Ring Expansion Research Articles

Ring Expansion of Pyrroles with Concomitant Nitrogen Deletion

Ring Expansion of Pyrroles with Concomitant Nitrogen Deletion

Phosphine-Mediated Reductive Insertion of α-Keto Esters and Isatins into Phthalic Anhydride Derivatives.

Herein, we report an unprecedented P(NMe2)3-mediated reductive insertion of 1,2-dicarbonyl compounds including α-keto esters and isatins into phthalic anhydride-derived alkenes and phthalic anhydrides, which furnishes the corresponding isochroman-1-ones and isochroman-1,4-diones, respectively, in moderate to excellent yields with high chemo- and regioselectivity. Furthermore, the asymmetric version of the ring expansion reaction could be realized by using a chiral auxiliary strategy. Mechanistically, the nucleophilic attack of the Kukhtin-Ramirez adduct, generated from P(NMe2)3 and 1,2-dicarbonyl compound, to the anhydride derivative, followed by a cascade ring-opening and ring-closure process, affords the ring expansion product. The reaction represents a novel metal-free carbon insertion ring expansion of aliphatic rings and also the first [1 + 5] annulation involving the Kukhtin-Ramirez adducts.

CYP3A-Mediated Carbon-Carbon Bond Cleavages in Drug Metabolism.

Cytochrome P450 enzymes (P450s) play a critical role in drug metabolism, with the CYP3A subfamily being responsible for the biotransformation of over 50% of marked drugs. While CYP3A enzymes are known for their extensive catalytic versatility, one intriguing and less understood function is the ability to mediate carbon-carbon (C-C) bond cleavage. These uncommon reactions can lead to unusual metabolites and potentially influence drug safety and efficacy. This review focuses on examining examples of C-C bond cleavage catalyzed by CYP3A, exploring the mechanisms, physiological significance, and implications for drug metabolism. Additionally, examples of CYP3A-mediated ring expansion via C-C bond cleavages are included in this review. This work will enhance our understanding of CYP3A-catalyzed C-C bond cleavages and their mechanisms by carefully examining and analyzing these case studies. It may also guide future research in drug metabolism and drug design, improving drug safety and efficacy in clinical practice.

A [2.2]Isoindolinophanyl-Based Carbene (iPC) Ligand: Synthesis, Electronic and Photophysical Properties, and Application in Photocatalysis.

Cyclic amino(alkyl) and cyclic amino(aryl) carbenes (cAACs/cAArCs) have been established as very useful ligands for catalytic and photonic applications of transition metal complexes. Herein, we describe the synthesis of a structurally related sterically demanding, electrophilic [2.2]isoindolinophanyl-based carbene (iPC) that bears a [2.2]paracyclophane moiety. The latter leads to more delocalized frontier orbitals and intense green fluorescence of (HiPC)OTf (2) from an intra-ligand charge transfer (1ILCT) state in the solid state. Base-promoted synthesis of the free carbene led to an unusual ring expansion and subsequent dimerization reaction, but the beneficial ligand properties can be exploited by trapping in situ at a metal center. The iPC ligand is a very potent π-chromophore, which participates in low energy metal-to-ligand (ML)CT transitions in [RhCl(CO)2(iPC)] (4) and IL-"through-space"-CT transitions in [Au(iPC)2]OTf (5). The steric demand of the iPC leads to high stability of 5 against air, moisture, or solvent attack, and ultralong-lived green phosphorescence with a lifetime of 185 μs is observed in solution. The beneficial photophysical and electronic properties of the iPC ligand, including a large accessible π surface area, were exploited by employing highly efficient energy transfer (EnT) photocatalysis in a [2+2] styrene cycloaddition reaction using 5, which outperformed other established photocatalysts in comparison.

De- and Rearomatisation of Pyridine in Silylene Chemistry.

Traditional methods relying on metal-ligand cooperation for activating pyridine bonds in de- and rearomatisation are being challenged by the abundant metal-free element species as alternatives. Here, we investigated the de/re-aromatisation of pyridine facilitated by pyridylamino-functionalised silylene reactions with ketones and ketene. The reactivity outcome is highly dependent on the substituents on the ketones. By carefully tuning the steric demand of the ketone, each intermediate of the reaction sequence could be isolated. At room temperature, benzophenone and acetophenone substrates led to dearomatisation of the pyridine moiety, with the case of acetophenone showing an intermediate silaoxirane preceding dearomatisation. However, when subjected to acetone or diphenylketene, only silaoxiranes were formed without dearomatisation of the pyridine moiety. Notably, only benzophenone-derived dearomatised species demonstrated rearomatisation upon heating. Furthermore, the reduced steric bulk of the ketene facilitated further ring expansion with another equivalent of the substrate, forming sila-1,3-dioxolanes. Both steric hindrance and aromatic groups collectively influence the dearomatisation of pyridine in pyridylaminosilylene reactions.

