Group-assisted Purification Research Articles

Synthesis of Polycyclic Chromeno[4,3,2‐ij]Isoquinoline‐3‐Carbonitriles in the Presence of Ammonium acetate as a Dual Rule Reagent‐Catalyst

AbstractIn this paper, a two‐step process is described for the chemoselective synthesis of highly fluorescent polycyclic chromeno[4,3,2‐ij]isoquinoline‐3‐carbonitriles using a sequential nucleophilic addition reaction involving 4‐chloro‐3‐vinyl coumarins, α,α‐dicyanoolefins and ammonium acetate as a source of nitrogen. In this process, it is believed that ammonium acetate is converted into ammonia and acetic acid during the reaction. Ammonia is the source of nitrogen, and the acid produced can catalyze the progress of the reaction. Single‐crystal X‐ray analysis was performed to confirm the structure of one of the typical products. In addition, the photophysical characteristics of the product 3 a were investigated through absorption and emission spectroscopy. This analysis reveals that the new heterocyclic system has impressive fluorescence characteristics. Several advantages of the presented synthetic strategy can be found in its simplicity, readily available starting materials, high‐efficiency products, highly chemoselective route, metal‐free catalyst, and ability to purify products by washing them with EtOH (96 %), a technique called GAP (Group‐Assisted‐Purification) chemistry.

Four-layer folding framework: design, GAP synthesis, and aggregation-induced emission.

The design and synthesis of a type of [1 + 4 + 2] four-layer framework have been conducted by taking advantage of Suzuki-Miyaura cross-coupling and group-assisted purification (GAP) chemistry. The optimized coupling of double-layer diboronic esters with 1-bromo-naphth-2-yl phosphine oxides resulted in a series of multilayer folding targets, showing a broad scope of substrates and moderate to excellent yields. The final products were purified using group-assisted purification chemistry/technology, achieved simply by washing crude products with 95% EtOH without the use of chromatography and recrystallization. The structures were fully characterized and assigned by performing X-ray crystallographic analysis. UV-vis absorption, photoluminescence (PL), and aggregation-induced emission (AIE) were studied for the resulting multilayer folding products.

An efficient, catalyst-free and aqueous ethanol-mediated synthesis of 5-((2-aminothiazol-5-yl)(phenyl)methyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives and their antioxidant activity.

In this study, we effectively developed a catalyst-free multicomponent synthesis of 5-((2-aminothiazol-5-yl)(phenyl)methyl)-6-hydroxypyrimidine-2,4(1H,3H)-dione derivatives employing 2-aminothiazole, N',N'-dimethyl barbituric acid/barbituric acid and different aldehydes at 80 °C in an aqueous ethanol medium (1 : 1) using group-assisted purification (GAP) chemistry. The essential characteristics of this methodology include superior green credential parameters, metal-free multicomponent synthesis, faster reaction times, greater product yields, simple product purification without column chromatography and higher product yields. All of the synthesized compounds were analyzed against the HepG2 cell line. Compounds 4j and 4k shows good anti-proliferative effects on HepG2 cells. Furthermore, the ABTS and DPPH scavenging assays were used to determine the antioxidant activity of all compounds (4a-r). In both ABTS and DPPH radical scavenging assays, compounds 4e, 4i, 4j, 4o and 4r exhibit excellent potency compared to the standard ascorbic acid.

Base-promoted synthesis of dihydrochromeno[4,3-d]pyrrolo[3,4-b]pyridines from 4-chloro-3-substituted coumarins and α-aminomaleimides.

This paper describes the base-mediated cascade reactions of 4-chloro-3-substituted coumarins with α-aminomaleimides, allowing the efficient synthesis of dihydrochromeno[4,3-d]pyrrolo[3,4-b]pyridines with interesting chemoselectivity. These transformations include the domino-style formation of C-C/C-N bonds through a base-mediated nucleophilic substitution, Michael addition, N-cyclization, and elimination. The presented synthetic strategy has several advantages: it is simple, uses readily available starting materials and an environmentally friendly solvent, has a highly chemoselective route, and allows the purification of products via washing with EtOH (96%), a technique called GAP (Group-Assisted-Purification) chemistry.

