Site-selective Photoredox-Catalyzed Late-stage Benzylic Hydrogen Isotope Exchange.

A highly regioselective visible light photoredox-catalyzed hydrogen isotope exchange (HIE) of benzylic positions in both simple and complex molecules is reported. The process follows a dual catalytic approach using an acridinium photocatalyst in combination with a thiol-based hydrogen atom transfer catalyst, while the use of D2O as an isotope source ensures operational simplicity and cost-effectiveness. High reactivity has been achieved for electron-rich benzylic positions. Moreover, targeted radical formation enables unprecedented selective HIE on intramolecular competing benzylic and alpha to heteroatom positions with moderate to excellent deuterium incorporation. The utility of the reaction was demonstrated on the late-stage HIE of several natural compounds and drug derivatives. Experimental studies and density functional theory (DFT) calculations suggested a single electron transfer (SET) mechanism followed by deprotonation to generate the benzylic radical, and revealed the importance of halogenated solvents or additives. Upon a weak complexation of the halogenated species to the substrate, an oxidation potential lowering effect is induced, as well as a stabilization of the radical-cation species through spin delocalization.

Formal [2σ + 2σ]-Cycloaddition of Aziridines with Bicyclo[1.1.0]butanes: Access to Enantiopure 2-Azabicyclo[3.1.1]heptane Derivatives.

Saturated nitrogen heterocycles are among the most significant structural components in small-molecule pharmaceuticals. Herein, a protocol for the construction of enantiopure 2-azabicyclo[3.1.1]heptane derivatives by a stereospecific intermolecular formal cycloaddition of aziridines with bicyclo[1.1.0]butanes is described. The reaction is run by using B(C6F5)3 as a catalytic additive to give access to a library of enantiopure 2-azabicyclo[3.1.1]heptane derivatives (37 examples) under mild and operationally simple conditions. Successful scale-up reactions, mechanistic experiments, density functional theory (DFT) calculations and synthetic applications are presented.

Photocatalytic PPh3-Mediated Synthesis of C3-Functionalized Indoles via Radical Annulation of Nitroarenes and Alkenes.

Oxidatively generated phosphine radical cations are reactive intermediates that can be used for the generation of carbon and heteroatom centered radicals via deoxygenation processes. Such P-radical cations can readily be generated via single electron transfer oxidation using a redox catalyst. Cheap and commercially available nitroarenes are ideal nitrogen sources for the construction of organic amines and N-containing heterocycles. Activation of nitroarenes with phosphines has been achieved in the ionic mode, which requires specially designed P-nucleophiles and high temperatures. Herein, we report an alternative mode of nitro activation that proceeds via a radical process. The radical strategy leads to open shell intermediates that show interesting unexplored reactivity. This is documented by the development of an economic and highly efficient synthesis of valuable indole derivatives through photocatalytic PPh3-mediated annulation of nitroarenes with alkenes showing large functional group tolerance. The method allows room-temperature activation of nitroarenes and a double C-H bond functionalization of alkenes is achieved to provide rapid access to C3-functionalized indoles, which are key structural components of diverse natural and drug molecules. Experimental mechanistic studies that are further supported by DFT calculations indicate that a nitrosoarene radical cation plays a key role in the annulation process.

Skeletal editing of pyridines through atom-pair swap from CN to CC.

Skeletal editing is a straightforward synthetic strategy for precise substitution or rearrangement of atoms in core ring structures of complex molecules; it enables quick diversification of compounds that is not possible by applying peripheral editing strategies. Previously reported skeletal editing of common arenes mainly relies on carbene- or nitrene-type insertion reactions or rearrangements. Although powerful, efficient and applicable to late-stage heteroarene core structure modification, these strategies cannot be used for skeletal editing of pyridines. Here we report the direct skeletal editing of pyridines through atom-pair swap from CN to CC to generate benzenes and naphthalenes in a modular fashion. Specifically, we use sequential dearomatization, cycloaddition and rearomatizing retrocycloaddition reactions in a one-pot sequence to transform the parent pyridines into benzenes and naphthalenes bearing diversified substituents at specific sites, as defined by the cycloaddition reaction components. Applications to late-stage skeletal diversification of pyridine cores in several drugs are demonstrated.

