Dynamic stereomutation of vinylcyclopropanes with metalloradicals.

The ever increasing demands for greater sustainability and lower energy usage in chemical processes call for fundamentally new approaches and reactivity principles. In this context, the pronounced prevalence of odd-oxidation states in less precious metals bears untapped potential for fundamentally distinct reactivity modes via metalloradical catalysis1-3. Contrary to the well-established reactivity paradigm that organic free radicals, upon addition to a vinylcyclopropane, lead to rapid ring opening under strain release-a transformation that serves widely as a mechanistic probe (radical clock)4 for the intermediacy of radicals5-we herein show that a metal-based radical, that is, a Ni(I) metalloradical, triggers reversible cis/trans isomerization instead of opening. The isomerization proceeds under chiral inversion and, depending on the substitution pattern, occurs at room temperature in less than 5 min, requiring solely the addition of the non-precious catalyst. Our combined computational and experimental mechanistic studies support metalloradical catalysis as origin of this profound reactivity, rationalize the observed stereoinversion and reveal key reactivity features of the process, including its reversibility. These insights enabled the iterative thermodynamic enrichment of enantiopure cis/trans mixtures towards a single diastereomer through multiple Ni(I) catalysis rounds and also extensions to divinylcyclopropanes, which constitute strategic motifs in natural product- and total syntheses6. While the trans-isomer usually requires heating at approximately 200 °C to trigger thermal isomerization under racemization to cis-divinylcyclopropane, which then undergoes facile Cope-type rearrangement, the analogous contra-thermodynamic process is herein shown to proceed under Ni(I) metalloradical catalysis under mild conditions without any loss of stereochemical integrity, enabling a mild and stereochemically pure access to seven-membered rings, fused ring systems and spirocycles.

Straightforward access to N-trifluoromethyl amides, carbamates, thiocarbamates and ureas.

Amides and related carbonyl derivatives are of central importance across the physical and life sciences1,2. As a key biological building block, the stability and conformation of amides affect the structures of peptides and proteins as well as their biological function. In addition, amide-bond formation is one of the most frequently used chemical transformations3,4. Given their ubiquity, a technology that is capable of modifying the fundamental properties of amides without compromising on stability may have considerable potential in pharmaceutical, agrochemical and materials science. In order to influence the physical properties of organic molecules-such as solubility, lipophilicity, conformation, pKa and (metabolic) stability-fluorination approaches have been widely adopted5-7. Similarly, site-specific modification with isosteres and peptidomimetics8, or in particular by N-methylation9, has been used to improve the stability, physical properties, bioactivities and cellular permeabilities of compounds. However, the N-trifluoromethyl carbonyl motif-which combines both N-methylation and fluorination approaches-has not yet been explored, owing to a lack of efficient methodology to synthesize it. Here we report a straightforward method to access N-trifluoromethyl analogues of amides and related carbonyl compounds. The strategy relies on the operationally simple preparation of bench-stable carbamoyl fluoride building blocks, which can be readily diversified to the corresponding N-CF3 amides, carbamates, thiocarbamates and ureas. This method tolerates rich functionality and stereochemistry, and we present numerous examples of highly functionalized compounds-including analogues of widely used drugs, antibiotics, hormones and polymer units.

Access to N-Difluoromethyl Amides, (Thio)Carbamates, Ureas, and Formamides.

The first efficient access to N-difluoromethyl amides, carbamates, thiocarbamates, ureas, formamides, and their derivatives is reported herein. The synthetic strategy relies on the initial synthesis and straightforward derivatization of N-CF2H carbamoyl fluorides, which were prepared through a desulfurization-fluorination of thioformamides (─NH─C(H)═S) coupled with carbonylation. The newly made N-CF2H carbonyl compounds proved to be highly robust and compatible with numerous chemical transformations and downstream derivatizations, underscoring the potential of this novel motif as a building block in complex functional molecules.

