Domino Michael/Oxa-Michael Reactions of the Unsymmetric Double Michael Acceptor for Access to Bicyclic Furo[2,3-b]pyrrole.

By creating an unsymmetric double Michael acceptor 1, we were able to synthesize the nonaromatic-fused bicyclic furo[2,3-b]pyrrole nucleus using a domino Michael/oxa-Michael reaction. Adopting benzoyl acetonitrile 2d (CN as the electron-withdrawing group) as a substrate, we discovered a (DHQ)2AQN-catalyzed method for high diastereo- and enantioselectivity of those products. The reaction path has been determined by isolating the reaction intermediates, and density functional theory calculations support these findings. Beyond providing a synthetic approach, this work illustrated the compounds' possible use in antitumor activity.

Hypervalent Iodine Promoted Selective [2 + 2 + 1] Cycloaddition of Aromatic Ketones and Methylamines: A One-Pot Access to 1-Pyrrolines.

Herein, a versatile highly regioselective three-component annulation of simple aromatic ketones and methylamines using a hypervalent iodine reagent for polyarylated 1-pyrrolines has been described in good to excellent yields. Meanwhile, unsymmetrical 1-pyrroline isomers could be realized and synthesized. Such an intriguing one-pot two-step tandem assembly strategy with green conditions and high regioselectivity shows predictable inspiration in related annulation reactions.

Cobalt-Catalyzed Hypervalent Iodine(III) Promoted Cascade Annulation Reaction of Anilines with Formamides for 2-Aminobenzoxazoles Synthesis.

Herein, we disclose a practical and simple procedure to synthesize 2-aminobenzoxaoles. Simple anilines and formamides were used as substrates. The C-H bond ortho to the amino group in the anilines was directly functionalized under cobalt-catalyzed conditions with high levels of functional group tolerance. Hypervalent iodine(III) was both an oxidant and a Lewis acid for this reaction. The mechanism study showed that this transformation may involve a radical process.

Synthesis of functionalized tetrahydrodibenzo[b,g][1,8]naphthyridin-1(2H)-ones through base-promoted annulation of quinoline-derived dipolarophiles and cyclic enaminones.

An eco-friendly and metal-free method for the synthesis of tetrahydrodibenzo[b,g][1,8]naphthyridin-1(2H)-ones was established. Quinoline-derived dipolarophiles and cyclic enaminones as starting materials undergo a 1,4-Michael addition/SNAr tandem annulation reaction affording the target products. This approach features transition metal-free conditions, good functional group tolerance and operational simplicity.

Synthesis of Unsymmetrical Diarylfumaronitriles via Tandem Michael Addition and Oxidation under K3Fe(CN)6/O2 System.

An efficient formal alkenyl C-H cyanation reaction has been developed for the general synthesis of unsymmetrical diarylfumaronitriles in good to excellent yields. The reaction was achieved through tandem Michael addition and an oxidative process. The merits of this transformation include the use of K3Fe(CN)6 as a safe and nontoxic cyanide source, without an external noble metal catalyst, oxygen-involved reactions, easily available raw materials, good functional group tolerance, high stereoselectivity, and potential further application of the products.

Antioxidant and Antitumor Activities of Newly Synthesized Hesperetin Derivatives.

Hesperetin is a class of natural products with a wide range of sources and remarkable biological activities. In this study, we described the synthesis of a series of novel hesperetin derivatives and evaluated the in vitro antioxidant and antitumor activity of these compounds. Eleven novel compounds were synthesized in moderate yields. The compounds synthesized in this work exhibited antioxidant activities against DPPH and ABTS free radicals in a dose-dependent manner. Among them, compound 3f had the best antioxidant activity, with IC50 of 1.2 µM and 24 µM for DPPH and ABTS, respectively. The antitumor activity of the compounds against human cancer cell lines, such as breast MCF-7, liver HepG2, and cervical Hela, was determined by a standard 3-(4,5-dimethyl-2-thiazolyl)-2,5-diphenyl-2-H-tetrazolium bromide (MTT) assay. Three compounds had moderate IC50 values. Interestingly, compound 3f had better biological activity than hesperetin, which matches the prediction by Maestro from Schrödinger. Therefore, the new hesperidin derivative is a promising drug for the treatment of cancer due to its effective antitumor activity. The results also suggested that the antitumor activities of hesperetin derivatives may be related to their antioxidant activities.

Hypervalent Iodine(III)-Promoted Radical Oxidative C-H Annulation of Arylamines with α-Keto Acids.

A novel catalyst-free radical oxidative C-H annulation reaction of arylamines with α-keto acids toward benzoxazin-2-ones synthesis under mild conditions was developed. This hypervalent iodine(III)-promoted process eliminated the use of a metal catalyst or additive with high levels of functional group tolerance. Hypervalent iodine(III) was both an oxidant and a radical initiator for this reaction. The synthetic utility of this method was confirmed by the synthesis of the natural product cephalandole A.

"On water" nano-Cu2O-catalyzed CO-free one-pot multicomponent cascade cyanation-annulation-aminolysis reaction toward phthalimides.

