9-Azahomocubane.

Homocubane, a highly strained cage hydrocarbon, contains two very different positions for the introduction of a nitrogen atom into the skeleton, e. g., a position 1 exchange results in a tertiary amine whereas position 9 yields a secondary amine. Herein reported is the synthesis of 9-azahomocubane along with associated structural characterization, physical property analysis and chemical reactivity. Not only is 9-azahomocubane readily synthesized, and found to be stable as predicted, the basicity of the secondary amine was observed to be significantly lower than the structurally related azabicyclo[2.2.1]heptane, although similar to 1-azahomocubane.

Synthesis and Properties of Fluorenone-Containing Cycloparaphenylenes and Their Late-Stage Transformation.

Cycloparaphenylenes (CPPs) are the smallest possible armchair carbon nanotubes, the properties of which strongly depend on their ring size. They can be further tuned by either peripheral functionalization or by replacing phenylene rings for other aromatic units. Here we show how four novel donor-acceptor chromophores were obtained by incorporating fluorenone or 2-(9H-fluoren-9-ylidene)malononitrile into the loops of two differently sized CPPs. Synthetically, we managed to perform late-stage functionalization of the fluorenone-based rings by high-yielding Knoevenagel condensations. The structures were confirmed by X-ray crystallographic analyses, which revealed that replacing a phenylene for a fused-ring-system acceptor introduces additional strain. The donor-acceptor characters of the CPPs were supported by absorption and fluorescence spectroscopic studies, electrochemical studies (displaying the CPPs as multi-redox systems undergoing reversible or quasi-reversible redox events), as well as by computations. The oligophenylene parts were found to comprise the electron donor units of the macrocycles and the fluorenone parts the acceptor units.

Boron-Nitrogen-Containing Benzene Valence Isomers.

Benzene is one of the most ubiquitous structural motifs in chemistry. The valence isomers of benzene have also attracted synthetic chemists' attention due to their unique structures, bonding, and reactivity. We have been investigating boron-nitrogen-containing benzene valence isomers via photoisomerization of 1,2-azaborines. In this contribution, we summarize recent developments of these highly strained BN-heterocyclic compounds including their synthesis, characterization, proposed mechanism of formation, and their potential applications.

Comment on "Asymmetric Bistricyclic Aromatic Enes".

This Correspondence argues against the use of the adjectives "symmetrical" and "asymmetric" in the recent publication entitled "Fluorenylidene-Cyclopentadithiophene Based Asymmetric Bistricyclic Aromatic Ene Compounds: Synthesis and Substituents Effects", by Beibei Xiao, Yongrui Yang, Shengnan Chen, Ye Zou, Xing Chen, Kanglei Liu, Nan Wang, Yali Qiao, and Xiaodong Yin (Chem. Eur. J., 2023, 29, e202301055).[1].

Unusually Short H⋠⋠⋠H Contacts in Intramolecularly Cyclized Helically Fused Anthracenes.

The intramolecular coupling of dichloro-substituted helically fused anthracenes using the Yamamoto coupling yielded cyclized products with sterically congested molecular structures. The X-ray analysis and DFT calculations showed that the aromatic framework adopted a nonplanar structure with a twisted conformation about the newly formed single bond, which acts as a chiral axis. Interestingly, the X-ray structure obtained through the Hirshfeld atom refinement revealed short interatomic distances between the inner hydrogen atoms (1.648-1.692 Å), much shorter than the sum of their van der Waals radii. Owing to these unusually short contacts, the 1H NMR spectrum exhibited a significant deshielding (12.5 ppm) and a large nuclear Overhauser effect (44 %). Additionally, the IR spectrum displayed a high-frequency shift of the C-H stretching vibration. These observations, along with the noncovalent interaction plot indicative of a characteristic steric environment, strongly support the presence of steric hindrance. Moreover, dynamic NMR measurement of the mesityl-substituted derivative yielded a barrier to helical inversion of 84 kJ mol-1. The optical properties and crystal packing of the cyclized products are also reported.

