Versatile Biocatalytic C(sp3)−H Oxyfunctionalization for the Site- Selective and Stereodivergent Synthesis of α- and β-Hydroxy Acids

C(sp³)−H oxyfunctionalization, the insertion of an O-atom into C(sp³)−H bonds, streamlines the synthesis of complex molecules from easily accessible precursors and represents one of the most challenging tasks in organic chemistry with regard to site and stereoselectivity. Biocatalytic C(sp³)−H oxyfunctionalization has the potential to overcome limitations inherent to small-molecule-mediated approaches by delivering catalyst-controlled selectivity. Through enzyme repurposing and activity profiling of natural variants, we have developed a subfamily of α-ketoglutarate-dependent iron dioxygenases that catalyze the site- and stereodivergent oxyfunctionalization of secondary and tertiary C(sp³)−H bonds, providing concise synthetic routes towards four types of 92 α- and β-hydroxy acids with high efficiency and selectivity. This method provides a biocatalytic approach for the production of valuable but synthetically challenging chiral hydroxy acid building blocks.     

Formation of C(sp3)–C(sp3) Bonds through Nickel‐Catalyzed Decarboxylative Olefin Hydroalkylation Reactions

Olefins and carboxylic acids are among the most important feedstock compounds. They are commonly found in natural products and drug molecules. We report a new reaction of nickel‐catalyzed decarboxylative olefin hydroalkylation, which provides a novel practical strategy for the construction of C(sp³)?C(sp³) bonds. This reaction can tolerate a variety of synthetically relevant functional groups and shows good chemo‐ and regioselectivity. It enables cross‐coupling of complex organic molecules containing olefin groups and carboxylic acid groups in a convergent fashion.     

Identification of halogen substituents in natural products by measurement of 13c spin-lattice relaxation times and integrated intensities

A method is proposed for differentiating brominated carbons from chlorinated carbons by means of natural-abundance ¹³C NMR spectroscopy. The basis of the method is that the spin-lattice relaxation behaviour of brominated carbons is influenced by carbon-bromine scalar interactions, which can lead to shortened ¹³C spin-lattice relaxation times and reduced values of the nuclear Overhauser enhancement. C-Cl scalar interactions make a negligible contribution to the spin-lattice relaxation of chlorinated carbons. These effects are illustrated by measurement of the ¹³C spin-lattice relaxation times and integrated intensities of chloro-, bromo and iodobenzene and chloro-, bromo- and iodocyclohexane. The method is then tested on four polyhalogenated marine natural products. The results indicate that ¹³C relaxation measurements can be used to distinguish brominated carbons from chlorinated carbons in the case of halogenated quaternary carbons, sp² hydridized methine carbons and some sp³ hydridized methine carbons, but not in the case of halogenated methylene carbons or gem-dihalo substituted methine carbons.     

Efficient C(sp3)−H Carbonylation of Light and Heavy Hydrocarbons with Carbon Monoxide via Hydrogen Atom Transfer Photocatalysis in Flow**

Despite their abundance in organic molecules, considerable limitations still exist in synthetic methods that target the direct C−H functionalization at sp³-hybridized carbon atoms. This is even more the case for light alkanes, which bear some of the strongest C−H bonds known in Nature, requiring extreme activation conditions that are not tolerant to most organic molecules. To bypass these issues, synthetic chemists rely on prefunctionalized alkyl halides or organometallic coupling partners. However, new synthetic methods that target regioselectively C−H bonds in a variety of different organic scaffolds would be of great added value, not only for the late-stage functionalization of biologically active molecules but also for the catalytic upgrading of cheap and abundant hydrocarbon feedstocks. Here, we describe a general, mild and scalable protocol which enables the direct C(sp³)−H carbonylation of saturated hydrocarbons, including natural products and light alkanes, using photocatalytic hydrogen atom transfer (HAT) and gaseous carbon monoxide (CO). Flow technology was deemed crucial to enable high gas-liquid mass transfer rates and fast reaction kinetics, needed to outpace deleterious reaction pathways, but also to leverage a scalable and safe process.     

