Manipulating the Substituent Sphere of a Bicyclic Silicon(I) Ring Compound Results in Anionic Cubane-Type Clusters and a Tetrahedral Silanide.

The reaction of the bicyclic silicon(I) ring compound Si4{N(SiMe3)Mes}4 1 with strong zwitterionic character and moderate sterical demand of the amido substituents with two equivalents of KC8 was investigated. This resulted in the unexpected abstraction of two amido substituents from 1 and additionally in dimerization to a dianionic Si8 cluster compound 2 with four unsubstituted silicon atoms and two [K([18]crown-6)]+ counter cations. Performing this reaction in the absence of [18]crown-6 results in release of only one amido substituent from 1 and dimerization to a dianionic Si8 cluster 3 with only two unsubstituted silicon atoms. This reaction with KC8 was repeated and trapping agents such as SiMe3Cl and tBuCl were added in-situ whereupon the second isolated homocyclic silylene 4 and a monoanionic hydride and tBu substituted Si8 cluster 5 with one unsubstituted silicon atom were isolated. Furthermore, 1 was reacted with KOtBu which resulted in the selective abstraction of one SiMe3 group and formation of the tetrahedral silanide 6 with one imido substituent bridging an edge of the tetrahedron.

Nitrogen-to-functionalized carbon atom transmutation of pyridine.

The targeted and selective replacement of a single atom in an aromatic system represents a powerful strategy for the rapid interconversion of molecular scaffolds. Herein, we report a pyridine-to-benzene transformation via nitrogen-to-carbon skeletal editing. This approach proceeds via a sequence of pyridine ring-opening, imine hydrolysis, olefination, electrocyclization, and aromatization to achieve the desired transmutation. The most notable features of this transformation are the ability to directly install a wide variety of versatile functional groups in the benzene scaffolding, including ester, ketone, amide, nitrile, and phosphate ester fragments, as well as the inclusion of meta-substituted pyridines which have thus far been elusive for related strategies.

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.

Intermolecular radical oxyalkylation of arynes with alkenes and TEMPO.

Radical transformations with arynes represent an underexplored research field and only a few examples have been disclosed. In this research article, the implementation of arynes in three-component reactions with TEMPO (2,2,6,6-tetramethylpiperidine 1-oxyl) and activated alkenes is demonstrated. TEMPO is added to arynes, which triggers a Meerwein-type arylation cascade where the final alkyl radial is eventually trapped by a second equivalent of TEMPO. This method is applicable to activated alkenes such as electron-deficient acrylates, styrenes and also vinyl acetate to provide various bisalkoxyamines. This work is a contribution to the emerging field of radical aryne chemistry.

Iron-catalyzed radical Markovnikov hydrohalogenation and hydroazidation of alkenes.

We herein report radical hydroazidation and hydrohalogenation of mono-, di- and trisubstituted alkenes through iron catalysis. The alkene moiety that often occurs as a functionality in natural products is readily transformed into useful building blocks through this approach. Commercially available tosylates and α-halogenated esters are used as radical trapping reagents in combination with silanes as reductants. The reported radical Markovnikov hydroazidation, hydrobromination, hydrochlorination, and hydroiodination occur under mild conditions. These hydrofunctionalizations are valuable and practical alternatives to ionic hydrohalogenations with the corresponding mineral acids that have to be run under harsher acidic conditions, which diminishes the functional group tolerance. Good to excellent diastereoselectivities can be obtained for the hydrofunctionalization of cyclic alkenes.

4-Trifluoromethoxy proline: synthesis of stereoisomers and lipophilicity study.

All four stereoisomers of 4-CF3O-proline have been synthesized through a fluorodesulfurization approach using the corresponding 4-hydroxyprolines as starting materials. The investigation of their lipophilicity characteristics and comparison with those of other 4-substituted proline analogs demonstrated a similar impact of CF3 and CF3O groups on log D.

Enantioselective, BroÌ·nsted Acid-Catalyzed Anti-selective Hydroamination of Alkenes.

