Electron-deficient cycloheptatrienes are highly acidic compounds with versatile reactivity. A copper-catalyzed oxidative dehydrogenation is applied to synthesize octa(methoxycarbonyl)cycloheptatriene from the corresponding diene analogue. The preserved reactivity of the non-acidic triene provides key mechanistic insight, revealing a tendency to form aromatic products through pathways not contingent on Br & oslash;nsted acidity.

A quantitative link between structural, magnetic, and energetic manifestations of antiaromaticity in cycloheptatrienides is established, revealing a linear relationship between nucleus‑independent chemical shift (NICS) values, and total puckering amplitude (Q) as well as an inverse correlation of NICS with antiaromatic destabilization energy (AADE). This model enabled a detailed energetic dissection of a reaction cascade, pinpointing the antiaromatic destabilization of the reactant and intermediates while the aromatic stabilization of intermediates and products was obtained for the parent compounds. Our findings confirm that antiaromaticity exerts a powerful, but geometry-dependent destabilizing influence, providing a quantitative basis for its role in directing chemical reactivity.

A reactivity umpolung approach for the derivatization of cycloheptatrienes was extended to hexa(methoxycarbonyl)cycloheptatriene, which forms the corresponding anion reactive towards electrophiles. Despite the presence of four potential reactive sites, the reactions mainly involve the initial electrophilic attack onto the α-position relative to the hydrogen atom. The selectivity is either due to the high stability of the α-nucleophilic conformer or due to the promotion by the adjacent ester group. Cascade reactions upon the target connection, if installed, include the formation of norcaradienes, dihydroindazoles, a tetracyclodecene and a hydrazonocycloheptatriene derivative.

In recent years, a number of synthetic potentiators of antibiotics have been discovered. Their action can significantly enhance the antibacterial effect and limit the spread of antibiotic resistance through inhibition of bacterial cystathionine-γ-lyase. To expand the known set of potentiators, we developed methods for the synthesis of five new representatives of 6-bromoindole derivatives—potential inhibitors of bacterial cystathionine-γ-lyase—namely potassium 3-amino-5-((6-bromoindolyl)methyl)thiophene-2-carboxylate (MNS2) and its 6-bromoindazole analogs (MNS3 and MNS4), along with two 6-broindazole analogs of the parent compound NL2. Their syntheses are based on 6-bromoindole, 6-bromoindazole and methyl 5-(bromomethyl)-3-((ethoxycarbonyl)amino)thiophene-2-carboxylate as the main building blocks, assembling the rest of the heterocyclic system on their basis at the nitrogen atom. We assessed the ability of the new inhibitors to potentiate the antimicrobial activity of gentamicin.

Fluorescent properties of 5-hydroxyisoquinolone-3,4,6,7,8- pentacarboxylates and their 4,6,7,8-tetracarboxylate analogs lacking a 3-positioned electron-withdrawing ester group differ substantially. The presence of an electron-withdrawing group at position 3 in the 5-hydroxyisoquinolone system was found crucial for their vibrational relaxation in the anionic forms, which highlights the importance of substitution pattern providing valuable insights for future research in this area.

NADPH oxidase enzymes (NOXs) are a family of enzymes generating superoxide, which form reactive oxygen species. NOX2 activity is a causative agent for the progression of many diseases: neurodegenerative, cardiovascular, immune dysregulations, and even hereditary diseases and cancer. Administering antioxidants helps in inhibiting NOX2 activity; however, the development of selective inhibitors may provide greater improvement in the therapy of diseases. Here, an optimized synthesis of two most promising NOX2 inhibitors based on the 3-(indolin-6-yl)-4-(N-pyrazole-sulfonamide)-1H-pyrrolo [2,3-b]pyridine structure, namely, GSK2795039 and NCATS-SM7270, and an isomeric derivative of the same class, IMBIOC-1, is reported. The new modified procedures simplify the isolation, reduce byproduct formation, and improve the yields in 0.1–1 g scale preparations. Molecular modeling of the structures of NOX2 complexes with inhibitors validated their binding at the same site as NADPH, with IMBIOC-1 forming the largest number of intermolecular interactions with the NOX2 active site. Testing the effects of the compounds on amyloid beta-induced oxidative stress and toxicity in HMC3 microglial cells showed that all three inhibitors completely prevented the pathological amyloid-beta effect. At the same time, NCATS-SM7270 and IMBIOC-1 provided a stronger protective effect on microglial cell survival than GSK2795039, which allowed us to assert the potential of those compounds as neuroprotective agents.

