Development of High Performance Heterogeneous Catalysts for Selective Cleavage of C−O and C−C Bonds of Biomass‐Derived Oxygenates

The environmental impact of CO₂ emissions via the use of fossil resources as chemical feedstock and fuels has stimulated research to utilize renewable biomass feedstock. The biogenic compounds such as polyols are highly oxygenated and their valorization requires the new methods to control the oxygen to carbon ratio of the chemicals. The catalytic cleavage of C?O bonds and C?C bonds is promising methods, but the conventional catalyst systems encounter the difficulty to obtain the high yields of the desired products. This review describes our recent development of the high performance heterogeneous catalysts for the valorization of the biogenic chemicals such as glycerol, furfural, and levulinic acid via selective cleavage of C?O bonds and C?C bonds in the liquid‐phase. Selective C?O bond cleavage by hydrogenolysis enables production of various diols useful as engineering plastics, antifreeze, and cosmetics in high yields. The success of the selective C?C bond scission of levulinic acid can be applied to a wide range of the biogenic oxygenates such as carboxylic acids, esters, lactones, and primary alcohols, in which the selective C?C bond scission at adjacent to the oxygen functional groups are achieved. Furthermore, valorization of glycerol by selective acetylation and acetalization, and of levulinic acid by hydrogenation is described. Our catalysts show excellent performance compared to the reported catalysts in the aforementioned valorization.     

Ruthenium‐Catalyzed Monoalkenylation of Aromatic Ketones by Cleavage of Carbon–Heteroatom Bonds with Unconventional Chemoselectivity

Ruthenium‐catalyzed selective monoalkenylation of ortho C? O or C? N bonds of aromatic ketones was achieved. The reaction allowed the direct comparison of the relative reactivities of the cleavage of different carbon‐heteroatom bonds, thus suggesting an unconventional chemoselectivity, where smaller, more‐electron‐donating groups are more easily cleaved. Selective monofunctionalization of C? O bonds in the presence of ortho C? H bonds was also achieved.     

Nickel‐Catalyzed Dimerization and Alkylarylation of 1,3‐Dienes with Alkyl Fluorides and Aryl Grignard Reagents

In the presence of a nickel catalyst, 1,3‐butadiene undergoes selective dimerization and alkylarylation with alkyl fluorides and aryl Grignard reagents to give 1,6‐octadienes with alkyl and aryl groups at the 3‐ and 8‐positions, respectively, by the consecutive formation of three carbon–carbon bonds. The formation of an anionic nickel complex plays an important role in forming C?C bonds with alkyl fluorides.     

Selective Carbon–Carbon Bond Cleavage for the Stereoselective Synthesis of Acyclic Systems

Most of the efforts of organic chemists have been directed to the development of creative strategies to build carbon–carbon and carbon–heteroatom bonds in a predictable and efficient manner. In this Review, we show an alternative approach where challenging molecular skeletons could be prepared through selective cleavage of carbon–carbon bonds. We demonstrate that it has the potential to be a general principle in organic synthesis for the regio‐, diastereo‐, and even enantioselective preparation of adducts despite the fact that C? C single bonds are among the least reactive functional groups. The development of such strategies may have an impact on synthesis design and can ultimately lead to new selective and efficient processes for the utilization of simple hydrocarbons.     

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.     

Copper‐Catalyzed Site‐Selective Intramolecular Amidation of Unactivated C(sp3)H Bonds

The intramolecular dehydrogenative amidation of aliphatic amides, directed by a bidentate ligand, was developed using a copper‐catalyzed sp³ C? H bond functionalization process. The reaction favors predominantly the C? H bonds of β‐methyl groups over the unactivated methylene C? H bonds. Moreover, a preference for activating sp³ C? H bonds of β‐methyl groups, via a five‐membered ring intermediate, over the aromatic sp² C? H bonds was also observed in the cyclometalation step. Additionally, sp³ C? H bonds of unactivated secondary sp³ C? H bonds could be functionalized by favoring the ring carbon atoms over the linear carbon atoms.     

Iridium‐Catalyzed Synthesis of Diaryl Ethers by Means of Chemoselective CF Bond Activation and the Formation of BF Bonds

Transition‐metal‐catalyzed C? F activation, in comparison with C? H activation, is more difficult to achieve and therefore less fully understood, mainly because carbon–fluorine bonds are the strongest known single bonds to carbon and have been very difficult to cleave. Transition‐metal complexes are often more effective at cleaving stronger bonds, such as C(sp²)? X versus C(sp³)? X. Here, the iridium‐catalyzed C? F activation of fluorarenes was achieved through the use of bis(pinacolato)diboron with the formation of the B? F bond and self‐coupling. This strategy provides a convenient method with which to convert fluoride aromatic compounds into symmetrical diaryl ether compounds. Moreover, the chemoselective products of the C? F bond cleavage were obtained at high yields with the C? Br and C? Cl bonds remaining.     

