Aromaticity‐promoted C−F Bond Activation in Rhodium Complex: A Facile Tautomerization

Fluorine is the most electronegative element in the periodic table. Thus, activation of the carbon–fluorine (C?F) bond, the strongest single bond to carbon, has attracted considerable interest from both experimentalists and theoreticians. In comparison with numerous approaches to activate C?F bonds, the aromaticity‐promoted method is less developed. Herein, we demonstrate that the C?F bond activation could be achieved by a facile tautomerization, benefitting from aromaticity, which can stabilize both the transition states and products. Our findings highlight an important application of aromaticity in the C?F bond activation, providing experimentalists with an alternative approach to activate C?F bonds.     

Asymmetric Desymmetrization via Metal‐Free C−F Bond Activation: Synthesis of 3,5‐Diaryl‐5‐fluoromethyloxazolidin‐2‐ones with Quaternary Carbon Centers

We disclose the first asymmetric activation of a non‐activated aliphatic C?F bond in which a conceptually new desymmetrization of 1,3‐difluorides by silicon‐induced selective C?F bond scission is a key step. The combination of a cinchona alkaloid based chiral ammonium bifluoride catalyst and N,O‐bis(trimethylsilyl)acetoamide (BSA) as the silicon reagent enabled the efficient catalytic cycle of asymmetric C_sp3?F bond cleavage under mild conditions with high enantioselectivities. The ortho effect of the aryl group at the prostereogenic center is remarkable. This concept was applied for the asymmetric synthesis of promising agrochemical compounds, 3,5‐diaryl‐5‐fluoromethyloxazolidin‐2‐ones bearing a quaternary carbon center.     

Direct α‐Siladifluoromethylation of Lithium Enolates with Ruppert‐Prakash Reagent via CF Bond Activation

The direct α‐siladifluoromethylation of lithium enolates with the Ruppert–Prakash reagent (CF₃TMS) is shown to construct the tertiary and quaternary carbon centers. The Ruppert–Prakash reagent, which is versatile for various trifluoromethylation as a trifluoromethyl anion (CF₃^?) equivalent, can be employed as a siladifluoromethyl cation (TMSCF₂⁺) equivalent by C?F bond activation due to the strong interaction between lithium and fluorine atoms.     

Transition‐Metal‐Mediated and ‐Catalyzed C−F Bond Activation by Fluorine Elimination

The activation of carbon–fluorine (C?F) bonds is an important topic in synthetic organic chemistry. Metal‐mediated and ‐catalyzed elimination of β‐ or α‐fluorine proceeds under milder conditions than oxidative addition to C?F bonds. The β‐ or α‐fluorine elimination is initiated from organometallic intermediates having fluorine substituents on carbon atoms β or α to metal centers, respectively. Transformations through these elimination processes (C?F bond cleavage), which are typically preceded by carbon–carbon (or carbon–heteroatom) bond formation, have been increasingly developed in the past five years as C?F bond activation methods. In this Minireview, we summarize the applications of transition‐metal‐mediated and ‐catalyzed fluorine elimination to synthetic organic chemistry from a historical perspective with early studies and from a systematic perspective with recent studies.     

HMPA‐Promoted Siladifluoromethylation of Di‐, and Triarylmethanes with the Ruppert–Prakash Reagent

A mild and efficientmethod for the synthesis of α‐siladifluoromethylated di‐, and triarylmethanes via the reaction of di‐, and triarylmethanes with Ruppert–Prakash reagents, using LDA and HMPA at room temperature, was developed.     

Desymmetrization‐Oriented Enantioselective Synthesis of Silicon‐Stereogenic Silanes by Palladium‐Catalyzed C−H Olefinations

A palladium‐catalyzed chelation‐assisted enantioselective C?H olefination of symmetrically diaryl‐substituted tetraorganosilicon derivatives was developed, enabling the generation of nitrogen‐containing silicon‐stereogenic tetraorganosilicon compounds with modest to good yields and good to excellent enantioselectivities (up to 95.5:4.5 e.r.). The Thorpe–Ingold effect exerted by the substituents on silicon was observed to have a profound influence on formation of olefinated products which were further converted into other relevant chiral organosilanes without the loss of enantiomeric purity, thus demonstrating the synthetic utility of the developed enantioselective olefination.     

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.     

Access to Silylated Pyrazole Derivatives by Palladium‐Catalyzed C−H Activation of a TMS group

A simple and efficient approach to new silylated heterocycles of potential interest in medicinal chemistry is presented. A set of bromophenyl trimethylsilyl pyrazole intermediates can be transformed by direct organometallic routes into two families of regioisomeric iodoaryl substrates; using either arylzinc or aryllithium chemistry, the TMS group remains on the pyrazole ring or translocates to the aryl moiety. These two families can then be efficiently transformed into benzo silino pyrazoles thanks to a single‐step cyclization relying on the Pd‐catalyzed activation of a non‐activated C(sp³)?H bond alpha to a silicon atom. The experimental conditions used, which are fully compatible with the pyrazole ring, suggest that this reaction evolves through a concerted metalation–deprotonation (CMD) mechanism.     

Enantioselective Access to 1H‐Isoindoles with Quaternary Stereogenic Centers by Palladium(0)‐Catalyzed C−H Functionalization

A catalytic enantioselective method for the synthesis of chiral 1H‐isoindoles bearing quaternary stereogenic centers is reported. Powered by readily accessible phosphordiamidite ligands, the presented palladium(0)‐catalyzed C?H functionalization uses trifluoroacetimidoyl chlorides as electrophilic components. It delivers previously inaccessible perfluoroalkylated 1H‐isoindoles in high yields and enantioselectivities. The subsequent diastereoselective addition of nucleophiles provides access to densely substituted and sterically hindered isoindolines.     

