Aryl Methyl Research Articles

Synthesis of Novel 1,3,4-Oxadiazole-Derived α-Aminophosphonates/α-Aminophosphonic Acids and Evaluation of Their In Vitro Antiviral Activity against the Avian Coronavirus Infectious Bronchitis Virus.

An efficient and simple approach has been developed for the synthesis of eight dialkyl/aryl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(aryl)methyl]phosphonates through the Pudovik-type reaction of dialkyl/arylphosphite with imines, obtained from 5-phenyl-1,3,4-oxadiazol-2-amine and aromatic aldehydes, under microwave irradiation. Five of them were hydrolyzed to lead to the corresponding phosphonic acids. Selected synthesized compounds were screened for their in vitro antiviral activity against the avian bronchitis virus (IBV). In the MTT cytotoxicity assay, the dose-response curve showed that all test compounds were safe in the range concentration of 540-1599 µM. The direct contact of novel synthesized compounds with IBV showed that the diethyl[(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethoxyphenyl)methyl]phosphonate (5f) (at 33 µM) and the [(5-phenyl-1,3,4-oxadiazol-2-ylamino)(4-trifluoromethylphenyl)methyl] phosphonic acid (6a) (at 1.23 µM) strongly inhibited the IBV infectivity, indicating their high virucidal activity. However, virus titers from IBV-infected Vero cells remained unchanged in response to treatment with the lowest non-cytotoxic concentrations of synthesized compounds suggesting their incapacity to inhibit the virus replication inside the host cell. Lack of antiviral activity might presumably be ascribed to their polarity that hampers their diffusion across the lipophilic cytoplasmic membrane. Therefore, the interactions of 5f and 6a were analyzed against the main coronavirus protease, papain-like protease, and nucleocapsid protein by molecular docking methods. Nevertheless, the novel 1,3,4-oxadiazole-based α-aminophosphonic acids and α-amino-phosphonates hold potential for developing new hygienic virucidal products for domestic, chemical, and medical uses.

“All-Aqueous” Tandem Boc-Deprotection and Alkylation of N-Bocbenzimidazole Derivatives under Visible Light with Alkyl Aryl Diazoacetates: Application to Site-Selective Insertion of Carbenes into the N–H Bond of Purines

Herein, we have reported a blue LED-induced tandem Boc-deprotection and NH-alkylation of benzimidazole derivatives with methyl aryl diazoacetates. The reactions occur in water at room temperature. The desired products are obtained in good to excellent yields. The putative mechanism of this reaction is discussed based on control experiments and supported by DFT studies. Additionally, the strategy is used to alkylate various purine derivatives via site-selective N1-alkylation to generate acyclic nucleoside analogues.

I2-catalyzed one-pot oxidative condensation of thiourea, methyl ketones, and aryl thiols into 5-sulfenylated 2-amino-1,3-thiazoles by DMSO.

A one-pot, efficient oxidative-condensation process for constructing both 4-alkyl and 4-aryl-5-(arylthio) thiazol-2-amines using DMSO/I2 is introduced. In this procedure, methyl ketones, thiourea, DMSO, and thiols are reacted together in the presence of molecular I2 at 80°C simply to produce 4-alkyl or aryl-5-(arylthio)thiazol-2-amines due to formation of a C-S bond between thiourea and methyl carbon linked to carbonyl group and the another C-S bond formation between thiol and thiazol ring. Under reaction conditions, both aryl and alkyl methyl ketones including acetophenone and substituted acetophenones also, 2-alkanones such as acetone, 2-butanone, 2-pentanone, and 2-heptanone yield those products successfully.

