Unsubstituted Benzene Ring Research Articles

(Invited) Effect of the Electron-Donating and Electron-Withdrawing Substituent on the Diels-Alder Cycloaddition Reaction of Hemifullerenes with 1,3-Butadiene

In the search for an efficient method to synthesize C60, the dimerization strategy of two C30H12 fragments has been considered (1,2). Scott et. al. (3) have demonstrated that the Diels-Alder cycloaddition reaction in the bay regions of a polycyclic aromatic hydrocarbon (PAH) can occur at low temperatures (below 150ᵒC), they have also shown that the use of nitroethylene as masked-acetylene in a DA reaction over the bay regions of perylene and 7,14-dimesitylbisanthene leads to a rapid conversion of the bay regions of the PAH to new unsubstituted benzene rings (4) .This findings allow us to think that the use of a set of substituents on the C30H12 fragment would be a good strategy to favor the DA reaction of substituted C30H12 fragment with butadiene and reduce the activation energies of the reaction. Our previous calculations showed that the DA reaction of 1,3-butadiene with the rim of the C30H12 fragment might be possible, having an activation energy close to that calculated for the DA reaction with 1,3-butadiene and ethylene (5). In this work a theoretical study of the electronic, thermodynamic and kinetic parameters of the Diels-Alder reaction of butadiene with the rims of the substituted C30H12 fragments (triindenetriphenylene 1 and pentacyclopentacorannulene 2) as well as the aromatization of the obtained adducts was carried out (6).(1) a) Scott, L.T. Angew. Chem. Int. Ed. 2004, 43, 4994.; b) Tsefrikas, V.M.; Scott, L.T. Chem. Rev. 2006, 106, 4868; c) Abdourazak, A.H.; Marcinow, Z.; Sygula, A.; Sygula, R.; Rabideau, P.W. J. Am. Chem. Soc. 1995, 117, 6410.(2) Richaud, A.; López, M.J.; Mojica, M.; Alonso, J. A, Méndez, F. RSC Adv., 2020, 10, 3689.(3) Fort, E.H.; Donovan, P.M.; L. T. Scott, L.T. J. Am. Chem. Soc., 2009, 131, 16006.(4) E. H. Fort, L. T. Scott, Angew. Chem. Int. Ed. 2010, 49, 6626.(5) Mojica, M.; Méndez, F.; Alonso, J.A. Molecules 2013, 18, 2243.(6) Mojica, M.; Méndez, F.; Alonso, J.A. Molecules 2016, 21, 200. Figure 1

Wang-OSO3H catalyzed green synthesis of 2-arylamino-3-cyanopyridine derivatives under ultrasound: Their assessment as potential inhibitors of SIRT1

New approaches / strategies to develop potential anticancer agents are necessary not only to address the increasing incidences of cancer worldwide but also to overcome the multifaceted problem of drug resistance. SIRT1, the most widely studied among all the sirtuins plays an important role in cancer and is considered as a promising pharmacological target for this disease. A new framework based on 2-arylamino-3-cyanopyridine was designed and assessed in silico for the identification of new and potential inhibitors of SIRT1. Initially, docking of a series of representative molecules in silico not only indicated their encouraging interactions with SIRT1 but also suggested their potential selectivity towards this protein over SIRT2. The study also suggested that H-bonding with residues ASN346 and ALA262 and other interactions with residues PHE273, PHE297, ILE411, ILE347, HIS363, GLN345 etc were common for several of these molecules. Thus, a library of molecules based on the designed framework was constructed for further pharmacological studies. These molecules were accessed conveniently via the ultrasound assisted 4-component reaction of appropriate ketone, aldehyde, aromatic amine and malononitrile in aqueous media under open air. The sulphonic acid-functionalized Wang resin (Wang-OSO3H) was explored as a polymeric and recoverable acidic catalyst for this purpose. The catalyst was recovered and recycled for a number of times without significant loss of its catalytic activity. A range of 2-arylamino-3-cyanopyridine derivatives were prepared in good (82–91%) yields using this green reaction. In vitro evaluation of these pyridine derivatives against SIRT1 revealed encouraging inhibitory activities (> 50% inhibition) thereby corroborating the outcome of docking studies. Indeed, the compounds 5a, 5g and 5j identified as most promising in the in silico docking studies were also found to be the most active pyridine derivatives in this in vitro assay. The Structure-Activity-Relationship (SAR) study revealed that an aryl group at C-4 position of the central pyridine ring was preferred over the heteroaryl or alkyl moiety whereas an unsubstituted benzene ring was favored over a substituted one at the C-6 position. Similarly, an unsubstituted phenyl group appeared to be better than the substituted one for the arylamino moiety at C-2 position. The reason for lower activity for a particular molecule was also investigated via in silico studies. Overall, according to the in silico as well as in vitro studies the pyridine derivatives 5a, 5g and 5j appeared as most potent among the compounds tested that were found to be several fold more potent than the known pyridine based inhibitor nicotinamide.