Organocatalytic C−H Functionalization of Simple Alkanes

The direct functionalization of inert C(sp³)-H bonds to form carbon-carbon and carbon-heteroatom bonds offers vast potential for chemical synthesis and therefore receives increasing attention. At present, most successes come from strategies using metal catalysts/reagents or photo/electrochemical processes. The use of organocatalysis for this purpose remains scarce, especially when dealing with challenging C−H bonds such as those from simple alkanes. Here we disclose the first organocatalytic direct functionalization/acylation of inert C(sp³)-H bonds of completely unfunctionalized alkanes. Our approach involves N-heterocyclic carbene catalyst-mediated carbonyl radical intermediate generation and coupling with simple alkanes (through the corresponding alkyl radical intermediates generated via a hydrogen atom transfer process). Unreactive C−H bonds are widely present in fossil fuel feedstocks, commercially important organic polymers, and complex molecules such as natural products. Our present study shall inspire a new avenue for quick functionalization of these molecules under the light- and metal-free catalytic conditions.     

Recent Developments in the Trifluoromethylation of Alkynes

In the last few years, the development of versatile methodologies to incorporate trifluoromethyl groups into organic molecules has attracted significant attention in synthetic chemistry. This review gives an overview over the development on the trifluoromethylation of alkynes, which have not been solely discussed before. Formation of diverse C(sp, sp², sp³)?CF₃ bonds are all covered in this review.     

Cross- and Multi-Coupling Reactions Using Monofluoroalkanes

Carbon-fluorine bonds are stable and have demonstrated sluggishness against various chemical manipulations. However, selective transformations of C−F bonds can be achieved by developing appropriate conditions as useful synthetic methods in organic chemistry. This review focuses on C−C bond formation at monofluorinated sp³-hybridized carbons via C−F bond cleavage, including cross-coupling and multi-component coupling reactions. The C−F bond cleavage mechanisms on the sp³-hybridized carbon centers can be primarily categorized into three types: Lewis acids promoted F atom elimination to generate carbocation intermediates; nucleophilic substitution with metal or carbon nucleophiles supported by the activation of C−F bonds by coordination of Lewis acids; and the cleavage of C−F bonds via a single electron transfer. The characteristic features of alkyl fluorides, in comparison with other (pseudo)halides as promising electrophilic coupling counterparts, are also discussed.     

Pd0‐Mediated Rapid Cross‐Coupling Reactions,the Rapid C‐[11C]Methylations,Revolutionarily Advancing the Syntheses of Short‐Lived PET Molecular Probes

Positron emission tomography is a noninvasive method for monitoring drug (or diagnostic) behavior and its localization on the target molecules in the living systems, including the human body, using a short‐lived positron‐emitting radionuclide. New methodologies for introducing representative short‐lived radionuclides, ¹¹C and ¹⁸F, into the carbon frameworks of biologically active organic compounds have been established by developing rapid C‐[¹¹C]methylations and C‐[¹⁸F]fluoromethylations using rapid Pd⁰‐mediated cross‐coupling reactions between [¹¹C]methyl iodide (sp³‐hybridized carbon) and an excess amount of organotributylstannane or organoboronic acid ester having sp²(phenyl, heteroaromatic, or alkenyl), sp(alkynyl), or sp³(benzyl and cinnamyl)‐hybridized carbons; and [¹⁸F]fluoromethyl halide (iodide or bromide) and an organoboronic acid ester, respectively. These rapid reactions provide a firm foundation for an efficient and general synthesis of short‐lived ¹¹C‐ or ¹⁸F‐labeled PET molecular probes to promote in vivo molecular imaging studies.     

Carbene-Catalyzed Intermolecular Dehydrogenative Coupling of Aldehydes with C(sp3)−H Bonds

The development of catalyst-controlled methods for direct functionalization of two distinct C−H bonds represents an appealing approach for C−C formations in synthetic chemistry. Herein, we describe an organocatalytic approach for straightforward acylation of C(sp³)−H bonds employing readily available aldehyde as “acyl source” involving dehydrogenative coupling of aldehydes with ether, amine, or benzylic C(sp³)−H bonds. The developed method affords a broad range of ketones under mild conditions. Mechanistically, simple ortho-cyanoiodobenzene is essential in the oxidative radical N-heterocyclic carbene catalysis to give a ketyl radical and C(sp³) radical through a rarely explored intermolecular hydrogen atom transfer pathway, rendering the acylative C−C formations in high efficiency under a metal- and light-free catalytic conditions. Moreover, the prepared products show promising anti-bacterial activities that shall encourage further investigations on novel agrochemical development.     

