Hantzsch Ester Research Articles

Recent Advances in the Synthesis of Dihydropyridine and Their Corresponding Fused Systems via Multi‐Component Hantzsch Reaction Using Catalytic Nanomaterials

Abstract1,4‐Dihydropyridines (1,4‐DHPs) represent a versatile class of organic compounds derived from pyridines, recognized for their extensive synthetic applications and significant medical significances. Among the various synthetic methodologies available, the Hantzsch dihydropyridine synthesis is particularly notable as it provides a reliable approach to the production of these compounds. Recent advancements have markedly improved the synthetic pathways leading to Hantzsch dihydropyridines and their derivatives. This review aims to thoroughly examine the recent progress in the synthesis of 1,4‐DHPs, 1,8‐dioxodecahydroacridines (AD), and polyhydroquinolines (PHQ). Emphasis is placed on novel synthetic strategies reported in recent years, specifically those that employ multicomponent reactions involving aldehydes, β‐ketoesters, and ammonium salts. Furthermore, these reactions are catalyzed by various nanocatalysts, including magnetic nanoparticles, nanocomposites, metal oxides, functionalized nanoparticles, and other environmentally friendly nanobiomaterials. The application of nanocatalysts in these processes is underscored by their contributions to structural integrity and activity enhancement, indicative of a paradigm shifts towards more sustainable and efficient synthetic methodologies. This review consolidates and assesses various synthetic routes facilitated by nanocatalysts while elucidating their distinct roles in improving the efficiency and selectivity of 1,4‐DHP synthesis. Hence, this review may pave the way for advancements in Hantzsch reactions by employing nanomaterial catalysts for the sustainable production of 1,4‐DHP derivatives.

Non-classical effective methods for reduction of heteroaromatic compounds

The review summarizes the known data on various methods for saturation and dearomatization of heterocyclic moieties, forming diverse aromatic compounds. Since the classical hydrogenation of substrates with molecular hydrogen has a number of fundamental drawbacks that hinder both its use at the laboratory level and its widespread implementation in industrial production, the main attention is paid to non-classical methods described in the literature over the last 20-25 years. The methods of ammonia-free Birch reduction, transfer hydrogenation, reduction by Hantzsch esters and some other reactions involving heterocyclic compounds are summarized and systematized. It is shown that such methods of reduction or dearomatization of heterocycles can in some cases be more efficient than classical procedures.<br> The bibliography includes 173 references.

Small gold nanoparticles for tandem cyclization/reduction and cyclization/hydroalkoxylation reactions

With peculiar structural features at the surface of small metal nanoparticles, some discrete sites can display catalytic behaviour similar to what could be observed with mononuclear metal catalysts in solution. We have studied the transfer of two catalytic tandem reactions from homogeneous to heterogeneous conditions. Tandem cyclisation/reduction of ortho-alkynyl benzaldehyde derivatives was successfully achieved with Au nanoparticles over TiO2 (Au NPs/TiO2) in the presence of Hantzsch ester with 45-98% yields for 15 examples (average yield: 70.4%). Similarly, tandem cyclisation/hydroalkoxylation of ortho-alkynyl benzaldehyde derivatives was successfully achieved with Au NPs/TiO2 in methanol or other alcohols with 62-96% yields for 17 examples (average yield: 84.9%). The application potential of this catalytic system was demonstrated with the total synthesis of a bioactive isochromene derivative featuring one of the developed reactions as the key step and the implementation of the tandem cyclisation/hydroalkoxylation in a continuous flow reactor, scaling up the reaction by a factor of 10 without loss of efficiency.