Pseudodimeric complexes of 4-styrylpyridine derivatives: Structure–property relationships and a stereospecific [2+2]-cross-photocycloaddition in solution

The study addresses the spectral and photochemical properties of N-(3-ammoniopropyl)-4-styrylpyridinium diperchlorate and its substituted analogs containing either electron-donating (OMe, SMe, NMe2) or electron-withdrawing (NO2, Cl) groups on the benzene ring. These styryl dyes in MeCN form pseudodimeric complexes with uncharged 18-crown-6-containing 4-styrylpyridine due to hydrogen bonding between the ammonium group and the crown ether oxygen atoms. The stability constants of the complexes were determined by spectrophotometric and 1H NMR titration methods. Owing to complexation, the dyes containing OMe or SMe groups and the dye with unsubstituted benzene ring undergo a stereospecific [2 + 2]-cross-photocycloaddition to the crown-containing styrylpyridine to give unsymmetrical cyclobutane derivatives as single rctt isomers. The structure of cyclobutanes was confirmed by X-ray diffraction analysis. The most probable conformations of the pseudodimeric complexes in MeCN were determined by density functional theory calculations. The cross-photocycloaddition quantum yields, measured upon selective excitation of the styryl dye, and other relevant data suggested that the barrier for this photoreaction increases with an increase in the reorganization energy of the singlet excited state of the dye.

Rhodium-Catalyzed Synthesis, Crystal Structures, and Photophysical Properties of [6]Cycloparaphenylene Tetracarboxylates.

The synthesis of C2-symmetrical [6]cycloparaphenylene (CPP) tetracarboxylates has been achieved via macrocyclization by the rhodium-catalyzed intermolecular stepwise cross-alkyne cyclotrimerization and subsequent reductive aromatization. The 1H NMR spectra of the thus-obtained C2-symmetrical [6]CPP-tetracarboxylates revealed that the rotation of unsubstituted benzene rings is slow at room temperature. These [6]CPPs formed columnar packing structures, and their absorption maxima were significantly blue-shifted compared to that of nonsubstituted [6]CPP due to the presence of four electron-withdrawing ester moieties.

Exploring the origin and magnitude of tetrasulfur tetranitrogen interaction with π-ring systems using first principle calculations

The tetrasulfur tetranitrogen (S4N4) compound has attracted attention for its unusual “extreme cradle” structure. We report here the nature and magnitude of non-covalent interactions of S4N4 with model π-ring systems. The σ-hole of sulfur atom interacts with the π electron density of benzene and naphthalene rings. The interaction energy of S4N4 with three naphthalene rings is ∼20.0 kcal/mol. The fluorinated benzene rings showed weaker interaction with S4N4 compared to unsubstituted benzene rings. The energy decomposition analysis (EDA) reveals the larger contribution of dispersion energy in such complexes.

Microbial Hydrolysis of Racemic β-Aryl-γ-ethylidene-γ-lactones and Antifeedant Activity of the Products against Alphitobius diaperinus Panzer.