Green multicomponent approach to novel 5‐[(2H‐Pyran‐3‐yl)(aryl)methyl]‐1,3‐dimethylpyrimidines

AbstractThe multicomponent green methodologies are an ideal instrument in organic synthesis. Environmentally benign, facile, and efficient multicomponent synthesis of [(2H‐pyran‐3‐yl)(aryl)methyl]‐1,3‐dimethylpyrimidines by the reaction of aromatic aldehydes, N,N′‐dimethylbarbituric acid and 4‐hydroxy‐6‐methyl‐2H‐pyran‐2‐one employing simple and eco‐friendly catalyst and solvent—sodium acetate and ethanol is reported. The reaction proceeds at reflux conditions with good and excellent yields (65%–97%). The isolation of final compounds does not require complex purification procedures. All novel synthesized compounds are characterized by 1H and 13C NMR spectroscopy, FT‐IR and mass spectrometry, and elemental analysis. The [(2H‐pyran‐3‐yl)(aryl)methyl]‐1,3‐dimethylpyrimidine structure was proven using 2D NMR spectroscopy methods.

Synthesis of novel glutarimide ligands for the E3 ligase substrate receptor Cereblon (CRBN): Investigation of their binding mode and antiproliferative effects against myeloma cell lines

To expand the chemical toolkit for targeted protein degradation, we report the generation of a new series of non-thalidomide Cereblon (CRBN) ligands. Readily available 2-methylidene glutarimide was converted to a series of 2-((hetero)aryl(methyl))thio glutarimides via the thio-Michael addition reaction. The compounds thus synthesized were evaluated for their affinity to the thalidomide-binding domain of human CRBN and their binding modes studied via X-ray crystallography. This helped identify several promising glutarimide derivatives which bind stronger to CRBN compared to thalidomide and contain a functional group which permits further chemical conjugation. Oxidation of the sulfur atom in a select group of 2-((hetero)aryl(methyl))thio glutarimides produced the respective sulfones which were found to possess a markedly stronger antiproliferative profile against multiple myeloma cell lines and a sophisticated structural binding mode with additional hydrogen bonding interactions. The newly identified Cereblon ligands form the basis for the synthesis of novel PROTAC protein degraders.

Iron‐Catalysed C(sp2)‐H Borylation with Expanded Functional Group Tolerance†

Comprehensive SummaryArene C(sp2)‐H bond borylation offers direct and efficient access to aryl boronic esters. Using in situ catalyst activation and photoirradiation, the iron‐catalysed C(sp2)‐H borylation reaction of carboarenes, pyrroles, and indoles has been developed using only bench‐stable pre‐catalysts and reagents. Good functional group tolerance was observed including those not reported using previous methods (ArNH2, ArOH, ArSiR3, ArP(O)(OR)2, ArC(O)NR2). Mechanistic studies revealed iron‐catalysed reductive deoxygenation, C—F protodefluorination, and a demethylation of aryl methyl ethers by C—O sigma bond hydroboration.

AlCl3-Catalyzed Cascade Reactions of 1,2,3-Trimethoxybenzene and Adipoyl Chloride: Spectroscopic Investigations and Density Functional Theory Studies.

The reaction of 1,2,3-trimethoxybenzene with adipoyl chloride in the presence of AlCl3 gave two isomeric cyclopentene derivatives, 1,6-bis(2,3,4-trimethoxyphenyl)hexane-1,6-dione, and two demethylation products of aryl methyl ethers. The cyclopentene derivatives including unconjugated or conjugated enones are products formed in a cascade reaction resulting from first the Friedel-Crafts acylation reaction and then aldol condensation. All compounds were optimized by density functional theory calculated using two functional levels, B3LYP and M06-2X, with the 6-311+G(d,p) basis set. The structural properties were established, natural bond orbital analysis of donor-acceptor interactions was carried out, and charges on the atoms and quantum chemical reactivity identifiers were determined to compare the strength of the intramolecular hydrogen bonds formed and their stabilities. To compare the experimental 1H and 13C NMR chemical shifts with the calculated values, NMR chemical shift calculations were carried out using the gauge-invariant atomic orbital method.

One-Pot Synthesis of Diaryl 1,2-Diketones via Zn-Mediated Reductive Coupling.

A reductive coupling reaction was established for the synthesis of diaryl 1,2-dicarbonyl compounds from aryl methyl ketones in good yields. The mechanistic study showed the reaction undergoes C(CO)-C(sp3) bond cleavage, with the reductive coupling reaction occurring through an electron transfer process. Notably, the reaction not only is simple to operate but also has mild reaction conditions and a wide range of applicable substrates.