Ring expansion strategy to access functionalized 2-oxazolines (microreview)

Ring expansion strategy to access functionalized 2-oxazolines (microreview)

Copper-catalyzed intermolecular formal [4 + 1] annulation of 1,5-diynes with benzocyclobutenones

The one-carbon ring expansion of benzocyclobutenones is an efficient methodology for the assembly of cyclic ketones. However, hazardous reagents or noble metal catalysts are frequently required. Herein, we disclose a copper-catalyzed intermolecular formal [4 + 1] annulation of 1,5-diynes with benzocyclobutenones, allowing the practical and atom-economical construction of diverse pyrryl 1-indanones in generally good yields under mild reaction conditions. This reaction represents an important advancement in the ring expansion of benzocyclobutenones via vinyl cation pathway.

Coordination Chemistry of Calix[3]Pyrrole-Related Macrocycles

Calix[3]pyrrole is a ring-contracted porphyrinogen-like macrocycle in which three pyrrole units are linked by three sp3-carbon atoms at the a-positions. While synthetic routes to calix[3]pyrrole and its furan and thiophene derivatives have been established using oligoketone precursors,[1–3] their coordination chemistry remains fully unexplored. Here, the author reports the direct macrocyclization synthesis and metal complexation properties of novel thiazole-containing calix[3]pyrrole analogues that exhibit better metal chelation than that of calix[3]pyrrole.Treatment of calix[3]pyrrole (1) with n-butyl lithium (4 eq.) resulted in the deprotonation of all the NH protons to generate a tridentate trianionic ligand. Successive reaction with BBr3 furnished a boron(III)-complex 2 in 25% isolated yield. However, attempts to synthesize stable complexes with other metal ions were unsuccessful. The obtained boron complex 2 were unusually stable towards acids; even in pure trifluoroacetic acid (TFA) or methanesulfonic acid, no deboronation was observed, instead, protonation at a pyrrole carbon atom was detected by NMR spectroscopy.In order to generate isolable metal complexes with calix[3]pyrrole-related macrocycles, we have designed calix[1]pyrrole[2]thiazole (4). Calix[1]furan[2]thiazole (3), a precursor of 4, was synthesized by direct macrocyclization between bis(a-bromoketone) and 2,2-dimethylpropanebis(thioamide) in 60% yield. While calix[3]pyrrole (1)undergoes a strain-induced ring expansion reaction to give calix[6]pyrrole under acidic conditions, less strained 3 was stable in TFA, thus its furan moiety was hydrolyzed to a diketone moiety. Further Paal–Knorr pyrrole formation reaction led to the formation of 4 in 78% yield.When macrocycle 4 was mixed with Et2Zn, monoethyl zinc complex 5 was formed in 72% yield. Single crystal X-ray analysis revealed that 4 adopted a C s-symmetric cone conformation to behave as a monoanionic tridentate ligand. Due to the steric protection of the ethyl zinc center by meso-methyl groups, organozinc complex 5 was stable in the presence of excess water or alcohol at room temperature.Complexation of 4 with Pd(MeCN)4(BF4)2 afforded cationic palladium complex 6 in which macrocycle 4 adopted a partial cone conformation to chelate a Pd2+ ion as a neutral bidentate ligand. Similar complexation behavior was also observed with AgBF4, demonstrating conformational flexibility of macrocycle 4 upon metal complexation. Furthermore, coordination-driven self-assembly was confirmed for Ag+ complex of 4.In this presentation, the detailed synthesis and electronic properties of the metal complexes of calix[3]pyrrole-related macrocycles will be discussed.

