Cyclization Research Articles

Dimethylnonacethrene - en route to a magnetic switch.

Dimethylnonacethrene is the first derivative of the cethrene family that is energetically more stable than the product of its electrocyclic ring closure. Compared to the shorter homologue dimethylcethrene, the new system is EPR-active, because of a significantly lowered singlet-triplet gap, and displays remarkable stability. Our results suggest that adjustment of the steric bulk in the fjord region can enable realisation of diradicaloid-based magnetic photoswitches.

Primary nitro compounds: progress in the synthesis of isoxazoles by condensation with aldehydes or activated ketones.

Among the known strategies directed towards the synthesis of isoxazole derivatives, the reactions of aldehydes with primary nitro compounds deserve a comprehensive treatment, including the historical development as well as the more recent applications. The reactions of aldehydes with primary nitro compounds in a 1 : 2 molar ratio have been shown to lead to isoxazoline-N-oxides or isoxazole derivatives, via β-dinitro derivatives. Several modifications of the process allowed the formation of products bearing substituents at various positions of the heterocyclic ring with control of regioselectivity. Ketones are reported to react with primary nitro compounds, only if activated (β-diketones, α-nitroketones, or strained ketones), to give isoxazole derivatives. Symmetric 2,4-dinitroglutarates formed from aromatic aldehydes and nitroacetate undergo ring closure to form isoxazole derivatives or, according to reaction conditions, 5-hydroxy-6-oxo-4-aryl-6H-1,2-oxazine-3-carboxylates ("oxazinones"), by loss of alcohol instead of water. Isoxazole-4-carbaldehydes are obtained by the reaction of 3-oxetanone with primary nitro compounds.

The effect of thread-like monomer structure on the synthesis of poly[n]catenanes from metallosupramolecular polymers.

The main-chain poly[n]catenane consists of a series of interlocked rings that resemble a macroscopic chain-link structure. Recently, the synthesis of such intriguing polymers was reported via a metallosupramolecular polymer (MSP) template that consists of alternating units of macrocyclic and linear thread-like monomers. Ring closure of the thread components has been shown to yield a mixture of cyclic, linear, and branched poly[n]catenanes. Reported herein are studies aimed at accessing new poly[n]catenanes via this approach and exploring the effect the thread-like monomer structure has on the poly[n]catenane synthesis. Specifically, the effect of the size of the aromatic linker and alkenyl chains of the thread-like monomer is investigated. Three new poly[n]catenanes (with different ring sizes) were prepared using the MSP approach and the results show that tailoring the structure of the thread-like monomer can allow the selective synthesis of branched poly[n]catenanes.

The xanthate route to tetralones, tetralins, and naphthalenes. A brief account.

The present account summarises routes to tetralones, tetralines, and naphthalenes based on the chemistry of xanthates developed in the authors' laboratory. The degenerative reversible transfer of xanthates allows radical addition even to unactivated, electronically unbiased alkenes, and tolerates a broad range of functional groups, in particular common polar groups such as esters, ketones, nitriles, amides, carbamates, etc. Xanthates also allow radical ring closures onto aromatic rings. This feature, in combination with the intermolecular addition to alkenes, can be used to construct tetralones and tetralines. With the appropriate appendages, the former can be converted into napthalenes with a variety of substitution patterns. This translates into a convergent approach to a vast array of building blocks of interest to the pharmaceutical and agrochemical industries, and to material sciences.

Rapid, room-temperature self-organization of polyarylated 1H-pyrroles from acetylenes and nitriles in the KOBut/DMSO system.

We have discovered that three molecules of arylacetylene are rapidly (15 min) assembled with one molecule of nitrile at room temperature in the KOBut/DMSO system to afford 2-aryl-3-arylethynyl-4-aryl-5-benzyl-1H-pyrroles in up to 76% yield. We assume that this unprecedented self-organization process involves the cascade addition of acetylenic carbanions, first to the CN, then to the CC and CC bonds of the intermediates, followed by pyrrole ring closure via the intramolecular nucleophilic addition of the NH functional group to the CC bond of the final intermediates.

Amidinoquinoxaline N-oxides: synthesis and activity against anaerobic bacteria.