Recent Developments with Organogermanes: their Preparation and Application in Synthesis and Catalysis.

Within the sphere of traditional Pd0 /PdII cross coupling reactions, organogermanes have been historically outperformed both in terms of scope and reactivity by more conventional transmetalating reagents. Subsequently, this class of compounds has been largely underutilized as a coupling partner in bond-forming strategies. Most recent studies, however, have shown that alternative modes of activation of these notoriously robust building blocks transform organogermanes into the most reactive site of the molecule-capable of outcompeting other functional groups (such as boronic acids, esters and silanes) for both C-C and C-heteroatom bond formation. As a result, over the past few years, the literature has increasingly featured methodologies that explore the potential of organogermanes as chemoselective and orthogonal coupling partners. Herein we highlight some of these recent advances in the field of organogermane chemistry both with respect to their synthesis and applications in synthetic and catalytic transformations.

Triply Selective & Sequential Diversification at Csp 3: Expansion of Alkyl Germane Reactivity for C-C & C-Heteroatom Bond Formation.

We report the triply selective and sequential diversification of a single Csp 3 carbon carrying Cl, Bpin and GeEt3 for the modular and programmable construction of sp3-rich molecules. Various functionalizations of Csp 3-Cl and Csp 3-BPin (e.g. alkylation, arylation, homologation, amination, hydroxylation) were tolerated by the Csp 3-GeEt3 group. Moreover, the methodological repertoire of alkyl germane functionalization was significantly expanded beyond the hitherto known Giese addition and arylation to alkynylation, alkenylation, cyanation, halogenation, azidation, C-S bond formation as well as the first demonstration of stereo-selective functionalization of a Csp 3-[Ge] bond.

Orthogonal C-O Bond Construction with Organogermanes.

We report a fully orthogonal C-O bond formation strategy, which involves the selective coupling of arylgermanes with alkyl alcohols (primary, secondary and tertiary) as well as carboxylic acids, tolerating otherwise widely employed coupling handles, such as aromatic (pseudo)halogens (C-I, C-Br, C-Cl, C-F, C-OTf, C-OFs), silanes and boronic acid derivatives. This unprecedented [Ge]-based C-O bond construction is rapid (15 min to few hours reaction time), air-tolerant, operationally simple and mild, as it is base-free and proceeds at room temperature.

Machine Learning-Guided Development of Trialkylphosphine Ni(I) Dimers and Applications in Site-Selective Catalysis.

Owing to the unknown correlation of a metal's ligand and its resulting preferred speciation in terms of oxidation state, geometry, and nuclearity, a rational design of multinuclear catalysts remains challenging. With the goal to accelerate the identification of suitable ligands that form trialkylphosphine-derived dihalogen-bridged Ni(I) dimers, we herein employed an assumption-based machine learning approach. The workflow offers guidance in ligand space for a desired speciation without (or only minimal) prior experimental data points. We experimentally verified the predictions and synthesized numerous novel Ni(I) dimers as well as explored their potential in catalysis. We demonstrate C-I selective arylations of polyhalogenated arenes bearing competing C-Br and C-Cl sites in under 5 min at room temperature using 0.2 mol % of the newly developed dimer, [Ni(I)(µ-Br)PAd2(n-Bu)]2, which is so far unmet with alternative dinuclear or mononuclear Ni or Pd catalysts.

Base-Mediated Radio-Iodination of Arenes by Using Organosilane and Organogermane as Radiolabelling Precursors.

The radio-iodination of arenes is investigated from organosilane and organogermane precursors using ipso-electrophilic halogenation (IEH). Discovery of a mild base mediated process allows radio-iodination in HFIP (1,1,1,3,3,3-hexafluoro-2-propanol) of either aryl silane or germane, with germanes being more reactive. Clinical potential of arylgermanes as radio-iodination precursors is demonstrated through the labelling of [125 I]IMTO (iodometomidate) and [125 I]MIBG (meta-iodobenzylguanidine) thus offering an alternative to radio-iododestannylation processes using non-toxic precursors.