Stereospecific 1,2-Migrations of Boronate Complexes Induced by Electrophiles

The stereospecific 1,2-migration of boronate complexes is one of the most representative reactions in boron chemistry. This process has been used extensively to develop powerful methods for asymmetric synthesis, with applications spanning from pharmaceuticals to natural products. Typically, 1,2-migration of boronate complexes is driven by displacement of an α-leaving group, oxidation of an α-boryl radical, or electrophilic activation of an alkenyl boronate complex. The aim of this article is to summarize the recent advances in the rapidly expanding field of electrophile-induced stereospecific 1,2-migration of groups from boron to sp² and sp³ carbon centers. It will be shown that three different conceptual approaches can be utilized to enable the 1,2-migration of boronate complexes: stereospecific Zweifel-type reactions, catalytic conjunctive coupling reactions, and transition metal-free sp²–sp³ couplings. A discussion of the reaction scope, mechanistic insights, and synthetic applications of the work described is also presented.     

Stereoselective Double Functionalization of Geminated C(sp3)-Organodimetallic Linchpins

Geminated C(sp³)-organodimetallics can serve as dinucleophilic linchpins for the rapid assembly of complex molecular structures through two consecutive electrophilic substitution reactions with two different electrophiles. Implementation of these double functionalization sequences in a stereoselective manner to develop tools for asymmetric synthesis has attracted considerable interest from the synthetic community over the last decade. The focus has been put mostly on 1,1-bimetallic reagents containing boron, zinc or zirconium, and different strategies have been applied for such a purpose, including the diastereoselective transformation of enantioenriched chiral reagents or the enantioselective conversion of achiral or racemic derivatives. Asymmetric catalysis is at stake in most of the approaches developed. In this review article, we highlight the key advances in the development of 1,1-bimetallic linchpins as tools for asymmetric synthesis, emphasizing the underlying general concepts.     

Iron-Catalyzed Cross-Coupling Reactions of Alkyl Grignards with Aryl Chlorobenzenesulfonates

Aryl sulfonate esters are versatile synthetic intermediates in organic chemistry as well as attractive architectures due to their bioactive properties. Herein, we report the synthesis of alkyl-substituted benzenesulfonate esters by iron-catalyzed C(sp²)–C(sp³) cross-coupling of Grignard reagents with aryl chlorides. The method operates using an environmentally benign and sustainable iron catalytic system, employing benign urea ligands. A broad range of chlorobenzenesulfonates as well as challenging alkyl organometallics containing β-hydrogens are compatible with these conditions, affording alkylated products in high to excellent yields. The study reveals that aryl sulfonate esters are the most reactive activating groups for iron-catalyzed alkylative C(sp²)–C(sp³) cross-coupling of aryl chlorides with Grignard reagents.     

Nickel-Catalyzed C−I-Selective C(sp2)−C(sp3) Cross-Electrophile Coupling of Bromo(iodo)arenes with Alkyl Bromides

Despite several methodologies established for C(sp²)−I selective C(sp²)−C(sp³) bond formations, achieving arene-flanked quaternary carbons by cross-coupling of tertiary alkyl precursors with bromo(iodo)arenes in a C(sp²)−I selective manner is rare. Here we report a general Ni-catalyzed C(sp²)−I selective cross-electrophile coupling (XEC) reaction, in which, beyond 3° alkyl bromides (for constructing arene-flanked quaternary carbons), 2° and 1° alkyl bromides are also demonstrated to be viable coupling partners. Moreover, this mild XEC displays excellent C(sp²)−I selectivity and functional group compatibility. The practicality of this XEC is demonstrated in simplifying the routes to several medicinally relevant and synthetically challenging compounds. Extensive experiments show that the terpyridine-ligated Ni^I halide can exclusively activate alkyl bromides, forming a Ni^I−alkyl complex through a Zn reduction. Attendant density functional theory (DFT) calculations reveal two different pathways for the oxidative addition of the Ni^I−alkyl complex to the C(sp²)−I bond of bromo(iodo)arenes, explaining both the high C(sp²)−I selectivity and generality of our XEC.     