Highly Efficient Synthesis of Imidazolecarboxylate Salts via Sequential Nucleophilic Addition-Intramolecular Cyclization Reactions

Abstract: In this work, we used a highly efficient and easy approach for synthesizing imidazolecarboxylate salt through the reaction between α-amidino carboxylic acids and α-halo ketones with as readily available starting materials in the presence of KHCO3 at THF under reflux. Targeted synthesis of this type of imidazole bearing the carboxylic acid group in a single structure, in addition to the biological properties enriched as a ligand, is very popular in the manufacture of catalysts. The salient features of this protocol include eco-friendly, high atom-economical, easy and mild conditions that led to the production of all products with high yields. Furthermore, all products were purified without the need for column chromatography through the GAP chemistry (group-assisted purification chemistry) technique.

Facile Synthesis of Benzo[c]chromen-6-ones via Base-Promoted Reaction of 4-Chloro-3-formylcoumarin and α,α-Dicyanoolefins

AbstractHerein, a chemoselective protocol for the facile and efficient synthesis of substituted benzo[c]chromen-6-ones is presented. The reaction took place under green and mild conditions with group-assisted purification (GAP) by using inexpensive and readily available precursors.

Liquid-Phase Peptide Synthesis (LPPS): A Third Wave for the Preparation of Peptides.

Since the last century, peptides have gained wide acceptance as drugs, with almost 100 already in the market and a large number in the pipeline. In this context, peptide synthesis has grown massively as a stringent field for pharmaceuticals around the globe. Three methodologies, namely, classical solution peptide synthesis (CSPS), solid-phase peptide synthesis (SPPS), and liquid-phase peptide synthesis (LPPS), have made significant contributions to the field. This review provides a comprehensive and integrated vision of LPPS as the third wave for peptide synthesis. LPPS combines the advantages of CSPS and SPPS, where peptide elongation is carried out in solution and the growing peptide chain is supported on a soluble tag, which confers characteristic properties. LPPS protocols allow the large-scale production of peptides and reduce the use of excess reagents and solvents, thus meeting the principles of green chemistry. In this review, tags associated with LPPS are broadly discussed under the following headings: polydisperse polyethylene glycol (PEG), membrane-enhanced peptide synthesis (MEPS), fluorous technology, ionic liquids (ILs), PolyCarbon, hydrophobic polymers, and group-assisted purification (GAP). It also highlights the signature accomplishments of LPPS tags and the limitations of the same.

Aggregation-Induced Synthesis (AIS): Asymmetric Synthesis via Chiral Aggregates.

A new chiral aggregate-based tool for asymmetric synthesis has been developed by taking advantage of chiral aggregates of GAP (Group-Assisted Purification) reagents, N-phosphonyl imines. This tool was proven to be successful in the asymmetric GAP synthesis of functionalized 2,3-dihydrobenzofurans by reacting salicyl N-phosphonyl imines with dialkyl bromomalonates in various cosolvent systems. The chiral induction can be controlled by differentiating between two asymmetric directions simply by changing the ratios of cosolvents which are commonly adopted in AIE (aggregation-induced emission) systems. The formation of chiral aggregates was witnessed by a new analytical tool—aggregation-induced polarization (AIP). The present synthetic method will be broadly extended for general organic synthesis, particularly, for asymmetric synthesis and asymmetric catalysis in the future.

Group-Assisted-Purification Chemistry Strategy for the Efficient Assembly of Cyclic Fused Pyridinones

AbstractA group-assisted-purification (GAP) chemistry strategy-based Ugi four-center three-component reaction (Ugi-4C-3CR) was explored. The reaction proceeded well to deliver the cyclic fused pyridinones selectively. Moreover, the reaction conditions were mild and avoided additional chromatography or recrystallization workup. Also, wide variations in substrates, such as anilines and aliphatic amines as well as amino alcohols and amino acid esters were all tolerated and pyridinones are achieved in good to excellent yields. Importantly, ladder-type cyclic fused pyridinones can be further constructed in excellent yield of 91%.

Regio- and Diastereoselective Vicinal Aminobromination of Electron Deficient Olefins via Phosphorus-Based GAP Protocol.