Rapid and Modular Access to Vinyl Cyclopropanes Enabled by Air-stable Palladium(I) Dimer Catalysis.

While vinyl cyclopropanes are valuable functional groups in drugs or natural products as well as established precursors to trigger a rich variety of synthetic transformations, their reactive nature can make their installation via direct catalytic approaches challenging. We herein present a modular access to (di)vinyl cyclopropanes under very mild conditions and full conservation of stereochemistry, allowing access to the cis or trans cyclopropane- as well as E or Z vinyl-stereochemical relationships. Our protocol relies on air-stable dinuclear PdI catalysis, which enables rapid (<30 min) and selective access to a diverse range of vinyl cyclopropane motifs at room temperature, even on gram scale.

Orthogonal Olefination with Organogermanes.

Reported herein is a fully orthogonal olefination, which involves the site- and E-selective coupling of aryl germanes with alkenes, tolerating otherwise widely employed coupling handles such as aromatic (pseudo)halogens (C-I, C-Br, C-Cl, C-F, C-OTf, C-OSO2 F), silanes and boronic acid derivatives as well as alternative functionalities. This unprecedented [Ge]-based oxidative Heck coupling proceeds at room temperature with high speed (10 min to 2 hours) and operational simplicity owing to its base-free and air-tolerant features.

Access to Cyclic N-Trifluoromethyl Ureas through Photocatalytic Activation of Carbamoyl Azides.

We report the mild activation of carbamoyl azides to the corresponding nitrenes using a blue light/[Ir]-catalyzed strategy, which enables stereospecific access to N-trifluoromethyl imidazolidinones and benzimidazolones. These novel structural motifs proved to be highly robust, allowing their downstream diversification. On the basis of our combined computational and experimental studies, we propose that an electron rebound with the excited metal catalyst is undergone, involving a reduction-triggered nitrogen loss, followed by oxidation to the corresponding carbamoyl nitrene and subsequent C-H insertion.

N-CF3 Imidazolidin-2-one Derivatives via Photocatalytic and Silver-Catalyzed Cyclizations.

While the N-trifluoromethylation of cyclic ureas is of interest for the potential to fundamentally change the properties of these biologically relevant moieties, the single synthetic procedure known to date describing their access only gives 4,4-disubstituted or fused aromatic cyclic N-CF3 urea derivatives. We herein report an alternative approach to unleash access to the 4-monosubstituted imidazolidinone motif. The strategy relies on straightforward cyclization of readily accessible acyclic ureas, enabled by Ag-catalysis or light-assisted proton coupled electron transfer. The cyclic core is shown to be highly robust and amenable to various derivatizations, such as tandem Ni-catalysis, C-B, C-N, C-C cross couplings or C-H functionalizations, tolerating basic, nucleophilic and/or oxidizing conditions.

Air-Stable PdI Dimer Enabled Remote Functionalization: Access to Fluorinated 1,1-Diaryl Alkanes with Unprecedented Speed.

While remote functionalization via chain walking has the potential to enable access to molecules via novel disconnections, such processes require relatively long reaction times and can be in need of elevated temperatures. This work features a remote arylation in less than 10 min reaction time at room temperature over a distance of up to 11 carbons. The unprecedented speed is enabled by the air-stable PdI dimer [Pd(µ-I)(PCy2 t Bu)]2 , which in contrast to its Pt Bu3 counterpart does not trigger direct coupling at the initiation site, but regioconvergent and chemoselective remote functionalization to yield valuable fluorinated 1,1-diaryl alkanes. Our combined experimental and computational studies rationalize the origins of switchability, which are primarily due to differences in dispersion interactions.

Access to N-CF3 Formamides by Reduction of N-CF3 Carbamoyl Fluorides.