Polar covalent apex-base bonding in borapyramidanes probed by solid-state NMR and DFT calculations.

Pyramidane molecules have attracted chemists for many decades due to their regular shape, high symmetry and their correspondence in the macroscopic world. Recently, experimental access to a number of examples has been reported, in particular the rarely reported square pyramidal bora[4]pyramidanes. To describe the bonding situation of the nonclassical structure of pyramidanes, we present solid-state Nuclear Magnetic Resonance (NMR) as a versatile tool for deciphering such bonding properties for three now accessible bora[4]pyramidane and dibora[5]pyramidane molecules. 11 B solid-state NMR spectra indicate that the apical boron nuclei in these compounds are strongly shielded (around -50 ppm vs. BF3 -Et2 O complex) and possess quadrupolar coupling constants of less than 0.9 MHz pointing to a rather high local symmetry. 13 C-11 B spin-spin coupling constants have been explored as a measure of the bond covalency in the borapyramidanes. While the carbon-boron bond to the -B(C6 F5 )2 substituents of the base serves as an example for a classical covalent 2-center-2-electron (2c-2e) sp2 -carbon-sp2 -boron σ-bond with 1 J(13 C-11 B) coupling constants in the order of 75 Hz, those of the boron(apical)-carbon(basal) bonds in the pyramid are too small to measure. These results suggest that these bonds have a strongly ionic character, which is also supported by quantum-chemical calculations.

Regioselective, catalytic 1,1-difluorination of enynes.

Fluorinated small molecules are prevalent across the functional small-molecule spectrum, but the scarcity of naturally occurring sources creates an opportunity for creative endeavour in developing routes to access these important materials. Iodine(I)/iodine(III) catalysis has proven to be particularly well-suited to this task, enabling abundant alkene substrates to be readily intercepted by in situ-generated λ3-iodanes and processed to high-value (di)fluorinated products. These organocatalysis paradigms often emulate metal-based processes by engaging the π bond and, in the case of styrenes, facilitating fluorinative phenonium-ion rearrangements to generate difluoromethylene units. Here we demonstrate that enynes are competent proxies for styrenes, thereby mitigating the recurrent need for aryl substituents, and enabling highly versatile homopropargylic difluorides to be generated in an operationally simple manner. The scope of the method is disclosed, together with application in target synthesis (>30 examples, up to >90% yield).

Molecular pyramids - from tetrahedranes to [6]pyramidanes.

The study of 3D architectures at a molecular scale has fascinated chemists for generations. This includes molecular pyramids with all-carbon frameworks, such as trigonal, tetragonal and pentagonal pyramidal geometries. A small number of substituted tetrahedranes and all-carbon [4]-[5]pyramidanes have been experimentally generated and studied. Although the hypothetical unsubstituted parent [3]-[6]pyramidanes have only been explored computationally, the formal replacement of carbon vertices with isolobal main group element fragments has provided a number of examples of stable hetero[m]pyramidanes, which have been isolated and amply characterized. In this Review, we highlight the synthesis and chemical properties of [3]-[6]pyramidanes and summarize the progress in the development of chemistry of pyramid-shaped molecules.

Light-enabled deracemization of cyclopropanes by Al-salen photocatalysis.

