Experimental and Computational Studies for the Synthesis of Functionalized Cyclopropanes from 2-Substituted Allylic Derivatives with Ethyl Diazoacetate.

The catalytic asymmetric synthesis of highly functionalized cyclopropanes from 2-substituted allylic derivatives is reported. Using ethyl diazo acetate, the reaction, catalyzed by a chiral ruthenium complex (Ru(II)-Pheox), furnished the corresponding easily separable cis and trans cyclopropanes in moderate to high yields (32-97 %) and excellent ee (86-99 %). This approach significantly extends the portfolio of accessible enantioenriched cyclopropanes from an underexplored class of olefins. DFT calculations suggest that an outer-sphere mechanism is operative in this system.

Copper-Catalyzed C-H (Phenylsulfonyl)difluoromethylation of Acrylamides: Scope, Mechanism, and Critical Role of Additives.

Herein, we report the Cu-complex catalyzed, native functional group-assisted, and TFA/NMF additives promoted (phenylsulfonyl)difluoromethylation of vinylic C(sp2 )-H bond of acrylamides. Using our in-home designed reagent, this reaction enables the construction of the C(sp2 )-CF2 SO2 Ph bond from simple C-H bond activation by copper catalysis under mild reaction conditions with total Z-selectivity. The versatility of utilized fluorinated group was illustrated by its conversion into value-added CF2 moieties as well as the remarkable =CHF residue. The performed experimental and computational mechanistic studies enabled to identify the true nature of active catalyst and substrate, as well as establish critical roles of TFA and NMF additives. In this reaction, the TFA acts as a promoter of the much-needed CuII /CuII →CuIII /CuI disproportionation, while the NMF facilitates the following ligand exchange and C-C coupling processes. We ruled out the generation of radical intermediates and established the C-H activation to be irreversible and the rate-determining step of the entire process.

Site-Selective Ortho/Ipso C-H Difunctionalizations of Arenes using Thianthrene as a Leaving Group.

Site-selective ortho/ipso C-H difunctionalizations of aromatic compounds were designed to afford polyfunctionalized arenes including challenging 1,2,3,4-tetrasubstituted ones (62 examples, up to 97 % yields). To ensure the excellent regioselectivity of the process while keeping high efficiency, an original strategy based on a "C-H thianthenation/Catellani-type reaction" sequence was developed starting from simple arenes. Non-prefunctionalized arenes were first regioselectively converted into the corresponding thianthrenium salts. Then, a palladium-catalyzed, norbornene (NBE)-mediated process allowed the synthesis of ipso-olefinated/ortho-alkylated polyfunctionalized arenes using a thianthrene as a leaving group (revisited Catellani reaction). Pleasingly, using a commercially available norbornene (NBE) and a unique catalytic system, synthetic challenges known for the Catellani reaction with aryl iodides were smoothly and successfully tackled with the "thianthrenium" approach. The protocol was robust (gram-scale reaction) and was widely applied to the two-fold functionalization of various arenes including bio-active compounds. Moreover, a panel of olefins and alkyl halides as coupling partners was suitable. Pleasingly, the "thianthrenium" strategy was successfully further applied to the incorporation of other groups at the ipso (CN/alkyl/H, aryl) and ortho (alkyl, aryl, amine, thiol) positions, showcasing the generality of the process.

Transition-metal-catalyzed C-H bond activation as a sustainable strategy for the synthesis of fluorinated molecules: an overview.

The last decade has witnessed the emergence of innovative synthetic tools for the synthesis of fluorinated molecules. Among these approaches, the transition-metal-catalyzed functionalization of various scaffolds with a panel of fluorinated groups (XRF, X = S, Se, O) offered straightforward access to high value-added compounds. This review will highlight the main advances made in the field with the transition-metal-catalyzed functionalization of C(sp2) and C(sp3) centers with SCF3, SeCF3, or OCH2CF3 groups among others, by C-H bond activation. The scope and limitations of these transformations are discussed in this review.