Site‐Selective Remote Radical C−H Functionalization of Unactivated C−H Bonds in Amides Using Sulfone Reagents

A general and practical strategy for remote site‐selective functionalization of unactivated aliphatic C?H bonds in various amides by radical chemistry is introduced. C?H bond functionalization is achieved by using the readily installed N‐allylsulfonyl moiety as an N‐radical precursor. The in situ generated N‐radical engages in intramolecular 1,5‐hydrogen atom transfer to generate a translocated C radical which is subsequently trapped with various sulfone reagents to afford the corresponding C?H functionalized amides. The generality of the approach is documented by the successful remote C?N₃, C?Cl, C?Br, C?SCF₃, C?SPh, and C?C bond formation. Unactivated tertiary and secondary C?H bonds, as well as activated primary C?H bonds, can be readily functionalized by this method.     

Iridium‐Catalyzed Reductive Carbon–Carbon Bond Cleavage Reaction on a Curved Pyridylcorannulene Skeleton

The cleavage of C? C bonds in π‐conjugated systems is an important method for controlling their shape and coplanarity. An efficient way for the cleavage of an aromatic C? C bond in a typical buckybowl corannulene skeleton is reported. The reaction of 2‐pyridylcorannulene with a catalytic amount of IrCl₃?n H₂O in ethylene glycol at 250 °C resulted in a structural transformation from the curved corannulene skeleton to a strain‐free flat benzo[ghi]fluoranthene skeleton through a site‐selective C? C cleavage reaction. This cleavage reaction was found to be driven by both the coordination of the 2‐pyridyl substituent to iridium and the relief of strain in the curved corannulene skeleton. This finding should facilitate the design of carbon nanomaterials based on C? C bond cleavage reactions.     

Site‐Selective Functionalization of (sp3)C−H Bonds Catalyzed by Artificial Metalloenzymes Containing an Iridium‐Porphyrin Cofactor

The selective functionalization of one C?H bond over others in nearly identical steric and electronic environments can facilitate the construction of complex molecules. We report site‐selective functionalizations of C?H bonds, differentiated solely by remote substituents, catalyzed by artificial metalloenzymes (ArMs) that are generated from the combination of an evolvable P450 scaffold and an iridium‐porphyrin cofactor. The generated systems catalyze the insertion of carbenes into the C?H bonds of a range of phthalan derivatives containing substituents that render the two methylene positions in each phthalan inequivalent. These reactions occur with site‐selectivity ratios of up to 17.8:1 and, in most cases, with pairs of enzyme mutants that preferentially form each of the two constitutional isomers. This study demonstrates the potential of abiotic reactions catalyzed by metalloenzymes to functionalize C?H bonds with site selectivity that is difficult to achieve with small‐molecule catalysts.     

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.     

α,α‐Dibromotoluene as a monomer for poly (substituted methylene) synthesis: Magnesium‐mediated polycondensation of α,α‐dibromotoluene and magnesium/copper‐mediated copolycondensation of α,α‐dibromotoluene with 1,6‐dibromohexane

α,α‐Dibromotoluene 1 was found to be polymerized by the reaction with excess Mg to give poly(phenylmethylene)s 2 , whose main chains were partially dehydrogenated to carbon–carbon double bonds (C?C). The C?Cs in 2 can be brominated by treatment with Br₂. The polymerization mechanism was presumed to include the formation of Grignard reagents of various species with benzylic C? Br bonds and the nucleophilic attacks of the Grignard reagents to various compounds with benzylic C? Br bonds. Copolymerization of 1 with dichlorodimethylsilane successfully proceeded. Mg/Cu‐mediated copolycondensation of 1 with 1,6‐dibromohexane proceeded to give polymers that have similar compositions to those of random copolymers of ethylene and styrene. © 2006Wiley Periodicals, Inc. J Polym Sci Part A: Polym Chem 44: 5661–5671, 2006     

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.     