Chemical synthesis based on Group-Assisted Purification chemistry (GAP) has been prolifically used as a powerful, greener and ecofriendly tool so far. Herein, we report hypervalent iodine (III) mediated regio- and diastereoselective aminobromination of electron-deficient olefins using group-assisted purification (GAP) method. By simply mixing the GAP auxiliary-anchored substrates with TsNH2–NBS as nitrogen/bromine sources and PhI(OAc)2 as a catalyst, a series of vicinal bromoamines with multifunctionalities were obtained in moderate to excellent yields (53–94%). The vicinal bromoamines were obtained without column chromatography and/or recrystallization simply by washing the crude mixtures with cosolvents and thus avoiding wastage of silica, solvents, time, and labor. The GAP auxiliary is recyclable and reusable.

Iodine-Promoted Formal [3+2] Cycloaddition of Enaminone: Access to 2-Hydroxy-1,2-dihydro-pyrrol-3-ones with Quaternary Carbon Center.

A novel iodine promoted cyclization of enaminone with aryl methyl ketones has been developed as a straightforward method for constructing 2-hydroxy-pyrrol-3(2H)-ones. This strategy affords structurally diverse 2-hydroxy-pyrrol-3(2H)-ones rings in high yields. Moreover, a quarternary alcohol has been constructed efficiently in the reaction. Product purification required only washing with CH2Cl2 solvent, thereby avoiding traditional chromatography and recrystallization, making this an example of group-assisted purification chemistry.

Highly efficient azido-Ugi multicomponent reactions for the synthesis of bioactive tetrazoles bearing sulfonamide scaffolds

Recent studies revealed that the contribution of the different bioactive scaffolds in one structure creates modern drugs/compounds with unique synergistic biological properties. In this regard, thanks to the interesting biological and medicinal properties of sulfonamide and tetrazole skeletons, this study describes the engagement of sulfonamides in the Ugi tetrazole reaction to access a library of tetrazole bearing sulfonamide. This four-component reaction was performed in a one-pot among available starting material, i.e., an isocyanide, a sulfonamide, an aldehyde and sodium azide in MeOH at 45 °C using ZnCl 2 as a catalyst, for the synthesis of very versatile products with high atom economy and yields. The key point in this strategy is the formation of an intermediate Schiff base and its activation in the azido-Ugi reaction by a Lewis acid catalyst. Importantly, all products are purified through the group-assisted purification (GAP) chemistry, which can avoid traditional purification such as recrystallization and chromatography methods. Also, the docking study between the synthesized compounds and human serum albumin (HSA) was stimulated to theoretically rationalize their biological activity and potential binding interactions.

Group-assisted purification chemistry principles to access highly substituted zwitterionic furans via fast, concise, and efficient one-pot three-component assembly

Novel highly substituted zwitterionic furans were generated through the in situ formation of phosphonium salts. Firstly, intermediate salts were obtained via nucleophilic attack of Huisgen zwitterion to 3-cyanochromones. Finally, these intermediate salts underwent a proton migration, intramolecular cyclization, and ring-opening reaction to convert to the target products. The synthesized furans could be easily purified without traditional purification techniques (chromatography and recrystallization).

Asymmetric synthesis of functionalized 2,3-dihydrobenzofurans using salicyl N-phosphonyl imines facilitated by group-assisted purification (GAP) chemistry.

In this work, we present a strategy for the preparation of functionalized 2,3-dihydrobenzofuran derivatives via the Cs2CO3-catalyzed domino annulation of enantiopure chiral salicyl N-phosphonyl imines with bromo malonates, which offers an avenue for the construction of 2,3-dihydrobenzofurans. Nineteen examples were synthesized in impressive chemical yields and diastereoselectivity. The products were purified simply by washing the crude mixtures with hexanes following group-assisted purification chemistry/technology to bypass traditional separation methods which often result in a loss of product. The absolute configuration was unambiguously assigned by X-ray structural analysis.

Asymmetric [4 + 2] cycloaddition synthesis of 4H-chromene derivatives facilitated by group-assisted-purification (GAP) chemistry.

In this work, we present a strategy for the preparation of functionalized 4H-chromene derivatives via a Cs2CO3-catalyzed [4 + 2] cycloaddition of enantiopure chiral salicyl N-phosphonyl imines with allenoates. Fifteen examples were achieved in excellent yields and diastereoselectivity. The products were purified simply by washing the crude mixture with hexanes following the Group-Assisted Purification (GAP) chemistry/technology to bypass traditional separation methods. The absolute configuration was unambiguously determined by X-ray structure analysis.

