Hantzsch Ester Research Articles

Multicomponent reactions in crop protection chemistry

An overview is given of the significance of multicomponent reactions in the synthesis of agrochemicals. The most important applications of multicomponent condensations, such as the Biginelli reaction, Bucherer-Bergs reaction, Hantzsch dihydropyridine synthesis, Kabachnik-Fields reaction, Mannich reaction, Passerini reaction, Petasis reaction, Strecker reaction, Ugi reaction and Willgerodt-Kindler reaction, to the synthesis of herbicidally, fungicidally and insecticidally active compounds are presented. Also the mode of action and biological activity of these multicomponent reaction products are reported.

Visible-light promoted regioselective amination and alkylation of remote C(sp3)-H bonds

The C-N cross coupling reaction has always been a fundamental task in organic synthesis. However, the direct use of N-H group of aryl amines to generate N-centered radicals which would couple with alkyl radicals to construct C-N bonds is still rare. Here we report a visible light-promoted C-N radical cross coupling for regioselective amination of remote C(sp3)-H bonds. Under visible light irradiation, the N-H groups of aryl amines are converted to N-centered radicals, and are then trapped by alkyl radicals, which are generated from Hofmann-Löffler-Freytag (HLF) type 1,5-hydrogen atom transfer (1,5-HAT). With the same strategy, the regioselective C(sp3)-C(sp3) cross coupling is also realized by using alkyl Hantzsch esters (or nitrile) as radical alkylation reagents. Notably, the α-C(sp3)-H of tertiary amines can be directly alkylated to form the C(sp3)-C(sp3) bonds via C(sp3)-H − C(sp3)-H cross coupling through the same photoredox pathway.

Nickel/Photoredox‐Catalyzed Asymmetric Reductive Cross‐Coupling of Racemic α‐Chloro Esters with Aryl Iodides

AbstractA unique nickel/organic photoredox co‐catalyzed asymmetric reductive cross‐coupling between α‐chloro esters and aryl iodides is developed. This cross‐electrophile coupling reaction employs an organic reductant (Hantzsch ester), whereas most reductive cross‐coupling reactions use stoichiometric metals. A diverse array of valuable α‐aryl esters is formed under these conditions with high enantioselectivities (up to 94 %) and good yields (up to 88 %). α‐Aryl esters represent an important family of nonsteroidal anti‐inflammatory drugs. This novel synergistic strategy expands the scope of Ni‐catalyzed reductive asymmetric cross‐coupling reactions.

Nickel/Photoredox-Catalyzed Asymmetric Reductive Cross-Coupling of Racemic α-Chloro Esters with Aryl Iodides.

A unique nickel/organic photoredox co-catalyzed asymmetric reductive cross-coupling between α-chloro esters and aryl iodides is developed. This cross-electrophile coupling reaction employs an organic reductant (Hantzsch ester), whereas most reductive cross-coupling reactions use stoichiometric metals. A diverse array of valuable α-aryl esters is formed under these conditions with high enantioselectivities (up to 94 %) and good yields (up to 88 %). α-Aryl esters represent an important family of nonsteroidal anti-inflammatory drugs. This novel synergistic strategy expands the scope of Ni-catalyzed reductive asymmetric cross-coupling reactions.

A photocatalyst-free photo-induced denitroalkylation of β-nitrostyrenes with 4-alkyl substituted Hantzsch esters at room temperature

A photocatalyst-free stereoselectively photo-induced strategy for the denitroalkylation of β-nitrostyrenes using 4-alkyl substituted Hantzsch esters as the alkyl source under xenon lamp irradiation is developed. The reaction proceeds at room temperature and affords the corresponding products in moderate to excellent yields. The oxidant di-t-butyl peroxide serves as an efficient radical initiator under irradiation of a Xenon lamp, initiating alkyl radicals from the 4-alkyl substituted Hantzsch esters.

Catalyst-Free N-Deoxygenation by Photoexcitation of Hantzsch Ester.

A mild and operationally simple protocol for the deoxygenation of a variety of heteroaryl N-oxides and nitroarenes has been developed. A mixture of substrate and Hantzsch ester is proposed to result in an electron donor-acceptor complex, which upon blue-light irradiation undergoes photoinduced electron transfer between the two reactants to afford the products. N-oxide deoxygenation is demonstrated with 22 examples of functionally diverse substrates, and the chemoselective reduction of nitroarenes to the corresponding hydroxylamines is also shown.

Boric acid catalyzed chemoselective reduction of quinolines.

Boric acid promoted transfer hydrogenation of substituted quinolines to synthetically versatile 1,2,3,4-tetrahydroquinolines (1,2,3,4-THQs) was described under mild reaction conditions using a Hantzsch ester as a mild organic hydrogen source. This methodology is practical and efficient, where isolated yields are excellent and reducible functional groups are well tolerated in the N-heteroarene moiety. The reaction parameters and tentative mechanistic pathways are demonstrated by various control experiments and NMR studies. The present work can also be scaled up to obtain gram quantities and the utility of the developed process is illustrated by the transformation of 1,2,3,4-THQs into a series of biologically important molecules including the antiarrhythmic drug nicainoprol.