Hydrolysis of (±)-β-aryl-γ-ethylidene-γ-lactones by fungal strain Aspergillus ochraceus AM370 afforded (−)-(S)-γ-ethylidene-γ-lactones 2a–d and (+)-(R)-γ-ketoacids 3a–d. Enantiomeric purity of the unreacted lactones was strictly related to a size of an aryl substituent at C-4 of γ-lactone ring, with the highest ee (77%) obtained for the (−)-(S)-γ-ethylidene-γ-lactone possessing unsubstituted benzene ring (2a) and the lowest one (15%) determined for the (−)-(S)-γ-ethylidene-γ-lactone with bulky 1,3-benzodioxole system (2d). Lactones 2a–d, both racemic and enantiomerically enriched, as well as products of their hydrolysis showed varying degrees of feeding deterrent activity against lesser mealworm, Alphitobius diaperinus Panzer, which depended on the structure of the compound and the developmental stage of the lesser mealworm. In the case of adults, more active were γ-lactones 2a–d, compared with ketoacids 3a–d. Only in the case of lactone 2a was the effect of configuration of stereogenic center on the activity found. Particularly strong deterrents against this stage (T > 180) were racemic and (−)-(S)-γ-ethylidene-γ-lactone with p-methoxysubstituted phenyl ring (2c).

Methods for the chemical synthesis of carbon nanotubes: an approach based on hemispherical polyarene templates

Abstract Hemispherical polyarenes represent attractive templates from which carbon nanotubes of the same diameter and rim structure (chirality) might be grown by repetitive annulation reactions. The resulting single-index (n,m) nanotubes would have one end open and the other end capped by the original template. Efforts in the author’s laboratory to synthesize (5,5) and (6,6) nanotube end-caps are described. Nitroethylene is shown to serve well as a “masked acetylene” for the conversion of polyarene bay regions into new unsubstituted benzene rings by a Diels-Alder cycloaddition/aromatization process. Benzyne reacts similarly, both in solution and in the gas phase. These annulation reactions are proposed as methods for elongating large-diameter templates that have bay regions on their rims into structurally uniform, single-walled carbon nanotubes. Unfortunately, the bay regions on the strongly curved rim of the small-diameter (5,5) nanotube end-cap 3 resist Diels-Alder cycloadditions with both nitroethylene and benzyne. Pentabenzocorannulene (14) is proposed as a promising candidate for surface-catalyzed cyclodehydrogenation to a surface-bound hemispherical polyarene that could serve as a template for synthesis of pure (5,5) carbon nanotubes.

Non-Imidazole Histamine H3 Ligands. Part VI. Synthesis and Preliminary Pharmacological Investigation of Thiazole-Type Histamine H3-Receptor Antagonists with Lacking a Nitrogen Nucleus in the Side Chain.

Antagonists to the H3 receptor are considered to be potential drugs for the treatment of Alzheimer's disease, attention deficit-hyperactive disorder, memory and learning deficits, and epilepsy. The initial development of potent H3 receptor antagonists focused on extensive modification of the natural ligand histamine. However, it has appeared that imidazole-containing ligands are associated with inhibition of cytochrome P450 enzymes, caused by imidazole nitrogen complexation to heme iron in the active site of the enzyme. For these reasons, the development of potent non-imidazole H3receptor antagonists was eagerly awaited. Previously, we reported the synthesis and pharmacological in vitro characterization of series of potent histamine H3receptor non-imidazole antagonists belonging to the class of substituted 2-thiazol-4-n-propylpiperazines. A lead compound 1 of this family was a derivative carrying the ethylaminomethylpropyl chain. With the aim of increasing lipophilicity, that will help the ligands to cross the blood-brain barrier, we synthesized a series of new 2-thiazol-4-n-propylpiperazines where the ethylaminomethylpropyl moiety was replaced by a p-substituted-, an unsubstituted benzene ring, and ω-phenylalkyl substituent at positions 4 and 5 of thiazole ring, respectively. All compounds were tested for H3 antagonistic effects in vitro using the electrically contracting guinea pig jejunum. The most active compounds of presented series 3d, 3e, and 3j showed lower affinity than the lead compound 1 and additionally, derivatives 3d and 3j possessed weak, competitive H1 antagonistic activity. This is in contrast to the lead compound 1 that has no affinity at H1 receptor. We can conclude that a side chain in the 2-thiazol-4-n-propylpiperazine scaffold should contain a basic center and should be present at a favorable position 5 of thiazole ring.