Nickel‐Catalyzed Site‐Selective Amidation of Unactivated C(sp3)H Bonds

Intramolecular dehydrogenative cyclization of aliphatic amides was achieved on unactivated sp³ carbon atoms by a nickel‐catalyzed C?H bond functionalization process with the assistance of a bidentate directing group. The reaction favors the C?H bonds of β‐methyl groups over the γ‐methyl or β‐methylene groups. Additionally, a predominant preference for the β‐methyl C?H bonds over the aromatic sp² C?H bonds was observed. Moreover, this process also allows for the effective functionalization of benzylic secondary sp³ C?H bonds.     

Site‐Selective δ‐C(sp3)−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle

The site‐selective functionalization of unactivated C(sp³)?H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site‐selective δ‐C(sp³)?H alkylation of amino acids and peptides with maleimides via a kinetically less favored six‐membered palladacycle in the presence of more accessible γ‐C(sp³)?H bonds. Experimental studies revealed that C?H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C?H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle that is generated by δ‐C?H activation. The selectivity can be explained by the Curtin–Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late‐stage peptide modifications. Notably, this process is also the first palladium(II)‐catalyzed Michael‐type alkylation reaction that proceeds through C(sp³)?H activation.     

Remote C−H Activation of Quinolines through Copper‐Catalyzed Radical Cross‐Coupling

Achieving site selectivity in carbon–hydrogen (C?H) functionalization reactions is a formidable challenge in organic chemistry. Herein, we report a novel approach to activating remote C?H bonds at the C5 position of 8‐aminoquinoline through copper‐catalyzed sulfonylation under mild conditions. Our strategy shows high conversion efficiency, a broad substrate scope, and good toleration with different functional groups. Furthermore, our mechanistic investigations suggest that a single‐electron‐transfer process plays a vital role in generating sulfonyl radicals and subsequently initiating C?S cross‐coupling. Importantly, our copper‐catalyzed remote functionalization protocol can be expanded for the construction of a variety of chemical bonds, including C?O, C?Br, C?N, C?C, and C?I. These findings provide a fundamental insight into the activation of remote C?H bonds, while offering new possibilities for rational design of drug molecules and optoelectronic materials requiring specific modification of functional groups.     

Site‐Selective Late‐Stage Aromatic [18F]Fluorination via Aryl Sulfonium Salts

Site‐selective functionalization of C?H bonds in small complex molecules is a long‐standing challenge in organic chemistry. Herein, we report a broadly applicable and site‐selective aromatic C?H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two‐step C?H [¹⁸F]fluorination of a series of marketed small‐molecule drugs.     

Catalyst‐Dependent Chemoselective Formal Insertion of Diazo Compounds into C−C or C−H Bonds of 1,3‐Dicarbonyl Compounds

A catalyst‐dependent chemoselective one‐carbon insertion of diazo compounds into the C?C or C?H bonds of 1,3‐dicarbonyl species is reported. In the presence of silver(I) triflate, diazo insertion into the C(=O)?C bond of the 1,3‐dicarbonyl substrate leads to a 1,4‐dicarbonyl product containing an all‐carbon α‐quaternary center. This reaction constitutes the first example of an insertion of diazo‐derived carbenoids into acyclic C?C bonds. When instead scandium(III) triflate was applied as the catalyst, the reaction pathway switched to formal C?H insertion, affording 2‐alkylated 1,3‐dicarbonyl products. Different reaction pathways are proposed to account for this powerful catalyst‐dependent chemoselectivity.     

Palladium‐Catalyzed Carbon–Fluorine and Carbon–Hydrogen Bond Alumination of Fluoroarenes and Heteroarenes

Through serendipitous discovery, a palladium bis(phosphine) complex was identified as a catalyst for the selective transformation of sp²C−F and sp²C−H bonds of fluoroarenes and heteroarenes to sp²C−Al bonds (19 examples, 1 mol % Pd loading). The carbon–fluorine bond functionalization reaction is highly selective for the formation of organoaluminium products in preference to hydrodefluorination products (selectivity=4.4:1 to 27:1). Evidence is presented for a tandem catalytic process in which hydrodefluorination is followed by sp²C−H alumination.     

Iridium‐Catalyzed Regioselective Silylation of Aromatic and Benzylic CH Bonds Directed by a Secondary Amine

Reported herein is an iridium‐catalyzed, regioselective silylation of the aromatic C? H bonds of benzylamines and the benzylic C? H bonds of 2,N‐dialkylanilines. In this process, (hydrido)silyl amines, generated in situ by dehydrogenative coupling of benzylamine or aniline with diethylsilane, undergo selective silylation at the C? H bond γ to the amino group. The products of this silylation are suitable for subsequent oxidation, halogenation, and cross‐coupling reactions to deliver benzylamine and arylamine derivatives.