Chiral pyrrolidines are common structural motives in natural products as well as active pharmaceutical ingredients, explaining the need for methods for their enantioselective synthesis. While several, often metal-catalyzed, methods for their preparation do exist, the enantioselective synthesis of pyrrolidines containing quaternary stereocenters remains challenging. Herein, we report a BroÌ·nsted acid-catalyzed intramolecular hydroamination that provides such pyrrolidines from simple starting materials in high yield and enantioselectivity. Key to an efficient reaction was the use of an electron-deficient protective group on nitrogen, the common nosyl-protecting group, to avoid deactivation of the BroÌ·nsted acid by deprotonation. The reaction proceeds as a stereospecific anti-addition indicating a concerted reaction. Furthermore, kinetic studies show Michaelis-Menten behavior, suggesting the formation of a precomplex similar to those observed in enzymatic catalysis.

Bicyclo[1.1.0]butyl Radical Cations: Synthesis and Application to [2π + 2σ] Cycloaddition Reactions.

As the chemistry that surrounds the field of strained hydrocarbons, such as bicyclo[1.1.0]butane, continues to expand, it becomes increasingly advantageous to develop alternative reactivity modes that harness their unique properties to access new regions of chemical space. Herein, we report the use of photoredox catalysis to promote the single-electron oxidation of bicyclo[1.1.0]butanes. The synthetic utility of the resulting radical cations is highlighted by their ability to undergo highly regio- and diastereoselective [2π + 2σ] cycloaddition reactions. The most notable feature of this transformation is the breadth of alkene classes that can be employed, including nonactivated alkenes, which have so far been elusive for previous strategies. A rigorous mechanistic investigation, in conjunction with DFT computation, was undertaken in order to better understand the physical nature of bicyclo[1.1.0]butyl radical cations and thus provides a platform from which further studies into the synthetic applications of these intermediates can be built upon.

Unlocking Photocatalytic Activity of Acridinium Salts by Anion-Binding Co-Catalysis.

The in situ generation of active photoredox organic catalysts upon anion-binding co-catalysis by making use of the ionic nature of common photosensitizers is reported. Hence, the merge of anion-binding and photocatalysis permitted the modulation of the photocatalytic activity of simple acridinium halide salts, building an effective anion-binding - photoredox ion pair complex able to promote a variety of visible light driven transformations, such as anti-Markovnikov addition to olefins, Diels-Alder and the desilylative C-C bond forming reactions. Anion-binding studies, together with steady-state and time-resolved spectroscopy analysis, supported the postulated ion pair formation between the thiourea hydrogen-bond donor organocatalyst and the acridinium salt, which proved essential for unlocking the photocatalytic activity of the photosensitizer.

Thermal and Photoinduced Radical Cascade Annulation using Aryl Isonitriles: An Approach to Quinoline-Derived Benzophosphole Oxides.

Herein, we present a radical cascade addition cyclization sequence to access quinoline-based benzophosphole oxides from ortho-alkynylated aromatic phosphine oxides using various aryl isonitriles as radical acceptors and inexpensive tert-butyl-hydroperoxide (TBHP) as a terminal oxidant in the presence of a catalytic amount of silver acetate. Alternatively, the same cascade can be realized through a sustainable photochemical approach utilizing 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene (4CzIPN) as an organic photocatalyst at room temperature. The introduced modular approach shows broad functional group tolerance and offers straightforward access to complex P,N-containing polyheterocyclic arenes. These novel π-extended benzophosphole oxides exhibit interesting photophysical and electrochemical properties such as absorption in the visible region, emission and reversible reduction at low potentials, which makes them promising for potential materials science applications. The photophysical properties can further be tuned by the addition of external Lewis and Brønsted acids.

γ-Amino Alcohols via Energy Transfer Enabled Brook Rearrangement.

In the long-standing quest to synthesize fundamental building blocks with key functional group motifs, photochemistry in the recent past has comprehensively established its attractiveness. Amino alcohols are not only functionally diverse but are ubiquitous in the biologically active realm of compounds. We developed bench-stable bifunctional reagents that could then access the sparsely reported γ-amino alcohols directly from feedstock alkenes through energy transfer (EnT) photocatalysis. A designed 1,3-linkage across alkenes is made possible by the intervention of a radical Brook rearrangement that takes place downstream to the EnT-mediated homolysis of our reagent(s). A combination of experimental mechanistic investigations and detailed computational studies (DFT) indicates a radical chain propagated reaction pathway.

Silver-Enabled Cycloaddition of Bicyclobutanes with Isocyanides for the Synthesis of Polysubstituted 3-Azabicyclo[3.1.1]heptanes.