The departure into unknown chemical space is essential for the discovery of new properties and function. We herein report the first synthetic access to N-trifluoromethylated formamides. The method involves the reduction of bench-stable NCF3 carbamoyl fluorides and is characterized by operational simplicity and mildness, tolerating a broad range of functional groups as well as stereocenters. The newly made N-CF3 formamide motif proved to be highly robust and compatible with diverse chemical transformations, underscoring its potential as building block in complex functional molecules.

Modular Generation of (Iodinated) Polyarenes Using Triethylgermane as Orthogonal Masking Group.

While the modular construction of molecules from suitable building blocks is a powerful means to more rapidly generate a diversity of molecules than through customized syntheses, the further evolution of the underlying coupling methodology is key to realize widespread applications. We herein disclose a complementary modular coupling approach to the widely employed Suzuki coupling strategy of boron containing precursors, which relies on organogermane containing building blocks as key orthogonal functionality and an electrophilic (rather than nucleophilic) unmasking event paired with air-stable PdI dimer based bond construction. This allows to significantly shorten the reaction times for the iterative coupling steps and/or to close gaps in the accessible compound space, enabling straightforward access also to iodinated compounds.

Site-Selective α-C-H Functionalization of Trialkylamines via Reversible Hydrogen Atom Transfer Catalysis.

Trialkylamines are widely found in naturally occurring alkaloids, synthetic agrochemicals, biological probes, and especially pharmaceuticals agents and preclinical candidates. Despite the recent breakthrough of catalytic alkylation of dialkylamines, the selective α-C(sp3)-H bond functionalization of widely available trialkylamine scaffolds holds promise to streamline complex trialkylamine synthesis, accelerate drug discovery, and execute late-stage pharmaceutical modification with complementary reactivity. However, the canonical methods always result in functionalization at the less-crowded site. Herein, we describe a solution to switch the reaction site through fundamentally overcoming the steric control that dominates such processes. By rapidly establishing an equilibrium between α-amino C(sp3)-H bonds and a highly electrophilic thiol radical via reversible hydrogen atom transfer, we leverage a slower radical-trapping step with electron-deficient olefins to selectively forge a C(sp3)-C(sp3) bond with the more-crowded α-amino radical, with the overall selectivity guided by the Curtin-Hammett principle. This subtle reaction profile has unlocked a new strategic concept in direct C-H functionalization arena for forging C-C bonds from a diverse set of trialkylamines with high levels of site selectivity and preparative utility. Simple correlation of site selectivity and 13C NMR shift serves as a qualitative predictive guide. The broad consequences of this dynamic system, together with the ability to forge N-substituted quaternary carbon centers and implement late-stage functionalization techniques, hold potential to streamline complex trialkylamine synthesis and accelerate small-molecule drug discovery.

Synthesis of N-CF3 Alkynamides and Derivatives Enabled by Ni-Catalyzed Alkynylation of N-CF3 Carbamoyl Fluorides.

The expansion of chemical space associated with ubiquitous motifs is key to unleash new properties and functions. In this context, alkynamides, prevalent in numerous drugs and materials, represent an untapped resource. We herein report the first synthetic access to N-trifluoromethyl alkynamides. Our strategy relies on a mild and operationally simple Ni-catalyzed coupling of N-CF3 carbamoyl fluorides with alkynyl silanes. The synthesized N-CF3 alkynamides proved to be highly robust and readily functioned as a platform to unlock access to valuable derivatives, such as N-CF3 decorated alkenyl amides, oxindoles, or quinolones, all of which were inaccessible to date.

Selective Synthesis of Z-Silyl Enol Ethers via Ni-Catalyzed Remote Functionalization of Ketones.

