Metal-Free Multicomponent Strategy for Amidine Synthesis.

Amidines are a ubiquitous class of bioactive compounds found in a wide variety of natural products; thus, efficient strategies for their preparation are in great demand. Specifically, their common structural core decorated with three substituents sets amidines as perfect candidates for multicomponent synthesis. Herein, we present a highly modular metal-free multicomponent strategy for the synthesis of sulfonyl amidines. This work was focused on selecting readily accessible reagents to facilitate the in situ formation of enamines by the addition of amines to ketones. These components were coupled with azides to provide a broad reaction scope with respect to all three coupling partners. Aromatic and aliphatic amines and ketones were tolerated under our reaction conditions. Likewise, the presence of a methyl group on the ketone was critical to reactivity, which was leveraged for the design of a highly regioselective reaction with aliphatic ketones. A biologically active compound was successfully synthesized in one step, demonstrating the practical utility of our methodology. Finally, the postulated mechanism was investigated and supported both experimentally and by means of a multivariate statistical model.

Redefining the Mechanistic Scenario of Carbon-Sulfur Nucleophilic Coupling via High-Valent Cp*CoIV Species.

The potential access to CoIV species for promoting transformations that are particularly challenging at CoIII still remains underexploited in the context of Cp*Co-catalyzed C-H functionalization reactions. Herein, we disclose a combined experimental and computational strategy for uncovering the participation of Cp*CoIV species in a Cp*Co-mediated C-S bond-reductive elimination. These studies support the intermediacy of high-valent Cp*Co species in C-H functionalization reactions, under oxidative conditions, when involving nucleophilic coupling partners.

Intramolecular C(sp3)-H Bond Amination Strategies for the Synthesis of Saturated N-containing Heterocycles.

The selective functionalization of C(sp³)-H bonds via intramolecular amination reactions represents a very attractive strategy for the construction of saturated N-containing heterocycles (SNHets). Over the past de- cades, the chemical community has devoted its efforts towards expanding the synthetic toolbox with the aim of facilitating access to these key fragments in a controllable, reproducible and efficient manner. This review covers selected examples of the most recent advances in intramolecular C(sp³)-N bond-forming reactions by three main approaches: (1) the Hofmann-Löffler-Freytag (HLF) reaction; (2) transition-metal-catalyzed nitrene C(sp³)-H inser- tion; and (3) transition-metal-catalyzed ligand-assisted C(sp³)-N bond-forming reactions via a reductive elimination step. We will discuss reactivity, selectivity and the major mechanistic insights into these transformations.

Emerging unconventional organic solvents for C-H bond and related functionalization reactions.

Solvent engineering is an increasingly essential topic in the chemical sciences. In this context, some recently appeared unconventional solvents have shown their large potential in the field of C-H bond functionalization reactions. This review aims not only at recognizing and classifying a short selection of these emerging solvents, in particular halogenated ones, but also at providing a medium term perspective of the possibilities they will offer for synthetic method development.

Weakly Coordinated Cobaltacycles: Trapping Catalytically Competent Intermediates in Cp*CoIII Catalysis.

Herein, we disclose the synthesis of metallacyclic Cp*CoIII complexes containing weakly chelating functional groups. We have employed these compounds not only as an exceptional platform for accessing some of the most widely invoked transient intermediates in C-H functionalization processes but also as competent catalysts in different Cp*Co-catalyzed transformations, including a benchmark coupling reaction.

Unravelling Molecular Aspects of the Migratory Insertion Step in Cp*CoIII Metallacyclic Systems.

This Forum Article describes the reactivity and regioselectivity of the insertion of electrophiles, such as alkynes and alkenes, into Co-C bonds in the context of Cp*Co-catalyzed C-H functionalization reactions. The mechanistic investigation, using diphenylacetylene as the model system, reveals that the rate-determining step of the insertion process depends on the temperature. The reaction of a catalytically relevant cobaltacycle, [Cp*CoIII(2-ppy)(MeCN)](BF4), with selected terminal electrophiles, such as phenylacetylene, styrene, and vinyl acetate, unravels different insertion modes depending on the nature of the unsaturated molecule. The inserted products were fully characterized by NMR spectroscopy, electrospray ionization mass spectrometry, and single-crystal X-ray diffraction. In addition, we performed a kinetic study to establish their relative reactivity.

