Selective C(aryl)-O bond cleavage in biorenewable phenolics.

Biorefining of lignocellulosic biomass via a lignin first approach delivers a range of products with high oxygen content. Besides pulp, a lignin oil rich in guaiacols and syringols is obtained bearing multiple C(aryl)-OH and C(aryl)-OMe groups, typically named phenolics. Similarly, technical lignin can be used but is generally more difficult to process providing lower yields of monomers. Removal of the hydroxy and methoxy groups in these oxygenated arenes is challenging due to the inherently strong C-O bonds, in addition to the steric and electronic deactivation by adjacent -OH or -OMe groups. Moreover, chemoselective removal of a specific group in the presence of other similar functionalities is non-trivial. Other side-reactions such as ring saturation and transalkylation further complicate the desired reduction process. In this overview, three different selective reduction reactions are considered. Complete hydrodeoxygenation removes both hydroxy and methoxy groups resulting in benzene and alkylated derivatives (BTX type products) which is often complicated by overreduction of the arene ring. Hydrodemethoxylation selectively removes methoxy groups in the presence of hydroxy groups leading to phenol products, while hydrodehydroxylation only removes hydroxy groups without cleavage of methoxy groups giving anisole products. Instead of defunctionalization via reduction transformation of C(aryl)-OH, albeit via an initial derivatization into C(aryl)-OX, into other functionalities is possible and also discussed. In addition to methods applying guaiacols and syringols present in lignin oil as model substrates, special attention is given to methods using mixtures of these compounds obtained from wood/technical lignin. Finally, other important aspects of C-O bond activation with respect to green chemistry are discussed.

Atropisomers with Axial and Point Chirality: Synthesis and Applications.

Enantiopure atropisomers have become increasingly important in asymmetric synthesis and catalysis, pharmaceutical science, and material science since the discovery of inherent features of axial chirality originating from rotational restriction. Despite the advances made in this field to date, it remains highly desirable to construct structurally diverse atropisomers with potentially useful functions. We propose superposition to match axial and point chirality as a potentially useful strategy to access structurally complex and diverse building blocks for organic synthesis and pharmaceutical science because merging atropisomeric backbones with one or more extra chiral elements can topologically broaden three-dimensional environments to create complex scaffolds with multiple tunable parameters. Over the past decade, we have successfully implemented a strategic design for the superposition of axial and point chirality to develop a series of enantiopure atropisomers and have utilized the synergistic functions of these molecules to enhance chirality transfer in various catalytic asymmetric transformations.In this Account, we present several novel atropisomers with superposed axial and point chirality developed in our laboratory. In our studies, this superposition strategy was used to design and synthesize both biaryl and non-biaryl atropisomers from commercially available chiral sources. Consequently, these atropisomers were used to demonstrate the importance of the synergetic functions of axial and point chirality in specific enantioselective reactions. For example, aromatic amide-derived atropisomers, simplified as Xing-Phos arrays, were broadly employed in Ag-catalyzed [3 + 2] cycloaddition by a series of reactions of aldiminoesters with activated alkenes and imines, as well as being used as chiral solvating agents for the discrimination of optically active mandelic acid derivatives. Considering the powerful potential of non-biaryl atropisomers for asymmetric catalysis, we also explored the transition-metal-catalyzed enantioselective construction of a novel backbone of non-biaryl atropisomers (Ar-alkene, Ar-N axis) bearing both axial and point chirality for the design and synthesis of chiral ligands and functional molecules.The studies presented herein are expected to stimulate further research efforts on the development of functional atropisomers by superposition of matching axial and point chirality. In addition to tunable electron and stereohindrance effects, the synergy between matching chiral elements of axial/point chirality and functional groups is proven to be a special function that cannot be ignored for promoting reactivity and chirality-transfer efficiency in enantioselective synthesis. Consequently, our novel types of scaffolds with superposed axial and point chirality that are capable of versatile coordination with various metal catalysts in asymmetric catalysis highlight the power of the superposition of matching axial and point chirality for the construction of synthetically useful atropisomers.

Enantioselective Palladium-Catalyzed Arylborylation/Cyclization of Alkenes to Access Boryl-Functionalized Heterocyclic Compounds Containing Quaternary Stereogenic Centers.

