carbonyl compounds in alpha-alkylation reactions. In spite of their possible role in prebiotic chemistry, enamines derived from aldehydes and 4-(alkylthio)-3-imidazolines (TIMs) have scarcely been studied. Their reactivities have now been classified on the Mayr nucleophilicity scale by kinetic measurements. In addition, their Lewis basicities have been determined by DFT calculations and equilibrium measurements.image

The incorporation of the CF2 motif within organic structures is known to affect the susceptibility of functional groups to oxidation, as well as altering conformation and reactivity. In this manuscript, the incorporation of the CF2 functional group within an isothiourea catalyst skeleton to give C(3)-F2-HBTM is reported. Effective gram-scale routes to both racemic and enantiopure heterocyclic Lewis bases are developed, with preliminary catalytic and kinetic activity evaluated.

A series of aryl-substituted ortho-quinone methides (oQMs) was synthesised and structurally characterised. Kinetic studies of the nucleophilic additions of carbanions (reference nucleophiles) to oQMs were used to determine second-order rate constants k2 for the carbon-carbon bond forming reactions (20 °C, DMSO) at the oQMs' exocyclic π-bond. Analysing the kinetic data by the linear free energy relationship lg k2=sN(N+E) revealed the Mayr electrophilicities E of the oQMs. The electrophilicities E of oQMs correlate linearly with Hammett substituent constants and experimentally determined reduction potentials Ep red as well as with quantum-chemically calculated methyl anion affinities (MAAs), which provides valuable tools for prediciting the reactivity of further types of oQMs. Embedding the oQMs in Mayr's reactivity scales enables to predict novel nucleophilic reaction partners for oQMs and can productively be used to prepare simple Michael adducts as well as 4+2 or 4+1 cyclisation products as demonstrated in this work by several novel reactions with neutral or negatively charged C-, N-, and S-nucleophiles.

The high reactivity of 2‐methylene‐1,2‐dihydropyridines also known as 2‐methylpyridinium derived N‐heterocyclic olefins (2‐pyNHOs) has been recognized in organic synthesis, yet a quantification of their nucleophilicity is lacking. Herein we used stopped‐flow photometry to determine the nucleophilicity of a series of 2‐pyNHOs from the kinetics of their reactions with quinone methides and benzhydrylium ions as reference electrophiles in four organic solvents at 20 °C. The kinetic data was evaluated by using the Mayr‐Patz equation, lg k(20 °C) = sN(N + E), which gave nucleophilicity parameters N (and sN). With N in the range of 19.4 to 21.2 (in DMSO), 2‐pyNHOs exceed the reactivity of classical enamines, such as pyrrolidino‐cyclopent‐1‐ene. The addition of 2‐pyNHOs to quinone methides resulted in the formation of zwitterionic adducts with pyridinium and phenolate moieties. Subsequent tautomerization yielded entirely neutral pyridine‐2(1H)‐ylidene‐phenol species in several cases. Formation of the zwitterionic adducts from 2‐pyNHOs and neutral electrophiles was almost equally fast in the polar solvents acetonitrile and DMSO, but proceeded one to two orders of magnitude slower in the less polar solvents dichloromethane or THF.

AbstractMesoionische Polarisation ermöglicht den Zugang zu elektronenreichen Olefinen, die als Organokatalysatoren, Liganden oder Nucleophile Anwendung finden. Wir berichten hier über die Synthese und Charakterisierung einer Reihe von 3‐Methylpyridinium‐abgeleiteten mesoionischen Olefinen (py‐mNHOs). Wir verwendeten ein mit DFT‐Rechnungen unterstütztes Designkonzept, das zeigte, dass Arylgruppen an den 1‐, 2‐, 4‐ und 6‐Positionen des heterocyclischen Kerns die kinetische Stabilisierung der neuartigen mesoionischen Verbindungen ermöglicht. Die elektronischen Tolman‐Parameter zeigen, dass py‐mNHOs bemerkenswert starke σ‐Donor‐Liganden für Übergangsmetalle und Hauptgruppen‐Lewis‐Säuren sind. Außerdem gehören sie zu den stärksten Nucleophilen auf der Mayr‐Reaktivitätsskala. Bei Reaktionen von py‐mNHOs mit elektronenarmen π‐Systemen wurde experimentell ein sukzessiver Übergang von der Bildung zwitterionischer Addukte über schrittweise zu konzertierten 1,3‐dipolaren Cycloadditionen beobachtet und durch quantenchemische Rechnungen analysiert.