We present herein an in-depth study on the activity of amidinoquinoxaline N-oxides 1 against Gram-positive and Gram-negative anaerobic bacteria. Based on 5-phenyl-2,3-dihydropyrimidoquinoxaline N-oxide 1a, the selected structural variations included in our study comprise the substituents α- to the N-oxide function, the benzofused ring, substitution and quaternization of the amidine moiety, and the amidine ring size. Compounds 1 showed good to excellent antianaerobic activity, evaluated as the corresponding CIM50 and CIM90 values, and an antimicrobial spectrum similar to metronidazole. Six out of 13 compounds 1 had CIM90 values significantly lower than the reference drug. Among them, imidazoline derivatives 1i-l were the most active structures. Such compounds were synthesized by base-promoted ring closure of the corresponding amidines. The N-oxides under study showed no significant cytotoxicity against RAW 264.7 cells, with high selectivity indexes. Their calculated ADME properties indicate that the compounds are potentially good oral drug candidates. The antianaerobic activity correlated satisfactorily with the electron affinity of the compounds, suggesting that they may undergo bioreductive activation before exerting their antibacterial activity.

Synthesis of benzo[a]carbazole derivatives via intramolecular cyclization using Brønsted acidic carbonaceous material as the catalyst.

In this work, a new procedure for the synthesis of benzo[a]carbazole from 1,3-diketones, primary amines, phenylglyoxal monohydrate, and malononitrile employing a solid acidic catalyst has been developed. The multicomponent reaction provided 3-cyanoacetamide pyrrole as an intermediate and then the formation of benzo[a]carbazole via intramolecular ring closure. The reaction was carried out for 2 h at 240 °C, resulting in the desired product with 73% yield. Acidic sites on the solid acid catalyst, made from rice husk-derived amorphous carbon with a sulfonic acid core (AC-SO3H), provided the best activity. Acidic sites on the surface of the catalyst, including carboxylic, phenolic, and sulfonic acids, were 4.606 mmol g-1 of the total acidity. AC-SO3H demonstrated low cost, low toxicity, porosity, stability, and flexibility of tuning and reusability.

Efficient Buchwald-Hartwig and nitrene-mediated five-membered ring closure approaches to the total synthesis of quindoline. Unexpected direct conversion of a nitro group into a phosphazene.

Two total syntheses of quindoline, which take place through the intermediacy of 3-nitroquinoline derivatives, are reported. The general synthetic sequence involves construction of the latter by mechanochemical condensation of benzaldehydes with 2-amino-nitrostyrene, followed either by reduction of the nitro group of the heterocycle and Buchwald-Hartwig cyclization or by a nitrene-mediated cyclization under solventless conditions. Use of PPh3 to generate the nitrene resulted in the unprecedented formation of a phosphazene in place of quindoline. This unexpected transformation was explained by means of DFT computations.

Dual and sequential locked/unlocked photo-switching effects on FRET processes by tightened/loosened nano-loops of diarylethene-based [1]rotaxanes.

The self-trapping nano-loop structures of [1]rotaxanes exhibited multiple Förster resonance energy transfer (FRET) patterns via dual and sequential locking/unlocking of pH-gated and UV exposure processes. As a tightened and constrained nano-loop in the acidic condition, dithienylethene (DTE) unit was locked in the highly bending open form to forbid ring closure upon UV irradiation.

Tuning the photochemical ring-closing reaction efficiency in diarylethene-based photoswitches through engineering of internal charge transfer.

The photochemical quantum yield is one of the key features for a photoswitch and its tuning is challenging. In an attempt to tackle this issue within the popular diarylethene-based switches, we have explored the potential to use internal charge transfer (CT), a readily controllable parameter, for an effective modulation of the photocyclization quantum yield. For this, a homogeneous family of terarylenes, a sub-class of diarylethenes, with different CT characters, but the same photochromic core was designed and its photochromic properties were fully investigated. A clear correlation was found between the cyclization quantum yield and the CT character of the switch. More precisely, almost linear relationships were established between the ring-closing quantum yield and (i) the electron density variation accompanying the S0 → S1 transition and (ii) the percentage of LUMO on the reactive carbon atoms. Such a correlation was rationalized by a joint spectroscopic analysis and theoretical modelling of both ground and first excited states, introducing the concept of "early" or "late" photochromes. Encouragingly, such a potentally predictive model also seemed relevant when applied to some other diarylethene-based switches reported in the literature.