Exploration of Synthesis and Coordination Chemistry of Thiazole-Containing Calix[3]Pyrroles

Calix[n]pyrroles have been used as powerful and specific receptors and as extractants for anions and ion pairs over the past 20 years. In the recent past, calix[4]pyrroles have been used as systems that can move ions and ion pairs over lipophilic membranes [1]. Unfortunately, the coordination chemistry of calix[n]pyrroles hardly explored. The ring-contracted analog of calix[n]pyrrole, calix[3]pyrrole, was synthesized and recently published [2]. The structure of calix[3]pyrrole and its analogues is strained, and they show an appealing strain-induced ring expansion response. On the other hand, the synthesis of calix[3]pyrrole requires multistep reactions including cyclization of hexaketone precursor and Paar–Knorr synthesis with the total yield of 4%. Extended use of calix[3]pyrrole analogues necessitates further refinement of the synthesis process.Here, we demonstrate the synthesis of new calix[3]pyrroles analogue, calix[1]pyrrole[2]thiazole (3). Direct macrocyclization between bis(α-bromoketone) and 2,2-dimethylpropane (bis-thioamide) produced the calix[1]furan[2]thiazole (1), with 60% yield. The furan unit of 1 was converted into pyrrole to give calix[1]pyrrole[2]thiazole 3 (Figure 1).Single-crystal X-ray analysis revealed a cone-shaped conformation of calix[1]pyrrole[2]thiazole 3, with all three heterocycles pointing in the same direction through strong intramolecular hydrogen bonding. However, unlike calix[3]pyrrole, calix[1]pyrrole[2]thiazole was completely stable under acidic conditions, which may be due to the basic nature of the thiazolimine units.Metal coordination of calix[1]pyrrole[2]thiazole was attempted and its Zn(II), Ag(I) and Pd(II) complexes were obtained by appropriate metalation procedures. The central metal ion of the Zn(II) complex is coordinated by a conical 3 and an axial ethyl group to behave as a monoanionic tridentate ligand. In contrast, it acts as a bidentate neutral ligand for Pd(II) or Ag(I) complexation. The synthesis of meso-aza calix[1]pyrrole[2]thiazole is in progress. Figure 1

Understanding the unusual life of the Cartwheel galaxy using stellar populations

Collisional ring galaxies (RiGs) are the result of the impact between two galaxies, with one of them passing close to the centre of the other, piercing its gaseous and stellar disc. In this framework, the impact generates a shock wave front that propagates within the disc of the target galaxy soon after the encounter, producing a characteristic expanding ring-shaped structure. RiGs represent one of the most extreme environments in which we can study the physical properties of galaxies and the transformations they undergo during collisions. The paradigm RiG is the Cartwheel galaxy at z = 0.03. This galaxy has been the object of both theoretical and observational studies, but the details of the mechanisms that lead to its peculiar morphology of double rings with connecting spokes and to its physical properties are still far from clear. To shed light on the history of the Cartwheel galaxy, we performed a spatially resolved analysis as a function of galactocentric distance, exploiting spectroscopic data from VLT/MUSE observations combined with photometric data covering a large wavelength range, from the UV GALEX to the IR JWST/MIRI. Using full-index fitting of the stellar spectra, an analysis of the nebular emission, and joint full spectral and photometry fitting, we derived stellar ages, gas and stellar metallicities, and star formation histories (SFHs) in four spatially distinct regions of the galaxy. We find that, apart from the peculiar morphology, a large fraction of the Cartwheel galaxy is not affected by the recent impact from the companion bullet, and retains the characteristics of a typical spiral galaxy. On the contrary, the outer ring is strongly affected by the recent impact, and is completely dominated by stars formed not earlier than ∼400 Myr ago. Our picture suggests that the collision shock wave, while moving forward to the external region of the galaxy, drags the already formed stars, sweeping the inner areas outwards, as proposed by recent collision models. At the same time, the ages found in the external ring are older than the predicted timescale of the ring expansion after the collision.

Photoinduced Ring Expansion for the Construction of Medium-Sized Lactams via Nitrogen Radicals

Photoinduced Ring Expansion for the Construction of Medium-Sized Lactams via Nitrogen Radicals

A high-rate, impact-driven biaxial fragmentation experiment for ductile materials

The experimental investigation of high strain rate fragmentation has generally been limited to one of two cases: analytically powerful but simple one-dimensional loading configurations, or complicated multiaxial experiments more closely approximating use applications. The former, exemplified by Mott-style ring fragmentation, promotes simple and confident analysis—forming the backbone of the field and revealing the basic nature of dynamic fragmentation in solids—but ignores some critical mechanisms in order to achieve that simplicity. The latter, while informing applications of interest such as ballistic impact, may provide limited insight and is often difficult to access diagnostically. This work presents an attempt to help bridge the gap between 1D ring expansion and 3D fragmentation experiments in the form of impact driven, high-strain-rate biaxial tensile fragmentation experiments. The impact target system consists of a thin specimen plate and a thick polymer impact buffer. The latter serves as a fluid-like medium allowing momentum transfer between an impacting projectile and a rapidly growing near-hemispherical bulge in the specimen plate. The deformation of the specimen and fragmentation pattern are observed using ultra-high-speed optical imaging as well as flash x-ray imaging, and individual fragments are recovered and characterized post-mortem. Using this method, the fragmentation behavior of 6061-T6 Aluminum is investigated at tensile strain rates exceeding 105s−1 and at higher stress triaxiality than that commonly achieved.