Metal-free iminyl radical-mediated C–C single bond cleavage/functionalization of redox-active oxime esters

By photoactivating Hantzsch ester (HE) to act as an electron donor, we have achieved single-electron reduction of cycloketone oxime esters, thus providing a novel catalyst-free strategy for alkylation, allylation, vinylation and alkynylation.

Theoretical investigation on the nature of 4-substituted Hantzsch esters as alkylation agents.

Recently, a variety of 4-substituted Hantzsch esters (XRH) with different structures have been widely researched as alkylation reagents in chemical reactions, and the key step of the chemical process is the elementary step of XRH˙+ releasing R˙. The purpose of this work is to investigate the essential factors which determine whether or not an XRH is a great alkylation reagent using density functional theory (DFT). This study shows that the ability of an XRH acting as an alkylation reagent can be reasonably estimated by its ΔG≠RD(XRH˙+) value, which can be conveniently obtained through DFT computations. Moreover, the data also show that ΔG≠RD(XRH˙+) has no simple correlation with the structural features of XRH, including the electronegativity of the R substituent group and the magnitude of steric resistance; therefore, it is difficult to judge whether an XRH can provide R˙ solely by experience. Thus, these results are helpful for chemists to design 4-substituted Hantzsch esters (XRH) with novel structures and to guide the application of XRH as a free radical precursor in organic synthesis.

Direct radical alkylation and acylation of 2H-indazoles using substituted Hantzsch esters as radical reservoirs

A platform approach for the direct synthesis of 3-substituted 2H-indazole derivatives has been developed using a Ag(i)/Na2S2O8 system.

σ-Bond initiated generation of aryl radicals from aryl diazonium salts.

σ-Bond nucleophiles and molecular oxygen transform aryl diazonium salts into aryl radicals. Experimental and computational studies show that Hantzsch esters transfer hydride to aryl diazonium species, and that oxygen initiates radical fragmentation of the diazene intermediate to produce aryl radicals. The operational simplicity of this addition-fragmentation process for the generation of aryl radicals, by a polar-radical crossover mechanism, has been illustrated in a variety of bond-forming reactions.

A metal-free route to alkynyl sulfones under photoinduced conditions with the insertion of sulfur dioxide

A metal-free route to alkynyl sulfones under photoinduced conditions is accomplished, starting from 4-alkyl Hantzsch esters, sulfur dioxide, and alkynyl bromides under visible light irradiation at room temperature.

Chiral and Regenerable NAD(P)H Models Enabled Biomimetic Asymmetric Reduction: Design, Synthesis, Scope, and Mechanistic Studies.

The coenzyme NAD(P)H plays an important role in electron as well as proton transmission in the cell. Thus, a variety of NAD(P)H models have been involved in biomimetic reduction, such as stoichiometric Hantzsch esters and achiral regenerable dihydrophenantheridine. However, the development of a general and new-generation biomimetic asymmetric reduction is still a long-term challenge. Herein, a series of chiral and regenerable NAD(P)H models with central, axial, and planar chiralities have been designed and applied in biomimetic asymmetric reduction using hydrogen gas as a terminal reductant. Combining chiral NAD(P)H models with achiral transfer catalysts such as Brønsted acids and Lewis acids, the substrate scope could be also expanded to imines, heteroaromatics, and electron-deficient tetrasubstituted alkenes with up to 99% yield and 99% enantiomeric excess (ee). The mechanism of chiral regenerable NAD(P)H models was investigated as well. Isotope-labeling reactions indicated that chiral NAD(P)H models were regenerated by the ruthenium complex under hydrogen gas first, and then the hydride of NAD(P)H models was transferred to unsaturated bonds in the presence of transfer catalysts. In addition, density functional theory calculations were also carried out to give further insight into the transition states for the corresponding transfer catalysts.

Light-Enabled Enantiodivergence: Stereospecific Reduction of Activated Alkenes Using a Single Organocatalyst Enantiomer.

Light-enabled enantiodivergence is demonstrated in which the alkene substrate configuration is manipulated (E → Z) prior to organocatalytic reduction with a chiral thiourea and Hantzsch ester. This allows stereodivergent reduction to be regulated at the substrate level with high fidelity and mitigates the need for a second, enantiomeric catalyst (up to 93:07 and 95:5 er). The synthetic utility of this strategy has been demonstrated in the synthesis of the weight-loss drug (R)-Lorcaserin (Belviq) and a potent AMPA modulator.

Chiral Chalcogen Bond Donors Based on the 4,4'-Bipyridine Scaffold.