Privileged chiral catalysts-those that share common structural features and are enantioselective across a range of reactions-continue to transform the chemical-research landscape1. In recent years, new reactivity modes have been achieved through excited-state catalysis, processes activated by light, but it is unclear if the selectivity of ground-state privileged catalysts can be matched. Although the interception of photogenerated intermediates by ground-state cycles has partially addressed this challenge2, single, chiral photocatalysts that simultaneously regulate reactivity and selectivity are conspicuously scarce3. So far, precision donor-acceptor recognition motifs remain crucial in enantioselective photocatalyst design4. Here we show that chiral Al-salen complexes, which have well-defined photophysical properties, can be used for the efficient photochemical deracemization5 of cyclopropyl ketones (up to 98:2 enantiomeric ratio (e.r.)). Irradiation at λ = 400 nm (violet light) augments the reactivity of the commercial catalyst to enable reactivity and enantioselectivity to be regulated simultaneously. This circumvents the need for tailored catalyst-substrate recognition motifs. It is predicted that this study will stimulate a re-evaluation of many venerable (ground-state) chiral catalysts in excited-state processes, ultimately leading to the identification of candidates that may be considered 'privileged' in both reactivity models.

Photocatalytic phosphine-mediated water activation for radical hydrogenation.

The chemical activation of water would allow this earth-abundant resource to be transferred into value-added compounds, and is a topic of keen interest in energy research1,2. Here, we demonstrate water activation with a photocatalytic phosphine-mediated radical process under mild conditions. This reaction generates a metal-free PR3-H2O radical cation intermediate, in which both hydrogen atoms are used in the subsequent chemical transformation through sequential heterolytic (H+) and homolytic (H•) cleavage of the two O-H bonds. The PR3-OH radical intermediate provides an ideal platform that mimics the reactivity of a 'free' hydrogen atom, and which can be directly transferred to closed-shell π systems, such as activated alkenes, unactivated alkenes, naphthalenes and quinoline derivatives. The resulting H adduct C radicals are eventually reduced by a thiol co-catalyst, leading to overall transfer hydrogenation of the π system, with the two H atoms of water ending up in the product. The thermodynamic driving force is the strong P=O bond formed in the phosphine oxide by-product. Experimental mechanistic studies and density functional theory calculations support the hydrogen atom transfer of the PR3-OH intermediate as a key step in the radical hydrogenation process.

Divergent access to fused N-heterocycle-thiazolines by solvent-dependent reaction of isoquinolinium thiolates with silylketene acetals.

A solvent-dependent, divergent synthesis of highly functionalized N,S-heterocycles presenting a thiazoline and an isoquinuclidine (DCE as solvent) or tetrahydroisoquinoline (DMF as solvent) scaffolds by cyclization reactions of isoquinolinium 1,4-zwitterionic thiolates is reported. The robustness and applicability of the method are also demonstrated by an efficient 6-times upscaling of the reaction and derivatization of the thiazoline-isoquinuclidine derivatives.

Azodioxy compounds as precursors for C-radicals and their application in thermal styrene difunctionalization.

An atom-economic thermal α,ß-difunctionalization of various styrenes with readily prepared azodioxy compounds is reported. Mechanistic studies reveal that the starting azodioxy compounds can thermally be cleaved to the corresponding C-nitroso compounds, which under these thermal conditions further homolyze to generate reactive C-radicals along with the persistent NO radical. In the presence of a styrene, C-radical addition with subsequent nitrosylation followed by tautomerization is occurring, resulting in an overall styrene ß-alkylation-α-oximation reaction.

Benzotriazolium Salts: Emergent Readily Accessible Bench-Stable Lewis Acid Catalysts.

In this work, benzotriazolium salts have been introduced as efficient, readily accessible, bench-stable Lewis acid catalysts. Though these sorts of N-heterocyclic compounds have found wide applications as ionic liquids or electrolytes, their Lewis acid catalytic activity remained unexplored. Herein, their potential as Lewis acid catalysts was demonstrated in two prototypical allylic and Nazarov cyclization reactions, showing a matching reactivity and allowing low catalytic loadings (down to 0.5 mol %).

Oxy-Borylenes as Photoreductants: Synthesis and Application in Dehalogenation and Detosylation Reactions.