Visible‐Light‐Induced Desulfurative Coupling of Alkyl Benzothiazolyl Sulfides with Electron‐Deficient Alkenes/Alkynes: Dual Role of Base‐Activated Hantzsch Esters

Hantzsch ester (HEH) is a bench‐stable compound used in hydrogenation and photo‐induced reactions, where it acts as a photoreductant and an electron donor. In this study, we describe a new use of this classical reductant in the visible‐light‐induced desulfurative coupling of alkyl benzothiazolyl sulfides with electron‐deficient alkenes/alkynes via activation with base additives. C(sp3)–S scission is achieved through catalyst‐free HEH anion‐mediated reactions and organo‐photocatalysis. The synthetic utility is illustrated with several examples of derivatization of natural products, including monosaccharides. In addition, mechanistic investigations reveal that the HEH anion acts as a photoreductant in catalyst‐free reactions and as a sacrificial reductant in the organo‐photocatalysis.

Selective Functionalization of White Phosphorus with Alkyl Bromides under Photocatalytic Conditions: A Chlorine-Free Protocol to Dialkyl and Trialkyl Phosphine Oxides.

A novel and efficient method for the direct selective alkylation of white phosphorus (P4) with alkyl bromides has been developed, utilizing 4DPAIPN as the photocatalyst and Hantzsch ester as the reductant. This method facilitates the synthesis of structurally diverse dialkyl phosphine oxides in good yields, offering a streamlined alternative to the traditional stepwise approach of chlorinating P4 with Cl2 and subsequently displacing the chlorine atom. Noteworthy features of this reaction include excellent product selectivity, remarkable functional group tolerance, and a broad substrate scope. Additionally, this method is effective for the synthesis of trialkyl phosphine oxides.

Visible-light-promoted direct desulfurization of glycosyl thiols to access C-glycosides

C-Glycosides are essential for the study of biological processes and the development of carbohydrate-based drugs. Despite the tremendous hurdles, glycochemists have often fantasized about the efficient, highly stereoselective synthesis of C-glycosides with the shortest steps under mild conditions. Herein, we report a desulfurative radical protocol to synthesize C-alkyl glycosides and coumarin C-glycosides under visible-light induced conditions without the need of an extra photocatalyst, in which stable and readily available glycosyl thiols that could be readily obtained from native sugars are activated in situ by pentafluoropyridine. The benefits of this procedure include high stereoselectivity, broad substrate scope, and easy handling. Mechanistic studies indicate that the in situ produced tetrafluoropyridyl S-glycosides form key electron donor–acceptor (EDA) complexes with Hantzsch ester (for C-alkyl glycosides) or Et3N (for coumarin C-glycosides), which, upon irradiation with visible light, trigger a cascade of glycosyl radical processes to access C-glycosides smoothly.

Deuterated-alkylation reagents based on sulfonium salts as cation and radical sources

Abstract The replacement of C–H bonds with more stable C–D bonds at the α-position of heteroatoms, which is the typical metabolic site for cytochrome P450, is important in drug discovery. Recently, we have developed dn (deuterated)-alkylated sulfonium salts (1a-dn), which were easily prepared by deuteration (H/D exchange reaction) with D2O of the corresponding alkyl diphenylsulfonium salts (1a), as electrophilic dn-alkylating reagents (cation sources). Herein, we newly report an improved preparation method of 1a and one-pot synthesis of dn-alkylated compounds via the deuteration of 1a with D2O and the subsequent nucleophilic substitution under basic conditions. Additionally, dn-alkyl thianthrenium salts (1b-dn) were also found to work as dn-alkylating reagents (cation sources). Furthermore, 1b-dn served as radical sources under photo-induced reaction conditions with Ir photocatalyst, Hantzsch ester, or triphenylamine to obtain various regioselectively deuterium-incorporated alkyl compounds. These dn-alkylating reagents will contribute to advance the drug discovery.

Exploration of Glycosyl Dithioimidocarbonates in Photoinduced Desulfurative Cross-Coupling Reactions.

Readily synthesized bench-stable glycosyl dithioimidocarbonates are useful C-glycoside precursors. Under mild photochemical conditions, these glycosides undergo desulfurative glycosyl radical generation in the presence of weak acid, 4CzIPN, and Hantzsch ester. These radicals perform well in Geise-like reactions to yield C-glycosides with high stereoselectivity.

