Betti Base Research Articles

Microwave-assisted Synthesis of Pyrroles, Pyridines, Chromenes, Coumarins, and Betti Bases via Alcohol Dehydrogenation with Chroman-4-one Amino Ligands

: This study outlines the development of a novel approach utilizing microwave assistance for the alcohol dehydrogenative reaction. The process is catalyzed by manganese (II) and cobalt (II) in conjunction with chroman-4-one amino ligands. This research introduces a unique catalytic system capable of synthesizing various heterocyclic compounds, including pyrroles, pyridines, Betti bases, chromenes, and coumarins via alcohol dehydrogenation. The synthesis involved the preparation and characterization of a series of chroman- 4-one amino ligands (C1-C6) using standard analytical techniques. These ligands, in combination with MnCl2‧4H2O and CoCl2, demonstrated remarkable catalytic activity, effectively driving alcohol dehydrogenation. The catalytic cycle was initiated by the in-situ formation of metal complexes with the ligands during the reaction. Characterization using ESI-MS confirmed the presence of metal complexes (Int-1) and other intermediates (Int-II and Int-III) throughout the catalytic cycle. Additionally, the controlled experiment corroborated the efficacy of the catalytic system, evidenced by the evolution of H2 gas.

Co(II) and Cu(II) Porphyrins Catalysed the Synthesis of Quinoline and Naphthoxazine via Dehydrogenative Reactions

: In this study, we developed a facile Co (II) and Cu (II)-porphyrin catalytic system for dehydrogenative coupling reaction of benzyl alcohol with acetophenone derivatives for quinoline synthesis and intramolecular cyclisation of Betti base for naphthoxazine synthesis. Functionalized porphyrins containing ester and quinoline ring (CoTPPBenzo(NPh)) and (CuTPPBenzo(NPh)) were synthesized and confirmed via various analytical techniques. These cobalt (II) and copper (II) porphyrins were tested for the synthesis of quinolines and naphthoxazines via a dehydrogenative coupling reaction. These cobalt and copper porphyrins showed excellent catalytic activity with broad substrate scope. Additionally, a series of controlled experiments were performed to support this work.

Recent advances in the transformation reactions of the Betti base derivatives.

Betti bases are the products resulting from the one-pot multicomponent reaction involving 1-naphthol/2-naphthol, aliphatic/aromatic aldehydes, and secondary amines. This chemical process is commonly referred to as the Betti reaction. The significance of Betti bases in medicinal chemistry has grown substantially due to their diverse array of pharmacological applications. Furthermore, their synthetic utility is considerable, given their use as catalysts and ligands in asymmetric synthesis. Moreover, Mannich products, incorporating diverse functional groups such as -OH and -NH, find application in a range of organic reactions. This utilization enables the synthesis of novel C-C bond linkages and diverse heterocycles, including biologically active naphthoxazines, which hold biological applications such as antibacterial, antifungal and anticancer. The focus of this review article is on the application of aminonaphthol derivatives in transformation reactions and the synthesis of organic compounds, with particular emphasis on heterocycles.

Efficient and Facile One-Pot Multi-Component Synthesis of Betti Bases Using Baker’s Yeast for the First Time

A green and facile synthesis of 1-(α-aminoalkyl)-2-naphthols, generally called Betti bases (BB) in the presence of Baker’s yeast (BY), acts as an efficient catalyst, and ethanol as a green solvent. In this methodology, the BY is used first time as a biocatalyst (enzyme). This protocol has some inherent advantages, such as mild reaction conditions, no environmental pollution, simple work up, no need of column chromatography, diversity of reactant and desired 1-(α-aminoalkyl)-2-naphthols (Betti bases) (4a-r) are obtained in good-to-excellent yields. This is the first report on Baker’s yeast-catalyzed (BYC) synthesis for BB. This present bio-catalytical route for synthesizing BB in the presence of biocatalysts like BY is anticipated to open a gateway to synthesized complexed biological active molecules counting BB.

