New derivatives from dehydrodieugenol B and its methyl ether displayed high anti-Trypanosoma cruzi activity and cause depolarization of the plasma membrane and collapse the mitochondrial membrane potential.

In the present work, dehydrodieugenol B (1) and its methyl ether (2), isolated from Nectandra leucantha twigs, were used as starting material for the preparation of two new derivatives (1a and 2a) containing an additional methoxycarbonyl unit on allyl side chains. Compounds 1a and 2a demonstrated activity against trypomastigotes (EC50 values of 13.5 and 23.0 µM, respectively) and against intracellular amastigotes (EC50 values of 10.2 and 6.1 µM, respectively). Additionally, compound 2a demonstrated no mammalian cytotoxicity up to 200 µM whereas compound 1a exhibited a CC50 value of 139.8 µM. The mechanism of action studies of compounds 1a and 2a demonstrated a significant depolarization of the plasma membrane potential in trypomastigotes, followed by a mitochondrial membrane potential collapse. Neither calcium level nor reactive oxygen species alterations were observed after a short-time incubation. Considering the potential of compound 2a against T. cruzi and its simple preparation from the natural product 2, isolated from N. leucantha, this compound could be considered a new hit for future drug design studies in Chagas disease.

C-H Bond Alkylation of Cyclic Amides with Maleimides via a Site-Selective-Determining Six-Membered Ruthenacycle.

The first example of a ruthenium-catalyzed C-H bond alkylation via six-membered ruthenacycles is presented. This is disclosed for the C-H bond alkylation of biologically relevant cyclic amides with maleimide derivatives. The cyclic tertiary amide core acted as a directing group (DG) enabling formation of six-membered cycloruthenated species responsible for the control of the regio- and site selectivity of the reaction as well as the excellent functional group tolerance. Unexpectedly, cyclic amides were found to be better DGs than pyridine-containing ones or cyclic imides for this type of C-H bond functionalization.

Site-Selective Ruthenium-Catalyzed C-H Bond Arylations with Boronic Acids: Exploiting Isoindolinones as a Weak Directing Group.

Biologically relevant N-arylisoindolinones efficiently underwent arylation reactions under ruthenium catalysis via C-H bond functionalization. The reactions exclusively led to monoarylated products, and only ortho selectivity was observed in the aromatic ring connected to the nitrogen atom. Interestingly, no C-H bond functionalization was observed in the other benzene ring in the ortho position with respect to the carbonyl group. This ruthenium-catalyzed reaction displayed a high functional group tolerance, and it employed readily available and benchmark stable boronic acid and potassium aryltrifluoroborate derivatives as coupling partners. An appealing late-stage functionalization of indoprofen applying this methodology is showcased.

Ruthenium(ii)-catalysed selective C(sp2)-H bond benzoxylation of biologically appealing N-arylisoindolinones.

Site- and regio-selective aromatic C-H bond benzoxylations were found to take place using biologically appealing N-arylisoindolinones under ruthenium(ii) catalysis in the presence of (hetero)aromatic carboxylic acid derivatives as coupling partners. Besides the presence of two potential C(sp2)-H sites available for functionalization in the substrates, exclusive ortho selectivity was achieved in the phenyl ring attached to the nitrogen atom. Notably, the reactions occurred in a selective manner as only mono-functionalized products were formed and they tolerated a large number of functional chemical groups. The ability of the cyclic tertiary amide within the isoindolinone skeleton to act as a weak directing group in order to accommodate six-membered ring ruthenacycle intermediates appears to be the key to reach such high levels of selectivity. In contrast, the more sterically demanding cyclic imides were unreactive under identical reaction conditions.

Iridium-Catalyzed Hydrogenation and Dehydrogenation of N-Heterocycles in Water under Mild Conditions.

An efficient catalytic method is presented for the hydrogenation of N-heterocycles. The iridium-based catalyst operates under mild conditions in water without any co-catalyst or stoichiometric additives. The catalyst also promotes the reverse reaction of dehydrogenation of N-heterocycles, hence displaying appropriate characteristics for a future hydrogen economy based on liquid organic hydrogen carriers (LOHCs).

Ru-Catalyzed Selective C-H Bond Hydroxylation of Cyclic Imides.

We report on cyclic imides as weak directing groups for selective monohydroxylation reactions using ruthenium catalysis. Whereas acyclic amides are known to promote the hydroxylation of the C(sp2)-H bond enabling five-membered ring ruthenacycle intermediates, the cyclic imides studied herein enabled the hydroxylation of the C(sp2)-H bond via larger six-membered ruthenacycle intermediates. Furthermore, monohydroxylated products were exclusively obtained (even in the presence of overstoichiometric amounts of reagents), which was rationalized by the difficulty to accommodate coplanar intermediates once the first hydroxyl group was introduced into the substrate. The same reactivity was observed in the presence of palladium catalysts.