Ru(II)-Catalyzed Hydroarylation of in†situ Generated 3,3,3-Trifluoro-1-propyne by C-H Bond Activation: A Facile and Practical Access to ß-Trifluoromethylstyrenes.

In this study, a practical and straightforward synthesis of ß-(E)-trifluoromethylstyrenes by ruthenium-catalyzed C-H bond activation was developed. The readily available and inexpensive 2-bromo-3,3,3-trifluoropropene (BTP), a non-ozone depleting reagent, was used as a reservoir of 3,3,3-trifluoropropyne. With this approach, the monofunctionalization of a panel of heteroarenes was possible in a safe and scalable manner (23 examples, up to 87 % yield). Mechanistic investigations and density functional theory (DFT) calculations were also conducted to get a better understanding of the mechanism of this transformation. These studies suggested that 1) a cyclometallated ruthenium complex enabled the transformation, 2) this complex exhibited high efficiency in this transformation compared to the commercially available [RuCl2 (p-cymene)]2 and 3) the mechanism proceeded through a bis-cyclometallated ruthenium intermediate for the carboruthenation step.

Directed Palladium Catalyzed C-H (Ethoxycarbonyl)difluoromethylthiolation Reactions.

The unprecedented Pd-catalyzed (ethoxycarbonyl)difluoromethylthiolation reaction of various unsaturated derivatives was studied. In the presence of the (ethoxycarbonyl)difluoromethylsulfenamide reagent I and under mild reaction conditions (60 °C), both 2-(hetero)aryl and 2-(α-aryl-vinyl)pyridine derivatives were smoothly functionalized with this methodology (37 examples, up to 87 % yield). Moreover, the synthetic interest of this fluorinated moiety was further showcased by its conversion into various original fluorinated residues. Finally, a plausible mechanism for this transformation was suggested.

Phospha-Michael Addition on α-Fluorinated Acrylates: A Straightforward Access to Polyfunctionalized Fine Chemicals.

α-Fluorinated acrylates could act as Michael acceptors and become a platform toward the synthesis of relevant complex molecules. Very few conjugate additions have been developed in the literature with these specific substrates, and herein, we reported the first phospha-Michael addition (PMA) on α-trifluoromethylacrylates and α-fluoromethylacrylates. The reaction proved to be highly tolerant and gave original products containing contiguous C-P and C-CFY2 (Y = F or H) bonds in good to excellent yields and diastereoselectivities.

Design and Use of Electrophilic Thiocyanating and Selenocyanating Reagents: An Interesting Trend for the Construction of SCN- and SeCN-Containing Compounds.

Organothiocyanate and organoselenocyanate compounds are of paramount importance in organic chemistry as they are key intermediates to access sulfur- and selenium-containing compounds. Therefore, among the different synthetic pathways to get SCN- and SeCN-containing molecules, original methodologies using electrophilic reagents have recently been explored. This Minireview will showcase the recent advances that have been made. In particular, the design of several electrophilic sources and their applications for the thiocyanation and the selenocyanation of various classes of compounds will be highlighted and discussed.

Radical-Promoted Distal C-H Functionalization of C(sp3 ) Centers with Fluorinated Moieties.

Due to their unique properties, fluorinated scaffolds are pivotal compounds in pharmaceuticals, agrochemicals, and materials science. Over the last years, the development of versatile strategies for the selective synthesis of fluorinated molecules by direct C-H bond functionalization has attracted a lot of attention. In particular, the design of novel transformations based on a radical process was a bottleneck for distal C-H functionalization reactions, offering synthetic solutions for the selective introduction of fluorinated groups. This Minireview highlights the major contributions in this blossoming field. The development of new methodologies for the remote functionalization of aliphatic derivatives with various fluorinated groups based on a 1,5-hydrogen atom transfer process and a ß-fragmentation reaction will be showcased and discussed.

Pd-Catalyzed Directed Thiocyanation Reaction by C-H Bond Activation.