Organocatalysis through chalcogen bonding (ChB) is in its infancy, as its proof-of-principle was only reported in 2016. Herein, we report the design and synthesis of new chiral ChB donors, as well as the catalytic activity evaluation of the 5,5′-dibromo-2,2′-dichloro-3-((perfluorophenyl)selanyl)-4,4′-bipyridine as organocatalyst. The latter is based on the use of two electron-withdrawing groups, a pentafluorophenyl ring and a tetrahalo-4,4′-bipyridine skeleton, as substituents at the selenium center. Atropisomery of the tetrahalo-4,4′-bipyridine motif provides a chiral environment to these new ChB donors. Their synthesis was achieved through either selective lithium exchange and trapping or a site-selective copper-mediated reaction. Pure enantiomers of the 3-selanyl-4,4′-bipyridine were obtained by high performance liquid chromatography enantioseparation on specific chiral stationary phase, and their absolute configuration was assigned by comparison of the measured and calculated electronic circular dichroism spectra. The capability of the selenium compound to participate in σ-hole-based interactions in solution was studied by 19F NMR. Even if no asymmetric induction has been observed so far, the new selenium motif proved to be catalytically active in the reduction of 2-phenylquinoline by Hantzsch ester.

Gold-Catalyzed Intramolecular Dearomatization Reactions of Indoles for the Synthesis of Spiroindolenines and Spiroindolines.

A gold-catalyzed dearomatization reaction of indole derivatives was realized in the presence of JohnPhosAuCl/AgOMs to afford a series of spiroindolenines in excellent yields (≤99%). In addition, when the Hantzsch ester was used as the hydrogen transfer reagent, various spiroindolines were obtained in a cascade fashion starting from readily available indole derivatives in modest to good yields (≤79%). Both reactions feature readily available substrates, mild conditions, and good functional group tolerance.

Rhodium-Catalyzed Diastereo- and Enantioselective Tandem Spirocyclization/Reduction of 3-Allenylindoles: Access to Functionalized Vinylic Spiroindolines.

A highly selective rhodium-catalyzed tandem spirocyclization/reduction of 3-allenylindoles is reported. By employing a Hantzsch ester as reductant, vinylic spiroindolines are obtained in excellent yields as well as diastereo- and enantioselectivity. In addition, the reaction's synthetic utility is highlighted by broad functional group compatibility and exemplified by a gram scale reaction with subsequent assorted transformations.

Visible-Light-Driven Intermolecular Reductive Ene-Yne Coupling by Iridium/Cobalt Dual Catalysis for C(sp3 )-C(sp2 ) Bond Formation.

A new methodology to form C(sp3)−C(sp2) bonds by visible‐light‐driven intermolecular reductive ene–yne coupling has been successfully developed. The process relies on the ability of the Hantzsch ester to contribute in both SET and HAT processes through a unified cobalt and iridium catalytic system. This procedure avoids the use of stoichiometric amounts of reducing metallic reagents, which is translated into high functional‐group tolerance and atom economy.

Organocatalytic Reductive Propargylation: Scope and Applications

An amino acid-catalyzed three-component reductive coupling protocol has been developed for the selective high-yielding synthesis of nearly fifty examples of propargylated cyclic/acyclic systems from the various propargyl aldehydes, cyclic/acyclic CH acids, and Hantzsch ester under ambient conditions. It is an economical, efficient, catalytic, metal-free protocol for the quick gram-scale synthesis of propargylated cyclic/acyclic compounds, and many of these coupling compounds were purified by a simple precipitation-filtration technique instead of column chromatography. Functionally rich propargylated cyclic-1,3-diketones were specifically transformed into dihydropyrans found in natural products and drugs through an annulative etherification reaction by using Lewis-acid (AgOTf) catalysis. Further, we developed the C-methylation reactions on propargylated cyclic-1,3-diketones, which are prolific synthons in natural products and medicinal chemistry.

Ruthenium-Catalyzed Reductive Cleavage of Unstrained Aryl-Aryl Bonds: Reaction Development and Mechanistic Study.

Cleavage of carbon-carbon bonds has been found in some important industrial processes, for example, petroleum cracking, and has inspired development of numerous synthetic methods. However, nonpolar unstrained C(aryl)-C(aryl) bonds remain one of the toughest bonds to be activated. As a detailed study of a fundamental reaction mode, here a full story is described about our development of a Ru-catalyzed reductive cleavage of unstrained C(aryl)-C(aryl) bonds. A wide range of biaryl compounds that contain directing groups (DGs) at 2,2' positions can serve as effective substrates. Various heterocycles, such as pyridine, quinoline, pyrimidine, and pyrazole, can be employed as DGs. Besides hydrogen gas, other reagents, such as Hantzsch ester, silanes, and alcohols, can be employed as terminal reductants. The reaction is pH neutral and free of oxidants; thus a number of functional groups are tolerated. Notably, a one-pot C-C activation/C-C coupling has been realized. Computational and experimental mechanistic studies indicate that the reaction involves a ruthenium(II) monohydride-mediated C(aryl)-C(aryl) activation and the resting state of the catalyst is a η4-coordinated ruthenium(II) dichloride complex, which could inspire development of other transformations based on this reaction mode.