Base-Free Dehydrogenation of Aqueous and Neat Formic Acid with Iridium(III) Cp*(dipyridylamine) Catalysts.

The selective dehydrogenation of formic acid by iridium(III) Cp*(dipyridylamine) catalysts is reported. The electron-enriched catalyst [IrIII Cp*{(4-dimethylaminopyridin-2-yl-κΝ)(pyridin-2'-yl-κΝ)amine}(OSO3 )] gave the best performances enabling the base free dehydrogenation of aqueous and neat formic acid. In both cases the reaction was selective with no carbon monoxide detectable. The IrIII complex demonstrated latent behavior, which may be of practical utility. Experimental results suggest an outer-sphere interaction with the ligand.

Ruthenium(II)-Catalyzed C-H (Hetero)Arylation of Alkenylic 1,n-Diazines (n = 2, 3, and 4): Scope, Mechanism, and Application in Tandem Hydrogenations.

A general ruthenium(II)-catalyzed methodology enabling the (hetero)arylation of alkenylic C-H bonds utilizing a series of synthetically appealing diazines as directing groups is presented. Despite the presence of additional nitrogen lone pairs remote from the C-H bond activation site, which could eventually poison the catalyst, the reaction times are short (3 h), thus being suitable for selective double C-H bond arylation. Mixtures of E:Z isomeric products were observed in some cases, which were further hydrogenated in a tandem manner in the presence of the remaining ruthenium catalyst from the first step, representing an alternative approach to more difficult C(sp3)-H bond functionalization. According to mechanistic studies, the unexpected E:Z product formation seems to occur by thermal C═C bond isomerization after the reductive elimination step.

Unmasking Amides: Ruthenium-Catalyzed Protodecarbonylation of N-Substituted Phthalimide Derivatives.

The unprecedented transformation of a wide range of synthetically appealing phthalimides into amides in a single-step operation has been achieved in high yields and short reaction times using a ruthenium catalyst. Mechanistic studies revealed a unique, homogeneous pathway involving five-membered ring opening and CO2 release with water being the source of protons.

Selective and Efficient Iridium Catalyst for the Reductive Amination of Levulinic Acid into Pyrrolidones.

The catalytic reductive amination of levulinic acid (LA) into pyrrolidones with an iridium catalyst using H2 as hydrogen source is reported. The chemoselective iridium catalyst displayed high efficiency for the synthesis of a variety of N-substituted 5-methyl-2-pyrrolidones and N-arylisoindolinones. N-Substituted 5-methyl-2-pyrrolidone was also evaluated as a biosourced substitute solvent to NMP (N-methylpyrrolidone) in the catalytic arylation of 2-phenylpyridine.

Ruthenium Phosphine-Pyridone Catalyzed Cross-Coupling of Alcohols To form α-Alkylated Ketones.

An efficient and green route to access diverse functionalized ketones via dehydrogenative-dehydrative cross-coupling of primary and secondary alcohols is demonstrated. Selective and tunable formation of ketones or alcohols is catalyzed by a recently developed proton responsive ruthenium phosphine-pyridone complex. Light alcohols such as ethanol could be used as alkylating agents in this methodology. Moreover, selective tandem double alkylation of isopropanol is achieved by sequential addition of different alcohols.

Ruthenium catalyzed ß-C(sp3)-H functionalization on the 'privileged' piperazine nucleus.

ß-C(sp3)-H functionalization on the 'privileged' piperazine nucleus has been disclosed using ruthenium catalysis. The ruthenium catalyzed synthesis of a variety of piperazine fused indoles from ortho-piperazinyl (hetero)aryl aldehydes is presented. This transformation takes place via the dehydrogenation of piperazine followed by an intramolecular nucleophilic addition of the transient enamine moiety onto the carbonyl group and aromatization cascade.

Palladium-Catalysed Cross-Coupling Reactions Controlled by Noncovalent Zn⋠⋠⋠N Interactions.