Photoresponsive reversible self-assembly of rod-coil amphiphiles containing spiropyran groups.

Stimuli-responsive assembly deformation is a key feature in constructing smart soft materials, which makes them versatile and autonomous. In this study, rod-coil amphiphilic compounds containing spiropyran (SP) groups were developed and synthesized to investigate their stimuli-responsive assembly in a solution system with 99% water content. In addition to photochromic phenomena, reversible light-mediated morphological alterations occurred in these molecular aggregates. Based on the different flexible chain segments of rod-coil amphiphiles, the initial assemblies underwent a dissociation-reassembly process under ultraviolet (UV) irradiation, whereupon they deformed or disassembled to assemblies. Furthermore, as the UV source was removed, the original nanostructures were gradually recovered again via the ring-closing reaction process. These compounds, interestingly, can selectively combine with copper ions to produce cross-linked co-assembled nanostructures. The copper ion complex solution of rod-coil amphiphilic compounds emitted unique bright blue fluorescence, which allowed for the specific visual identification of copper ions in aqueous solutions.

Predictable incorporation of nitrogen into carbon dots: insights from pinacol rearrangement and iminium ion cyclization.

Nitrogen-doped carbon dots (CDs) have attracted considerable attention across various research areas and applications due to their enhanced optical properties and photostability. However, the mechanism of nitrogen incorporation in CDs remains elusive, hampering the precise control over nitrogen-incorporated structures and the investigation of the effects of nitrogen on the electronic structure and optical properties of CDs. In this study, we employed a rational design approach, utilizing glucosamine and ethylene glycol as the carbon source and co-reagent, respectively, to synthesize N-doped CDs. Our synthesis strategy involved pinacol rearrangement and iminium ion cyclization reactions, enabling the reliable formation of N-doped CDs. Notably, the resulting CDs exhibited distinctive emissive states attributed to heteroatomic defect structures, including oxygenic and nitrogenic polycyclic aromatic hydrocarbons. To gain further insights into their energy levels and electronic transitions, we conducted comprehensive investigations, employing extended Hückel calculations and pump-probe spectroscopy. The synthesized CDs displayed great promise as bioimaging and photodynamic therapy agents, highlighting their potential for biomedical applications. Moreover, our study significantly contributes valuable insights into the rational design of N-doped CDs with controllable chemical and electronic structures, thereby paving the way for advancements in their diverse range of applications.

Ring-Opening Metathesis Polymerization and Related Olefin Metathesis Reactions in Benzotrifluoride as an Environmentally Advantageous Medium

A tremendous number of solvents, either as liquids or vapors, contaminate the environment on a daily basis worldwide. Olefin metathesis, which has been widely used as high-yielding protocols for ring-opening metathesis polymerization (ROMP), ring-closing metathesis (RCM), and isomerization reactions, is typically performed in toxic and volatile solvents such as dichloromethane. In this study, the results of our systematic experiments with the Grubbs G1, G2, and Hoveyda-Grubbs HG2 catalysts proved that benzotrifluoride (BTF) can replace dichloromethane (DCM) in these reactions, providing high yields and similar or even higher reaction rates in certain cases. The ROMP of norbornene resulted not only in high yields but also in polynorbornenes with a high molecular weight at low catalyst loadings. Ring-closing metathesis (RCM) experiments proved that, with the exception of the G1 catalyst, RCM occurs with similar high efficiencies in BTF as in DCM. It was found that isomerization of (Z)-but-2-ene-1,4-diyl diacetate with the G2 and HG2 catalysts proceeds at significantly higher initial rates in BTF than in DCM, leading to rapid isomerization with high yields in a short time. Overall, BTF is a suitable solvent for olefin metathesis, such as polymer syntheses by ROMP and the ring-closing and isomerization reactions.