Bisphosphonium Benzene Diimides.

The incorporation of cationic groups onto electron-poor compounds is a viable strategy for achieving potent electron acceptors, as evidenced by reports of air-stable radical forms of large aromatic diimides such as naphthalene and perylene diimides. These ions have also been observed to exhibit anion-π interaction tendencies of interest in molecular recognition applications. The benefits of phosphonium incorporation, however, have not yet been extended to the smallest benzene diimides. Here, we report that dibrominated pyromellitic diimide and mellophanic diimide both readily undergo substitution reactions with phosphine sources to yield bisphosphonium compounds. In the single crystalline form, these dications display anion-π interactions and, in the case of mellophanic diimide, the stabilization of a bromide-water H-bonding ring pattern. The reaction of these dications with chemical reductants readily provides the singly and doubly reduced redox states, which were characterized by UV-vis spectroscopy and found to exhibit intense absorptions extending into the near-IR region. Taken together, this work demonstrates that phosphonium incorporation onto congested aromatic diimide scaffolds is synthetically viable and produces unusual electron-poor compounds.

Organometallic Bridge Diversification of Bicyclo[1.1.1]pentanes.

Bicyclo[1.1.1]pentane (BCP) derivatives have attracted significant recent interest in drug discovery as alkyne, tert-butyl and arene bioisosteres, where their incorporation is frequently associated with increased compound solubility and metabolic stability. While strategies for functionalisation of the bridgehead (1,3) positions are extensively developed, platforms allowing divergent substitution at the bridge (2,4,5) positions remain limited. Recent reports have introduced 1-electron strategies for arylation and incorporation of a small range of other substituents, but are limited in terms of scope, yields or practical complexity. Herein, we show the synthesis of diverse 1,2,3-trifunctionalised BCPs through lithium-halogen exchange of a readily accessible BCP bromide. When coupled with medicinally relevant product derivatisations, our developed 2-electron "late stage" approach provides rapid and straightforward access to unprecedented BCP structural diversity (>20 hitherto-unknown motifs reported). Additionally, we describe a method for the synthesis of enantioenriched "chiral-at-BCP" bicyclo[1.1.1]pentanes through a novel stereoselective bridgehead desymmetrisation.

Synthesis, Characterization and Energetic Properties of Hydroxymethyl-Bishomocubanone Derivatives.

The present work reports synthesis, characterization and theoretical insights on novel hydroxymethyl-bishomocubanone derivatives. Twelve new bishomocubanes (BHCs) were synthesized and fully characterized by various spectroscopic techniques and single crystal X-ray analysis. The densities of the title compounds were in the range of 1.30-1.59 g/cm3. Density-functional theory (DFT) based calculations at B3LYP/6-311++G(d,p) level of theory were performed on ten selected BHC based cage compounds. Propulsive and ballistic properties of newly synthesized hydroxymethyl-bishomocubanone derivatives in solid and liquid propulsion systems were calculated, and the results suggested that these compounds are superior to conventional fuel RP1 and binder HTPB. The detonation parameters revealed that these compounds are not explosive in nature and safe to use as solid propellants. Furthermore, kinetic and thermal stabilities of the title compounds were determined by HOMO-LUMO energy gap, ESP maps, impact sensitivity (h50) and bond dissociation energies (BDEs) followed by thermogravimetric analysis (TGA) and differential thermal analysis (DTA). Three compounds, a dinitroazide (Isp,vac=310.98 s), a dinitrate (Isp,vac=309.51 s), and a dinitronitrate (Isp,vac=309.20s) were found to be excellent candidates for volume limited applications.

Switching between the [2π+2σ] and Hetero-[4π+2σ] Cycloaddition Reactivity of Bicyclobutanes with Lewis Acid Catalysts Enables the Synthesis of Spirocycles and Bridged Heterocycles.