TBN as Organic Redox Cocatalyst for Oxidative Tiffeneau-Demjanov-Type Rearrangement Using O2 as Sole Oxidant.

The Tiffeneau-Demjanov-type rearrangement is a ring-expansion reaction involving the cationic rearrangement of cyclic alcohols. The carbocation intermediates can be generated in situ via various means, including Wacker oxidation. In near recent reports on the reinvestiagtions by Wahl et al. (Sietmann, J.; Tenberge, M.; Wahl, J. M. Wacker Oxidation of Methylenecyclobutanes: Scope and Selectivity in an Unusual Setting. Angew. Chem., Int. Ed. 2023, 62, e202215381) and Zhu et al. (Feng, Q.; Wang, Q.; Zhu, J.-P. Oxidative Rearrangement of 1,1-Disubstituted Alkenes to Ketones. Science 2023, 379, 1363-1368), stoichiometric oxidants were involved. In this work, we report the Tiffeneau-Demjanov-type rearrangement can be smoothly promoted by the Pd-TBN cocatalyzed aerobic Wacker oxidation using molecular oxygen as the sole oxidant. tert-Butanol is essential for achieving high yields. Since the first report by Grigg et al. in 1977 (Boontanonda, P.; Grigg, R. J. Palladium (II)-Catalysed Ring Expansion of Methylenecyclobutanes and Related Systems. J. Chem. Soc. Chem. Commun. 1977, 17, 583-584), the five-decade journey of Pd-catalyzed Tiffeneau-Demjanov-type rearrangement returns to the aerobic again.

The downregulation of genes encoding muscle proteins have a potential role in the development of scrotal hernia in pigs.

Testicular descent is a physiological process regulated by many factors. Eventually, disturbances in the embryological/fetal development path facilitate the occurrence of scrotal hernia, a congenital malformation characterized by the presence of intestinal portions within the scrotal sac due to the abnormal expansion of the inguinal ring. In pigs, some genes have been related to this anomaly, but the genetic mechanisms involved remain unclear. This study aimed to investigate the expression profile of a set of genes potentially involved with the manifestation of scrotal hernia in the inguinal ring tissue. Tissue samples from the inguinal ring/canal of normal and scrotal hernia-affected male pigs with approximately 30 days of age were used. Relative expression analysis was performed using qPCR to confirm the expression profile of 17 candidate genes previously identified in an RNA-Seq study. Among them, the Myosin heavy chain 1 (MYH1), Desmin (DES), and Troponin 1 (TNNI1) genes were differentially expressed between groups and had reduced levels of expression in the affected animals. These genes encode proteins involved in the formation of muscle tissue, which seems to be important for increasing the resistance of the inguinal ring to the abdominal pressure, which is essential to avoid the occurrence of scrotal hernia. The downregulation of muscular candidate genes in the inguinal tissue clarifies the genetic mechanisms involved with this anomaly in its primary site, providing useful information for developing strategies to control this malformation in pigs and other mammals.

Post-Synthetic Modification of Calix[4]arene Framework by Iridium-Mediated Alkyne Insertion into an Inert C-C Bond: A Novel Strategy for Unsymmetrical Macrocycles.

As a novel synthetic method for unsymmetrical macrocycles, we herein developed a post-synthetic modification of calix[4]arenes by insertion of a terminal alkyne into an inert C(methylene)-C(aryl) bond of the macrocyclic framework. In this transformation, C-iridated calix[4]arenes, readily synthesized through C-H bond activation of the parent calix[4]arene, undergoes C(methylene)-C(aryl) bond cleavage followed by insertion of an alkyne to provide a ring-expanded calix[4]arene complex. Removal of the iridium metal from the resulting complex was readily accomplished by a simple treatment with an acid. The developed sequential method affords novel unsymmetrical, monofunctionalized macrocyclic compounds via 3 steps from the parent calix[4]arene in good yield. The unique unsymmetrical structures of the alkyne-inserted macrocycles were evaluated by X-ray single crystal analyses. On the basis of theoretical calculations, we propose a reaction mechanism involving an uncommon C-C bond cleavage step through δ-carbon elimination for the ring enlargement process.

