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.

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.

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.

Post-Transition-State Dynamic Effects in the Transmetalation of Pd(II)-F to Pd(II)-CF3.

The observation of post-transition-state dynamic effects in the context of metal-based transformation is rare. To date, there has been no reported case of a dynamic effect for the widely employed class of palladium-mediated coupling reactions. We performed an experimental and computational study of the trifluoromethylation of Pd(II)F, which is a key step in the Pd(0)/Pd(II)-catalyzed trifluoromethylation of aryl halides or acid fluorides. Our experiments show that the cis/trans speciation of the formed Pd(II)CF3 is highly solvent- and transmetalation reagent-dependent. We employed GFN2-xTB- and B3LYP-D3-based molecular dynamics trajectory calculations (with and without explicit solvation) along with high-level QM calculations and found that depending on the medium, different transmetalation mechanisms appear to be operative. A statistically representative number of Born-Oppenheimer molecular dynamics (MD) simulations suggest that in benzene, a difluorocarbene is generated in the transmetalation with R3SiCF3, which subsequently recombines with the Pd via two distinct pathways, leading to either the cis- or trans-Pd(II)CF3. Conversely, GFN2-xTB simulations in MeCN suggest that in polar/coordinating solvents an ion-pair mechanism is dominant. A CF3 anion is initially liberated and then rebinds with the Pd(II) cation to give a cis- or trans-Pd(II). In both scenarios, a single transmetalation transition state gives rise to both cis- and trans-species directly, owing to bifurcation after the transition state. The potential subsequent cis- to trans isomerization of the Pd(II)CF3 was also studied and found to be strongly inhibited by free phosphine, which in turn was experimentally identified to be liberated through displacement by a polar/coordinating solvent from the cis-Pd(II)CF3 complex. The simulations also revealed how the variation of the Pd-coordination sphere results in divergent product selectivities.

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.

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.

Site-Selective Nitration of Aryl Germanes at Room Temperature.

We report a site-selective ipso-nitration of aryl germanes in the presence of boronic esters, silanes, halogens, and additional functionalities. The protocol is characterized by operational simplicity, proceeds at room temperature, and is enabled by [Ru(bpy)3](PF6)2/blue light photocatalysis. Owing to the exquisite robustness of the [Ge] functionality, nitrations of alternative functional handles in the presence of the germane are also feasible, as showcased herein.

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.

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.

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.

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.

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.

Direct C-H Dehydrogenative Germylation of Terminal Alkynes with Hydrogermanes.

A direct C(sp)-H germylation of terminal alkynes with triethyl germanium hydride is reported. The method is operationally simple and makes use of B(C6F5)3 catalysis in combination with 2,6-lutidine as an organic base. Exclusive selectivity for dehydrogenative germylation of the alkyne over the competing hydrogermylation is observed.

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.

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.

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.

Hydrogermylation of Alkenes via Organophotoredox-Initiated HAT Catalysis.

This Letter discloses the straightforward hydrogermylation of olefins under visible-light organophotoredox-initiated HAT catalysis conditions to yield primary and secondary alkyl germanes at room temperature. The protocol is operationally simple, metal-free, and tolerant of various functional groups. The synthesized alkyl germanes proved to be highly robust toward acidic, basic, or oxidizing conditions and chemical transformations of Csp2-GeEt3 or Csp2-BPin functionalities in their presence.

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.

Accelerated dinuclear palladium catalyst identification through unsupervised machine learning.

Although machine learning bears enormous potential to accelerate developments in homogeneous catalysis, the frequent need for extensive experimental data can be a bottleneck for implementation. Here, we report an unsupervised machine learning workflow that uses only five experimental data points. It makes use of generalized parameter databases that are complemented with problem-specific in silico data acquisition and clustering. We showcase the power of this strategy for the challenging problem of speciation of palladium (Pd) catalysts, for which a mechanistic rationale is currently lacking. From a total space of 348 ligands, the algorithm predicted, and we experimentally verified, a number of phosphine ligands (including previously never synthesized ones) that give dinuclear Pd(I) complexes over the more common Pd(0) and Pd(II) species.