AbstractMesoionische, 1,2,3‐Triazol‐abgeleitete N‐heterocyclische Olefine (mNHOs) mit außerordentlich elektronenreicher, exocyclischer CC–Doppelbindung wurden synthetisiert und spektroskopisch charakterisiert, z. T. durch Röntgenstrukturanalyse. Die Kinetik der mNHO‐Reaktionen mit Arylidenmalonaten (ArCH=C(CO2Et)2) zu zwitterionischen Addukten wurde photometrisch in THF bei 20 °C verfolgt. Die resultierenden Geschwindigkeitskonstanten 2. Ordnung k2(20 °C) korrelieren linear mit zuvor bestimmten Elektrophilieparametern E der Arylidenmalonate (Referenzelektrophile) und liefern gemäß der Beziehung lg k2(20 °C)=sN(N+E) die nucleophilspezifischen N‐ und sN‐Parameter der mNHOs. Die mNHOs sind mit 21<N<32 viel stärkere Nucleophile als herkömmliche NHOs. Einige mNHOs übertreffen sogar die Reaktivität von mono‐ und diakzeptor‐substituierten Carbanionen. Es wird an Beispielen gezeigt, dass es die so bestimmten Reaktivitätsparameter ermöglichen, die Geschwindigkeitskonstanten für mNHO‐Reaktionen mit weiteren Michael‐Akzeptoren zu berechnen. Auch die Reaktionen mit anderen elektrophilen Reaktionspartnern, inklusive Kohlenstoffdioxid, das zwitterionische mNHO‐Carboxylate bildet, lassen sich vorhersagen. Die Nucleophilie‐Parameter N korrelieren linear mit einer Linearkombination der quantenchemisch berechneten Methylkation‐Affinitäten und %Vbur („buried volumes“) der mNHOs, was ein wertvolles Werkzeug liefert, um Reaktivitäten starker Kohlenstoff‐Nucleophile maßzuschneidern.

A series of mesoionic, 1,2,3-triazole-derived N-heterocyclic olefins (mNHOs), which have an extraordinarily electron-rich exocyclic CC-double bond, was synthesized and spectroscopically characterized, in selected cases by X-ray crystallography. The kinetics of their reactions with arylidene malonates, ArCH=C(CO2 Et)2 , which gave zwitterionic adducts, were investigated photometrically in THF at 20 °C. The resulting second-order rate constants k2 (20 °C) correlate linearly with the reported electrophilicity parameters E of the arylidene malonates (reference electrophiles), thus providing the nucleophile-specific N and sN parameters of the mNHOs according to the correlation lg k2 (20 °C)=sN (N+E). With 21<N<32, the mNHOs are much stronger nucleophiles than conventional NHOs. Some mNHOs even excel the reactivity of mono- and diacceptor-substituted carbanions. It is exemplarily shown that the reactivity parameters thus obtained allow to calculate the rate constants for mNHO reactions with further Michael acceptors and predict the scope of reactions with other electrophilic reaction partners including carbon dioxide, which gives zwitterionic mNHO-carboxylates. The nucleophilicity parameters N correlate linearly with a linear combination of the quantum-chemically calculated methyl cation affinities and buried volumes of mNHOs, which offers a valuable tool to tailor the reactivities of strong carbon nucleophiles.

Cyclopropanes that carry an electron-accepting group react as electrophiles in polar, ring-opening reactions. Analogous reactions at cyclopropanes with additional C2 substituents allow one to access difunctionalized products. Consequently, functionalized cyclopropanes are frequently used building blocks in organic synthesis. The polarization of the C1-C2 bond in 1-acceptor-2-donor-substituted cyclopropanes not only favorably enhances reactivity toward nucleophiles but also directs the nucleophilic attack toward the already substituted C2 position. Monitoring the kinetics of non-catalytic ring-opening reactions with a series of thiophenolates and other strong nucleophiles, such as azide ions, in DMSO provided the inherent S(N)2 reactivity of electrophilic cyclopropanes. The experimentally determined second-order rate constants k (2) for cyclopropane ring-opening reactions were then compared to those of related Michael additions. Interestingly, cyclopropanes with aryl substituents at the C2 position reacted faster than their unsubstituted analogues. Variation of the electronic properties of the aryl groups at C2 gave rise to parabolic Hammett relationships.

