Synthesis Of Phthalimides Research Articles

Rhodium-catalysed additive-free carbonylation of benzamides with diethyl dicarbonate as a carbonyl source.

Phthalimides are prevalent in numerous pharmaceuticals, prompting various phthalimide syntheses through C-H activation. Nevertheless, the necessity for stoichiometric additives limits their practicality and versatility. Herein, we introduced diethyl dicarbonate as a carbonyl source for an additive-free carbonylation of benzamides. This transformation signifies an operationally simple and CO-free phthalimide synthesis.

Benzannulation with Et3N as 1,3-Diene Variants.

With triethylamine as a 1,3-diene variant, a simple and practical process for the synthesis of phthalimides has been developed from readily available maleimide. The transformation can be performed in the absence of a metal catalyst with high levels of functional group tolerance. Various phthalimide compounds were constructed in moderate to good yields under mild conditions. Mechanism research indicates that oxygen and acid also play crucial roles in this reaction.

Synthesis of phthalimide and naphthalimide derived Biginelli compounds and evaluation of their anti-inflammatory and anti-oxidant activities

In the present work, synthesis of phthalimide and naphthalimide derived Biginelli compounds was performed. Allylation of phthalic & naphthalic anhydride, followed by ozonolysis resulted in the formation of N-phathalimido/naphpthalimido acetaldehyde (2 and 7). These aldehydes were subjected to Biginelli reaction using urea/thiourea and divergent β-keto esters in the presence of sulfated tin oxide (5 mol%) as catalyst in ethanol reflux to produce the corresponding dihydropyrimidinone compounds (5a-j and 8a-h). Additionally, both their antioxidant and anti-inflammatory functions were carried out. Compounds 5e, 5f, 5i, and 5j have shown potent to moderate potent activity for both antioxidant and anti-inflamamtory activities when compared to standard. Compounds 8c and 8g have shown potent antioxidant and anti-inflamamtory activities when compared to other compounds.

A facile synthesis of phthalimides from o-phthalaldehyde and amines via tandem cyclocondensation and α-C-H oxidation by an electrochemical oxygen reduction reaction.

Electrochemical synthesis of phthalimides from o-phthalaldehyde and amines via tandem cyclocondensation and α-C-H oxygenation of isoindolinone was achieved. The α-C-H oxidation proceeded with molecular oxygen via an oxygen reduction reaction (ORR) on the cathode under electrochemical conditions. The synthetic utility of this protocol was successfully demonstrated by employing gram-scale synthesis and obtaining bioactive molecules such as thalidomide and 2-(2,6-diisopropylphenyl)-5-hydroxyisoindoline-1,3-dione. Mechanistic studies and control experiments indicate that molecular oxygen provides oxygen atoms for the reaction.

Direct synthesis of phthalimides via palladium-catalysed double carbonylation of o-dihaloarenes with nitroarenes.

The direct carbonylation of readily available nitro compounds is more attractive and straightforward than the use of traditional amines as nucleophiles. Herein, a practical palladium-catalysed double carbonylation of nitroarenes with o-dihaloarenes has been developed for the construction of various N-aryl phthalimides. Key to the success of this transformation is the use of Mo(CO)6, which acts as both a reducing agent and a solid carbonyl source. A wide range of nitroarenes and o-dihaloarenes as well as o-iodobenzoic acids reacted smoothly to give phthalimides in 27-94% yields.

Supported-Pd catalyzed carbonylative synthesis of phthalimides and isoindolinones using Oxalic acid as in situ CO surrogate with 2-iodobenzamides and 2-iodobenzylanilines in ppm-level catalyst loading

Polystyrene supported palladium (Pd@PS) nanoparticles (NPs) catalyzed intramolecular aminocarbonylation of 2-iodobenzamides and 2-iodobenzylanilines using bench stable Oxalic acid as in situ CO source for the synthesis of phthalimides and isoindolin-1-one is described. Low catalyst loadings (0.2 mol%, 2000 ppm Pd) with appreciable recyclability up to six cycles, external base free, Oxalic acid as inexpensive and safer in situ C1 source and vast substrate scope are some remarkable features of the present protocol. Furthermore, we scale up the present reaction up to 1.5 gram.

Modular Synthesis of Carbazole-Substituted Phthalimides as Potential Photocatalysts

AbstractThe modular synthesis of carbazole functionalized phthalimides (PIs) and their applicability as catalyst in selected photocatalytic transformations are reported. The developed synthetic approach provides high variability of phthalimide considering that the synthesis of the phthalimide core can be easily performed. Starting from fluorophthalic acid anhydrides, the corresponding fluorophthalimides were prepared with various amines, and the fluoro function ensured the introduction of carbazoles into the phthalimide framework through aromatic nucleophilic substitution. Besides the synthetic developments, some of the carbazolyl phthalimides were tested in four different photocatalytic transformations, which showed attractive and comparable activity to the known 4-CzIPN and noble metal complexes.