Synthesis and coordination of a dipyrrin appended N-confused porphyrin

A hexapyrrane P6 with a terminal N-confused pyrrole was synthesized by acid-catalyzed [3+3] condensation followed by oxidation with DDQ, which did not afford the expected N-confused hexaphyrin. In stead, a rearranged product, i.e., [Formula: see text]-dipyrrin appended N-confused porphyrin 1 was obtained in a yield of 46%. Chelation of 1 with Pt(II) afforded the peripheral complex 1-Pt, which was further coordinated with Rh(I) in the cavity to afford the corresponding bimetallic complex 1-Pt-Rh. Both 1-Pt and 1-Pt-Rh exhibit split Soret-like bands and noticeable Q-like bands tailing to the NIR region up to ca. 1200 nm. Single crystal X-ray diffraction analyses of 1 and 1-Pt revealed that the peripheral coordination of Pt(II) slightly modifies the interplanar angle between the porphyrin macrocycle and the dipyrrin unit, which may modulate the absorption spectra. The results of this work compose an interesting example of synthesizing porphyrinoids appended with conjugated peripheral chains by the oxidative ring closure reaction of an oligopyrrane containing a terminal N-confused pyrrole, and such compounds may be used for both inner and peripheral coordination to afford complexes with tunable NIR absorption.

2-[2-(Diphenylphosphoryl)phenyl]-1H-perimidine

In this paper, we report the crystal structure of 2-[2-(diphenylphosphoryl)phenyl]-1H-perimidine (L1) obtained from the ring closure reaction of 1,8-diaminonaphthalene and 2-(diphenylphosphino)benzaldehyde, followed by the dehydrogenation reaction with sodium metabisulfite (Na2S2O5). L1 was characterised using 1H, 13C & 31P NMR, FT-IR and X-ray single structure analyses.

Preparation and Functionalization of Mono- and Polyfluoroepoxides via Fluoroalkylation of Carbonyl Electrophiles.

We outline a new synthetic method to prepare mono- and poly-fluoroepoxides from a diverse pool of electrophiles (ketones, acyl chlorides, esters) and fluoroalkyl anion equivalents. The initially formed α-fluoro alkoxides undergo subsequent intramolecular ring closure when heated. We demonstrated the versatility of the method through the isolation of 16 mono- and poly- fluoroepoxide products. These compounds provide unique entry points for further diversification via either fluoride migration coupled with ring opening, or defluorinative functionalization reactions, the latter of which can be used as a late-stage method to install select bioactive moieties. The reaction sequences described herein provide a pathway to functionalize the commonly observed products formed from 1,2-addition into carbonyl electrophiles.

The thermodynamic and kinetic aspects of midazolam ring closure from benzophenone to benzodiazepine form, its acid–base equilibria and aromaticity: a quantum-chemical study

The process of midazolam ring closure was studied from the thermodynamic and kinetic points of view by means of quantum-chemical methods. B3LYP/6–311 + + G(d,p) model was employed for gas phase and water environment (polarizable continuum model) calculations. It was concluded that the reaction rate determining step is the first step—carbinolamine formation from amine and carbonyl ends of the opened benzodiazepine ring. The Gibbs free energy of activation was calculated as 35.1 kcal/mol for gas- phase and 33.9 kcal/mol for water environment. Intrinsic reaction coordinate calculations were performed to verify that the transition state really connects the substrate and product. Thermodynamically, this reaction is endoergic with ΔG = 9.6 kcal/mol for gas phase and 10.0 kcal/mol for water environment. However, the next step—carbinolamine protonation with immediate water molecule loss is expected to be fast and activation barrierless, which enables further progress of the ring closure, despite the positive ΔG of the fist step. Next, the protonated imine undergoes deprotonation to final closed ring, pharmacologically active molecule of midazolam. The whole chain of reaction is exoergic with ΔG equal to − 5.6 kcal/mol for gas phase and − 7.7 kcal/mol for water environment. In order to understand the role of other than benzodiazepine/imidazole molecular fragments on the ring closure process, a model was build which contains only benzodiazepine and imidazole rings. The activation barrier for the carbinolamine formation of the model is similar to midazolam in the gas phase but higher by about 10 kcal/mol for water environment. The most interesting difference is however that for the model, the carbinolamine formation step is exoergic with ΔG equal to − 2.2 kcal/mol for gas phase and − 1.8 kcal/mol for water environment. This difference can be connected to complicated conformational shape of the midazolam molecule, which during the ring closure undergoes unfavorable deformations with accompanying rise of the energy of the molecule. The protonation sites for both midazolam and the model were also studied. In the case of midazolam, the preferred protonation site is the imidazole ring nitrogen atom, but in the case of the model it is the benzodiazepine ring nitrogen atom. The aromaticity of the 5- and 7-membered rings were analyzed using two aromaticity—HOMA and pEDA. It follows that larger stability of the cation protonated at the benzodiazepine ring is accompanied with substantial increase of the 7-ring aromaticity in the model of midazolam. The complexes of midazolam and its model with a water molecule were analyzed because they are needed for evaluation of the energy of the whole process of ring closure. In the case of midazolam, the water molecule preferentially connects to imidazole ring, but in the case of the model, complexes with both imidazole and benzodiazepine rings have similar stability.