An efficient nano-Cu2O-catalyzed cascade multicomponent reaction of 2-halobenzoic acids and trimethylsilyl cyanide with diverse amines was developed using water as a solvent, affording versatile N-substituted phthalimide derivatives in moderate to excellent yields. This novel strategy features carbon monoxide gas-free, environmentally benign, one-pot multistep transformation, commercially available reagents, a cheap catalyst without any additives, wide functional group tolerance, and operational convenience.

Acyl Cyanides as Bifunctional Reagent: Application in Copper-Catalyzed Cyanoamidation and Cyanoesterification Reaction.

Cu-catalyzed domino decyanation and cyanation reaction of acyl cyanides with amines or alcohols have been developed. The cyano sources were generated in situ via C-CN cleavage yielding the corresponding cyano substituted amides or esters in moderate to excellent yields. This approach features a cheap copper catalyst, domino decyanation and cyanation reaction, readily available starting materials, broad substrate scope, operational simplicity, and the potential for further transformation of the cyano group.

Lewis Acid-Catalyzed Intermolecular Annulation: Three-Component Reaction toward Imidazo[1,2-a]pyridine Thiones.

A Lewis acid-catalyzed three-component annulation reaction of 2-aminopyridines and ynals with elemental sulfur was established. A series of imidazo[1,2-a]pyridine thiones was obtained in moderate to excellent yields. The merits of this transformation include easily available starting materials, multiple C-heteroatom bond formation in one pot, good functional group tolerance, elemental sulfur as S source, operational simplicity, etc.

Metal-Free Aminothiation of Alkynes: Three-Component Tandem Annulation toward Indolizine Thiones from 2-Alkylpyridines, Ynals, and Elemental Sulfur.

A metal-free three-component annulation reaction for the synthesis of indolizine thiones via tandem C-C/C-N/C-S bond formation was developed. Various 2-alkylpyridines with aromatic ynals and elemental sulfur proceeded smoothly under catalyst-free conditions, and the desired products were obtained in moderate to excellent yields.

Reactions of Isocyanides with Metal Carbyne Complexes: Isolation and Characterization of Metallacyclopropenimine Intermediates.

η2-Iminoketenyl species have often been postulated as the intermediates in nucleophile-induced carbyne-isocyanide C-C coupling processes. However, such species are elusive. Here we report direct formation of η2-iminoketenyl complexes from reactions of metallapentalyne with isocyanides. Our studies show that steric effects of N-substituents of the isocyanides play an important role in the stability of the three-membered metallacycles of the η2-iminoketenyl complexes. Sterically bulky isocyanides, such as tert-butyl or 1-adamantyl isocyanides, inhibit bending at the isocyanide nitrogen atoms, a requirement for formation of η2-iminoketenyl structures. Reactions of metallapentalyne with excess isocyanide allow the metal-bridged metallaindene derivativesto be isolated as a result of the isocyanide insertion into the M-Cα σ bond of metallapentalyne.

cine-Substitution reactions of metallabenzenes: an experimental and computational study.

Alkali-resistant osmabenzene [(SCN)2(PPh3)2Os{CHC(PPh3)CHCICH}] (2) can undergo nucleophilic aromatic substitution with MeOH or EtOH to give cine-substitution products [(SCN)2(PPh3)2Os{CHC(PPh3)CHCHCR}] (R=OMe (3), OEt(4)) in the presence of strong alkali. However, the reactions of compound 2 with various amines, such as n-butylamine and aniline, afford five-membered ring species, [(SCN)2(PPh3)2Os{CH=C(PPh3)CH=C(CH=NHR')}] (R'=nBu(8), Ph(9)), in addition to the desired cine-substitution products, [(SCN)2(PPh3)2Os{CHC(PPh3)CHCHC(NHR')}] (R'=nBu(6), Ph(7)), under similar reaction conditions. The mechanisms of these reactions have been investigated in detail with the aid of isotopic labeling experiments and density functional theory (DFT) calculations. The results reveal that the cine-substitution reactions occur through nucleophilic addition, dissociation of the leaving group, protonation, and deprotonation steps, which resemble the classical "addition-of-nucleophile, ring-opening, ring-closure" (ANRORC) mechanism. DFT calculations suggest that, in the reaction with MeOH, the formation of a five-membered metallacycle species is both kinetically and thermodynamically less favorable, which is consistent with the experimental results that only the cine-substitution product is observed. For the analogous reaction with n-butylamine, the pathway for the formation of the cine-substitution product is kinetically less favorable than the pathway for the formation of a five-membered ring species, but is much more thermodynamically favorable, again consistent with the experimental conversion of compound 8 into compound 6, which is observed in an in situ NMR experiment with an isolated pure sample of 8.

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.

Switching the Regioselectivity Access to Pyrroles and Isoquinolines from Ketoxime Acetates and Ynals.

A novel formal [3+2] and [4+2] annulation of ketoxime acetates and ynals for the synthesis of pyrroles and isoquinolines has been developed. By simply switching the catalyst and solvent, the reaction proceeds via two pathways. The reactions are achieved under mild conditions with broad substrate scope and excellent regioselectivity.