Sustainable Knowledge-Driven Approaches in Transition-Metal-Catalyzed Transformations.

The sustainable synthesis of relevant scaffolds for their use in the pharmaceutical, agrochemical, and materials sectors constitutes one of the most urgent challenges that the chemical community needs to overcome. In this context, the development of innovative and more efficient catalytic processes based on a fundamental understanding of the underlying reaction mechanisms remains a largely unresolved challenge for academic and industrial chemists. Herein, selected examples of computational and experimental knowledge-driven approaches for the rational design of transition-metal-catalyzed transformations are discussed.

Exploring the Role of Coinage Metalates in Trifluoromethylation: A Combined Experimental and Theoretical Study.

Despite the known nucleophilic nature of [M(CF3 )2 ]- (M=Cu, Ag, Au) complexes, their participation in trifluoromethylation reactions of aryl halides remains unexplored. Here, for the first time, selective access to a [Cu(CF3 )2 ]- species is reported, which is ubiquitous in Cu-mediated trifluoromethylations, and we rationalize its complex mechanistic scenario as well as its behavior compared to its silver and gold congeners through a combination of experimental and computational approaches.

Beyond the traditional roles of Ag in catalysis: the transmetalating ability of organosilver(i) species in Pd-catalysed reactions.

Silver salts are one of the most widely used additives in Pd-catalysed transformations. Apart from acting as a halide scavenger and/or an external oxidant, over the past decade it has been revealed that silver salts can play other roles such as a C-H activation promoter or decarboxylating agent, generating organosilver(i) species. These nucleophiles can promote innovative transformations by reacting with PdII intermediates through a transmetalation step. This review article covers different Pd-catalysed C-C bond-forming reactions where silver complexes have been proposed to act as nucleophilic coupling partners. We will also provide relevant mechanistic features associated with these transformations.

Highlights from the 53rd EUCHEM conference on stereochemistry, Bürgenstock, Switzerland, May 2018.

When we first heard of the Bürgenstock conference it was described as a guarded meeting in a remote location, undisturbed by modern diversions, with mysterious customs and a secret handshake. All of these rumors turned out to be completely true. We arrived at an undisclosed location and three young men, who knew our names upon sight, greeted us and gave us an agenda in which we discovered the identity of the speakers, moderators and other participants. We then had a few moments to bask in their glory before being treated to a delicious dose of chemistry. During the banquet, before the first lecture, this year's president, Prof. Ilan Marek, gave the opening address from a balcony reserved only for these meetings, rumors hold that it stands vacant all year in anticipation. He mentioned several of the traditions of the meeting, which we are not allowed to share of course, and described the joy of putting together this year's exciting program with the help of an exceptional organizing committee that included Prof. Cristina Nevado, Prof. Christian Bochet, Dr Fabrice Gallou and Dr Alain De Mesmaeker. He also introduced this year's guest of honor, Prof. Yitzhak Apeloig, and wished the best luck to the current Vice President and future President, Prof. Véronique Gouverneur, not only for preparing the 54th Bürgenstock Conference, but also with her duty this year, maintaining the good weather for the whole week. Although the official title of the conference is the EUCHEM conference on stereochemistry, the topics covered span a broad range of cutting edge chemical transformations and insights, which can appeal to anyone working in chemistry and its interfaces with other disciplines. We will briefly describe each of the talks following one of our favorite citable quotes from these inspiring speakers.

HFIP-Assisted C-H Functionalization by Cp*CoIII : Access to Key Reactive Cobaltacycles and Implication in Catalysis.

