Alexandre Vasseur

Remote functionalization through alkene isomerization

Exploiting the reactivity of one functional group within a molecule to generate a reaction at a different position is an ongoing challenge in organic synthesis. Effective remote functionalization protocols have the potential to provide access to almost any derivatives but are difficult to achieve. The difficulty is more pronounced for acyclic systems where flexible alkyl chains are present between the initiating functional group and the desired reactive centres. In this Review, we discuss the concept of remote functionalization of alkenes using metal complexes, leading to a selective reaction at a position distal to the initial double bond. We aim to show the vast opportunity provided by this growing field through selected and representative examples. Our aim is to demonstrate that using a double bond as a chemical handle, metal-assisted long-distance activation could be used as a powerful synthetic strategy.

Dehydrogenative Heck Reaction of Furans and Thiophenes with Styrenes under Mild Conditions and Influence of the Oxidizing Agent on the Reaction Rate

Transition-metal-catalyzed reactions dealing with CH activation is a challenging task in organic chemistry. [1] The Pdcatalyzed couplings of arenes with alkenes through CH activation, also called intermolecular dehydrogenative Heck reactions (DHRs), have gained interest these past years. [2] Despite noticeable progresses, the substrate scope is often limited to olefins bearing an electron-withdrawing group as the coupling partner, which limits the applications of these reactions. We have recently reported an efficient method for the coupling of furans with styrenes, which allowed the use of chlorinated and fluorinated substrates. [3] However, brominated substrates were reluctant to react. These compounds would allow the synthesis of valuable products for further functionalization through other cross-coupling reactions. Glorius et al. have recently shown that brominated compounds can be formed with no proto-debromination using Rh catalysts; however few examples have been reported and the scope of substrates remains to be developed. [4] A recent example has been reported by Zhang et al. using palladium catalysts, but the method requires the presence of a removable pyridylsulfinyl group on the arenes. [5] Among the arenes used in DHRs, furans and thiophenes have received little attention. The former are acid sensitive and the latter require elevated temperatures, [6] due to their higher aromatic resonance energy and stability. [7] We report herein the DHRs, under mild conditions, of furans and thiophenes with styrenes, including brominated substrates. The influence and the role of the oxidizing agent on the activity of the catalyst are also discussed. We noticed an induction period during our previous study

A unique Pd-catalysed Heck arylation as a remote trigger for cyclopropane selective ring-opening

Combining functionalization at a distant position from a reactive site with the creation of several consecutive stereogenic centres, including the formation of a quaternary carbon stereocentre, in acyclic system represents a pinnacle in organic synthesis. Here we report the regioselective Heck arylation of terminal olefins as a distant trigger for the ring-opening of cyclopropanes. This Pd-catalysed unfolding of the strained cycle, driving force of the chain-walking process, remarkably proved its efficiency and versatility, as the reaction proceeded regardless of the molecular distance between the initiation (double bond) and termination (alcohol) sites. Moreover, employing stereodefined polysubstituted cyclopropane vaults allowed to access sophisticated stereoenriched acyclic scaffolds in good yields. Conceptually, we demonstrated that merging catalytically a chain walking process with a selective C–C bond cleavage represents a powerful approach to construct linear skeleton possessing two stereogenic centres.

Secondary Phosphine Oxides as Multitalented Preligands En Route to the Chemoselective Palladium‐Catalyzed Oxidation of Alcohols

Secondary phosphine oxides O=PHR2 (SPOs) were identified as multitalented preligands for the chemoselective Pd‐catalyzed oxidation of alcohols by a hydrogen‐abstracting methodology. SPOs were found to promote the hydrogen‐abstraction step as well as hydrogen transfer to a Michael acceptor by generating a putative active H−Pd species. The catalytic system operates under neutral conditions and was proven to be compatible with various electrophilic and nucleophilic functionalities within the substrates as well as water‐ and air‐sensitive functional groups.

Merging allylic C-H bond activation and C-C bond cleavage en route to the formation of a quaternary carbon stereocenter in acyclic systems

This protocol describes a diastereoselective approach for the synthesis of complex molecular architectures containing two stereogenic centers in a 1,4 relationship, one of which being an all-carbon quaternary stereogenic center. Such molecules could be intermediates in the synthesis of steroids, for example. Conceived as a single-flask synthetic sequence from ω-ene cyclopropanes, the protocol involves a concerted allylic C–H and C–C bond activation promoted by the Negishi reagent (Cp2Zr(η2-butene)). This zirconium-promenade-based procedure affords bifunctionalized products in high diastereomeric ratios after reaction of ω-ene cyclopropanes with the Negishi complex, followed by a thermal treatment and sequential addition of two different electrophiles. The method proves to be particularly efficient when carbonyl compounds are used as first electrophiles and hydrogen or elemental halides are used as second electrophiles. In addition, it offers the opportunity to create new C–C bonds via remote functionalization of a (sp3)–C–H bond, a result of a copper or copper/palladium transmetalation step that extends the scope of the process to alkyl, acyl and aromatic halide compounds as second electrophiles. The typical described protocol allows the synthesis of the highly diastereo-enriched 2-((1R*,2S*)-2-butyl-2 propylcyclopropyl)ethanol and may provide a new entry to access complex molecular segments of natural products such as steroids or C30 botryococcene. It requires a simple reaction setup and takes ∼18.5 h to run the reaction and 2 h for isolation and purification.

Zirconocene-Mediated Selective C–C Bond Cleavage of Strained Carbocycles: Scope and Mechanism

Several approaches using organozirconocene species for the remote cleavage of strained three-membered ring carbocycles are described. ω-Ene polysubstituted cyclopropanes, alkylidenecyclopropanes, ω-ene spiro[2.2]pentanes, and ω-ene cyclopropyl methyl ethers were successfully transformed into stereodefined organometallic intermediates, allowing an easy access to highly stereoenriched acyclic scaffolds in good yields and, in most cases, excellent selectivities. DFT calculations and isotopic labeling experiments were performed to delineate the origin of the obtained chemo- and stereoselectivities, demonstrating the importance of microreversibility.

CCDC 1500847: Experimental Crystal Structure Determination

Related Article: Sukhdev Singh, Jeffrey Bruffaerts, Alexandre Vasseur, Ilan Marek|2017|Nat.Commun.|8|14200|doi:10.1038/ncomms14200