Asymmetric palladium-catalyzed arylboration/cyclization of both nonactivated and activated alkenes with B2pin2 was developed. A wide range of N-allyl-o-iodobenzamides and o-iodoacryanilides reacted with B2pin2 to afford borylated 3,4-dihydroisoquinolinones and oxindoles, respectively, in high yields with high enantioselectivities. The synthetic utility of this enantioselective protocol was highlighted by synthesizing various chiral 3,4-dihydroisoquinolinone and oxindole derivatives containing quaternary stereogenic carbon centers, including enantioenriched Roche anticancer agent (S)-RO4999200.

Selective Nickel-Catalyzed Hydrodeacetoxylation of Aryl Acetates.

Acetate serves as a renewable and easily installed leaving group for selective deoxygenation of phenolics (ArOH). Ni-catalyzed hydrodeacetoxylation of aryl acetates (Ar-OAc) with HBpin in a green carbonate solvent selectively delivers the corresponding deoxygenated arenes (ArH). The method is also applicable to highly challenging guaiacyl and syringyl acetates, leaving -OMe groups intact without arene reduction. Renewable 4-propylguaiacol obtained from pine can also be transformed without significant loss in yield versus oil derived feedstock. The observed chemoselectivity for Ar-OAc versus ArO-Ac bond cleavage was rationalized based on mechanistic experiments and DFT calculations. ArOH side-product formation is attributed to direct competitive Ni-catalyzed reduction of the C=O bond. Hydrodeacyloxylation of a set of aryl alkanoates featured interesting chemoselectivity with a dramatic influence of the length and structure of the alkyl chain on catalysis.

Catalytic asymmetric oxidative carbonylation-induced kinetic resolution of sterically hindered benzylamines to chiral isoindolinones.

A highly enantioselective kinetic resolution of sterically hindered benzylamines has been achieved for the first time through transition-metal-catalyzed oxidative carbonylation, in which the new KR strategy offered a new approach to afford chiral isoindolinones (er up to 97 : 3) and the origin of chemoselectivity and stereoselectivity was confirmed by density functional theory (DFT) calculations.

Pd/Cu-Catalyzed Enantioselective Sequential Heck/Sonogashira Coupling: Asymmetric Synthesis of Oxindoles Containing Trifluoromethylated Quaternary Stereogenic Centers.

An asymmetric palladium and copper co-catalyzed Heck/Sonogashira reaction between o-iodoacrylanilides and terminal alkynes to synthesize chiral oxindoles was developed. In particular, a wide range of CF3 -substituted o-iodoacrylanilides reacted with terminal alkynes, affording the corresponding chiral oxindoles containing trifluoromethylated quaternary stereogenic centers in high yields with excellent enantioselectivities (94-98 % ee). This asymmetric Heck/Sonogashira reaction provides a general approach to access oxindole derivatives containing quaternary stereogenic centers including CF3 -substituted ones.

Tertiary amine-directed and involved carbonylative cyclizations through Pd/Cu-cocatalyzed multiple C-X (X = H or N) bond cleavage.

A novel Pd/Cu-cocatalyzed carbonylative cyclization by C-H activation and N-dealkylative C-N bond activation has been developed for the chemoselective construction of synthetically useful heterocycles. The N,N-dimethylamine group on o-indolyl-N,N-dimethylarylamines was found to act as both the directing group and reactive component in this C-H carbonylative cyclization reaction. Furthermore, a unique C-H oxidation/carbonylative lactonization of diarylmethylamines is firstly demonstrated under modified reaction conditions, which could be easily applicable to the one-step synthesis of multi-substituted phthalides bearing an N,O-ketal skeleton that is difficult to access by previously reported methods. Mechanistic studies implicate that Pd/Cu-cocatalyzed C-H oxidation/carbonylative lactonization is a sequential reaction system via Cu-catalyzed C(sp3)-H oxidation and Pd-catalyzed oxidative carbonylation of the C(sp2)-H bond. It was found that trace amounts of water are essential to promote the Cu-catalyzed C(sp3)-H oxidation of diarylmethylamine for the formation of the hydroxyl group, which could act as an in situ-formed directing group in the intramolecular carbonylative lactonization step.

Palladium-catalyzed olefination of aryl/alkyl halides with trimethylsilyldiazomethane via carbene migratory insertion.

The direct olefination of aryl/alkyl halides with trimethylsilyldiazomethane (TMSD) as a C1- or C2-unit was achieved successfully via a metal carbene migratory insertion process, which offered a new access to afford (E)-vinyl silanes and (E)-silyl-substituted α,ß-unsaturated amides in good yields and high chemoselectivity.

Ligand-Controlled Inversion of Diastereo- and Enantioselectivity in Silver-Catalyzed Azomethine Ylide-Imine Cycloaddition of Glycine Aldimino Esters with Imines.

