Easy access to polyhalogenated biaryls: regioselective (di)halogenation of hypervalent bromines and chlorines.

Polyhalogenated biaryls are unique motifs offering untapped potential as versatile building blocks for the expedient synthesis of complex biaryl compounds. Overcoming the limitations of conventional syntheses, we introduce a novel, metal-free, operationally simple and one-pot approach to regioselectively (di)halogenate biaryl compounds under mild conditions using cyclic biaryl hypervalent bromine and chlorine substrates as masked arynes. Through chemoselective post-functionalizations, these valuable products can expand the toolbox for synthesizing biaryl-containing scaffolds, addressing a critical gap in the field.

Iron-catalyzed stereoselective C-H alkylation for simultaneous construction of C-N axial and C-central chirality.

The assembly of chiral molecules with multiple stereogenic elements is challenging, and, despite of indisputable advances, largely limited to toxic, cost-intensive and precious metal catalysts. In sharp contrast, we herein disclose a versatile C-H alkylation using a non-toxic, low-cost iron catalyst for the synthesis of substituted indoles with two chiral elements. The key for achieving excellent diastereo- and enantioselectivity was substitution on a chiral N-heterocyclic carbene ligand providing steric hindrance and extra represented by noncovalent interaction for the concomitant generation of C-N axial chirality and C-stereogenic center. Experimental and computational mechanistic studies have unraveled the origin of the catalytic efficacy and stereoselectivity.

Cyclic Diaryl λ3-Bromanes as a Precursor for Regiodivergent Alkynylation Reactions.

Regiodivergent reactions are a fascinating tool to rapidly access molecular diversity while using identical coupling partners. We have developed a new approach for regiodivergent synthesis using the dual character of hypervalent bromines. In addition to the recently reported reactivity of hypervalent bromines as aryne precursors, the first transition metal-catalyzed reaction is reported. Accordingly, the development of these two complementary transformations allows for the alteration of regioselectivity to furnish both ortho- and meta-substituted alkynylation products. Mechanistic and computational studies show how these selectivities are controlled.

Diaryl hypervalent bromines and chlorines: synthesis, structures and reactivities.

In the field of modern organic chemistry, hypervalent compounds have become indispensable tools for synthetic chemists, finding widespread applications in both academic research and industrial settings. While iodine-based reagents have historically dominated this research field, recent focus has shifted to the potent yet relatively unexplored chemistry of diaryl λ3-bromanes and -chloranes. Despite their unique reactivities, the progress in their development and application within organic synthesis has been hampered by the absence of straightforward, reliable, and widely applicable preparative methods. However, recent investigations have uncovered innovative approaches and novel reactivity patterns associated with these specialized compounds. These discoveries suggest that we have only begun to tap into their potential, implying that there is much more to be explored in this captivating area of chemistry.

Micellar catalysis: a green solution to enable undirected and mild C-H activation of (oligo)thiophenes at the challenging ß-position.

The unexpected potential of micellar medium to achieve challenging ß-selective direct arylation of (oligo)thiophenes is reported. Thanks to the use of a water/surfactant solution in combination with natural feedstock-derived undecanoic acid as an additive, this high-yielding C-H coupling could be performed regioselectively at room temperature.

One reaction - double stereoinduction: C-H activation as a privileged route towards complex atropisomeric molecules.

Expanding the importance of chirality and implementation of stereogenic information within complex molecular design has recently reached a new level: design of innovative enantiopure scaffolds bearing multiple chiral elements. In particular, regarding sustainability aspects and straightforward use of relatively simple substrates, the C-H activation strategy offers unique opportunities to assemble complex chiral molecules with unique topologies while controlling two stereoselective events in a single transformation. Herein, the emerging field of asymmetric C-H activation allowing rapid construction of atropisomeric molecules bearing a second chirality element, such as a stereogenic center, vicinal chiral axis or planar chirality, is described. Aiming at in-depth comprehension of such innovative systems, the emphasis is put on the nature of stereodiscriminant steps, allowing the simultaneous control of both chiral elements.

Sulfoxide-Directed or 3d-Metal Catalyzed C-H Activation and Hypervalent Iodines as Tools for Atroposelective Synthesis.