The exploration of the complex chemical diversity of bicyclo[n.1.1]alkanes and their use as benzene bioisosteres has garnered significant attention over the past two decades. Regiodivergent syntheses of thiabicyclo[4.1.1]octanes (S-BCOs) and highly substituted bicyclo[2.1.1]hexanes (BCHs) using a Lewis acid-catalyzed formal cycloaddition of bicyclobutanes (BCBs) and 3-benzylideneindoline-2-thione derivatives have been established. The first hetero-(4+3) cycloaddition of BCBs, catalyzed by Zn(OTf)2, was achieved with a broad substrate scope under mild conditions. In contrast, the less electrophilic BCB ester undergoes a Sc(OTf)3-catalyzed [2π+2σ] reaction with 1,1,2-trisubstituted alkenes, yielding BCHs with a spirocyclic quaternary carbon center. Control experiments and preliminary theoretical calculations suggest that the diastereoselective [2π+2σ] product formation may involve a concerted cycloaddition between a zwitterionic intermediate and E-1,1,2-trisubstituted alkenes. Additionally, the hetero-(4+3) cycloaddition may involve a concerted nucleophilic ring-opening mechanism.

Divergent Synthesis of Sulfur-Containing Bridged Cyclobutanes by Lewis Acid Catalyzed Formal Cycloadditions of Pyridinium 1,4-Zwitterionic Thiolates and Bicyclobutanes.

Bridged cyclobutanes and sulfur heterocycles are currently under intense investigation as building blocks for pharmaceutical drug design. Two formal cycloaddition modes involving bicyclobutanes (BCBs) and pyridinium 1,4-zwitterionic thiolate derivatives were described to rapidly expand the chemical space of sulfur-containing bridged cyclobutanes. By using Ni(ClO4)2 as the catalyst, an uncommon higher-order (5+3) cycloaddition of BCBs with quinolinium 1,4-zwitterionic thiolate was achieved with broad substrate scope under mild reaction conditions. Furthermore, the first Lewis acid-catalyzed asymmetric polar (5+3) cycloaddition of BCB with pyridazinium 1,4-zwitterionic thiolate was accomplished. In contrast, pyridinium 1,4-zwitterionic thiolates undergo an Sc(OTf)3-catalyzed formal (3+3) reaction with BCBs to generate thia-norpinene products, which represent the initial instance of synthesizing 2-thiabicyclo[3.1.1]heptanes (thia-BCHeps) from BCBs. Moreover, we have successfully used this (3+3) protocol to rapidly prepare thia-BCHeps-substituted analogues of the bioactive molecule Pitofenone. Density functional theory (DFT) computations imply that kinetic factors govern the (5+3) cycloaddition reaction between BCB and quinolinium 1,4-zwitterionic thiolate, whereas the (3+3) reaction involving pyridinium 1,4-zwitterionic thiolates is under thermodynamic control.

Eu(OTf)3 -Catalyzed Formal Dipolar [4π+2σ] Cycloaddition of Bicyclo-[1.1.0]butanes with Nitrones: Access to Polysubstituted 2-Oxa-3-azabicyclo[3.1.1]heptanes.

Herein, we have synthesized multifunctionalized 2-oxa-3-azabicyclo[3.1.1]heptanes, which are considered potential bioisosteres for meta-substituted arenes, through Eu(OTf)3 -catalyzed formal dipolar [4π+2σ] cycloaddition of bicyclo[1.1.0]butanes with nitrones. This methodology represents the initial instance of fabricating bicyclo[3.1.1]heptanes adorned with multiple heteroatoms. The protocol exhibits both mild reaction conditions and a good tolerance for various functional groups. Computational density functional theory calculations support that the reaction mechanism likely involves a nucleophilic addition of nitrones to bicyclo[1.1.0]butanes, succeeded by an intramolecular cyclization. The synthetic utility of this novel protocol has been demonstrated in the concise synthesis of the analogue of Rupatadine.

Enantioselective Hydrofunctionalization of Cyclobutenones: Total Synthesis of gem-Dimethylcyclobutane Natural Products.