Synthesis of bicyclic scaffolds has emerged as an important research topic in modern drug development because they can serve as saturated bioisosters to enhance the physicochemical properties and metabolic profiles of drug candidates. Here we report a remarkably simple silver-enabled strategy to access polysubstituted 3-azabicyclo[3.1.1]heptanes in a single operation from readily accessible bicyclobutanes (BCBs) and isocyanides. The process is proposed to involve a formal (3+3)/(3+2)/retro-(3+2) cycloaddition sequence. This novel protocol allows for rapid generation of molecular complexity from simple starting materials, and the products can be easily derivatized, further enriching the BCB cycloaddition chemistry and the growing set of valuable sp3-rich bicyclic building blocks.

Catalytic Ring Expanding Difluorination: An Enantioselective Platform to Access ß,ß-Difluorinated Carbocycles.

Cyclic ß,ß-difluoro-carbonyl compounds have a venerable history as drug discovery leads, but limitations in the synthesis arsenal continue to impede chemical space exploration. This challenge is particularly acute in the arena of fluorinated medium rings where installing the difluoromethylene unit subtly alters the ring conformation by expanding the internal angle (∠C-CF2-C>∠C-CH2-C): this provides a handle to modulate physicochemistry (e.g. pKa). To reconcile this disparity, a highly modular ring expansion has been devised that leverages simple α,ß-unsaturated esters and amides, and processes them to one-carbon homologated rings with concomitant geminal difluorination (6 to 10 membered rings, up to 95 % yield). This process is a rare example of the formal difluorination of an internal alkene and is enabled by sequential I(III)-enabled O-activation. Validation of enantioselective catalysis in the generation of unprecedented medium ring scaffolds is reported (up to 93 : 7 e.r.) together with X-ray structural analyses and product derivatization.

Regio- and Stereo-Selective Isomerization of Borylated 1,3-Dienes Enabled by Selective Energy Transfer Catalysis.

Configurationally-defined dienes are pervasive across the bioactive natural product spectrum, where they typically manifest themselves as sorbic acid-based fragments. These C5 motifs reflect the biosynthesis algorithms that facilitate their construction. To complement established biosynthetic paradigms, a chemical platform to facilitate the construction of stereochemically defined, functionalizable dienes by light-enabled isomerization has been devised. Enabled by selective energy transfer catalysis, a variety of substituted ß-boryl sorbic acid derivatives can be isomerized in a regio- and stereo-selective manner (up to 97 : 3). Directionality is guided by a stabilizing nO→pB interaction in the product: this constitutes a formal anti-hydroboration of the starting alkyne. This operationally simple reaction employs low catalyst loadings (1 mol %) and is complete in 1 h. X-ray analysis supports the hypothesis that the nO→pB interaction leads to chromophore bifurcation: this provides a structural foundation for selective energy transfer.

Borylative transition metal-free couplings of vinyl iodides with various nucleophiles, alkenes or alkynes.

Alkyl boronic esters are highly valuable compounds in organic chemistry and related fields due to their good stability and highly versatile reactivity. In this edge article, stereoselective borylative couplings of vinyl iodides with various nucleophiles, alkenes or alkynes is reported. These coupling reactions proceed through stereospecific hydroboration and subsequent stereospecific 1,2-metallate rearrangement. The cascades utilize readily available reagents and proceed without the need of a transition metal catalyst.

Chemoselective Heterogeneous Hydrogenation of Sulfur Containing Quinolines under Mild Conditions.

Sulfur, alongside oxygen and nitrogen, holds a prominent position as one of the key heteroatoms in nature and medicinal chemistry. Its significance stems from its ability to adopt different oxidation states, rendering it valuable as both a polarity handle and a hydrogen bond donor/acceptor. Nevertheless, the poisonous nature of its free electron pairs makes sulfur containing substrates inaccessible for many catalytic protocols. Strong and (at low temperatures) irreversible chemisorption to the catalyst's surface is in particular detrimental for heterogeneous catalysts, possessing only few catalytically active sites. Herein, we present a novel heterogeneous Ru-S catalyst that tolerates multiple sulfur functionalities, including thioethers, thiophenes, sulfoxides, sulfones, sulfonamides, and sulfoximines, in the hydrogenation of quinolines. The utility of the products was further demonstrated by subsequent diversifications of the sulfur functionalities.