Zinc Carbenoid-Promoted Methylene Insertion in Saturated Heterocycles: Mechanistic Insights and Reactivity Profiles

AbstractThe ring expansion of saturated heterocycles through methylene insertion into N–O bonds using a zinc carbenoid is described. This transformation is applied to 1,2-oxazetidines and 1,2-oxazolidines, while N-tosylated 1,2-oxazinane affords a ring-opened product. Density functional theory calculations suggest a stepwise reaction mechanism of the ring expansion and elucidate the origins of the different reactivities observed.

Rearrangement, Elimination, and Ring-Opening Reactions of Cyclopropyl-Substituted Nitrenium Ions: A Computational and Experimental Investigation.

N-(4-Biphenylyl)-N-cyclopropyl nitrenium ion 5 and N-benzyl-N-cyclopropyl nitrenium ion (6) were generated through photolysis of their corresponding N-aminopyridinium ion photoprecursors. In the case of 5, stable products result from a combination of cyclopropyl ring expansion (N-biphenylazetium ion) and ethylene elimination (biphenylisonitrilium ion). When present in high concentrations, methanol can add to the cyclopropyl ring-forming N-3-methoxypropyl-N-biphenyl iminium ion. In contrast, the only detectable product from the N-benzyl-N-cyclopropyl nitrenium ion (6) is benzylisonitrile, resulting from the elimination of ethylene. Density functional theory (DFT) calculations predict the product distributions from the more stable biphenyl system 5 with reasonable accuracy. However, product distributions from the less stable benzyl system 6 are forecast with less accuracy.

Cu‐Catalyzed Synthesis of [1,2,3]triazolo[1,5‐c]quinazolin‐5(6H)‐one Derivatives via Sequential Reaction of Ethyl‐2‐(2‐oxoindolin‐3‐ylidene)acetate with Sodium Azide

AbstractHerein, we report a novel and efficient method for the synthesis of new class of 5‐oxo‐5,6‐dihydro‐[1,2,3]triazolo[1,5‐c]quinazoline derivatives by copper‐catalyzed reaction of α, β‐unsaturated keto/ester methyleneindolinone with sodium azide at room temperature via an azide‐alkene cyclization and ring expansion rearrangement. This method is applicable to a variety of α, β‐unsaturated keto/ester methyleneindolinone and displayed wide functional group tolerance.

Aromatic 1,4,2,3-Diazadiborole Featuring an Unsymmetrical B=B Entity: A Versatile Synthon for Unusual Boron Heterocycles.

The replacement of a CC unit with an isoelectronic BN unit in aromatic systems can give rise to molecules and materials with fascinating properties. We report here the synthesis, characterization, and reactivity of a 1,4,2,3-diazadiborole species, 2, featuring an unprecedented 6π-aromatic BN-heterocyclic moiety that is isoelectronic to cyclopentadienide (Cp-). Bearing an unsymmetrical B=B entity, 2 exhibits reactivity toward oxidants, protic reagents, electrophiles, and unsaturated substrates. This reactivity facilitates the synthesis of a variety of novel mono- and bicyclic organoboron derivatives through mechanisms including ring retention, cleavage/recombination, annulation, and expansion. These findings reveal innovative synthetic routes to BN-embedded aromatic compounds via desymmetrization, affording unique building blocks for synthetic chemistry.

Aromatic 1,4,2,3‐Diazadiborole Featuring an Unsymmetrical B=B Entity: A Versatile Synthon for Unusual Boron Heterocycles

AbstractThe replacement of a CC unit with an isoelectronic BN unit in aromatic systems can give rise to molecules and materials with fascinating properties. We report here the synthesis, characterization, and reactivity of a 1,4,2,3‐diazadiborole species, 2, featuring an unprecedented 6π‐aromatic BN‐heterocyclic moiety that is isoelectronic to cyclopentadienide (Cp−). Bearing an unsymmetrical B=B entity, 2 exhibits reactivity toward oxidants, protic reagents, electrophiles, and unsaturated substrates. This reactivity facilitates the synthesis of a variety of novel mono‐ and bicyclic organoboron derivatives through mechanisms including ring retention, cleavage/recombination, annulation, and expansion. These findings reveal innovative synthetic routes to BN‐embedded aromatic compounds via desymmetrization, affording unique building blocks for synthetic chemistry.