Cyclobutanes with a gem-dimethyl group are common motifs in natural products. However, strategies for constructing enantioenriched gem-dimethyl cyclobutanes are still underdeveloped. Herein, we report an enantioselective approach to synthesize a broad group of chiral 2,3-disubstituted cyclobutanones through sequential 1,4-conjugate addition/trapping/cross-coupling of readily available cyclobutenones. The intermediate 2-bromocyclobutanone provides a valuable synthetic handle for further coupling transformations. In addition, this strategy was successfully utilized to synthesize gem-dimethyl cyclobutane-containing natural products, including (+)-ß-caryophyllene, (-)-raikovenal, (-)-1ß,9αH-5-linoleoyloxy-4,5-secocaryophyllen-4-one, and (-)-rumphellanones A-C.

Total Synthesis of Isoxeniolide A.

Isoxeniolide A is a highly strained xenicane diterpenoid of marine origin. This natural product is representative for a subfamily of xenicanes incorporating an allylic hydroxy group in the nine-membered ring; members of this xenicane subfamily so far have not been targeted by total synthesis. Herein, we describe the first asymmetric total synthesis of isoxeniolide A. Key to forming the challenging E-configured cyclononene ring was a diastereoselective intramolecular Nozaki-Hiyama-Kishi reaction. Other important transformations include an enzymatic desymmetrization for absolute stereocontrol, a diastereoselective cuprate addition and the use of a bifunctional vinyl silane building block. Our strategy also permits access to the enantiomer of the natural product and holds potential to access a multitude of xenicane natural products and analogs for structure-activity relationship studies.

Synthesis of 1-azabicyclo[2.1.1]hexanes via formal single electron reduction of azabicyclo[1.1.0]butanes under photochemical conditions.

C(sp3)-rich heterocycles are privileged building blocks for pharmaceuticals and agrochemicals. Therefore, synthetic methods that provide access to novel saturated nitrogen-containing heterocycles are in high demand. Herein, we report a general synthesis of 1-azabicyclo[2.1.1]hexanes (1-aza-BCH) via a formal cycloaddition of azabicyclo[1.1.0]butanes (ABB) with styrenes under photochemical conditions. To overcome the challenging direct single electron reduction of ABBs, we designed a polar-radical-polar relay strategy that leverages a fast acid-mediated ring-opening of ABBs to form bromoazetidines, which undergo efficient debrominative radical formation to initiate the cycloaddition reaction. The reaction is applicable to a broad range of ABB-ketones and we demonstrate the 1-aza-BCH products can be further functionalised to access larger saturated, conformationally rigid heterocycles.

Four-Step Synthesis of (-)-4-epi-Presilphiperfolan-8α-ol by Intramolecular Iron Hydride Atom Transfer-Mediated Ketone-Alkene Coupling and Studies to Access trans-Hydrindanols with a Botryane Scaffold.

From an (R)-(+)-pulegone-derived building block that incorporates the stereo-defined tertiary carbon bearing a methyl group, as found in the targeted sesquiterpenoid, a four-step synthesis of (-)-4-epi-presilphiperfolan-8-α-ol was achieved. The key processes involved are a ring-closing metathesis leading to a bridged alkene-tethered ketone and its subsequent FeIII -mediated metal-hydride atom transfer (MHAT) transannular cyclization. This synthetic method, implying an irreversible addition of a carbon-centered radical upon a ketone by means of a hydrogen atom transfer upon the alkoxy radical intermediate, was also applied in the synthesis of trans-fused hydrindanols structurally related to botrydial compounds.

Unexpectedly Large Structural Variations in Benzyl-Substituted Sila[1]ferrocenophanes.

A set of four planar-chiral sila[1]ferrocenophanes equipped with a benzyl group in the α-position, either on one or both Cp rings, and substituted on the bridging silicon atom, either by methyl or phenyl groups, were prepared. While NMR, UV/Vis, and DSC measurements did not show anything uncommon, single crystal X-ray analyses revealed unexpectedly large variations of the dihedral angles between both Cp rings (α tilt angle). While DFT calculations predicted α between 19.6 and 20.8°, measured values were found between 16.6(2) and 21.45(14)°. However, experimentally determined conformers differ significantly from those calculated for the gas phase. For the sila[1]ferrocenophane with the largest mismatch between the experimental and predicted α angle, it was shown that the orientation of benzyl groups have a significant influence on the ring-tilted structure. Packing of molecules in the crystal lattice forces benzyl groups into unusual orientations, resulting in a significantly reduced α angle through steric repulsions.