Synthesis of Imide and Amine Derivatives via Deoxyamination of Alcohols Using N-Haloimides and Triphenylphosphine.

A deoxyamination methodology of activated and unactivated alcohols is presented. The reaction is mediated by phosphonium intermediates generated in situ from N-haloimides and triphenylphosphine. The protocol allows for the synthesis of phthalimide and amine derivatives in moderate to good yields at room temperature. A series of NMR experiments have provided insight into the reactive intermediates involved and the mechanism of this deoxyamination reaction.

Synthesis of phthalimides, isoindolin-1-ones and isoindolines bearing aminobenzoic acids as a new fluorescent compounds

Both experimental and theoretical methods were used in order to study the fluorescent properties of nine new compounds based on phthalimides, isoindolin-1-ones and isoindolines bearing aminobenzoic acids (2-aminobenzoic acid, 3-aminobenzoic acid and 4-aminobenzoic acid), which were obtained under mild reaction conditions. The photophysical properties of all the compounds were studied by electronic absorption and fluorescence spectroscopy in methanol solutions. All compounds exhibited fluorescence emission and high quantum yields. Additionally, it was found that the intramolecular charge in these donor-acceptor systems is significantly depending on electron-withdrawing substituents at the carboxylic acid position.

An Efficient Synthesis of Phthalimides and Their Biological Activities

Practical and efficient synthesis of phthalimides compounds 3 were described and characterized. The synthesized compounds were screened for their antimicrobial activities against gram-positive bacterial strains (Micrococcus luteus, Listeria monocytogenes, Staphylococcus aureus and Bacillus cereus), a gram-negative bacterial strain (Salmonella typhimurium) and a fungus (Candida albicans). Cytotoxicity studies of the of phthalimides 3 were conducted in two human cancer cell lines, MDA-MB-231 and MCF-7.

Synthesis of phthalimides cross-conjugated with an azulene ring, and their structural, optical and electrochemical properties.

The preparation of phthalimides cross-conjugated with an azulene ring was established by a one-pot Diels-Alder reaction of the corresponding 2-aminofuran derivatives with several maleimides, without the isolation of the intermediately formed [4 + 2] cycloadducts. The structure, optical and electrochemical properties of the novel phthalimide derivatives were clarified by single-crystal X-ray analysis, UV/Vis and fluorescence spectra, spectroelectrochemistry and voltammetry experiments, and theoretical calculations. These results indicated that the substituents on the azulene ring greatly affect the optical and electrochemical properties of the molecules.

Cobalt-Catalyzed Carbonylative Synthesis of Phthalimides from N-(Pyridin-2-ylmethyl)benzamides with TFBen as the CO Source.

A cobalt-catalyzed direct carbonylative synthesis of phthalimide motifs from N-(pyridin-2-ylmethyl)benzamides has been developed. Various phthalimide derivatives were obtained in moderate to excellent yields (up to 98%) by using 2-picolylamine as an efficient directing group and benzene-1,3,5-triyl triformate (TFBen) as a convenient CO surrogate.

New Water-Soluble Oxyamino Chitosans as Biocompatible Vectors for Efficacious Anticancer Therapy via Co-Delivery of Gene and Drug.

Among the many nonviral gene delivery vectors, chitosan, being a polysaccharide of natural origin, has gained special importance. In this report, chitosan (CS) has been solubilized in water by preparing its O-carboxymethyl derivative, CS(CH2COOH), with an optimum degree of carboxymethylation. This has been further derivatized to get the pyridine-substituted product (py)CS(CH2COOH), where the degree of pyridine substitution (47%) was optimized based on zeta potential measurements. The optimized formulation showed a high gene binding ability, forming nanosized positively charged polyelectrolyte complexes with DNA. These polyplexes were stable to DNase and physiological polyanions such as heparin. They also exhibited minimal toxicity in vitro and showed transfection levels comparable to the commercial standard Lipofectamine 2000 and much higher than polyethylenimine (MW, 25 kDa). Additionally, in this study, a hitherto unknown oxyamine derivative of chitosan has been prepared by phthaloyl protection, tosylation, and Gabriel's phthalimide synthesis. Nearly 40% of the primary alcohols were successfully converted to oxyamino functionality, which was used for forming oxime with the anticancer drug doxorubicin. The pH sensitivity of the oxime ether linkage and stability under biologically relevant conditions were then used to establish the compound as a versatile drug delivery vector. Co-delivery of functional gene (p53) and drug (doxorubicin) was accomplished in vitro and in vivo with the chitosan-pyridine imine vector (py)CS(CH2COOH) and the newly synthesized doxorubicin oxime ether CS(Dox). Complete tumor regression with no tumor recurrence and appreciable survivability point to the in vivo effectiveness and biocompatibility of the designed composite formulation. Overall, the pH sensitivity of the oxime linkage aiding slow and steady drug release, together with the sustained gene expression by pyridine-tethered carboxymethyl chitosan, allows us to generate a nanobiocomposite with significantly high anticancer therapeutic potential.

