Current Organic Synthesis - Volume 19, Issue 5, 2022

Background: Betti bases are pharmaceutically and synthetically important scaffolds due to their diverse range of biological activities and applications in key synthetic transformations in organic synthesis. Objective: This work has been sought to contribute to the development, design, and implementation of an improved green methodology with higher atom economy and lower E-factor values for the synthesis of Betti bases. Methods: To realize our objectives, we screened out different catalysts and reaction conditions using one-pot multicomponent modified Mannich reaction/Betti reaction by employing 2-naphthol, benzaldehyde and pyrrolidine as model substrates. Results: The developed methodology afforded functionalized Betti bases in 60-100% yields via FeCl3•6H2O catalyzed one-pot multi-component Betti reaction under neat conditions at 110 °C (5-15 min) using several aromatic aldehydes and secondary amines. Conclusion: A facile synthetic methodology with higher atom economy and lower E-factor values to synthesize Betti bases via FeCl3•6H2O catalyzed one-pot multicomponent Betti reaction of 2-naphthol, aromatic aldehydes, and secondary amines under neat conditions at 110 °C has been reported. The developed methodology offers various advantages, such as excellent yields (60-100%), short reaction time (5-15 min), wide substrate scope (12 examples), green reaction conditions, use of readily available catalyst, and easy purification (without column chromatography).

Background: 1,2,4-triazoles scaffolds display significant biological activities due to hydrogen bonding, solubility, dipole character, and rigidity. Objective: The core motif of 1,2,4-triazoles plays a vital role in clinical drugs such as Rizatriptan (antimigraine), Ribavirin (antiviral), anastrozole (anticancer), etizolam (anxiolytic), estazolam (anticonvulsant), alprazolam (anti-hypnotic), letrozole (aromatase inhibitor), loreclezole (anticonvulsant), trazadone (antidepressant) etc. Methods: Epoxide ring opening of tert-butyl 6-oxa-3-azabicyclo [3.1.0] hexane-3-carboxylate followed by methylation under basic conditions and de-protection gave the corresponding trans 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole hydrochloride salt as the precursor. This precursor on reaction with substituted benzoyl chlorides and benzyl bromides gave the desired amide and amine products. Results: A library of 14 N-substituted pyrrolidine derivatives i.e. trans3-methoxy-4-(1H-1,2,4-triazol- 1-yl) pyrrolidin-1-yl) (phenyl)methanone and trans 1-benzyl-4-methoxypyrrolidin-3-yl)-1H-1,2,4- triazole were prepared. Conclusion: Eight novel amides (6a-h) and six amines (8a-f) derivatives were synthesized using 1-(4- methoxypyrrolidin-3-yl)-1H-1,2,4-triazole 4 salt with substituted benzoyl chlorides and benzyl bromides.

Background: SKLB1039 is a potent, highly selective, and orally bioavailable EZH2 inhibitor, which significantly inhibited breast tumor growth and metastasis in pre-clinical studies. In a previously reported synthesis of SKLB1039, the yields of several steps were low, which led to an overall yield of less than 10%. In addition, flash chromatography was required for the purification of several intermediates using this route. Objective: To optimize the synthesis and establish an efficient commercial-scale method for the production of SKLB1039. Methods: The reaction time, solvent, reactant ratio, temperature, and mode of addition of reactants in the reductive amination, hydrolysis, hexahydroisoquinoline formation, hydrogenolysis, condensation and Suzuki crosscoupling reactions were optimized. Results: A chromatography-free seven-step process starting from a commercially available material was developed that afforded SKLB1039 in 36% overall yield with > 99% purity. Conclusion: A cost-effective, high-yielding, and convergent kilo-scale synthesis for the EZH2 inhibitor SKLB1039 was developed. The operation was simple, and the pure product was easily obtained without column chromatography. This method will be economical and convenient for the subsequent industrial scale-up production of SKLB1039, which will be conducive for this promising EZH2 inhibitor to enter clinical studies of its antitumor effects.

Background: Arylidenemalononitriles are valuable synthons for the construction of a variety of novel complex heterocyclic motifs, fused heterocycle derivatives, and spirocyclic compounds. They are versatile chemical intermediates and have increasing applications in industry, agriculture, medicine, and biological science. Objective: The aim of this review is to highlight the preparation methods and reactions of arylidenemalononitriles in the synthesis of various heterocyclic compounds. Conclusion: In this review, we have presented the application of arylidenemalononitriles to construct a variety of heterocycles. Various catalysts for the preparation of arylidnemalononitriles have been described.