Conjugated, trans‐Spanning Ligands as Models for Multivalent p‐Phenyleneethynylenes

AbstractA conjugated, pyridine‐containing, phenylethynyl ligand that forms complexes with AgI and PdII has been developed. NMR titration studies with PdII reveal a stoichiometric binding of the ligand to the metal atom, while similar studies with AgI reveal a binding that is dynamic on the NMR timescale. Analysis of the NMR spectroscopic data by Job's plot analysis and non‐linear curve fitting of a titration curve reveals a 1:1 binding ratio of ligand/silver cation and an association constant of Ka = 53 M–1. X‐ray crystal structures of the ligand–metal complexes suggest ample room for the nearly barrierless rotation of the unsubstituted central benzene ring of the para‐phenylethynyl chain. Subtle electronic differences in substituted systems provide some evidence of impaired rotation.

Synthesis of β-aryl-γ-lactones and relationship: Structure – antifeedant and antifungal activity

Eighteen racemic β-aryl-γ-lactones derived from simple aromatic aldehydes have been obtained in the chemical synthesis. Iodolactones (5c and 6c) were synthesized from (E)-4-(benzo[d][1′,3′]-dioxol-5′-yl)-but-3-en-2-one (1). Reductive dehalogenation of iodolactones 5a–c and 6a–c afforded γ-ethyl-γ-lactones (7a–c, 8a–c) whereas the unsaturated lactones (9a–c, 10a–c) were obtained by dehydrohalogenation of iodolactones. All synthesized lactones were fully characterized by spectroscopic data (NMR, IR, HRMS) and subjected to the tests on the antifeedant activity towards Tribolium confusum, Trogoderma granarium and Sitophilus granaries as well to the tests on the antifungal activity towards four Fusarium species. The biological tests allowed to find some relationships between the structure and biological activity of the compounds studied. γ-Ethyl- γ-lactones 7a–c, 8a–c and unsaturated lactones 9a–c, 10a-c were usually stronger antifeedants than their parent iodolactones 5a–c and 6a–c. trans-Iodolactones 6a–c were more active than cis isomers 5a-c both in antifeedant and antifungal assays. The structure of aromatic substituent was the key factor in antifungal activity. The lactones with benzo [d][1,3]dioxole ring (5c, 6c, 7c, 8c, 9c) were the most active whereas those with unsubstituted benzene ring exhibited almost no activity. Eighteen racemic β-aryl-γ-lactones have been synthesized and subjected to the tests on the antifeedant towards storage pests and antifungal activity towards some Fusarium species. γ-Ethyl-γ-lactones and unsaturated lactones were usually stronger antifeedants than their parent iodolactones. The lactones with benzo [d][1,3]dioxole ring exhibited the highest activity.

A facile synthesis and microtubule-destabilizing properties of 4-(1H-benzo[d]imidazol-2-yl)-furazan-3-amines

A series of 4-(1H-benzo[d]imidazol-2-yl)-furazan-3-amines (BIFAs) were prepared in good yields (60–90% for each reaction step) via a novel procedure from aminofurazanyl hydroximoyl chlorides and o-diaminobenzenes. The synthetic sequence was run under mild reaction conditions, it was robust and did not require extensive purification of intermediates or final products. Furthermore, there was no need for protection of reactive moieties allowing for the parallel synthesis of diverse BIFA derivatives. Subsequent biological evaluation of the resulting compounds revealed their anti-proliferative effects in the sea urchin embryo model and in cultured human cancer cell lines. The most active compounds showed 0.2–2 μM activities in both assay systems. The unsubstituted benzene ring of the benzoimidazole template as well as the unsubstituted amino group in the furazan ring were essential prerequisites for the antimitotic activity of BIFAs. Compound 57 bearing the 2-chlorophenyl acetamide substituent at the nitrogen atom of the imidazole ring was the most active molecule in the examined set.