Petasis Sequence Reactions for the Scaffold-Diverse Synthesis of Bioactive Polycyclic Small Molecules.

The multicomponent Petasis reaction is a versatile method to access functionalized amines. The combination of Petasis reaction with subsequent ring-closing reactions is a powerful strategy to build novel polycyclic scaffolds. In this study, we report the generation of a diverse set of small molecules with polycyclic scaffolds featuring a high content of sp3-hybridized carbon atoms and multiple stereogenic centers by employing three-component Petasis reaction (3C-PR)-Intramolecular Diels-Alder (IMDA) and 3C-PR-ring-closing metathesis (RCM)-IMDA sequence reactions. This work demonstrates the wide substrate tolerance and broad applicability to access unexplored polycyclic scaffolds of biological interest using Petasis sequence reactions.

Methyl 12-Methyl-3,9-dinitro-5,6,7,12-tetrahydro-13-oxodibenzo[b.g]bicyclo[3.3.1]nonane-6-carboxylate and Related Compounds

A synthesis of the title compound and related structures is reported. The procedure involves double alkylation of a β-ketoester followed by double SNAr ring closure from the γ carbon to give a dibenzo[3.3.1]bicyclic unit. This paper appears to be the first to generate a mid-sized bicyclic target by a double SNAr process. The synthesis can be performed in one step, but yields are superior (52–62%) when a two-stage procedure is used.

Dual and Sequential Locked/Unlocked Photochromic Effects on FRET Controlled Singlet Oxygen Processes by Contracted/Extended Forms of Diarylethene-Based [1]Rotaxane Nanoparticles.

Manipulations of singlet oxygen (1 O2 ) generations by the integration of both aggregation-induced emission luminogen (AIEgen) photosensitizer and photochromic moieties have diversified features in photodynamic therapy applications. Through Förster resonance energy transfer (FRET) pathway to induce red PL emissions (at 595nm) for 1 O2 productions, [1]rotaxane containing photosensitive tetraphenylethylene (TPE) donor and photochromic diarylethene (DAE) acceptor is introduced to achieve dual and sequential locked/unlocked photoswitching effects by pH-controlled shuttling of its contracted/extended forms. Interestingly, the UV-enabled DAE ring closure speeds follow the reversed trend of DAE self-constraint degree as: contracted < extended < noninterlocked forms in [1]rotaxane analogues, thus FRET processes can be adjusted in contracted/extended forms of [1]rotaxane upon UV irradiations. Accordingly, the contracted form of [1]rotaxane is FRET-OFF locked and inert to UV exposure due to the larger bending conformation of DAE parallel (p-)conformer, compared with its extended and noninterlocked analogues possessing switchable FRET-OFF/ON behaviors activated by dual and sequential pH- and photoswitching. Owing to the advantages of 1 O2 productions tuned by multistimuli inputs (pH, UV, and blue light), an useful logic circuit for toxicity outputs of the surface modified [1]rotaxane nanoparticles (NPs) has been demonstrated to offer promising 1 O2 productions and managements based on mechanically interlocked molecules for future bioapplications.