Described here is a synthetic approach to access two of the most widely invoked cationic cobaltacycles in Cp*CoIII -catalyzed C-H functionalization reactions by C-H activation. The unique stabilizing capability of MeCN was used to surmount the previously proposed reversible nature of the C-H metalation step. Moreover, it is revealed the boosting effect of 1,1,1,3,3,3-hexafluoroisopropanol in the metalation step and in the reaction between N-pyrimidinylindole and diphenylacetylene under catalytic conditions.

New Vistas in Transmetalation with Discrete "AgCF3 " Species: Implications in Pd-Mediated Trifluoromethylation Reactions.

This work describes the employment of discrete "AgCF3 " complexes as efficient transmetalating agents to PdII to surmount overlooked challenges related to the transmetalation step in Pd-catalyzed trifluoromethylation processes. We report the participation of a unique silver ate (Cs)[Ag(CF3 )2 ] complex, under stoichiometric and catalytic conditions, in the unprecedented one-pot formation of PhCF3 using PhI as starting material. Moreover, we show that the transmetalation step, which is often ignored in these transformations, can also determine the success or failure of the coupling process.

Capturing Elusive Cobaltacycle Intermediates: A Real-Time Snapshot of the Cp*CoIII -Catalyzed Oxidative Alkyne Annulation.

Despite Cp*CoIII catalysts having emerged as a very attractive alternative to noble transition metals for the construction of heterocyclic scaffolds through C-H activation, the structure of the reactive species remains uncertain. Herein, we report the identification and unambiguous characterization of two long-sought cyclometalated Cp*CoIII complexes that have been proposed as key intermediates in C-H functionalization reactions. The addition of MeCN as a stabilizing ligand plays a crucial role, allowing the access to otherwise highly reactive species. Mechanistic investigations demonstrate the intermediacy of these species in oxidative annulations with alkynes, including the direct observation, under catalytic conditions, of a previously elusive post-migratory insertion seven-membered cobaltacycle.

Experimental and Computational Assessment of Reactivity and Mechanism in C(sp(3))-N Bond-Forming Reductive Elimination from Palladium(IV).

This report describes a combined experimental and computational investigation of the mechanism of C(sp(3))-N bond-forming reductive elimination from sulfonamide-ligated Pd(IV) complexes. After an initial experimental assessment of reactivity, we used ZStruct, a computational combinatorial reaction finding method, to analyze a large number of multistep mechanisms for this process. This study reveals two facile isomerization pathways connecting the experimentally observed Pd(IV) isomers, along with two competing SN2 pathways for C(sp(3))-N coupling. One of these pathways involves an unanticipated oxygen-nitrogen exchange of the sulfonamide ligand prior to an inner-sphere SN2-type reductive elimination. The calculated ΔG(⧧) values for isomerization and reductive elimination with a series of sulfonamide derivatives are in good agreement with experimental data. Furthermore, the simulations predict relative reaction rates with different sulfonamides, which is successful only after considering competition between the proposed operating mechanisms. Overall, this work shows that the combination of experimental studies and new computational tools can provide fundamental mechanistic insights into complex organometallic reaction pathways.

C(sp³)-O bond-forming reductive elimination from Pd(IV) with diverse oxygen nucleophiles.

This article describes an investigation of C(sp(3))-O bond-forming reductive elimination reactions from Pd(IV) complexes. Phenoxide, acetate, difluoroacetate, dimethylphosphate, tosylate, and nitrate nucleophiles are shown to participate in this reaction. In all cases, C(sp(3))-O bond formation occurs with high selectivity over potentially competing C(sp(2))-O coupling. Additives have a profound impact on the chemoselectivity of these reductive elimination reactions. An excess of RO(-) was found to limit competing C(sp(3))-C(sp(2)) bond-forming reductive elimination, while the presence of Lewis acidic cations was found to suppress competing C(sp(3))-F coupling. Mechanistic investigations were conducted, and the available data are consistent with a sequence involving pre-equilibrium dissociation of the oxyanion ligand (RO(-)) followed by nucleophilic attack of RO(-) on a cationic Pd(IV)-alkyl intermediate.

Competition between sp³-C-N vs sp³-C-F reductive elimination from Pd(IV) complexes.