Synthesis, Docking Studies, and Biological Evaluation of Betti Bases as Promising Anti-tubercular Agents

Background: The occurrence of Tuberculosis (TB) has significantly increased worldwide. The extensively drug-resistant tuberculosis (XDR-TB) and multi-drug resistant tuberculosis (MDR-TB) have made it more challenging to treat this mycobacterial infection caused by the Mycobacterium tuberculosis MTB-H37Rv strain. The present treatments for tuberculosis are of long duration and with side effects. Thus, it is necessary to discover new drugs with short-term chemotherapy, fewer health hazards, and cost effectiveness. Objective: The objective of the study was to divulge the antitubercular properties of Betti base scaffolds. Method: Betti bases were designed, synthesized 4a-4h, 6a-6h, and investigated for their in vitro antitubercular activity using Microplate Alamar Blue assay (MABA) against the MTB-H37Rv strain. Their binding affinity with amino acids was studied by performing molecular docking studies using InhA (PDB ID: 2NSD) present in the MTB-H37Rv strain. Cytotoxicity assay and neutrophil function test (NFT) were also performed. Results: The Betti bases (4a-4h, 6d) showed minimum inhibitory concentration (MIC) values ranging from 1.6 μg/mL to 6.25 μg/mL against the MTB-H37Rv strain. The compounds (4a-4h, 6a-6h) were investigated for their ADME properties and good pharmacokinetic profiles were observed. In molecular docking studies, a strong binding affinity between InhA and the compounds (4a-4h, 6a-6h) was observed, which provided theoretical insight into the inhibitory action of the synthesized compounds (4a-4h, 6a-6h) against InhA. NFT of the compounds (4a-4h, 6a-6h) showed no harmful effects on the functions of neutrophils. In vitro cytotoxicity assay against Vero cell lines revealed the non-cytotoxic behavior of the compounds. Conclusion: Betti bases can be considered to be a promising class of molecular entities that can lead to the development of new anti-tubercular leads.

Application of chiral Betti base-copper complexes in enantioselective allylic oxidation of olefins, computational studies of the Betti bases, and docking of the resulting chiral allylic esters

Chiral (R)- and (S)-Betti bases have been initially synthesized from resolution of the corresponding racemic mixture by diastereomeric recrystallization method using l-(+)-tartaric acid, and then the copper complexes of the Betti bases have been studied in enantioselective allylic CH bond oxidation of olefins. This kind of ligands gave enantioenriched allylic esters with good to high yields and satisfactory enantioselectivities under optimized conditions. In addition, the thermodynamic stability of the Betti base mixture and binding energy between the racemic Betti bases and l-(+)-tartaric acid in the resolution process have been calculated using the M06–2X method and 6–311++G(d,p) basis set. Furthermore, the bioactivity of the synthesized chiral allylic esters has been investigated towards the PI3Kα enzyme with the use of AutoDock Vina.

C–H functionalization of aromatic amines for azidation catalyzed by Betti base coordinated copper(ii) complexes under ultrasonication

Five new Betti base copper(ii) complexes (C1–C5) are successfully synthesized and characterized spectroscopically.

Cover Feature: Catalyst‐Free Accelerated Three‐Component Synthesis of Betti Bases in Microdroplets (ChemPlusChem 2/2023)

Cover Feature: Catalyst‐Free Accelerated Three‐Component Synthesis of Betti Bases in Microdroplets (ChemPlusChem 2/2023)

Water Promoted One Pot Synthesis of Sesamol Derivatives as Potent Antioxidants: DFT, Molecular Docking, SAR and Single Crystal Studies

A one pot water mediated synthesis of sesamol analogous using Betti Base synthetic approach. The reaction was optimized with various solvents and catalysts, but the product formed with a high yield in aqueous ethanol condition. The examined strategy offers many advantages such as green solvent, purification without column chromatography, and catalyst-free synthesis. The synthesized molecules were investigated for molecular docking and DFT studies. In silico parameter showed that the compound 4h has the lowest affinity score as well as high charge transformations. From the result of theoretical approaches, we evaluate compounds for in vitro antioxidant assay toward the DPPH, H2O2 and NO method with 50 µg/mL concentration. In vitro bioassay revealed that the compound 4 h had excellent inhibition capacity.

Construction of chiral Betti base precursors containing a congested quaternary stereogenic centerviachiral phosphoric acid-catalyzed arylation of isoindolinone-derived ketimines

Synthesis of enantioenriched Betti base precursors containing a congested quaternary stereocenter.

Betti base derived P-stereogenic phosphine-diamidophosphite ligands with a single atom spacer and their application in asymmetric catalysis

Small bite-angle P-chirogenic PNP ligands have been synthesized stereo-selectively and employed in Rh-catalyzed asymmetric hydrogenation and Pd-catalyzed asymmetric allylic substitution resulting in moderate to excellent enantioselectivities.