A highly diastereo- and enantioselective silver-catalyzed azomethine ylide-imine (AYI) cycloaddition reaction of glycine aldimino esters with imines was developed in which the Xing-Phos-controlled syn-selective or DTBM-Segphos-induced anti-selective AYI cycloaddition reaction could be applied to the synthesis of a variety of stereodivergent 1-alkyl-2,5-substituted imidazolidines with high yields and excellent enantioselectivities (up to 99% ee) as well as good diastereoselectivities (up to 99:1 dr) under mild reaction conditions.

Palladium-catalyzed tandem allylic substitution/cyclization and cascade hydrosilylated reduction: the influence of reaction parameters and hydrosilanes on the stereoselectivity.

To shed light on the influence of reaction parameters on palladium-catalyzed tandem allylic alkylation in the presence of Fei-Phos (a chiral trans-1,2-diaminocyclohexane-derived phosphine ligand), the effect of different phosphine ligands, inorganic or organic bases, Brønsted acids, and other additives on the asymmetric palladium-catalysed alkylation of catechol with allylic diacetate was investigated. In this reaction, 2-vinyl-2,3-dihydro-benzo[1,4]dioxin products with promising enantioselectivity were achieved in good yields. In addition, a novel palladium-catalyzed three-component and one-pot allylic substitution/cyclization/reduction reaction assisted by methylphenylsilane was reported with good selectivity.

Asymmetric Synthesis of Glutamic Acid Derivatives by Silver-Catalyzed Conjugate Addition-Elimination Reactions.

The enantioselective construction of a family of chiral glycine-derived aldimino esters is described. The asymmetric tandem conjugate addition-elimination procedure is characterized by its exceptional mild reaction conditions and features with an exquisite enantioselectivity profile using commercially available silver/DTBM-SegPhos catalyst, allowing for the facile preparation of a variety of substituted and chiral glutamic acid derivatives (up to 99% ee) bearing Schiff base in a straightforward manner.

Lewis-Base-Mediated Diastereoselective Silylations of Alcohols: Synthesis of Silicon-Stereogenic Dialkoxysilanes Controlled by Chiral Aryl BINMOLs.

In the past years, stereoselective functionalizations of hydroxyl groups of alcohol substrates with chlorosilanes leading to silyl ether formation have evolved from a functional-group protection to an enantioselective synthetic strategy. This work comprises a controlled desymmetrization of dichlorosilanes by using a family of structurally specific chiral diols, chiral 1,1'-binaphthalene-2-α-arylmethanol-2'-ol (Ar-BINMOL). This process led to the facile construction of silicon-stereogenic organosilicon compounds with high yields and good diastereoselectivities. In addition, the diasteroselective silylation of chiral diols might not only be of interest for the development of highly stereoselective nucleophilic silylation, but also shed light on the construction of novel chiral phosphine ligands bearing a silicon-stereogenic center.

Cs2CO3-Initiated Trifluoro-Methylation of Chalcones and Ketones for Practical Synthesis of Trifluoromethylated Tertiary Silyl Ethers.

It was found that 1,2-trifluoromethylation reactions of ketones, enones, and aldehydes were easily accomplished using the Prakash reagent in the presence of catalytic amounts of cesium carbonate, which represents an experimentally convenient, atom-economic process for this anionic trifluoromethylation of non-enolisable aldehydes and ketones.

Transition-Metal-Free Oxidative C(sp2 )-H Hydroxylation of Terpyridines: A HOMO-Raising Strategy for the Construction of a New Super-Stable Terpyridine Chromophores.

Direct functionalization of terpyridines is an increasingly important topic in the field of dyes and catalysis as well as supramolecular chemistry, but its synthesis and transformation is usually challenging. Herein, a HOMO-raising strategy is reported for the construction of a super-stable novel terpyridine chromophores, in which the selective oxidation of terpyridines at its 3-position was determined successfully to the synthesis of phenol-functionalization of terpyridines (TPyOHs) bearing a hydrogen bonding group. The corresponding TPyOHs displayed strong aggregation-induced emission and exhibited highly selective and visual detection of ZnII cation with a record green terpyridine-based luminophore with nanomolar sensitivity (125 nm).

Asymmetric Michael Addition of Aldimino Esters with Chalcones Catalyzed by Silver/Xing-Phos: Mechanism-Oriented Divergent Synthesis of Chiral Pyrrolines.