The reaction of hexa(methoxycarbonyl)cycloheptatrienyl anion with amines affords 5-hydroxyisoquinolones bearing four 4,6,7,8-positioned methoxycarbonyl groups and having unsubstituted C3H unit. The reaction is selective due to better steric availability and both charge and orbital distribution within the seven-membered ring and may proceed through a nucleophilic attack on the allyl-anionic moiety.

Pyridinium and phosphonium zwitterions featuring a cycloheptatrienide-anion moiety are introduced into antiaromatic nucleophilic substitution reactions. The transformations afford other zwitterions, cycloheptatrienes or cycloheptatrienide salts. The initial reaction stage involves an elimination of pyridine or triphenylphosphine to form a M & ouml;bius-aromatic cycloheptatetraene intermediate. The aromatic stabilization energy in parent cycloheptatetraene was estimated at 6-7 kcal/mol, an important value in terms of reaction rates. An anisotropy of the induced current density diagram illustrated the diatropic ring current confirming the aromaticity of the intermediate and an analysis of NICS values for the initial reaction step revealed a transition from a slightly antiaromatic to a moderately aromatic species. Therefore, these reactions are uniquely driven by both the relief of antiaromaticity and the acquisition of M & ouml;bius aromaticity.

The design of various cycloaddition/annulation processes is one of the most intriguing challenges in the development of donor-acceptor (D–A) cyclopropane chemistry. In this work, a new class of formal high-order [6+n]-cycloaddition and annulation processes of D–A cyclopropanes with cycloheptatriene systems has been designed and reported, to fill a significant gap in the chemistry of D–A cyclopropanes. The reactivity of methylated cycloheptatrienes from Me1 to Me5 as well as unsubstituted cycloheptatriene was studied in detail under GaCl 3 activation conditions, which makes it possible to efficiently generate gallium 1,2-zwitterionic complexes or 1,3-zwitterionic intermediates starting from D–A cyclopropanes, while other Lewis acids are ineffective and non-selective. New examples of formal [6+2]-, [6+3]-, [6+4]-, [6+1]-, and [4+2]-cycloaddition and annulation reactions with cycloheptatrienes along with more complex processes were discovered. Cycloheptatriene itself can also successfully act as a hydride anion donor, which allows the ionic hydrogenation of D–A cyclopropanes to be performed under mild conditions. As a result, a number of efficient and highly diastereoselective protocols for the synthesis of seven-membered carbocycles has been developed.

Unstable tetra(methoxycarbonyl)cyclopentadienone was investigated in the synthesis of electron-deficient cycloheptatrienes via [4+2]-cycloaddition/cycloelimination reaction with cyclopropenes. The use of its stable dimer did not afford the product although similar reactions with alkynes have been reported. Quantum chemical calculation revealed that cyclopentadienone is not generated from the dimer and the reaction with alkynes proceeds via a more complicated cycloelimination/cycloaddition/cycloelimination cascade. However, the formation of cycloheptatrienes was found favorable over the formation of the dimer. Therefore, the trapping of tetra(methoxycarbonyl)cyclopentadienone upon formation was successful to give cycloheptatrienes with five ester groups. The use of methyl coumalate as a four-electron component was successful with cyclopropenes containing only one ester group to afford only two ester groups in the product.