Synthesis of New Chiral N-alkyl Betti-base Ligands via One-Pot Three Component Strategy

Background: Betti base derivatives were employed as chiral ligands or as chiral auxiliaries in asymmetric transformations. In particular, N-alkyl Betti base derivatives are gaining importance as excellent ligands in asymmetric reactions. However, no appropriate method exists for regioselective N-alkylation of Betti base. Therefore, there is an urgent need to develop a new protocol for the regioselective N-alkylation of chiral Betti-base. Methods: An efficient method has been developed for one-pot synthesis of chiral N-alkyl Bettibase ligands from (S)-(+)-Betti base, arylglyoxals and cyclic 1,3-C,N-binucleophiles under catalyst- free conditions. Results: The chiral N-alkyl Betti-base ligands were obtained in good yields with excellent enantioselectivities. This method is rapid, clean and does not require a catalyst or chromatographic purification. Conclusion: We have developed an efficient one-pot three component strategy for the synthesis of new chiral N-alkyl Betti-base ligands from (S)-(+)-Betti base, arylglyoxals and cyclic 1,3-C,Nbinucleophiles in the absence of a catalyst.

Aminomethylated Hydroxinaphthalenes: Synthesis and Application

The analysis of the literature is carried out and the results of the synthetic approaches to the aminomethylation of hydroxy derivatives of naphthalenes developed over the past 20 years are presented. Most of the described aminomethylation processes proceed as Mannich aminomethylation or, as a special case of a similar condensation --- aminobenzylation according to Betti. The results of all studies are grouped according to the nature of the amine used in the synthesis: primary, secondary, tertiary. Most of the examples were considered for 2-naphthol, however, as the analysis of literature data shows, similar methods are applicable to 1-naphthol and dihydroxynaphthalenes with different positions of OH groups in the ring --- often only the yields of the target product differ. Both the classical methods for the preparation of Mannich and Betti bases using the carbonyl component (formaldehyde, benzaldehyde and its derivatives, respectively) and special cases of synthesis, in which condensation is carried out by means of halogen derivatives, substituted azacrown ethers, etc., are presented. Particular attention is paid to the use of various catalysts and activators, allowing to significantly simplify the synthetic procedures and increase the yields of target compounds. The main fields of application of aminomethylated derivatives of hydroxynaphthalenes are presented

Regioselectivity of aminomethylation in 3-acetyl-7-hydroxycoumarins: Mannich bases and Betti bases

The atomic electron density distribution in 3-acetyl-7-hydroxycoumarin was analysed to elucidate the regioselectivity of aminomethylation.

DNA binding and cleavage studies of novel Betti base substituted quaternary Cu(II) and Zn(II) phthalocyanines

Betti base substituted zinc and copper phthalocyanines (ZnBBPc and CuBBPc) and their quaternized derivatives qZnBBPc and qCuBBPc were synthesized and characterized for the first time. The photophysical quantum yield (ΦF) and singlet oxygen quantum yield (ΦΔ) of ZnBBPc and qZnBBPc were measured using comparative and 1,3-diphenylisobenzofuran (DPBF) absorption titration methods respectively. The DNA binding activities of qZnBBPc and qCuBBPc against Calf-Thymus DNA (CT-DNA) were investigated using UV–visible absorption titrations, fluorescent displacement assays with classical intercalator ethidium bromide (EB) and minor groove binder Hoechst dye (HD), as well as by carrying out viscosity measurements in Tris-NaCl buffer (pH 7.4). The results indicated that qCuBBPc and qZnBBPc phthalocyanines showed strong affinities for CT-DNA through intercalation with binding constants (Kb) of the order of 105 M−1. The cleavage activities of compounds on supercoiled pBR322 plasmid DNA were determined by agarose gel electrophoresis in the presence and absence of light and additives. The compound qCuBBPc showed hydroxyl radical mediated oxidative cleavage, while the complex qZnBBPc exhibited singlet oxygen mediated photocleavage.

Crystallization-Induced Diastereoisomer Transformation of Dihydroartemisinic Aldehyde with the Betti Base.

Artemisinin is an important drug to fight malaria. It is produced either by extraction or via a semisynthetic route involving enzyme engineering. A key intermediate to produce artemisinin by the enzymatic route is dihydroartemisinic aldehyde (DHAAl). However, control of the absolute configuration of the stereocenter α to the aldehyde is highly challenging. Herein we report a protocol that allows the diastereomeric enrichment of a mixture of (11R)/(11S)-DHAAl to the desired (11R)-DHAAl by utilizing a crystallization-induced diastereomer transformation induced by the Betti base. In addition, the Betti base can be quantitatively recovered and reused after the reaction.