Perfluorocyclobutyl aryl ether-inserted vinyl silicone oil for crosslinking of fluorosilicone rubber

Vinyl silicone oil containing perfluorocyclobutyl aryl ether in the backbone (PFCB–VSO) was prepared by polycondensation of silane monomer containing perfluorocyclobutyl aryl ether (M4), dimethyldimethoxysilane, and methyl vinyl dimethoxysilane in the acetic acid system. Fluorosilicone rubber was designed by using PFCB-VSO as a non-telechelic crosslinker. The effects of PFCB-VSO on the mechanical properties, thermal properties, and hydrophobic properties of fluorosilicone rubber were studied. The cross-link network of fluorosilicone rubber was investigated. The cross-link point was concentrated by the introduction of PFCB-VSO, which was demonstrated by cross-link density. The mechanical properties were enhanced by the growth of the non-telechelic cross-link network. The tensile strength was 10.35 MPa, the tear strength was 21.78 kN/m, and the elongation at break was 735%. The thermal stabilities and the hydrophobic properties of fluorosilicone rubber were increased by PFCB-VSO.

I2-DMSO mediated N1/C5 difunctionalization of anthranils with aryl methyl ketones: A facile access to multicarbonyl compounds

An I2-DMSO promoted remote difunctionalization reaction of anthranils is reported. This cross-coupling process realizes simultaneous N1- and C5-dicarbonylation of anthranils with a highly atom- and step-economy. The mechanism involves the copper-catalyzed N–O bond cleavage of anthranils and the construction of a new C–C and a C–N bond respectively. The transformation proceeds smoothly in gram-scale, and the product of the reaction could be transformed into other valuable heterocyclic structures.

Kinetics of chromium(V)-oxo and chromium(IV)-oxo porphyrins: Reactivity and mechanism for sulfoxidation reactions

In this work, chromium(IV)-oxo porphyrins [CrIV(Por)(O)] (2) (Por = porphyrin) were produced either by oxidation of [CrIII(Por)Cl] (1) with iodobenzene diacetate or visible light photolysis of porphyrin‑chromium(III) chlorates. Subsequent oxidation of 2 with silver perchlorate gave chromium(V)-oxo porphyrins [CrV(Por)(O)](ClO4) (3) in three porphyrin ligands, including 5,10,15,20-tetramesitylporphyrin(TMP, a), 5,10,15,20-tetrakis(2,6-difluorophenyl)porphyrin(TDFPP, b), and 5,10,15,20-tetrakis(pentafluorophenyl)porphyrin (TPFPP, c). Complexes 2 and 3 reacted with thioanisoles to produce the corresponding sulfoxides, and their kinetics of sulfoxidation reactions with a series of aryl methyl sulfides(thioanisoles) were studied in organic solutions. Chromium(V)-oxo porphyrins are several orders of magnitudes more reactive than chromium(IV)-oxo species, and representative second-order rate constants (kox) for the oxidation of thioansole are (0.40 ± 0.01) M−1 s−1 (3a), and (2.82 ± 0.20) × 102 M−1 s−1 (3b), and (2.20 ± 0.01) × 103 M−1 s−1 (3c). The order of reactivity for 2 and 3 follows TPFPP > TDFPP > TMP, in agreement with the electrophilic nature of metal-oxo complexes. Hammett analyses indicate significant charge transfer in the transition states for oxidation of para-substituted thioanisoles by [CrV(Por)(O)]+. The ρ+ constants are −1.69 for 3a, −2.63 for 3b, and − 2.89 for 3c, respectively, mirror values found previously for related metal-oxo species. A mechanism involving the electrophilic attack of the CrV-oxo at sulfides to form a sulfur cation intermediate in the rate-determining step is suggested. Competition studies with chromium(III) porphyrin chloride and PhI(OAc)2 gave relative rate constants for oxidations of competing thioanisoles that closely match ratios of absolute rate constants from chromium(V)-oxo species, which are true oxidants under catalytic conditions.