1,4-Conjugate addition of ((chloromethyl)sulfonyl)benzenes to arylideneisoxazol-5-ones, followed by one-pot, N-selective trapping in the presence of electrophiles, was investigated. This strategy led to the synthesis of new, stable N-protected isoxazol-5-ones in good yields and high diastereolectivity. The study of the reactivity of obtained products in the presence of the Mo(CO)6/H2O system allowed the development of a cascade reaction leading to novel methyl ketones in high yields and unchanged dr bearing an uncommon chloromethinearylsulfonyl end group.

The enantioselective synthesis of a broad variety of novel differently functionalized α-halogenated α-aryl-β2,2-amino acid derivatives by means of an ammonium-salt-catalyzed asymmetric α-halogenation of isoxazolidin-5-ones was accomplished. Key to success to obtain high levels of enantioselectivities was the use of Maruoka's spirocyclic binaphthyl-based ammonium salts, and detailed accompanying mechanistic studies using density functional theory methods revealed the key features for the catalyst-substrate interactions.

We herein report the ammonium salt-catalyzed synthesis of chiral 3,3-disubstituted isoindolinones bearing a heteroatom functionality in the 3-position. A broad variety of differently substituted CF3S- and RS-derivatives were obtained with often high enantioselectivities when using Maruoka's bifunctional chiral ammonium salt catalyst. In addition, a first proof-of-concept for the racemic synthesis of the analogous F-containing products was obtained as well, giving access to one of the rare examples of a fairly stable α-F-α-amino acid derivative.

A new family of CF3‐containing para‐quinone methides (CF3‐QMs) was systematically investigated for its suitability in organic synthesis. Addition of different nucleophiles gives access to target molecules with a benzylic CF3‐containing stereogenic center straightforwardly. The electrophilicity parameter E of the prototypical CF3‐QM 2,6‐di‐tert‐butyl‐4‐(2,2,2‐trifluoroethylidene)cyclohexa‐2,5‐dien‐1‐one was determined to be –11.68 according to the Mayr scale, making it one of the most reactive quinone methides known so far.

We herein report a novel entry towards chiral α-SCF3-β2,2-amino acids by carrying out the ammonium salt-catalyzed α-trifluoromethylthiolation of isoxazolidin-5-ones. This approach allowed for high enantioselectivities and high yields and the obtained heterocycles proved to be versatile platforms to access other targets of potential interest.

The highly enantioselective (>99.5% ee) synthesis of a new class of densely functionalized β2,2-amino acid derivatives by reacting isoxazolidin-5-ones with para-quinone methides in the presence of chiral ammonium salt phase-transfer catalysts was developed. The reaction proceeds with exceptionally low catalyst loadings down to 20 ppm on gram scale and the utilization of the primary addition products towards further manipulations was demonstrated for selected examples.

The electrophilic reactivity of a series of 8-arylated vinyl p-quinone methides (pVQMs) was determined by analyzing the kinetics of their reactions with carbanions in DMSO at 20 °C according to the linear free energy relationship log k = sN(N + E). The electrophilicity parameters E for pVQMs were used to successfully predict Michael-additions with structurally diverse C-, N-, S-, and H-nucleophiles.

Isoxazol-5-ones and isoxazolidin-5-ones represent two important classes of heterocycles, with several applications as bioactive compounds and as versatile building blocks for further transformations. Unlike the parent aromatic isoxazoles, the presence of one or two stereocenters in the ring renders their asymmetric construction particularly important. In this review, starting from the description of general features and differences between these two related compound families, we present an overview on the most important enantioselective synthesis strategies to access these heterocycles. Both chiral metal catalysts and organocatalysts have recently been successfully employed for this task and some of the most promising approaches will be discussed.