Hypervalent Iodine (III) Catalyzed Regio- and Diastereoselective Aminochlorination of Tailored Electron Deficient Olefins via GAP Chemistry

Herein, we report a protocol for highly efficient hypervalent iodine (III) mediated, group-assisted purification (GAP) method for the regioselectivities and stereoselective aminochlorination of electron-deficient olefins. A series of vicinal chloramines with multifunctionalities were acquired in moderate to excellent yields (45–94%), by merely mixing the GAP auxiliary-anchored substrates with dichloramine T and tosylamide as chlorine/nitrogen sources and iodobenzene diacetate as a catalyst. The vicinal chloramines were obtained without any column chromatographic purification and recrystallization simply by washing the reaction mixture with a minimum amount of common inexpensive solvents and thus avoiding wastage of silica, solvents, time, and labor. The GAP auxiliary is recyclable and reusable. This strategy is easy to handle, cost-effective, greener, sustainable, environmentally benign, and mostly suitable for the syntheses of vicinal haloamines from various electron-deficient alkenes.

Chemo‐ and Diastereoselective Synthesis of Pyrazolo‐tetrahydropyridines via Multicomponent Sequential Aza‐Diels‐Alder Reactions in Water

AbstractIn this study, we report a novel and an efficient strategy for the synthesis of chemo‐ and diastereoselective synthesis of pyrazolo‐tetrahydropyridines via a one‐pot multi‐component intramolecular Aza‐Diels–Alder reactions (ADARs) from benzoylacetonitrile derivatives, phenylhydrazine, salicylaldehyde derivatives, and styrenesulfonyl or cinnamoyl chloride in H2O as a green solvent. This synthesis procedure was also designed to follow the group‐assisted purification (GAP) chemistry, which can avoid traditional purification such as recrystallization and chromatography methods.

Group-assisted Purification (GAP) Chemistry/Technology in Synthesizing the Chiral Intermediate of Rivastigmine and Its α-Alkyl Benzylamine Analogues

Introduction of (S)-configuration is the key step in the synthesis of the anti-dementia drug Rivastigmine. Twenty-one alkylation products were obtained through simple washing with hexane/ethyl acet...

Facile one-pot synthesis of novel highly functionalized dihydro-1H-pyrrole derivatives catalyzed by molecular iodine

An efficient, environmentally benign and molecular iodine promoted protocol was described for cascade synthesis of two kinds of novel dihydro-1H-pyrrole derivatives, 5 and 7. Compounds 5 were prepared via four-component reaction between diethyl acetylenedicarboxylate (DEAD), aromatic amines and phenylglyoxal monohydrate catalyzed by 10 mol% of iodine in ethanol at room temperature. In addition, using same reaction conditions, a three-component reaction between (E)-N-methyl-1-(methylthio)-2-nitroethenamine (NMSM), aromatic amines and arylglyoxal monohydrate was performed to access product 7. These transformations apparently proceed through an imine intermediate followed by iodine induced Mannich reaction and subsequent intra-molecular cyclization sequences. The protocol involves the formation of CN, CC and OH bonds leading to the preparation of a hexa substituted five membered ring with two stereo centres. The syntheses avoid the use of traditional column chromatography and recrystallization purification methods and, hence, follow the group-assisted purification (GAP) chemistry process.

One-pot four-component domino reaction for the synthesis of bifunctionalized spiro[indazolo[3,2-b]quinazoline-7,3′-indoline hybrids: A green approach

An efficient tandem route to obtain novel spiro[indazolo[3,2-b]quinazoline-7,3′-indolines has been explored. The one-step domino reaction proceeds via in situ generation of the 1H-indazol-3-amines followed by its reaction with the cyclic 1,3-dicarbonyls and isatin derivatives to furnish complex N-fused spiro-polyheterocyclic frameworks. This protocol describes a valuable route to concisely and feasibly obtain spiro[indazolo[3,2-b]quinazoline-7,3′-indolines from isatin derivatives. The present protocol is particularly attractive because of the following features: group-assisted-purification (GAP) chemistry process, low-cost solvent, convenience of operation, excellent atom economy, and high yields.