This communication describes the design of a model system that allows direct investigation of competing sp(3)-C-N and sp(3)-C-F bond-forming reductive elimination from a Pd(IV) fluoro sulfonamide complex. The reductive elimination selectivity varies dramatically as a function of reaction additives. A mechanism is proposed that provides a rationale for these effects.

Strong metallophilic interactions in the palladium arylation by gold aryls.

It's the second step that counts: arylation of Pd by Au takes place through transition states and intermediates featuring strong Au⋅⋅⋅Pd metallophilic interactions. However, the aryl transfer from [AuArL] to [PdArClL(2)] is thermodynamically disfavored and will not occur unless an irreversible Ar-Ar coupling from [PdAr(2)L(2)] follows.

Bimetallic catalysis using transition and Group†11 metals: an emerging tool for C-C coupling and other reactions.

Bimetallic catalysis refers to homogeneous processes in which either two transition metals (TM), or one TM and one Group 11 (G11) element (occasionally Hg also), cooperate in a synthetic process (often a C-C coupling) and their actions are connected by a transmetalation step. This is an emerging research area that differs from the isolated or tandem applications of the now classic processes (Stille, Negishi, Suzuki, Hiyama, Heck). Most of the reactions used so far combine Pd with a second metal, often Cu or Au, but syntheses involving very different TM couples (e.g., Cr/Ni in the catalyzed vinylation of aldehydes) have also been developed. Further development of the topic will soon demand a good knowledge of the mechanisms involved in bimetallic catalysis, but this knowledge is very limited for catalytic processes. However, there is much information available, dispersed in the literature, coming from basic research on exchange reactions occurring out of any catalytic cycle, in polynuclear complexes. These are essentially the same processes expected to operate in the heart of the catalytic process. This Review gathers together these two usually isolated topics in order to stimulate synergy between the bimetallic research coming from more basic organometallic studies and the more synthetic organic approaches to this chemistry.

C-C reductive elimination in palladium complexes, and the role of coupling additives. A DFT study supported by experiment.

A DFT study of R-R reductive elimination (R = Me, Ph, vinyl) in plausible intermediates of Pd-catalyzed processes is reported. These include the square-planar tetracoordinated systems cis-[PdR(2)(PMe(3))(2)] themselves, possible intermediates cis-[PdR(2)(PMe(3))L] formed in solution or upon addition of coupling promoters (L = acetonitrile, ethylene, maleic anhydride (ma)), and tricoordinated intermediates cis-[PdR(2)(PMe(3))] (represented as L = empty). The activation energy ranges from 0.6 to 28.6 kcal/mol in the gas phase, increasing in the order vinyl-vinyl < Ph-Ph < Me-Me, depending on R, and ma < "empty" < ethylene < PMe(3) approximately MeCN, depending on L. The effect of added olefins was studied for a series of olefins, providing the following order of activation energy: p-benzoquinone < ma < trans-1,2-dicyanoethylene < 3,5-dimethylcyclopent-1-ene < 2,5-dihydrofuran < ethylene < trans-2-butene. Comparison of the calculated energies with experimental data for the coupling of cis-[PdMe(2)(PPh(3))(2)] in the presence of additives (PPh(3), p-benzoquinone, ma, trans-1,2-dicyanoethylene, 2,5-dihydrofuran, and 1-hexene) reveals that: (1) There is no universal coupling mechanism. (2) The coupling mechanism calculated for cis-[PdMe(2)(PMe(3))(2)] is direct, but PPh(3) retards the coupling for cis-[PdMe(2)(PPh(3))(2)], and DFT calculations support a switch of the coupling mechanism to dissociative for PPh(3). (3) Additives that would provide intermediates with coupling activation energies higher than a dissociative mechanism (e.g., common olefins) produce no effect on coupling. (4) Olefins with electron-withdrawing substituents facilitate the coupling through cis-[PdMe(2)(PR(3))(olefin)] intermediates with much lower activation energies than the starting complex or a tricoordinated intermediate. Practical consequences are discussed.