Reserving Electrons in Cofactor Decorated Coordination Capsules for Biomimetic Electrosynthesis of α-Hydroxy/amino Esters.

Sustainable electricity-to-chemical conversion via the utilization of artificial catalysts inspired by redox biological systems holds great significance for catalyzing synthesis. Herein, we develop a biomimetic electrosynthesis strategy mediated by a nicotinamide adenine dinucleotide (NADH) mimic-containing coordination capsule for efficiently producing α-hydroxy/amino esters. The coordination saturated metal centers worked as an electron relay to consecutively accept single electrons while donating two electrons to the NAD+ mimics simultaneously. The protonation of the intermediate generated active NADH mimics for biomimetic hydrogenation of the substrates via the conventional enzymatic manifold with or without the presence of natural enzymes. The pocket of the capsule encapsulated the substrate and enforced the close proximity between the substrate and the NADH mimics, forming a preorganized intermediate to shift the redox potential by 0.4 V anodically. The cobalt capsule gave methyl mandelate over a range of applied potentials, with an improved yield of 92% when operated at -1.2 V compared to that of Hantzsch ester or natural NADH. Kinetic experiments revealed a Michaelis-Menten mechanism with a Km of 7.5 mM and a Kcat of 1.1 × 10-2 s-1. This extended strategy in tandem with an enzyme exhibited a TON of 650 molE-1 with an initial TOF of 185 molE-1·h-1, outperforming relevant Rh-mediated enzymatic electrosynthesis systems and providing an attractive avenue toward advanced artificial electrosynthesis.

Asymmetric 1,4-Reduction of Pyrano[2,3-b]indoles with Hantzsch Ester by Chiral Phosphoric Acid.

A highly regioselective and enantioselective transfer hydrogenation of pyrano[2,3-b]indoles with Hantzsch ester has been successfully realized using spiro-chiral phosphoric acid, affording a series of optically active 1,4-reductive adducts, 4,9-dihydropyrano[2,3-b]indoles, in 34-99% yields with 61-99% ee.

Photodriven Sm(III)-to-Sm(II) Reduction for Catalytic Applications.

The selectivity of SmI2 as a one electron-reductant motivates the development of methods for reductive Sm-catalysis. Photochemical methods for SmI2 regeneration are desired for catalytic transformations. In particular, returning SmIII-alkoxides to SmII is a crucial step for Sm-turnover in many potential applications. To this end, photochemical conditions for reduction of both SmI3 and a model SmIII-alkoxide to SmI2(THF)n are described here. The Hantzsch ester can serve either as a direct photoreductant or as the reductive quencher for an Ir-based photoredox catalyst. In contrast to previous SmIII reduction methodologies, no Lewis acidic additives or byproducts are involved, facilitating selective ligand coordination to Sm. Accordingly, SmII species can be generated photochemically from SmI3 in the presence of protic, chiral, and/or Lewis basic additives. Both the photoreductant and photoredox methods for SmI2 generation translate to intermolecular ketone-acrylate coupling as a proof-of-concept demonstration of a photodriven, Sm-catalyzed reductive cross-coupling reaction.

Photocatalytic Hantzsch Ester-Mediated Pinacol-Type Coupling of Aldehydes and Ketones.

We have developed a photocatalyst-free reaction system that uses Hantzsch esters as photoreducing agents to promote the coupling of carbonyl compounds to 1,2-diols. The system fully utilizes the single electron transfer and proton donor roles of Hantzsch esters. The system shows a wide range of substrate application. Aromatic ketones, aliphatic ketones, and aldehydes can be applied to the catalytic system. Both self-coupling and cross-coupling can achieve ideal results.

Photocatalyzed Selective Hydrocarbonation of Alkenes with Hantzsch Esters toward 4-Alkyl-Hantzsch Esters.