ConspectusThe expanding applications of atropisomeric compounds combined with the growing diversity of such chiral molecules translate into an urgent need for innovative synthetic strategies allowing their rapid, efficient, and sustainable synthesis. Recently, the C-H activation approach has provided new opportunities for synthesizing axially chiral compounds. The two complementary approaches allowing implementation of the C-H activation methodology toward the synthesis of the chiral molecules imply either ortho-functionalization of the preexisting prochiral or atropo-unstable biaryl substrates or direct C-H arylation of sterically encumbered aromatics. The first approach required the preinstallation of a directing group on a biaryl precursor, which drastically limits the diversity of thus generated products. To tackle this important synthetic limitation, we have envisioned using a chiral sulfoxide as both directing group and chiral auxiliary. Indeed, in addition to efficiently coordinating the Pd-catalyst thus allowing chiral induction, the sulfoxide moiety can be easily removed, via the sulfoxide/lithium exchange, after the C-H activation step, thus guaranteeing an almost unlimited postdiversification of the atropisomeric products. The efficiency and generality of this concept could be illustrated by developing atropo-diastereoselective oxidative Heck reaction, direct acetoxylation, and iodination, as well as direct arylation. Besides, the synthetic utility of this methodology was demonstrated by designing an expedient synthesis of a direct steganone precursor. This unique transformation also allowed us to build up unprecedented triaryl scaffolds with two perfectly controlled chiral axes, original chiral skeletons for new ligand design. While considering the atroposelective direct arylations, the clear antagonism between the harsh reaction conditions frequently required for the coupling of two sterically hindered compounds and the atropo-stability of the new product, resulted in the scarcity of such transformations. To solve this fundamental challenge, we have focused on the application of a low-valent cobalt catalyst, prompted to catalyze C-H activation of indoles at the C2 position under extremely mild reaction conditions (room temperature). Accordingly, atroposelective C2-arylation of indoles could be achieved using an original carbene ligand and delivering the uncommon atropoisomerically pure indoles in excellent yields and enantioselectivities. Detailed combined experimental and theoretical mechanistic studies shed light on the mechanism of this transformation, providing strong evidence regarding the origin of the enantioselectivity. Finally, the antagonism between steric hindrance required to guarantee the atropo-stability of a molecule and harsh reaction conditions required to couple two partners is a strong limitation not only for the development of atroposelective C-H arylation reaction but also for the development of direct synthesis of the C-N axially chiral compounds. Despite the long history and incredible advances achieved in Ullmann-Goldberg and Buchwald-Hartwig couplings, atroposelective versions of such transformations have remained unprecedented until recently. Our idea to tackle this challenging issue consisted in using hypervalent iodines as highly reactive coupling partners, thus allowing the desired N-arylations to occur at room temperature. This hypothesis could be validated by reporting first atropo-diastereoselective Cu-catalyzed N-arylation, using sulfoxide λ3-iodanes as the coupling partners. Subsequently, the enantioselective version of this atroposelective N-arylation was successfully established by using a chiral Cu-complex bearing a BOX ligand. In conclusion, we report herein designing tailored-made solutions to provide new synthetic strategies to construct the atropisomeric molecules, including biaryls and C-N axially chiral molecules.

Cyclic Diaryl λ3-Chloranes: Reagents and Their C-C and C-O Couplings with Phenols via Aryne Intermediates.

Hypervalent chloranes are a class of rare and poorly explored reagents. Their unique electronic properties confer reactivity that is complementary to that of the common iodanes and emerging bromanes. Highly chemo- and regioselective, metal-free, and mild C-C and C-O couplings are reported here. Experimental and computational mechanistic studies elucidate the unprecedented reactivities and selectivities of these systems and the intermediacy of aryne intermediates. The synthetic potential of these transformations is further demonstrated via the post-functionalization of C-C and C-O coupling products obtained from reactions of chloranes with phenols under different conditions.

Cobalt-Catalyzed Enantioselective C-H Arylation of Indoles.