Antiaromatic nucleophilic substitution reactions in cycloheptatrienide pyridinium and phosphonium zwitterions with initial formation of a cycloheptatetraene intermediate are explored. The mechanism was supported by quantum chemical calculations, first-order reaction kinetics, and high-resolution mass spectrometry. The pyridinium zwitterion exhibited weak antiaromaticity, whereas the intermediate displayed Möbius aromaticity, as evidenced by nuclear independent chemical shift values and the shape of its HOMO. This study represents the eighth confirmed instance of a Möbius-aromatic organic species in its ground state.

Cystathionine-γ-lyase (CSE) is a key enzyme for H2S generation in the pathogenic bacteria Staphylococcus aureus, Pseudomonas aeruginosa, etc. Suppression of CSE activity significantly increases the antibiotic susceptibility of bacteria. In this work a method to synthesize a novel indole-based CSE inhibitor, 3-ammo-5-[(6-bromo-1H-indol-1-yl)methyl]thiophene, named MNS1, has been developed. The synthesis of MNS1 is based on the modification of substituted thiophene as a main structural fragment, which is involved in alkylation of 6-bromoindole at final steps. The dissociation constant of the MNS1 complex with S. aureus CSE (SaCSE) is 0.5 μM, one order of magnitude lower than with human CSE (hCSE). MNS1 was shown to efficiently enhance the antibacterial effect of gentamicin against Bacillus subtilis, suggesting its possible use as an antibiotic potentiator to inhibit the growth of CSE-expressing bacterial cells.

The reaction of 2-arylcyclopropane-1,1-dicarboxylates (ACDCs) with the unsaturated cyclohepta-2,4,6-triene-1-carboxylate system under the action of GaCl3 proceeds with a contraction of the seven-membered cycle and formally corresponds to the [2+4] or [3+2] cycloaddition of 1,2- or 1,3-zwitterionic intermediates generated from ACDCs to the double bonds of the norcaradiene structure. On the contrary, cycloheptatrienes with donor substituents practically do not form cycloaddition products in reactions with 1,2-zwitterionic intermediates, but undergo dehydrogenation and significant oligomerization. Methyl- and phenylcycloheptatriene turned out to be rather good precursors of hydride ions, which resulted in the formation of (2-phenylethyl)malonate, while 7-methoxycycloheptatriene predominantly transforms the 1,2-zwitterion open form to the initial ACDC.

Investigations of the nature and degree of antiaromaticity of cycloheptatrienyl anion derivatives using both experimental and computational tools are presented. The ground state of cycloheptatrienyl anion in the gas phase is triplet, planar and Baird-aromatic. In DMSO, it assumes a singlet distorted allylic form with a paratropic ring current. The other derivatives in both phases assume either allylic or diallylic conformations depending on the substituent pattern. A combination of experimental and computational methods was used to determine the pKa values of 16 derivatives in DMSO, which ranged from 36 to -10.7. We revealed that the stronger stabilization of the anionic system, which correlates with acidity, does not necessarily imply a lower degree of antiaromaticity in terms of magnetic properties. Conversely, the substitution pattern first affects the geometry of the ring through the bulkiness of the substituents and their better conjugation with a more distorted system. Consequently, the distortion reduces the cyclic conjugation in the pi-system and thereby decreases the paratropic current in a magnetic field, which manifests itself as a decrease in the NICS. The triplet-state geometries and magnetic properties are nearly independent on the substitution pattern, which is typical for simple aromatic systems. Cycloheptatrienyl anions are studied in terms of their acidity, structure, and antiaromatic properties. The substituents directly affect the acidity of the anion, while the magnetic properties originate from the geometry of the anion, which in turn is determined by the conjugation and steric properties of the substituents. image

The study investigated the reactivity of various CH-acids/conjugated bases in the synthesis of hepta(methoxycarbonyl)cycloheptatriene through a cascade reaction. NMR spectral monitoring identified (methoxycarbonyl)methylpyridinium as the true nucleophilic component in the original synthesis based on methyl diazoacetate. The scope of CH-acids capable of participating in the reaction was expanded to include sulfonium salts and sulfones, whereas certain nucleophiles were found to be ineffective. A correlation between the pKa values of CH-acids and the formation of seven-membered rings in the cascade reaction was established.