Synthesis of Ferrocenyl Based Betti Bases by a Mannich-Type Three-Component Reaction and Investigation of Their Electrochemical Behavior

Ferrocenyl based Betti base derivatives, 1-[aryl(4-(4-ferrocenylbutyl)piperazin-1-yl)methyl]naphthalen-2-ol, were synthesized through one-pot three-component reaction by treatment of 1-(4-ferrocenylbutyl)piperazine, naphthalene-2-ol and benzaldehyde derivatives in ethanol as solvent in the presence of triethanolamine as catalyst under reflux condition. 1-(4-ferrocenylbutyl)piperazine was prepared by treatment of 4-chlorobutylferrocene and piperazine. Various benzaldehydes were applied to the synthesis of some new ferrocenyl Betti bases and the new ferrocenyl compounds were obtained in rather good yields (59–75%). The electrochemical performance of these new ferrocenyl based Betti bases were investigated by cyclic voltammetry in dry acetonitrile in the presence of 0.1 M LiClO4 as the electrolyte. The electrochemical studies revealed that the synthesized compounds contain a single electron quasi-reversible redox couple assigned to the ferrocenyl moiety.

Betti base and its modified phthalonitrile derivative for the turn on fluorimetric detection of Hg2+ and Cr3+ ions

The Betti Base Phenyl-(2-pyridinylamino)-methyl-2-naphthalenol (BB) derived by the multicomponent Mannich aminoalkylations reaction from 2-naphthol, 2-aminopyridine and benzaldehyde. The modified phthalonitrile 4-((1-(phenyl(pyridin-2-ylamino)methyl)naphthalen-2-yl)oxy)phthalonitrile BBPN was obtained by aromatic nucleophilic coupling reaction of 4-nitrophthalonitrile with BB. The compounds were successfully characterized by common spectroscopic and single crystal XRD techniques. The compounds BB and BBPN was exhibited a selective and sensitive fluorescence detection tendency towards mercuric Hg2+ and chromium Cr3+ ions respectively by the fluorescence turn on processes. Job’s plot method is employed to obtain idea about the stoichiometric interaction of metal ions with fluorescent probes. Theoretical calculation was done by Density Functional Theory DFT-B3YLP in order to get atomistic insights into the coordination geometry of Hg2+ and Cr3+ with BB and BBPN respectively. The limit of detection (LOD) of Hg2+ with BB and Cr3+ with BBPN was estimated respectively as 9.7 × 10−7 mol/L and 7.03 × 10−6 mol/L. The fluorescence enhancement of both compounds were induced by the inhibition of Photoinduced Electron Transfer (PET) process in which electron transfer happens from amino group to the fluorophore naphthol unit. The PET process was blocked upon binding of the sensors BB and BBPN with Hg2+ and Cr3+ respectively.

Synthesis and application of novel 1,2,3‐triazolylferrocene‐containing ionic liquid supported on Fe3O4 nanocatalyst in the synthesis of new pyran‐substituted Betti bases

A novel magnetic ferrocene‐labelled ionic liquid based on triazolium, [Fe3O4@SiO2@Triazol‐Fc][HCO3], has been synthesized and has been successfully introduced as a recyclable heterogeneous nanocatalyst. The catalytic activity of the novel magnetic nanoparticles was evaluated in the one‐pot three‐component synthesis of a wide variety of Betti bases. A simple, facile and highly efficient green method has been developed for the synthesis of kojic acid‐containing Betti base derivatives at room temperature. Additionally, this new protocol has notable advantages such as short reaction times, green reaction conditions, high yields and simple workup and purification steps. Also, the novel nanocatalyst could be easily recovered using an external magnetic field and reused for six consecutive reaction cycles without significant loss of activity. The newly synthesized nanocatalyst was characterized using Fourier transform infrared spectroscopy, X‐ray diffraction, energy‐dispersive X‐ray spectroscopy, field emission scanning electron microscopy, transmission electron microscopy and Brunauer–Emmett–Teller measurements.

Synthesis and Characterization of Betti Bases Derivatives via Green Mannich Reaction by NS-PCS and FHS as the Catalyst

In the current world, issues that pertain to our environment are of especial importance. One of these issues is the pollution caused by chemical compounds during their production process. As a result, finding chemical synthesis methods that are consistent with environmental protocols are also important. The catalytic performance of the α-aminoalkyl-β-naphthol derivative material, in water as a green solvent has been examined in the synthesis via MCR Mannich reaction of aldehydes, β-naphthol, and amines by porous carbon spheres which doped by Nitrogen and Sulfur (NS-PCS) and Ferric Hydrogen Sulfate (FHS). The catalysts were easily differentiated from the reaction mixture and reused for several consecutive runs without significant loss of their catalytic efficiency.