Here, we describe a mild photoredox-neutral reaction system that enables the selective hydrocarbonation of alkenes with Hantzsch esters, affording structurally diverse 4-alkyl-Hantzsch esters. This straightforward protocol can be performed under an air atmosphere without the need for any transition metals. The synthetic potential of this method is well exemplified by the late-stage structural modification of a series of pharmaceutically relevant complex molecules.

Visible Light-Induced, Nickel-Catalyzed Late-Stage 4-Alkylation of Hantzsch Esters with Alkyl Bromide.

Herein, visible light-induced, nickel-catalyzed direct functionalization of the Hantzsch esters (HEs) with readily accessible alkyl bromides has been successfully achieved by taking advantage of HE as the reductant and substrate through an aromatization-dearomatization process. In this strategy, the single electron reduction of alkyl bromides by reactive Ni(I) species is essential for the success of this late-stage transformation. A wide range of 4-alkyl-1,4-dihydropyridines were rapidly assembled in moderate to good yields under mild conditions, rendering this photoinduced approach attractive for synthetic and medicinal chemistry.

Expanding the Chemical Space of Electrophilic β-Glycosyl β-Lactams through Photoinduced Diastereoselective Functionalization.

Herein, we present a photoinduced diastereoselective C-3 functionalization of electrophilic β-glycosyl β-lactams. The developed protocol is simple, mild, and scalable and explores the use of 3-exomethylene β-lactams as reaction partners in a Giese type reaction. The key nucleophilic alkyl radical is generated by a photoinduced electron transfer process in the EDA complex formed by NHPI and Hantzsch esters. The diastereoselective hydrogen atom transfer to the β-lactam radical intermediate enables the synthesis of various N-phenyl β-glycosyl β-lactams.

Organo‐Photocatalytic Anti‐Markovnikov Hydroamidation of Alkenes with Sulfonyl Azides: A Combined Experimental and Computational Study

AbstractThe construction of C(sp3)−N bonds via direct N‐centered radical addition with olefins under benign conditions is a desirable but challenging strategy. Herein, we describe an organo‐photocatalytic approach to achieve anti‐Markovnikov alkene hydroamidation with sulfonyl azides in a highly efficient manner under transition‐metal‐free and mild conditions. A broad range of substrates, including both activated and unactivated alkenes, are suitable for this protocol, providing a convenient and practical method to construct sulfonylamide derivatives. A synergistic experimental and computational mechanistic study suggests that the additive, Hantzsch ester (HE), might undergo a triplet‐triplet energy transfer manner to achieve photosensitization by the organo‐photocatalyst under visible light irradiation. Next, the resulted triplet excited state 3HE* could lead to a homolytic cleavage of C4−H bond, which triggers a straightforward H‐atom transfer (HAT) style in converting sulfonyl azide to the corresponding key amidyl radical. Subsequently, the addition of the amidyl radical to alkene followed by HAT from p‐toluenethiol could proceed to afford the desired anti‐Markovnikov hydroamidation product. It is worth noting that mechanistic pathway bifurcation could be possible for this reaction. A feasible radical chain propagation mechanistic pathway is also proposed to rationalize the high efficiency of this reaction.

Organo-Photocatalytic Anti-Markovnikov Hydroamidation of Alkenes with Sulfonyl Azides: A Combined Experimental and Computational Study.