Atropoisomeric (hetero)biaryls are scaffolds with increasing importance in the pharmaceutical and agrochemical industries. Although it is the most obvious disconnection to construct such compounds, the direct enantioselective C-H arylation through the concomitant induction of the chiral information remains extremely challenging and uncommon. Herein, the unprecedented earth-abundant 3d-metal-catalyzed atroposelective direct arylation is reported, furnishing rare atropoisomeric C2-arylated indoles. Kinetic studies and DFT computation revealed an uncommon mechanism for this asymmetric transformation, with the oxidative addition being the rate- and enantio-determining step. Excellent stereoselectivities were reached (up to 96% ee), while using an unusual N-heterocyclic carbene ligand bearing an essential remote substituent. Attractive dispersion interactions along with positive C-H---π interactions exerted by the ligand were identified as key factors to guarantee the excellent enantioselection.

Cyclometallated complexes as catalysts for C-H activation and functionalization.

The development of novel catalysts for C-H activation reactions with increased reactivity and improved selectivities has been attracting significant interest over the last two decades. More recently, promising results have been developed using tridentate pincer ligands, which form a stable C-M bond. Furthermore, based on mechanistic studies, the unique catalytic role of some metallacyclic intermediate species has been revealed. These experimental observations have subsequently translated into the rational design of advanced C-H activation catalysts in both Ru- and Ir-based systems. Recent breakthroughs in the field of C-H activation catalysed by metallacyclic intermediates are thus discussed.

Cyclic Diaryl λ3-Bromanes: A Rapid Access to Molecular Complexity via Cycloaddition Reactions.

Biaryls have widespread applications in organic synthesis. However, sequentially polysubstituted biaryls are underdeveloped due to their challenging preparation. Herein, we report the synthesis of dissymetric 2,3,2',3',4-substituted biaryls via pericyclic reactions of cyclic diaryl λ3-bromanes. The functional groups tolerance and atom economy allow access to molecular complexity in a single reaction step. Continuous flow protocol has been designed for the scale-up of the reaction, while postfunctionalizations have been developed taking advantage of the residual Br-atom.

Cyclic Diaryl λ3 -Bromanes as Original Aryne Precursors.

Despite the widespread application of hypervalent iodines, the corresponding λ3 -bromanes are less explored. Herein we report a general, safe, and high-yielding strategy to access cyclic diaryl λ3 -bromanes. These unique compounds feature reactivity that is appealing and complementary to that of λ3 -iodanes, generating arynes under mild reaction conditions and in the presence of a weak base. Accordingly, formal meta-selective transition-metal-free C-O and C-N couplings may be achieved. Mechanistic studies unambiguously support the aryne generation mechanism.

Towards Atropoenantiopure N-C Axially Chiral Compounds via Stereoselective C-N Bond Formation.

N-C axial chirality, although disregarded for decades, is an interesting type of chirality with appealing applications in medicinal chemistry and agrochemistry. However, atroposelective synthesis of optically pure compounds is extremely challenging and only a limited number of synthetic routes have been designed. In particular, asymmetric N-arylation reactions allowing atroposelective N-C bond forming events remain scarce, although great advances have been achieved recently. In this minireview we summarize the synthetic approaches towards synthesis of N-C axially chiral compounds via stereocontrolled N-C bond forming events. Both organo-catalyzed and metal-catalyzed transformations are described, thus illustrating the diversity and specificity of both strategies.

When metal-catalyzed C-H functionalization meets visible-light photocatalysis.

While aiming at sustainable organic synthesis, over the last decade particular attention has been focused on two modern fields, C-H bond activation, and visible-light-induced photocatalysis. Couplings through C-H bond activation involve the use of non-prefunctionalized substrates that are directly converted into more complex molecules, without the need of a previous functionalization, thus considerably reduce waste generation and a number of synthetic steps. In parallel, transformations involving photoredox catalysis promote radical reactions in the absence of radical initiators. They are conducted under particularly mild conditions while using the visible light as a cheap and economic energy source. In this way, these strategies follow the requirements of environment-friendly chemistry. Regarding intrinsic advantages as well as the complementary mode of action of the two catalytic transformations previously introduced, their merging in a synergistic dual catalytic system is extremely appealing. In that perspective, the scope of this review aims to present innovative reactions combining C-H activation and visible-light induced photocatalysis.