While the range of accessible borylenes has significantly broadened over the last decade, applications remain limited. Herein, we present tricoordinate oxy-borylenes as potent photoreductants that can be readily activated by visible light. Facile oxidation of CAAC stabilized oxy-borylenes (CAAC)(IPr2 Me2 )BOR (R=TMS, CH2 CH2 C6 H5 , CH2 CH2 (4-F)C6 H4 ) to their corresponding radical cations is achieved with mildly oxidizing ferrocenium ion. Cyclovoltammetric studies reveal ground-state redox potentials of up to -1.90 V vs. Fc+/0 for such oxy-borylenes placing them among the strongest organic super electron donors. Their ability as photoreductants is further supported by theoretical studies and showcased by the application as stoichiometric reagents for the photochemical hydrodehalogenation of aryl chlorides, aryl bromides and unactivated alkyl bromides as well as the detosylation of anilines.

Formation of a Hybrid 1-Bora-3-boratabenzene Heteroarene Anion Derivative.

The B(C6 F5 )2 -substituted borole 2⋅SMe2 was obtained from the phenyl bis(trimethylsilylethynyl) borane SMe2 adduct (1⋅SMe2 ) by a synthetic sequence containing a rare 1,1-hydroboration reaction. Subsequent thermolysis at 50 °C converted it to the bicyclic borenium/borate zwitterion 3⋅SMe2 . Photolysis of 3⋅SMe2 gave the diboracyclohexadiene derivative 4⋅SMe2 , which after ligand exchange with N,N-dimesitylimidazolylidene and deprotonation gave the 1-bora-3-boratabenzene anion derivative as its potassium salt 6. Some unique follow-up reactions of the unsaturated diboron containing six-membered heterocycles were investigated.

Borole/Borapyramidane Relationship.

Boroles and borapyramidanes are classical and nonclassical constitutional isomers, respectively. It is here shown that they can indeed be interconverted. Treatment of the bis(alkynyl)B(C6F5) SMe2 adduct 3·SMe2 with HB(C6F5)2 gave borole 1·SMe2, featuring trimethylsilyl substituents in both α positions to boron, by means of a 1,1-hydroboration/alkenylboration sequence. Photolysis of the classical borole adduct 1·SMe2 resulted in rearrangement to its nonclassical structural isomer, borapyramidane 2, in high yield, which exhibits a vicinal pair of trimethylsilyl substituents at the square pyramidane base. Neutral borapyramidane 2 is a rare example of an isoster of the (CH)5+ pyramidane cation. Thermolysis of borapyramidane 2 in the presence of SMe2 at 60 °C re-formed borole 1·SMe2, which converted at 100 °C to 2,3-bis-silyl-substituted borole isomer 8·SMe2. Its photolysis also gave borapyramidane 2. Prolonged photolysis of 2 at elevated temperatures converted this to borapyramidane isomer 10 containing a pair of trimethylsilyl groups in 1,3-position at its square C4-pyramidal base. The borole and borapyramidane isomers were characterized by X-ray diffraction, and the system was analyzed by density functional theory (DFT) calculations.

Synthesis and Reactivity of a Neutral Homocyclic Silylene.

Isolation of the neutral homocyclic silylene 2 is possible via amine ligand abstraction with potassium graphite (KC8 ) and subsequent reaction with SiMe3 Cl from a bicyclic silicon(I) amide J. This reaction proceeds via an anionic homoaromatic silicon ring compound 1 as an intermediate. The twofold-coordinated silicon atom in the homocyclic silylene 2 is stabilized by an allyl-type π-electron delocalization. 2 reacts in an oxidative addition with two equivalents of MeOH and in cycloadditions with ethene, phenylacetylene, diphenylacetylene and with 2,3-dimethyl-1,3-butadiene to afford novel functionalized ring compounds.

Photoswitchable Nitrogen Superbases: Using Light for Reversible Carbon Dioxide Capture.