The construction of C(sp3)-N bonds via direct N-centered radical addition with olefins under benign conditions is a desirable but challenging strategy. Herein, we describe an organo-photocatalytic approach to achieve anti-Markovnikov alkene hydroamidation with sulfonyl azides in a highly efficient manner under transition-metal-free and mild conditions. A broad range of substrates, including both activated and unactivated alkenes, are suitable for this protocol, providing a convenient and practical method to construct sulfonylamide derivatives. A synergistic experimental and computational mechanistic study suggests that the additive, Hantzsch ester (HE), might undergo a triplet-triplet energy transfer manner to achieve photosensitization by the organo-photocatalyst under visible light irradiation. Next, the resulted triplet excited state 3HE* could lead to a homolytic cleavage of C4-H bond, which triggers a straightforward H-atom transfer (HAT) style in converting sulfonyl azide to the corresponding key amidyl radical. Subsequently, the addition of the amidyl radical to alkene followed by HAT from p-toluenethiol could proceed to afford the desired anti-Markovnikov hydroamidation product. It is worth noting that mechanistic pathway bifurcation could be possible for this reaction. A feasible radical chain propagation mechanistic pathway is also proposed to rationalize the high efficiency of this reaction.

Turn-on fluorescence of mirabegron for its sensitive detection in human plasma: Box-Behnken-Design for optimization

Here, a novel fluorescence strategy was established for the detection of mirabegron (MBG) sensitively on the basis of hantzsch dihydropyridine synthesis. The developed method adopts turn-on fluorescence of MBG for the first time, permitting its selective determination in spiked human plasma at 486 nm after excitation at 410 nm. The developed method exhibited a good linear range from 0.5 μgmL-1 to 2.0 μgmL-1 with detection and quantification limits of 0.05 and 0.2 (μgmL-1), respectively. The profitable applicability of the developed method in spiked human plasma samples was demonstrated, achieving limit of detection below the previously levels reported by spectroscopic methods, allowing application of the developed method for selective determination of MBG in its tablets and spiked human plasma samples with good recovery.

Oxidant-Assisted Sulfonylation/Cyclization Cascade Synthesis of Alkylsulfonylated Oxindoles via the Insertion of SO2.

An oxidant-assisted tandem sulfonylation/cyclization of electron-deficient alkenes with 4-alkyl-substituted Hantzsch esters and Na2S2O5 for the preparation of 3-alkylsulfonylated oxindoles under mild conditions in the absence of a photocatalyst and transition metal catalyst is established. The mechanism studies show that the alkyl radicals, which come from the cleavage of the C-C bond in 4-substituted Hantzsch esters under oxidant conditions, subsequently undergo the in situ insertion of sulfur dioxide to generate the crucial alkylsulfonyl radical intermediates. This three-component reaction provides an efficient and facile route for the construction of alkylsulfonylated oxindoles and avoids the use of highly toxic alkylsulfonyl chlorides or alkylsulfonyl hydrazines as alkylsulfonyl sources.

Humic Acid: A Promising and Green Bioorganic Catalyst in Organic Syntheses

AbstractThe growing pollution and threat to the environment demand green synthetic methods. Green chemistry mainly focuses on minimizing the waste and utilization of green solvents, energy sources, and catalysts and prefers one‐pot reactions. In this context, humic acid (HA), a natural bioorganic catalyst found in rivers, peat coal and sewage; is a high molecular weight macromolecule containing multifunctional groups, mainly contains quinone, phenolic OH, and COOH groups which make it acidic and activate carbonyl groups by protonation. Owing to its green aspect such as biodegradability, recyclability and reusability, humic acid is considered as sustainable bioorganic catalyst which meets the criteria for industrial requirements. The HA is mild acidic in nature, thus many functional groups tolerate in the HA catalyzed reactions. After few initial reports in 2001 and 2009, the HA catalyzed reactions gained much attention by the organic synthetic community from 2019 in aldol condensation, Knoevenagel condensation, Claisen‐Schmidt reaction, Michael addition, Strecker synthesis, tetrazole synthesis, Hantzsch dihydropyridine synthesis, hydrosilylation of terminal alkenes, hydrogenation, α‐aminophosphonate synthesis, cross coupling reactions such as Heck and Suzuki coupling reactions. Herein we report the comprehensive analysis on the role of HA in organic transformations providing diverse array of molecular scaffolds till date and future perspective.