Non-covalent interactions between halopyridine substrates and catalytically inert building blocks, namely zinc(II)-porphyrins and zinc(II)-salphens, influence the catalytic outcome of Suzuki-Miyaura and Mizoroki-Heck palladium-catalysed cross-coupling reactions. The weak Zn⋅⋅⋅N interactions between halopyridine substrates and zinc(II)-containing porphyrins and salphens, respectively, were studied by a combination of 1 H NMR spectroscopy, UV/Vis studies, Job-Plot analysis and, in some cases, X-ray diffraction studies. Additionally, the former studies revealed unique supramolecular polymeric and dimeric rearrangements in the solid state featuring weak Br⋅⋅⋅N (halogen bonding), C-H⋅⋅⋅π, Br⋅⋅⋅π and π⋅⋅⋅π interactions. The reactivity of halopyridine substrates in homogeneous palladium-catalysed cross-coupling reactions was found to correlate with the binding strength between the zinc(II)-containing scaffolds and the corresponding halopyridine. Such observation is explained by the unfavourable formation of inactive over-coordinated halopyridine⋅⋅⋅palladium species. The presented approach is particularly appealing for those cases in which substrates and/or products deactivate (or partially poison) a transition-metal catalyst.

Ethenolysis: A Green Catalytic Tool to Cleave Carbon-Carbon Double Bonds.

Remarkable innovations have been made in the field of olefin metathesis due to the design and preparation of new catalysts. Ethenolysis, which is cross-metathesis with ethylene, represents one catalytic transformation that has been used with the purpose of cleaving internal carbon-carbon double bonds. The objectives were either the ring opening of cyclic olefins to produce dienes or the shortening of unsaturated hydrocarbon chains to degrade polymers or generate valuable shorter terminal olefins in a controlled manner. This Review summarizes several aspects of this reaction: the catalysts, their degradation in the presence of ethylene, some parameters driving their productivity, the side reactions, and the applications of ethenolysis in organic synthesis and in potential industrial applications.

Cross metathesis of unsaturated epoxides for the synthesis of polyfunctional building blocks.

The cross metathesis of 1,2-epoxy-5-hexene (1) with methyl acrylate and acrylonitrile was investigated as an entry to the synthesis of polyfunctional compounds. The resulting cross metathesis products were hydrogenated in a tandem fashion employing the residual ruthenium from the metathesis step as the hydrogenation catalyst. Interestingly, the epoxide ring remained unreactive toward this hydrogenation method. The saturated compound resulting from the cross metathesis of 1 with methyl acrylate was transformed by means of nucleophilic ring-opening of the epoxide to furnish a diol, an alkoxy alcohol and an amino alcohol in high yields.

Efficient Domino Hydroformylation/Benzoin Condensation: Highly Selective Synthesis of α-Hydroxy Ketones.

An improved domino hydroformylation/benzoin condensation to give α-hydroxy ketones has been developed. Easily available olefins are smoothly converted into the corresponding α-hydroxy ketones in high yields with excellent regioselectivities. Key to success is the use of a specific catalytic system consisting of a rhodium/phosphine complex and the CO2 adduct of an N-heterocyclic carbene.

Selective ruthenium-catalyzed hydrochlorination of alkynes: one-step synthesis of vinylchlorides.

An unprecedented ruthenium-catalyzed direct and selective alkyne hydrochlorination is reported and leads to vinylchlorides in excellent yields with atom economy. The reaction proceeds at room temperature from terminal alkynes and provides a variety of chloroalkenes. Only the regioisomer resulting from the formal Markovnikov addition is selectively formed. Mechanistic studies show the stereoselective syn addition of HCl to alkynes at room temperature and suggest a chloro hydrido Ru(IV) species as a key intermediate of the reaction.

Vicinal α,ß-functionalizations of amines: cyclization versus dehydrogenative hydrolysis.

Direct vicinal α,ß-difunctionalization of tertiary cyclic amines is achieved in the presence of ruthenium or iridium transition-metal complexes featuring phosphine-sulfonate chelates. By varying the reaction conditions, α-alkylated lactams were obtained by a formal dehydrogenative hydrolysis in which one molecule of hydrogen is generated from water.

Ruthenium-containing phosphinesulfonate chelate for the hydrogenation of aryl ketones.

Various ruthenium(II) complexes that contain phosphinesulfonate chelate have been synthesized. Arene-free complexes were found to be efficient in the base-free hydrogenation of various aryl ketones, whereas the arene-containing precatalysts required the presence of an amine as an additive. The seminal asymmetric hydrogenation reaction by using the new Sulfo-Binepine ligand was also investigated for the possible intervention of a dihydride species.

A straightforward access to guaiazulene derivatives using palladium-catalysed sp2 or sp3 C-H bond functionalisation.

A novel palladium-catalysed direct arylation of guaiazulenes with a variety of aryl bromides is reported. Both sp(2) and sp(3) C-H bonds have been functionalised, as the nature of the cation of the base was found to allow the control of the regioselectivity of the arylation giving rise to C2 or C3 arylated guaiazulenes and also to 4-benzylguaiazulenes.