Using light as an external stimulus to alter the reactivity of Lewis bases is an intriguing tool for controlling chemical reactions. Reversible photoreactions associated with pronounced reactivity changes are particularly valuable in this regard. We herein report the first photoswitchable nitrogen superbases based on guanidines equipped with a photochromic dithienylethene unit. The resulting N-heterocyclic imines (NHIs) undergo reversible, near quantitative electrocyclic isomerization upon successive exposure to UV and visible irradiation, as demonstrated over multiple cycles. Switching between the ring-opened and ring-closed states is accompanied by substantial pKa shifts of the NHIs by up to 8.7 units. Since only the ring-closed isomers are sufficiently basic to activate CO2 via the formation of zwitterionic Lewis base adducts, cycling between the two isomeric states enables the light-controlled capture and release of CO2 .

Insights into Ergochromes of the Plant Pathogen Claviceps purpurea.

Claviceps purpurea is an ergot fungus known for its neurotropic alkaloids, which have been identified as the main cause of ergotism, a livestock and human disease triggered by ergot consumption. Tetrahydroxanthone dimers, the so-called ergopigments, presumably also contribute to this toxic effect. Overexpression of the cluster-specific transcription factor responsible for the formation of these pigments in C. purpurea led to the isolation of three new metabolites (8-10). The new pigments were characterized utilizing HRMS, NMR techniques, and CD spectroscopy and shown to be xanthone dimers. Secalonic acid A and its 2,4'- and 4,4'-linked isomers were also isolated, and their absolute configuration was investigated. The contribution of secalonic acid A, its isomers, and new metabolites to the toxicity of C. purpurea was investigated in HepG2 and CCF-STTG1 cells. Along with cytotoxic properties, secalonic acid A was found to inhibit topoisomerase I and II activity.

The Bis(η6 -benzene)lithium Cation: A Fundamental Main-Group Organometallic Species.

The synthesis and characterization of the bis(η6 -benzene)lithium cation, the benzene metallocene of the lightest metal, is reported. The boron compound FmesBCl2 [Fmes: 2,4,6-tris(trifluoromethyl)phenyl] reacted with three molar equivalents of the lithio-acetylene reagent Li-C≡C-Fmxyl [Fmxyl: 3,5-bis(trifluoromethyl)phenyl]. Subsequent crystallization from benzene gave the [bis(η6 -benzene)Li]+ cation with the [{FmesB(-C≡C-Fmxyl)3 }2 Li]- anion. This parent [(arene)2 Li]+ cation shows an eclipsed arrangement of the pair of benzene ligands at the central lithium cation with uniform carbon-lithium bond lengths. The corresponding [(η6 -toluene)2 Li]+ and [(η6 -durene)2 Li]+ containing salts were similarly prepared. The bis(arene)lithium cations were characterized by X-ray diffraction, by solid-state 7 Li MAS NMR spectroscopy and their bonding features were analyzed by DFT calculations.

Radical Aryl Migration from Boron to Carbon.

Radical aryl migration reactions represent a unique type of organic transformations that involve the intramolecular migration of an aryl group from a carbon or heteroatom to a C- or heteroatom-centered radical through a spirocyclic intermediate. Various elements, including N, O, Si, P, S, Sn, Ge, and Se, have been reported to participate in radical aryl migrations. However, radical aryl migration from a boron center has not been reported to date. In this communication, radical 1,5-aryl migration from boron to carbon in aryl boronate complexes is presented. C-radicals readily generated through radical addition onto alkenyl aryl boronate complexes are shown to engage in 1,5-aryl migration reactions to provide 4-aryl-alkylboronic esters. As boronate complexes can be generated in situ by the reaction of alkenylboronic acid esters with aryl lithium reagents, the aryl moiety is readily varied, providing access to a series of arylated products starting from the same alkenylboronic acid ester via divergent chemistry. Reactions proceed with high diastereoselectivity under mild conditions, and also the analogous 1,4-aryl shifts are feasible. The suggested mechanism is supported by DFT calculations.