6-Methoxy-4-(2,4,5-trimethoxyphenyl)-2,2′-bipyridine-5-carbonitrile

In the title 3-cyano­pyridine derivative, C21H19N3O4, the 3-cyano-substituted pyridine ring forms dihedral angles of 2.35 (5) and 41.60 (5)° with the unsubstituted pyridine and 2,4,5-trimeth­oxy-substituted benzene rings, respectively. The dihedral angle between the unsubstituted pyridine and benzene rings is 39.84 (5)°. The meth­oxy groups form Cmeth­yl—O—C—(C,N) torsion angles in the range 0.80 (15)–11.45 (15)°. In the crystal, mol­ecules related by 21 screw axes are linked by weak C—H⋯N hydrogen bonds along [010]. In addition, weak C—H⋯π inter­actions and π–π stacking inter­actions between pyridine rings, with a centroid–centroid distance of 3.6448 (6) Å, are observed.

3-(4-Chloro-phen-yl)-1-cyclo-propyl-2-(2-fluoro-phen-yl)-5-phenyl-pentane-1,5-dione.

In the title compound, C26H22ClFO2, the cyclo­propane ring is disordered over two orientations, with site-occupancy factors of 0.64 (2) and 0.36 (2). The major occupancy component of the cyclo­propane ring makes dihedral angles of 47.6 (7), 50.4 (7) and 65.4 (7)° with the fluoro-, chloro- and unsubstituted benzene rings, respectively [the corresponding values for the minor occupancy component are 47.6 (12), 51.0 (12) and 60.9 (12)°]. An intra­molecular C—H⋯O hydrogen bond occurs. The F and Cl atoms deviate by 0.0508 (12) and 0.0592 (7) Å from the planes of their attached benzene rings. In the crystal, C—H⋯F hydrogen bonds link the mol­ecules into chains along the b-axis direction.

Synthesis and Antifungal Activity of 2-Chloromethyl-1H-benzimidazole Derivatives against Phytopathogenic Fungi in Vitro

A series of 35 benzimidazole derivatives were synthesized from 2-chloromethyl-1H-benzimidazole in good yields. Their structures were characterized by (1)H and (13)C NMR and HRESIMS. Antifungal activities of all of the synthesized compounds were evaluated against five phytopathogens fungi (Cytospora sp., Colletotrichum gloeosporioides, Botrytis cinerea, Alternaria solani, and Fusarium solani) using the mycelium growth rate method. Compound 4m displayed strong growth inhibition of C. gloeosporioides, A. solani, and F. solani with IC50 of 20.76, 27.58, and 18.60 μg/mL, respectively. Selective inhibition of B. cinerea instead of the other fungal pathogenes was observed with 7f (IC50 of 13.36 μg/mL), comparable to that of positive control, a commercial agricultural fungicide hymexazol (IC50 of 8.92 μg/mL). Compound 5b exhibited remarkable antifungal properties against Cytospora sp., C. gloeosporioides, B. cinerea, and F. solani with IC50 values of 30.97, 11.38, 57.71, and 40.15 μg/mL, respectively; among the target fungi, 5b was the most active compound and superior to the reference against C. gloeosporioides alone. Structure-activity relationship (SAR) data of these compounds are as follows: (1) introduction of the chlorine atom on para-position in the benzene ring help to increase activity (4f vs 4c; 7f vs 7n), (2) the sulfonyl group is critical for the inhibition of C. gloeosporioides (5b and 5c vs 5a), and (3) the unsubstituted benzene ring improve activity (4m vs 4n, 4e and 4a). Thus, compounds 5b, 4m, and 7f emerged as a new leading structure for the development of new fungicides.