Sodium Alginate Biopolymer: An Efficient, Recyclable Green Catalyst for the Synthesis of Chalcone Derivatives under Mild Conditions

AbstractOne‐pot chemical synthesis of highly pure chalcone under mild conditions using biocompatible Na‐alginate biopolymer is reported. Several chalcone derivatives are prepared by magnetic stirring the equimolar quantities of the appropriate methyl ketone and aryl aldehyde with sodium alginate in ethanol under neutral conditions at room temperature. It is observed that in the presence of recyclable sodium alginate biocatalyst, highly pure chalcone with excellent yields in a very short time are obtained. The chalcone derivatives obtained are well characterized by UVDRS and FTIR techniques. The easily separable Na‐alginate biocatalyst acts as a Bronsted acid and may be reused up to five cycles.

Visible Light-Mediated Enantioselective Addition of α-Aminoalkyl Radicals to Ketones Catalyzed by Chiral Oxazaborolidinium Ion.

The development of a visible light-mediated synthetic method for chiral 1,2-amino tertiary alcohols is described. In the presence of a chiral oxazaborolidinium ion catalyst and photosensitizer, the enantioselective addition of an α-aminoalkyl radical to aryl methyl ketones under visible light provides chiral 1,2-amino tertiary alcohol derivatives in high yields (up to 88%) with excellent enantioselectivities (up to 98% ee). With mechanistic studies such as radical trapping analysis, radical clock analysis, and the measurement of quantum yield, a plausible catalytic cycle is proposed.

Rapid and Mild Cleavage of Aryl‐Alkyl Ethers to Liberate Phenols

AbstractWe report that the Piers‐Rubinsztajn reaction enables rapid deprotection of aryl alkyl ethers under ambient conditions. This chemistry leverages tris(pentafluorophenyl)borane and silyl hydrides to convert aryl methyl ethers to siloxanes, which can then be cleaved using 1 % HCl in EtOH. We examined 26 derivatives and routinely obtained yields >85 %, even in the presence of sterically demanding groups and complex substrate structures. Other alkyl ethers including ethyl, propyl, isopropyl, tert‐butyl, and benzyl groups were also easily removed.

Mechanistic Investigation of the Nickel-Catalyzed Metathesis between Aryl Thioethers and Aryl Nitriles

Functional group metathesis is an emerging field in organic chemistry with promising synthetic applications. However, no complete mechanistic studies of these reactions have been reported to date, particularly regarding the nature of the key functional group transfer mechanism. Unraveling the mechanism of these transformations would not only allow for their further improvement but would also lead to the design of novel reactions. Herein, we describe our detailed mechanistic studies of the nickel-catalyzed functional group metathesis reaction between aryl methyl sulfides and aryl nitriles, combining experimental and computational results. These studies did not support a mechanism proceeding through reversible migratory insertion of the nitrile into a Ni-Ar bond and provided strong support for an alternative mechanism involving a key transmetalation step between two independently generated oxidative addition complexes. Extensive kinetic analysis, including rate law determination and Eyring analysis, indicated the oxidative addition complex of aryl nitrile as the resting state of the catalytic reaction. Depending on the concentration of aryl methyl sulfide, either the reductive elimination of aryl nitrile or the oxidative addition into the C(sp2)-S bond of aryl methyl sulfide is the turnover-limiting step of the reaction. NMR studies, including an unusual 31P-2H HMBC experiment using deuterium-labeled complexes, unambiguously demonstrated that the sulfide and cyanide groups exchange during the transmetalation step, rather than the two aryl moieties. In addition, Eyring and Hammett analyses of the transmetalation between two Ni(II) complexes revealed that this central step proceeds via an associative mechanism. Organometallic studies involving the synthesis, isolation, and characterization of all putative intermediates and possible deactivation complexes have further shed light on the reaction mechanism, including the identification of a key deactivation pathway, which has led to an improved catalytic protocol.

Iodine-Mediated Multicomponent Cascade Cyclization and Sulfenylation/Selenation: Synthesis of Imidazo[2,1-a]isoquinoline Derivatives.