The Pd-catalyzed directed thiocyanation reaction of arenes and heteroarenes by C-H bond activation was achieved. In the presence of an electrophilic SCN source, this original methodology offered an efficient tool to access a panel of functionalized thiocyanated compounds (21 examples, up to 78 % yield). Post-functionalization reactions further demonstrated the synthetic utility of the approach by converting the SCN-containing molecules into value-added scaffolds.

N-Heterocyclic Carbene-Catalyzed Formal [6+2] Annulation Reaction via Cross-Conjugated Aza-Trienolate Intermediates.

The diverse reactivity of N-heterocyclic carbenes (NHCs) in organocatalysis is due to the possibility of different modes of action. Although NHC-bound enolates and dienolates are known, the related NHC-bound cross-conjugated aza-trienolates remain elusive. Herein, we demonstrate the NHC-catalyzed formal [6+2] annulation of nitrogen-containing heterocyclic aldehydes with α,α,α-trifluoroacetophenones leading to the formation of versatile pyrrolooxazolones (29 examples). The catalytically generated cross-conjugated aza-trienolates (aza-fulvene type) underwent smooth [6+2] annulation with electrophilic ketones to afford the product in moderate to good yields under mild conditions. Preliminary DFT studies on the mechanism are also provided.

Organocatalyzed Sulfa-Michael Addition of Thiophenols on Trisubstituted α-Fluoroacrylates, a Straightforward Access to Chiral Fluorinated Compounds.

In this manuscript, a simple and efficient sulfa-Michael addition reaction of aryl thiols to trisubstituted α-fluoro-α,ß-unsaturated esters both in racemic and, for the first time, in enantioselective version is reported. The commercially available dimer of cinchona derivatives (DHQ)2PYR was used as a catalyst. This strategy showed a great tolerance for various substrates and substituents, providing fair to excellent yields, moderate to excellent diastereoselectivities (2:1 to >99:1), and low to good enantioselectivities (2 to 87%). The reaction has been applied to the synthesis of fluorinated analogues of diltiazem and tiazesim, both therapeutic agents.

Advances in the Synthesis of Fluorinated Scaffolds by Transition Metal-Catalyzed C-H Bond Activation.

Thanks to the unique features of the fluorine atom and the fluorinated groups, fluorine-containing molecules are essential. Therefore, the search for new fluorinated groups as well as straightforward and original methodologies for their installation is of prime importance. Especially, the combination of organofluorine chemistry with transition metal-catalyzed C-H bond functionalization reactions offered straightforward tools to access original fluorinated scaffolds. In this context, over the last years, our group focused on the development of original methodologies to synthesize fluorine-containing molecules with a special attention to emergent fluorinated groups. The present account highlights our recent contributions to the synthesis of highly value-added fluorine-containing compounds by transition metal-catalyzed C-H bond activation.

Copper-based fluorinated reagents for the synthesis of CF2R-containing molecules (R ≠ F).

Over the years, the development of new methodologies for the introduction of various fluorinated motifs has gained a significant interest due to the importance of fluorine-containing molecules in the pharmaceutical and agrochemical industries. In a world eager to eco-friendlier tools, the need for innovative methods has been growing. To address these two challenges, copper-based reagents were developed to introduce CF2H, CF2RF, CF2CH3, CF2PO(OEt)2 and CF2SO2Ph motifs on a broad range of substrates. Copper-based fluorinated reagents have the advantage of being inexpensive and generally in situ generated or prepared in a few steps, which make them convenient to use. In this review, an overview of the recent advances made for the synthesis of fluorinated molecules using copper-based fluorinated reagents will be given.

Access to Isothiazolones from Simple Acrylamides by Pd-Catalyzed C-H Bond Activation.

A new methodology was developed to access isothiazolone derivatives from simple acrylamides by transition metal catalyzed C-H bond functionalization. This Pd-catalyzed reaction using an electrophilic SCN source offered an efficient tool to access a panel of functionalized isothiazolone derivatives (21 examples, up to 71% yield).