Synthesis and antitumor activity of novel quinazoline derivatives containing thiosemicarbazide moiety

Series of novel derivatives of quinazoline containing thiosemicarbazide moiety 5 and 9 have been synthesized and tested for their antitumor activities in vitro against a panel of five human cancer cell lines. Bioassay results indicated that most of the prepared compounds exhibited cytotoxicity against various cancer cells. From the structure–activity relationships it was found that unsubstituted quinazoline ring and benzene ring or halogen substituted benzene ring in quinazoline derivatives 5 and 9 would be the most favorable for their antitumor activity.

(2S,5S,6R)-5-(4-Methylphenyl)-3-phenyl-4,8-dioxa-3-azatricyclo[7.4.0.02,6]trideca-1(13),9,11-triene-6-carbonitrile

In the title compound, C24H20N2O2, the six-membered pyran ring adopts a half-chair conformation with one C atom deviating from the mean plane of the remaining ring atoms by 0.654 (6) Å. The five-membered isoxazole ring adopts an N-envelope conformation with the N atom displaced by 0.742 (5) Å from the mean plane formed by the remaining ring atoms. The carbonitrile side chain is almost linear, with a C—C—N angle of 178.6 (5)°. The crystal packing is stabilized by inter­molecular C—H⋯N inter­actions, through bifurcated acceptor hydrogen bonds formed between the carbonitrile N atom and two alternate C atoms in the unsubstituted benzene ring. The mol­ecular structure and crystal packing are further stabilized by intra­molecular and inter­molecular C—H⋯π inter­actions.

Diels–Alder cycloaddition of acetylene gas to a polycyclic aromatic hydrocarbon bay region

The direct conversion of a polycyclic aromatic hydrocarbon bay region to a new, unsubstituted benzene ring by Diels-Alder cycloaddition of acetylene gas is reported for the first time. At 140 °C in dimethylformamide, under 1.8 atm pressure of acetylene gas, 7,14-dimesitylbisanthene is slowly converted to 7,14-dimesitylbenzo[ghi]bisanthene (21% conversion in 48 h).

Ethyl 3-(4-chlorophenyl)-1-(2-oxo-2-phenylethyl)-1H-pyrazole-5-carboxylate

In the title compound, C20H17ClN2O3, the dihedral angles between the pyrazole ring and the substituted and unsubstituted benzene rings are 3.64 (13) and 81.15 (17)°, respectively. Mol­ecules are connected via three pairs of weak hydrogen bonds into a centrosymmetric dimer. The crystal structure is stabilized by inter­molecular C—H⋯O and C—H⋯π inter­actions.

Nitration of primary aminofurazans with aqueous nitric acid

A convenient procedure for the synthesis of N-nitroaminofurazans by nitration of primary 3-amino-4-R-furazans (R = Me, NO2, phenyl-, methyl-NNO-azoxy-, tert-butyl-NNO-azoxy-, tert-butyldiazenyl-, etc.) with 66–77% aqueous nitric acid was developed. Depending on the concentration of HNO3, the reaction is carried out at a temperature from 18 to 55 °C, the yield of the products is 80–99%. 3-Nitramino-4-phenylfurazan with unsubstituted benzene ring was obtained by nitration of 3-amino-4-phenylfurazan.

One‐Step Conversion of Aromatic Hydrocarbon Bay Regions into Unsubstituted Benzene Rings: A Reagent for the Low‐Temperature, Metal‐Free Growth of Single‐Chirality Carbon Nanotubes

A tube ride: The controlled chemical synthesis of uniform, single-walled carbon nanotubes from short hydrocarbon templates, such as aromatic belts and geodesic nanotube end-caps, by a Diels–Alder cycloaddition/rearomatization strategy requires a potent “masked acetylene” capable of transforming hydrocarbon bay regions into new unsubstituted benzene rings in a single operation. Nitroethylene has been found to effect such benzannulations (see scheme).