Synthesis and Applications of Bicyclo[1.1.0]butyl and Azabicyclo[1.1.0]butyl Organometallics.

The use of metalated (aza)bicyclo[1.1.0]butanes in synthesis is currently experiencing a renaissance, as evidenced by the numerous reports in the last 5 years that have relied on such intermediates to undergo unique transformations or generate novel fragments. Since their discovery, these species have been demonstrated to participate in a wide range of reactions with carbon and heteroatom electrophiles, as well as metal complexes, to facilitate the rapid diversification of (aza)bicyclo[1.1.0]butane-containing compounds. Key to this is the relative acidity of the bridgehead C-H bonds which promotes facile deprotonation and subsequent functionalization of an unsubstituted position on the carbon framework via the intermediacy of a metalated (aza)bicyclo[1.1.0]butane. Additionally, the late-stage incorporation of deuterium atoms in strained fragments has led to the elucidation of numerous reaction mechanisms that involve strained bicycles. The continued investigation into the inimitable reactivity of metalated bicycles will cement their importance within the field of organometallic chemistry.

Synthesis of Twisted [n]Cycloparaphenylene by Alkene Insertion.

Mono-alkene-inserted [n]cycloparaphenylenes 1 [(ene)-[n]CPP] with n=6, 8, and 10, mono-ortho-phenylene-inserted [6]CPP 2, and di-alkene-insertved [n]CPP 3 [(ene)2 -[n]CPP] with n=4, 6, and 8 were synthesized by fusing CPP precursors and alkene or ortho- phenylene groups through coupling reactions. Single-crystal X-ray diffraction analyses reveal that the strips formed by the π-surfaces of 1 and 2 exhibited a Möbius topology in the solid state. While the Möbius topology in the parent 1 and 2 in solution was lost due to the free rotation of the paraphenylene unit even at low temperatures, ene-[6]CPP 4 with eight 1-pyrrolyl groups preserved the Möbius topology even in solution. Despite a twist, 1 has in-plane conjugation and possesses a unique size dependence of the electronic properties: namely, the opposite size dependency of the HOMO-LUMO energy relative to conventional π-conjugated molecules.

Silver-Catalyzed Dearomative [2π+2σ] Cycloadditions of Indoles with Bicyclobutanes: Access to Indoline Fused Bicyclo[2.1.1]hexanes.

Bicyclo[2.1.1]hexanes (BCHs) are becoming ever more important in drug design and development as bridged scaffolds that provide underexplored chemical space, but are difficult to access. Here a silver-catalyzed dearomative [2π+2σ] cycloaddition strategy for the synthesis of indoline fused BCHs from N-unprotected indoles and bicyclobutane precursors is described. The strain-release dearomative cycloaddition operates under mild conditions, tolerating a wide range of functional groups. It is capable of forming BCHs with up to four contiguous quaternary carbon centers, achieving yields of up to 99 %. In addition, a scale-up experiment and the synthetic transformations of the cycloadducts further highlighted the synthetic utility.

Collective Synthesis of Chiral Tetrasubstituted Cyclobutanes Enabled by Enantioconvergent Negishi Cross-Coupling of Cyclobutenones.

Cyclobutenones provide a straightforward four-carbon ring platform for further structural elaborations in that every carbon atom of the ring could be potentially functionalized. We report here a nickel catalyzed enantioconvergent Negishi coupling of 4-iodocyclobutenones with an array of aryl or alkenyl zinc reagents to access enantioenriched 4-substituted cyclobutenones, from which a modular approach to the synthesis of 1,2,3,4-tetrasubstituted cyclobutanes was demonstrated.