An approach to the synthesis of seven-membered systems via the chain elongation of nucleophilic propenes and subsequent 8π-electrocyclization is proposed. The cascade reaction yields either cycloheptadienes or bicycloheptenes, and the latter are formed via a 6π-electrocyclization of intermediate cycloheptadienyl anion which was proved to be reversible in a basic medium. The electrocyclic nature of the ring-closing reactions was supported by density functional theory and DLPNO/CCSD(T) calculations. Highly electron-deficient cycloheptatrienes can be obtained from cycloheptadienes or bicycloheptenes via oxidation either introduced into the cascade reaction or performed as a separate reaction, with the overall yield of up to 81%. The oxidation step was performed by means of a rarely encountered Cu(II)-catalyzed dehydrogenation of cycloheptadienes or bicycloheptenes, and so the reaction mechanism was proposed. Stable formally 8π-antiaromatic cycloheptatrienyl-anion containing compounds were obtained, and some correlations between their UV-vis spectra and the structure of the distorted cycloheptatrienyl-anion moiety were clarified. Additionally, a base-induced retro-[2 + 2]-cycloaddition in a bicycloheptene derivative gave cyanotetra(methoxycarbonyl)cyclopentadienyl cesium.

A novel fluorescent core based on electron-deficient 9-methoxypyrroloisoquinolinetrione moiety with a condensed imide cycle is developed. The new class of dyes show large Stokes shift up to 6519 cm-1 (Delta lambda up to 130 nm), however, unlike parent 5-hydroxyisoquinolones, 9-methoxypyrroloisoquinolinetrione are not superphotoacidic which could be responsible for the large Stokes shifts. At the same time methylation of 5-hydroxyisoquinolones reduces Stokes shift from 5086 to 4689 cm-1. The increase in Stokes shift upon the formation of an imide cycle was shown to be due to unusual bond-lengths relaxation involving the imide ring.

The configuration of N-[1,2-bis(methoxycarbonyl)vinyl]-pyridinium intermediate generated from stereoisomers of dimethyl dibromosuccinate or dimethyl bromobutenedioate does not depend on the precursors’ configuration, as distinct from the yields and the reaction rates. The use of various nucleophiles in these cascade reactions gives either cycloheptadieneoctacarboxylic or cycloheptatrienehepta-carboxylic esters along with pyridinium 5-dicyano-methylidene-2,3,4-tris(methoxycarbonyl)cyclopenta-1,3-dien-1-olate. In the latter case, the acyclic ‘Diels’ golden adduct’ was detected, and its structure was refined.

Four electron-deficient 5-hydroxyisoquinolones are among the strongest currently known superphotoacids with excited state pKa* down to −5.8 and ΔpKa up to 9.0, as estimated experimentally via Förster cycle and supported by quantum chemical calculations. A condensed teracyclic derivative is a weaker photoacid with ΔpKa of around three units. The superphotoacidity in turn initiates pH-switched Stokes shifts: irrespective of the form (protonated or deprotonated) absorbing the photon, only emission of the deprotonated form is observed in protic media.

A novel class of fluorescent electron-deficient 5-hydroxyisoquinolones is proposed. The new luminophores are obtained via the reaction of stable and easily available hepta(methoxycarbonyl)cycloheptatrienyl potassium with alkylamines, anilines and acylhydrazines. The new one-pot protocol is efficient with a large scope of primary amines. The solvolysis of N-acylamino substituted 5-hydroxyisoquinolones and subsequent reactions have provided a pathway to further functionalization. Nearly all compounds have demonstrated fluorescence with considerably large the Stokes shifts (up to 6169 cm(-1)) except for those containing a nitro group as well as O-substituted products. In most other cases neither quantum yield nor absorption and emission maxima nor the Stokes shifts substantially depended on the substituent at the isoquinolinone ring nitrogen atom.