Enantioselective Pallada‐Electrocatalyzed C−H Activation by Transient Directing Groups: Expedient Access to Helicenes

Asymmetric pallada‐electrocatalyzed C?H olefinations were achieved through the synergistic cooperation with transient directing groups. The electrochemical, atroposelective C?H activations were realized with high position‐, diastereo‐, and enantio‐control under mild reaction conditions to obtain highly enantiomerically‐enriched biaryls and fluorinated N?C axially chiral scaffolds. Our strategy provided expedient access to, among others, novel chiral BINOLs, dicarboxylic acids and helicenes of value to asymmetric catalysis. Mechanistic studies by experiments and computation provided key insights into the catalyst's mode of action.     

Cobalt‐Catalyzed Tandem C−H Activation/C−C Cleavage/C−H Cyclization of Aromatic Amides with Alkylidenecyclopropanes

A cobalt‐catalyzed chelation‐assisted tandem C?H activation/C?C cleavage/C?H cyclization of aromatic amides with alkylidenecyclopropanes is reported. This process allows the sequential formation of two C?C bonds, which is in sharp contrast to previous reports on using rhodium catalysts for the formation of C?N bonds. Here the inexpensive catalyst system exhibits good functional‐group compatibility and relatively broad substrate scope. The desired products can be easily transformed into polycyclic lactones with m‐CPBA. Mechanistic studies revealed that the tandem reaction proceeds through a C?H cobaltation, β‐carbon elimination, and intramolecular C?H cobaltation sequence.     

Chemically Non‐Innocent Cyclic (Alkyl)(Amino)Carbenes: Ligand Rearrangement,C−H and C−F Bond Activation

A cyclic (alkyl)(amino)carbene (CAAC) was found to undergo unprecedented rearrangements and transformations of its core structure in the presence of Group 1 and 2 metals. Although the carbene was also found to be prone to intramolecular C?H activation, it was competent for intermolecular activation of a variety of sp‐, sp²‐, and sp³‐hybridized C?H bonds. Double C?F activation of hexafluorobenzene was also observed in this work. These processes all hold relevance to the role of these carbenes in catalysis, as well as to their use in the synthesis of new and unusual main group or transition metal complexes.     

Enantioselective Synthesis of C−N Axially Chiral N‐Aryloxindoles by Asymmetric Rhodium‐Catalyzed Dual C−H Activation

The first enantioselective Satoh–Miura‐type reaction is reported. A variety of C?N axially chiral N‐aryloxindoles have been enantioselectively synthesized by an asymmetric rhodium‐catalyzed dual C?H activation reaction of N‐aryloxindoles and alkynes. High yields and enantioselectivities were obtained (up to 99 % yield and up to 99 % ee). To date, it is also the first example of the asymmetric synthesis of C?N axially chiral compounds by such a C?H activation strategy.     

Combination of Cp*RhIII‐Catalyzed C−H Activation and a Wagner–Meerwein‐Type Rearrangement

A combination of Cp*Rh^III‐catalyzed C−H activation and Wagner–Meerwein‐type rearrangement was successfully achieved for the first time. Thus, bridged polycyclic molecules that are not readily accessible by other means were accessed under mild conditions with high efficiency (as low as 0.5 mol % Rh catalyst) in the coupling of N ‐phenoxyacetamide with 7‐azabenzonorbornadiene.     

Carbon Monoxide Activation by a Molecular Aluminium Imide: C−O Bond Cleavage and C−C Bond Formation

Anionic molecular imide complexes of aluminium are accessible via a rational synthetic approach involving the reactions of organo azides with a potassium aluminyl reagent. In the case of K₂[( NON )Al(NDipp)]₂ ( NON =4,5‐bis(2,6‐diisopropylanilido)‐2,7‐di‐tert‐butyl‐9,9‐dimethyl‐xanthene; Dipp=2,6‐diisopropylphenyl) structural characterization by X‐ray crystallography reveals a short Al?N distance, which is thought primarily to be due to the low coordinate nature of the nitrogen centre. The Al?N unit is highly polar, and capable of the activation of relatively inert chemical bonds, such as those found in dihydrogen and carbon monoxide. In the case of CO, uptake of two molecules of the substrate leads to C?C coupling and C≡O bond cleavage. Thermodynamically, this is driven, at least in part, by Al?O bond formation. Mechanistically, a combination of quantum chemical and experimental observations suggests that the reaction proceeds via exchange of the NR and O substituents through intermediates featuring an aluminium‐bound isocyanate fragment.     

Computational SN2‐Type Mechanism for the Difluoromethylation of Lithium Enolate with Fluoroform through Bimetallic C−F Bond Dual Activation

The reaction mechanism for difluoromethylation of lithium enolates with fluoroform was analyzed computationally (DFT calculations with the artificial force induced reaction (AFIR) method and solvation model based on density (SMD) solvation model (THF)), showing an S_N2‐type carbon–carbon bond formation; the “bimetallic” lithium enolate and lithium trifluoromethyl carbenoid exert the C?F bond “dual” activation, in contrast to the monometallic butterfly‐shaped carbenoid in the Simmons–Smith reaction. Lithium enolates, generated by the reaction of 2 equiv. of lithium hexamethyldisilazide (rather than 1 or 3 equiv.) with the cheap difluoromethylating species fluoroform, are the most useful alkali metal intermediates for the synthesis of pharmaceutically important α‐difluoromethylated carbonyl products.