Use of ArSO2SRf reagents: an efficient tool for the introduction of SRf moieties.

In recent years, a renewal of interest was shown to the quest for new synthetic solutions to directly introduce emergent fluorinated groups (SRf) onto molecules. In this context, a new generation of reagents (ArSO2SRf) as efficient sources of SCF3, SCF2H and more generally SRf groups, was designed. Hence, potent solutions were developed for the synthesis of SRf-containing molecules, compounds of interest for drug and agrochemical research. This review highlights the recent advances made in the synthesis and the use of this new class of reagents, considerably extending the portfolio of tools for the direct introduction of SRf moieties.

A comprehensive overview of directing groups applied in metal-catalysed C-H functionalisation chemistry.

The present review is devoted to summarizing the recent advances (2015-2017) in the field of metal-catalysed group-directed C-H functionalisation. In order to clearly showcase the molecular diversity that can now be accessed by means of directed C-H functionalisation, the whole is organized following the directing groups installed on a substrate. Its aim is to be a comprehensive reference work, where a specific directing group can be easily found, together with the transformations which have been carried out with it. Hence, the primary format of this review is schemes accompanied with a concise explanatory text, in which the directing groups are ordered in sections according to their chemical structure. The schemes feature typical substrates used, the products obtained as well as the required reaction conditions. Importantly, each example is commented on with respect to the most important positive features and drawbacks, on aspects such as selectivity, substrate scope, reaction conditions, directing group removal, and greenness. The targeted readership are both experts in the field of C-H functionalisation chemistry (to provide a comprehensive overview of the progress made in the last years) and, even more so, all organic chemists who want to introduce the C-H functionalisation way of thinking for a design of straightforward, efficient and step-economic synthetic routes towards molecules of interest to them. Accordingly, this review should be of particular interest also for scientists from industrial R&D sector. Hence, the overall goal of this review is to promote the application of C-H functionalisation reactions outside the research groups dedicated to method development and establishing it as a valuable reaction archetype in contemporary R&D, comparable to the role cross-coupling reactions play to date.

Copper-Mediated Introduction of the CF2 PO(OEt)2 Motif: Scope and Limitations.

Herein, a general procedure to access CF2 PO(OEt)2 -containing molecules is reported. The reagent CuCF2 PO(OEt)2 is accessible by a simple protocol and a broad range of substrates can be functionalised. The procedure allows the conversion of aryl diazonium salts, as well as aryl, heteroaryl, vinyl and alkynyl iodonium salts, into the corresponding fluorinated molecules at room temperature. Mechanistic studies were performed to gain a better understanding of the reaction pathway. Under similar conditions, vinyl and aryl iodides, allyl halides, and benzyl bromides were also functionalised, and the scope and limitations of the reaction were studied. Finally, the procedure was extended to disulfides to offer new access to SCF2 PO(OEt)2 -containing molecules.

Recent Advances in the Synthesis of SCF2 H- and SCF2 FG-Containing Molecules.

In recent years, much interest has been paid to difluoromethylthiolated molecules as the "SCF2 " moiety is a key motif in drug and agrochemical research. Consequently, the development of versatile strategies for the selective synthesis of SCF2 H- and SCF2 FG-containing molecules (FG=functional group) has attracted a lot of attention and inspired the scientific community to design new tools. This Minireview highlights the major progress made in this field. Particularly, methodologies developed for the difluoromethylation of sulfur-containing molecules and the direct construction of C-SCF2 bonds in various classes of compounds are showcased and discussed.

New Prospects toward the Synthesis of Difluoromethylated Phosphate Mimics.

The difluoromethyl phosphonate motif plays a crucial role in the development of bioactive molecules as it is considered as a phosphate bioisoster. Since 2010, a renewal of interest to enlarge the panel of reactions to access these difluoromethylated phosphonate-containing molecules has been witnessed. This Concept article charts the recent progress that has been made.