The mechanism-oriented reaction design for the divergent synthesis of chiral molecules from simple starting materials is highly desirable. In this work, aromatic amide-derived nonbiarylatropisomer/silver (silver/Xing-Phos) complex was used to catalyze the Michael addition of glycine aldimino esters to chalcones and successfully applied to the subsequent cyclocondensation to afford substituted cis-Δ(1)-pyrroline derivatives with up to 98 % ee. Besides the inherent performance of the chiral Ag/Xing-Phos catalyst system, it was found that the workup of such reactions played an important role for the stereoselective construction of stereodivergent Δ(1)-pyrrolines, in which an epimerization of the cis-Δ(1)-pyrrolines to the trans-isomers during was revealed.

Decarboxylative Coupling Reaction in ESI(-)-MS/MS of 4-Nitrobenzyl 4-Hydroxybenzoates: Triplet Ion-Neutral Complex-Mediated 4-Nitrobenzyl Transfer.

In negative electrospray ionization mass spectrometry of 4-nitrobenzyl 4-hydroxybenzoates, a decarboxylation reaction, which was significantly promoted by the presence of a nitro group on the benzyl group, competed with radical elimination reactions. Density functional theory calculations indicated that decarboxylation of deprotonated 4-nitrobenzyl vanillate occurred via a radical route involving homolytic cleavage of the Cbenzyl-O bond to give a triplet ion-neutral complex, followed by decarboxylative coupling.

Observation of the intermediates of in-source aldolization reaction in electrospray ionization mass spectrometry analysis of heteroaromatic aldehydes.

Electrospray ionization mass spectrometry (ESI-MS) analyses of 2-(1,2,4-triazole-1-yl)-6-methyl-3- quinolinecarboxaldehyde were carried out by using an ion trap mass spectrometer in a positive-ion mode. Interestingly, several unusual [M + 15](+), [M + 33](+), and [M + 47](+) ions were observed with a high abundance in the ESI-MS spectrum when methanol was used as the ESI solvent. However, only the protonated molecule was obtained with acetonitrile as the ESI solvent. These unusual ions have been proposed as the intermediates of an aldolization reaction occurring in the ESI source, which have been validated by a tandem mass spectrometry experiment, high-performance liquid chromatography/mass spectrometry analysis, and theoretical calculations. A full understanding of this reaction can contribute to the avoidance of analysis errors in the ESI-MS analysis of unknown heteroaromatic aldehydes.

Aromatic amide-derived non-biaryl atropisomers as highly efficient ligands in silver-catalyzed asymmetric cycloaddition reactions.

The synthesis of a series of aromatic amide-derived non-biaryl atropisomers with a phosphine group and multiple stereogenic centers is reported. The novel phosphine ligands exhibit high diastereo- and enantioselectivities (up to >99:1 d.r., 95-99 % ee) as well as yields in the silver-catalyzed asymmetric [3+2] cycloaddition of aldiminoesters with nitroalkenes, which provides a highly enantioselective strategy for the synthesis of optically pure nitro-substituted pyrrolidines. In addition, the experimental results with regard to the carbon stereogenic center as well as the amide stereochemistry confirmed the potential of hemilabile atropisomers as chiral ligand in catalytic asymmetric [3+2] cycloaddition reaction.

Silicon-based bulky group-induced remote control and conformational preference in the synthesis and application of isolable atropisomeric amides with secondary alcohol or amine moieties.

Remote stereocontrol through conformational transmission along a carbon chain is highly important in synthetic systems and molecular architectures. In this work, the interactional reactivity between a remote silicon-based bulky group and an O-/N-containing functional group has been revealed and determined by lateral lithiation-substitution, desilylation, as well as desilylation-olefination with benzaldehyde. The results suggest considerable information transmission and steric hindrance that can be exploited for the controllable synthesis of atropisomeric molecules. Based on the remote steric effect of a functional group across the aromatic ring of an amide, the construction of isolable atropisomeric amides with functional groups, such as alcohol, amine, and olefin was successfully achieved. All these new atropisomers were obtained in reasonable yield in pure diastereomeric form, and the specific configuration of representative products was confirmed by X-ray crystallography.

Hydrosilane and bismuth-accelerated palladium catalyzed aerobic oxidative esterification of benzylic alcohols with air.

In a palladium-catalyzed oxidative esterification, hydrosilane can serve as an activator of palladium catalyst with bismuth, thus leading to a novel ligand- and silver-free palladium catalyst system for facile oxidative esterification of a variety of benzylic alcohols in good yields.