2,3-Diaminomaleonitrile (DAMN), a tetramer of hydrogen cyanide, displays weakly basic properties and has reactivity comparable to o-phenylenediamine. It has emerged as a versatile, cheap as well as a readily accessible building block towards the synthesis of a variety of organic compounds. The present review focuses on the applications of 2,3-diaminomaleonitrile for the synthesis of Schiff’s base, imidazoles, pyrazines, quinoxolines, benzodiazocines, 1,4-diazepines, purines, pyrimidines, pyrazine-tetrazole hybrids, triazoles, thiadiazole, thiazolidines, porphyrazines, formamidines, 1,3,5-triazepines, pyrrolo[3,4-b][1,4]diazepin-6(3H)-ones, triaza[22]annulenes, pyrrolo[3,4-f][1,3,5]triazepines, spiro compounds, pyrazoles and 2,3-dicyano-5,7- bismethylthieno[3,4-b]pyrazine.

Chalcone-derived isoxazole scaffolds remain the central focus due to their greater biological, clinical, and pharmacological properties. The present study reviews the synthesis of various chalcone derived - 5- membered isoxazoline and isoxazole scaffolds with the available literature until 2021.

Aims and Objective: Condensation of 5-hetarylidene-2,2-dimethyl-1,3-dioxane-4,6- diones with 5,5-dimethyl-3-arylamino-2-cyclohexanones yields 1-aryl-4-hetaryl-7,7-dimethyl-2,5- dioxo-l,2,3,4,5,5,7,8-octahydro-quinolines. The structures of all the synthesized compounds have been verified by IR, 1H-NMR, 13C-NMR, and mass spectral methods. The 13C-NMR assignments were supported by HSQC and HMBC experiments. Moreover, spin decoupling and NOE experiments have been carried out in order to elucidate stereoisomeric configurations of the compounds. It has been established that the N-phenyl ring, which projects from the plane of the octahydroquinolinedione ring, has a shielding effect on the magnetic field of the protons at 7- and 8-positions of the ring in the molecules of the compounds synthesized. Materials and Methods: The NMR spectra were recorded on a Varian Gemini spectrometer [400 MHz (1H) and 100 MHz (13C)]. EI mass spectra were obtained with a Hewlett Packard GC/MS 6890/5973 machine. MALDI-TOF mass measurements were recorded on a Bruker auto-flex III smart beam. Results: Various reaction conditions were applied in order to find an optimum and convenient procedure for the formation of octahydroquinoline derivates having hetaryl group. The highest yields (40-50 %) were achieved using acetic acid as solvent, p-toluenesulphonic acid as acidic catalyst, and excess enaminone (1.5 equiv). Conclusion: We synthesized eight new 1-aryl-7,7-dimethyl-4-hetaryl-1,2,3,4,5,6,7,8-octahydroquinoline- 2,5-dione compounds containing thienyl core as a result of Michael addition reaction of Knoevenagel products of Meldrum’s acid with dimedone enaminone compounds. Optimum circumstances were established using various reaction conditions and catalyzers throughout the research. The structures of all the synthesized compounds were analyzed by IR, 1H-NMR, 13CNMR, and mass spectral methods. Furthermore, the structures were verified with the help of 2D (HSQC and HMBC), spin decoupling, and NOE NMR techniques.

Background: In today’s world, rising temperature due to global warming is caused by higher concentration of carbon dioxide (CO2) emissions in the atmosphere. Metal-Organic Framework (MOF) materials have the potential to be used in carbon dioxide capture and utilization technology. Objective: The purpose of this work is to prepare metal-organic framework materials by a benign synthesis method using water as the solvent, followed by the characterization and property evaluation for CO2 adsorption study. Methods: MIL-101-Cr metal-organic framework and its derivatives with alkali ion dopants were prepared by benign hydrothermal synthesis route, which were characterized by powder X-ray diffraction method. The adsorption isotherms of CO2 for MIL-101-Cr and its derivatives were studied to comprehend the influence of alkali dopants on CO2 sorption behaviour. The equilibrium uptakes of CO2 were further evaluated by fitting the isotherms with Langmuir, Toth and Dubinin - Astakohv adsorption models to determine the adsorption parameters. Results: The crystalline structural integrity of MIL-101-Cr is not affected by doping with alkali ions. The isosteric heat of CO2 adsorption is diminished with an increase in alkali dopant size, while the induced surface structural heterogeneity increases with increasing alkali dopant size. Conclusion: The equilibrium and thermodynamic parameters calculated from this study are useful for applications in carbon dioxide capture and utilization technology.