We report a remote functionalization strategy, which allows the Z-selective synthesis of silyl enol ethers of (hetero)aromatic and aliphatic ketones via Ni-catalyzed chain walking from a distant olefin site. The positional selectivity is controlled by the directionality of the chain walk and is independent of thermodynamic preferences of the resulting silyl enol ether. Our mechanistic data indicate that a Ni(I) dimer is formed under these conditions, which serves as a catalyst resting state and, upon reaction with an alkyl bromide, is converted to [Ni(II)-H] as an active chain-walking/functionalization catalyst, ultimately generating a stabilized η3-bound Ni(II) enolate as the key selectivity-controlling intermediate.

Organogermanes as Orthogonal Coupling Partners in Synthesis and Catalysis.

Since the advent of metal-catalyzed cross-coupling technology more than 40 years ago, the field has grown to be ever-increasingly enabling, yet the employed coupling partners are largely still those that were originally employed in the context of Pd-catalyzed cross-coupling, namely, arylboronic esters/acids, aryl silanes, aryl stannanes, or organometallic reagents (RMgX, RZnX). Aryl germanes have little precedent in the literature; they were historically explored in the context of Pd0/PdII-catalyzed cross-coupling reactions but were found to be much less reactive than the already established reagents. Consequently, few efforts were made by the community on their further mechanistic or synthetic exploration.In 2019, our group described trialkyl aryl germanes as robust, convenient, and nontoxic reagents. Although structurally similar to trialkyl aryl stannanes or silanes, the GeEt3 site does not engage in the traditional transmetalation mode of PdII complexes. Our studies instead provided strong support for an unprecedented and orthogonal reactivity of organogermanes that follows electrophilic aromatic substitution (SEAr)-type reactivity. This mode of bond activation allowed us to devise a number of synthetic strategies in which the Ge functionality was for the first time more reactive and exclusively functionalized in preference over several of the established coupling partners (e.g., silanes, boronic acids/esters, halogens).Within the past year we have showcased the unique reactivity of organogermanes in C-C and C-X bond-forming transformations. Because of the exquisite mode of bond activation, the new strategies offer access to complementary chemical transformations, tolerating other cross-coupling enabling functionalities, and allow for their further downstream diversification. We have for instance demonstrated that organogermanes can be coupled efficiently with aryl halides under Pd nanoparticle conditions with tolerance of all other established cross-coupling partners, while under homogeneous Pd0/PdII catalysis all of the other established groups can be functionalized preferentially over the Ge functionality. We similarly were able to harness this orthogonal reactivity mode in oxidative gold catalysis, where organogermanes proved to be more reactive than the established silanes or boronic esters. We have also developed an orthogonal approach for metal-free halogenation of organogermanes with convenient halogenation agents, offering access to the chemo- and regioselective installation of valuable halide motifs in the presence of alternative groups that can also engage in electrophilic halogenations.In this Account, we wish to provide an overview of (i) the historic versus current reactivity findings and synthetic utility of organogermanes, (ii) the current state of mechanistic understanding of their reactivity, and (iii) the synthetic repertoire and ease of installing the germanium functionality in organic molecules.

Catalysis with Palladium(I) Dimers.

Dinuclear PdI complexes have found widespread applications as diverse catalysts for a multitude of transformations. Initially their ability to function as pre-catalysts for low-coordinated Pd0 species was harnessed in cross-coupling. Such PdI dimers are inherently labile and relatively sensitive to oxygen. In recent years, more stable dinuclear PdI -PdI frameworks, which feature bench-stability and robustness towards nucleophiles as well as recoverability in reactions, were explored and shown to trigger privileged reactivities via dinuclear catalysis. This includes the predictable and substrate-independent, selective C-C and C-heteroatom bond formations of poly(pseudo)halogenated arenes as well as couplings of arenes with relatively weak nucleophiles, which would not engage in Pd0 /PdII catalysis. This Minireview highlights the use of dinuclear PdI  complexes as both pre-catalysts for the formation of highly active Pd0 and PdII -H species as well as direct dinuclear catalysts. Focus is set on the mechanistic intricacies, the speciation and the impacts on reactivity.