The Affinity of Some Lewis Bases for Hexafluoroisopropanol as a Reference Lewis Acid: An ITC/DFT Study.

To figure out the possible role of 1,1,1,3,3,3-hexafluoropropan-2-ol (HFIP) as well as to provide reference thermochemical data in solution, the formation of Lewis acid-base complexes between HFIP (Lewis acid) and a series of 8 different Lewis bases (3 sulfoxides, 3 Nsp2 pyridine derivatives, 1 aromatic amine, 1 cyclic aliphatic ether) was examined by isothermal titration calorimetry (ITC) experiments and static density functional theory augmented with Dispersion (DFT-D) calculations. Measured ITC association enthalpy values (ΔHa ) lie between -9.3 and -14 kcal mol-1 . Computations including a PCM implicit solvation model produced similar exothermicity of association of all studied systems compared to the ITC data with ΔHa values ranging from -8.5 to -12.7 kcal mol-1 . An additional set of calculations combining implicit and explicit solvation by chlorobenzene of the reactants, pointed out the relatively low interference of the solvent with the HFIP-base complexation: its main effect is to slightly enhance the Gibbs energy of the HFIP-Lewis base association. It is speculated that the interactions of bulk HFIP with Lewis bases therefore may significantly intervene in catalytic processes not only via the dynamic microstructuring of the medium but also more explicitly by affecting bonds' polarization at the Lewis bases.

Enantioselective Synthesis of N-C Axially Chiral Compounds by Cu-Catalyzed Atroposelective Aryl Amination.

N-C axially chiral compounds have emerged recently as appealing motifs for drug design. However, the enantioselective synthesis of such molecules is still poorly developed and surprisingly no metal-catalyzed atroposelective N-arylations have been described. Herein, we disclose an unprecedented Cu-catalyzed atroposelective N-C coupling that proceeds at room temperature. Such mild reaction conditions, which are a crucial parameter for atropostability of the newly generated products, are operative thanks to the use of hypervalent iodine reagents as a highly reactive coupling partners. A large panel of the N-C axially chiral compounds was afforded with very high enantioselectivity (up to >99 % ee) and good yields (up to 76 %). Post-modifications of thus accessed atropisomeric compounds allows further expansion of the diversity of these appealing compounds.

Cobalt-Catalyzed Oxidative C-H Activation: Strategies and Concepts.

Inexpensive cobalt-catalyzed oxidative C-H functionalization has emerged as a powerful tool for the construction of C-C and C-Het bonds, which offers unique potential for transformative applications to modern organic synthesis. In the early stage, these transformations typically required stoichiometric and toxic transition metals as sacrificial oxidants; thus, the formation of metal-containing waste was inevitable. In contrast, naturally abundant molecular O2 has more recently been successfully employed as a green oxidant in cobalt catalysis, thus considerably improving the sustainability of such transformations. Recently, a significant momentum was gained by the use of electricity as a sustainable and environmentally benign redox reagent in cobalt-catalyzed C-H functionalization, thereby preventing the consumption of cost-intensive chemicals while at the same time addressing the considerable safety hazards related to the use of molecular oxygen in combination with flammable organic solvents. Considering the unparalleled potential of the aforementioned approaches for sustainable green synthesis, this Review summarizes the recent progress in cobalt-catalyzed oxidative C-H activation until early 2020.

Enantioselective C-H Activation with Earth-Abundant 3d Transition Metals.

Molecular syntheses largely rely on time- and labour-intensive prefunctionalization strategies. In contrast, C-H activation represents an increasingly powerful approach that avoids lengthy syntheses of prefunctionalized substrates, with great potential for drug discovery, the pharmaceutical industry, material sciences, and crop protection, among others. The enantioselective functionalization of omnipresent C-H bonds has emerged as a transformative tool for the step- and atom-economical generation of chiral molecular complexity. However, this rapidly growing research area remains dominated by noble transition metals, prominently featuring toxic palladium, iridium and rhodium catalysts. Indeed, despite significant achievements, the use of inexpensive and sustainable 3d metals in asymmetric C-H activations is still clearly in its infancy. Herein, we discuss the remarkable recent progress in enantioselective transformations via organometallic C-H activation by 3d base metals up to April 2019.