A novel multicomponent cascade cyclization and sulfenylation/selenation using aryl methyl ketones, isoquinolin-1-amine, and sodium arylsulfinates/1,2-diphenyldiselane to synthesize imidazo[2,1-a]isoquinoline derivatives in one-pot via the construction of two C-N bonds and one C-S/C-Se bond has been reported. This multicomponent reaction realizes simultaneous C(sp3)-H amination and sulfenylation/selenation, avoiding complicated prior substrate preparation. This process has simple operating conditions and good substrate compatibility.

QSAR, ADMET In Silico Pharmacokinetics, Molecular Docking and Molecular Dynamics Studies of Novel Bicyclo (Aryl Methyl) Benzamides as Potent GlyT1 Inhibitors for the Treatment of Schizophrenia.

Forty-four bicyclo ((aryl) methyl) benzamides, acting as glycine transporter type 1 (GlyT1) inhibitors, are developed using molecular modeling techniques. QSAR models generated by multiple linear and non-linear regressions affirm that the biological inhibitory activity against the schizophrenia disease is strongly and significantly correlated with physicochemical, geometrical and topological descriptors, in particular: Hydrogen bond donor, polarizability, surface tension, stretch and torsion energies and topological diameter. According to in silico ADMET properties, the most active ligands (L6, L9, L30, L31 and L37) are the molecules having the highest probability of penetrating the central nervous system (CNS), but the molecule 32 has the highest probability of being absorbed by the gastrointestinal tract. Molecular docking results indicate that Tyr124, Phe43, Phe325, Asp46, Phe319 and Val120 amino acids are the active sites of the dopamine transporter (DAT) membrane protein, in which the most active ligands can inhibit the glycine transporter type 1 (GlyT1). The results of molecular dynamics (MD) simulation revealed that all five inhibitors remained stable in the active sites of the DAT protein during 100 ns, demonstrating their promising role as candidate drugs for the treatment of schizophrenia.

Iodine-Catalyzed Multicomponent Synthesis of Highly Fluorescent Pyrimidine-Linked Imidazopyridines.

Herein, we report a metal-free one-pot three-component reaction of aryl methyl ketones, 2-aminopyridines, and barbituric acids for the synthesis of pyrimidine-linked imidazopyridines using a catalytic amount of molecular iodine in DMSO medium. This process involves a one-pot C–H oxidation, followed by the formation of one C–C and two C–N bonds. A wide variety of aryl methyl ketones and 2-aminopyridines were found to be suitable for this methodology. The UV and fluorescence properties of the synthesized products were studied in water and DMSO media. Most of the synthesized products exhibited very good to excellent fluorescence quantum yield. Among all the products, compounds 4p and 4q showed the maximum fluorescence quantum yield (0.36) in water medium under basic conditions and compound 4c showed the maximum fluorescence quantum yield (0.75) in DMSO medium.

Synthesis and assessment of substituent effect of some 3-((E)-3-substituted phenylacryloyl)benzonitriles

Some novel Chalcones including 3-((E)-3-substituted phenylacryloyl)benzonitriles have been synthesized by Claisen-Schmidt condensation of aryl methyl ketones including 3-acetylbenzonitrile and substituted benzaldehydes. All the synthesized compounds have been characterized by their physical constants, UV, IR, 1H, 13C NMR and Mass spectral data. These spectral data of functional groups and chemical shifts of these 3-benzonitrile chalcones have been correlated with Hammett substituent constants, F and R parameters using single and multi-linear regression analyses. From the results of statistical analysis, the effect of substituents on the functional group absorptions was discussed.

Aryl Methyl Ketones: Versatile Synthons in the Synthesis of Heterocyclic Compounds.

The synthesis of aromatic heterocycles has attracted substantial attention due to the abundance of these heterocycles in drug molecules, natural products, and other compounds of biological interest. Accordingly, there is a demand for straightforward synthetic protocols toward such compounds using readily available starting materials. In the past decade, there have been substantial developments in heterocycle synthesis, especially in metal-catalyzed and iodine-assisted approaches. This graphical review focuses on notable reactions from the past decade using aryl and heteroaryl methyl ketones as starting materials, including representative reaction mechanisms.