Double Strain-Release [2π+2σ]-Photocycloaddition.

In pursuit of potent pharmaceutical candidates and to further improve their chemical traits, small ring systems can serve as a potential starting point. Small ring units have the additional merit of loaded strain at their core, making them suitable reactants as they can capitalize on this intrinsic driving force. With the introduction of cyclobutenone as a strained precursor to ketene, the photocycloaddition with another strained unit, bicyclo[1.1.0]butane (BCB), enables the reactivity of both π-units in the transient ketene. This double strain-release driven [2π+2σ]-photocycloaddition promotes the synthesis of diverse heterobicyclo[2.1.1]hexane units, a pharmaceutically relevant bioisostere. The effective reactivity under catalyst-free conditions with a high functional group tolerance defines its synthetic utility. Experimental mechanistic studies and density functional theory (DFT) calculations suggest that the [2π+2σ]-photocycloaddition takes place via a triplet mechanism.

α-D-2'-Deoxyadenosine, an irradiation product of canonical DNA and a component of anomeric nucleic acids: crystal structure, packing and Hirshfeld surface analysis.

α-D-2'-Deoxyribonucleosides are products of the γ-irradiation of DNA under oxygen-free conditions and are constituents of anomeric DNA. They are not found as natural building blocks of canonical DNA. Reports on their conformational properties are limited. Herein, the single-crystal X-ray structure of α-D-2'-deoxyadenosine (α-dA), C10H13N5O3, and its conformational parameters were determined. In the crystalline state, α-dA forms two conformers in the asymmetric unit which are connected by hydrogen bonds. The sugar moiety of each conformer is arranged in a `clamp'-like fashion with respect to the other conformer, forming hydrogen bonds to its nucleobase and sugar residue. For both conformers, a syn conformation of the nucleobase with respect to the sugar moiety was found. This is contrary to the anti conformation usually preferred by α-nucleosides. The sugar conformation of both conformers is C2'-endo, and the 5'-hydroxyl groups are in a +sc orientation, probably due to the hydrogen bonds formed by the conformers. The formation of the supramolecular assembly of α-dA is controlled by hydrogen bonding and stacking interactions, which was verified by a Hirshfeld and curvedness surface analysis. Chains of hydrogen-bonded nucleobases extend parallel to the b direction and are linked to equivalent chains by hydrogen bonds involving the sugar moieties to form a sheet. A comparison of the solid-state structures of the anomeric 2'-deoxyadenosines revealed significant differences of their conformational parameters.

Photoredox-Enabled Dearomative [2π + 2σ] Cycloaddition of Phenols.

Dearomative photocycloaddition of monocyclic arenes is an appealing strategy for comprehending the concept of "escape from flatland". This brings the replacement of readily available planar aromatic hydrocarbon units with a 3D fused bicyclic core with sp3-enriched carbon units. Herein, we outline an intermolecular approach for the dearomative photocycloaddition of phenols. In order to circumvent the ground-state aromaticity and to construct conformationally restrained building blocks, bicyclo[1.1.0]butanes were chosen as coupling partners. This dearomative approach renders straightforward access to a bicyclo[2.1.1]hexane unit fused to a cyclic enone moiety, which further contributed as a synthetic linchpin for postmodifications. Mechanistic experiment advocates for a plausible onset from both the reactants, depending on the redox potential.

para-Selective dearomatization of phenols by I(i)/I(iii) catalysis-based fluorination.

The regio- and enantio-selective dearomatization of phenols has been achieved by I(i)/I(iii) catalysis enabled fluorination. The process is highly para-selective, guiding the fluoride nucleophile to the distal C4 position of the substrate to generate fluorinated cyclohexadienones in an operationally simple manner. Extensive optimization has revealed key parameters that orchestrate enantioselectivity in this historically challenging transformation. A range of diversely substituted substrates are disclosed (20 examples, up to 92 : 8 e.r.) and the reaction displays efficiency that is competitive with the current state of the art in hydroxylation chemistry: this provides a preparative platform to enable OH to F bioisosterism to be explored. Finally, the utility of the products in accessing densely functionalized cyclic scaffolds with five contiguous stereocenters is disclosed together with crystallographic analyses to unveil fluorine-carbonyl non-covalent interactions.