PPh3/I2/HCOOH: An efficient CO source for the synthesis of phthalimides

A straightforward and general method has been developed for the synthesis of phthalimide derivatives from 2-iodobenzamides and PPh3/I2/HCOOH in the presence of a catalytic amount of Pd(OAc)2. The reaction results demonstrate that PPh3/I2/HCOOH is a facile, efficient and safe CO source. The whole process is carried out in toluene at 80 °C and furnishes the desired products in good to excellent yields.

Efficient Synthesis of Phthalimides via Cobalt‐Catalyzed C(sp2)−H Carbonylation of Benzoyl Hydrazides with Carbon Monoxide

AbstractA cobalt‐catalyzed C−H carbonylation of benzoyl hydrazides has been developed by using 2‐(1‐methylhydrazinyl)pyridine as the bidentate directing group. This transformation is mild, efficient, operationally simple, and highly functional‐group‐tolerant. The protocol has generated a broad range of phthalimide derivatives in good to excellent yields. The ligand moiety can be readily removed through hydrogenolysis.magnified image

Synthesis of Phthalimides: A New Entry via TBAI-Catalyzed Intramolecular Cyclization of 2-(Hydroxymethyl)benzamides

Herein we report an unprecedented metal-free TBAI/TBHP mediated C–N bond formation via intramolecular cyclization of 2-(hydroxymethyl)benzamides to furnish N-substituted phthalimides in excellent yields.

Selective formation of phthalimides from amines, aldehydes and CO by Pd-catalyzed oxidative C–H aminocarbonylation

The Pd/Cu-catalyzed intramolecular C–H bond aminocarbonylation utilizing imines as the amine source has been developed. This transformation provides an efficient and straightforward protocol for the synthesis of phthalimides which widely exist in natural products, pharmaceutical and functional materials. Various functional groups are tolerated and the yields are up to 99%.

Carbonylation Access to Phthalimides Using Self-Sufficient Directing Group and Nucleophile.

Herein we report a novel palladium-catalyzed oxidative carbonylation reaction for the synthesis of phthalimides with high atom- and step-economy. In our strategy, the imine and H2O, which are generated in situ from the condensation of aldehyde and amine, serve as self-sufficient directing group and nucleophile, respectively. This method provides rapid access to phthalimides starting from readily available materials in a one-pot manner. Various phthalimide derivatives are constructed efficiently, including medicinally and biologically active phthalimide-containing compounds.

Synthesis of phthalimide disperse dyes and study on the interaction energy

Three azo dyes had been synthesized using N-ethyl substituted, dibromo-substituted and dicyano-substituted phthalimides as diazo components. All of the synthesized intermediates and dyes have been characterized by MS, 1H NMR, IR and elemental analyses. The dyeing behavior and fastness properties of these dyes have been investigated. Modeling the interaction energy of benzene-benzene, phthalimide-benzene and phthalimide-phthalimide rings, molecule optimization and the interaction energy researching have been done with density functional theory ωB97XD, 6-311G++(d,p) basis set. The results showed that: phthalimide molecule has better coplanarity. Molecule energy of benzene-benzene, phthalimide-benzene and phthalimide-phthalimide rings decreased first and then increased with the increase of the distance between the rings, the lowest energy happened when the distance was about 3.5 Å. Electrostatic force affected the interaction energy most. Substituent groups mainly altered the dispersion force and reduced the energy of the system. The optimization interaction energy of phthalimide-phthalimide, phthalimide-benzene and benzene-benzene was −47.78 kJ/mol, −34.66 kJ/mol and −17.59 kJ/mol. Substituted dibromo group reduced the dipole interaction of the dye.

Synthesis of Various N‐Substituted 4‐Aryloxy/Thiophenoxy/Thioisopropyloxy‐Phthalimides

AbstractN‐substituted phthalimides have been used to target many biological systems with examples that are clinically used as drugs. Furthermore, N‐substituted phthalimides can also be used in other settings such as in the preparation of polymers, as catalysts, and as protective groups. Because of all these important fields of application, the synthesis of phthalimides is well reported. However, synthetic methods to phthalimides with different heteroatom substituents in position 4 are lacking. The present work describes the development of robust synthetic methods to N‐substituted 4‐aryloxy/thiophenoxy/thioisopropyloxy‐phthalimides. The developed methods allow for the introduction of these substituents through an atom efficient one‐step synthesis, which gives good to excellent yields and tolerate a wide range of substituents.