Stereospecific 1,2‐Migrations of Boronate Complexes Induced by Electrophiles

The stereospecific 1,2‐migration of boronate complexes is one of the most representative reactions in boron chemistry. This process has been used extensively to develop powerful methods for asymmetric synthesis, with applications spanning from pharmaceuticals to natural products. Typically, 1,2‐migration of boronate complexes is driven by displacement of an α‐leaving group, oxidation of an α‐boryl radical, or electrophilic activation of an alkenyl boronate complex. The aim of this article is to summarize the recent advances in the rapidly expanding field of electrophile‐induced stereospecific 1,2‐migration of groups from boron to sp² and sp³ carbon centers. It will be shown that three different conceptual approaches can be utilized to enable the 1,2‐migration of boronate complexes: stereospecific Zweifel‐type reactions, catalytic conjunctive coupling reactions, and transition metal‐free sp²–sp³ couplings. A discussion of the reaction scope, mechanistic insights, and synthetic applications of the work described is also presented.     

Economical,Green, and Safe Route Towards Substituted Lactones by Anodic Generation of Oxycarbonyl Radicals

A new electrochemical methodology has been developed for the generation of oxycarbonyl radicals under mild and green conditions from readily available hemioxalate salts. Mono‐ and multi‐functionalised γ‐butyrolactones were synthesised through exo‐cyclisation of these oxycarbonyl radicals with an alkene, followed by the sp³–sp³ capture of the newly formed carbon‐centred radical. The synthesis of functionalised valerolactone derivatives was also achieved, demonstrating the versatility of the newly developed methodology. This represents a viable synthetic route towards pharmaceutically important fragments and further demonstrates the practicality of electrosynthesis as a green and economical method to activate small organic molecules.     

Ni- and Pd-based homogeneous catalyst systems for direct oxygenation of C(sp3)-H groups

Developing catalytic approaches to selective activation and functionalization of C–H bonds in hydrocarbons and complex organic molecules has been considered as a challenging goal. Recently, significant efforts have been aimed at the search for efficient nickel- and palladium-based catalyst systems, capable of conducting direct aliphatic C–H oxygenation with high and predictable chemoselectivity and regioselectivity. The present review focuses on the advances in homogeneous oxidation of hydrocarbon C(sp³)–H groups, catalyzed by nickel and palladium complexes, and covers the publications of the past 15 years. Correlations between the structure of the metal-based catalyst, steric and electronic properties of the ligands, catalytic conditions, and the catalytic reactivity (efficiency, chemoselectivity, and regioselectivity) are discussed.     

Economical,Green, and Safe Route Towards Substituted Lactones by Anodic Generation of Oxycarbonyl Radicals

A new electrochemical methodology has been developed for the generation of oxycarbonyl radicals under mild and green conditions from readily available hemioxalate salts. Mono‐ and multi‐functionalised γ‐butyrolactones were synthesised through exo‐cyclisation of these oxycarbonyl radicals with an alkene, followed by the sp³–sp³ capture of the newly formed carbon‐centred radical. The synthesis of functionalised valerolactone derivatives was also achieved, demonstrating the versatility of the newly developed methodology. This represents a viable synthetic route towards pharmaceutically important fragments and further demonstrates the practicality of electrosynthesis as a green and economical method to activate small organic molecules.     

Plasmonic Silver-Nanoparticle-Catalysed Hydrogen Abstraction from the C(sp3)−H Bond of the Benzylic Cα atom for Cleavage of Alkyl Aryl Ether Bonds

Selective activation of the C(sp³)−H bond is an important process in organic synthesis, where efficiently activating a specific C(sp³)−H bond without causing side reactions remains one of chemistry's great challenges. Here we report that illuminated plasmonic silver metal nanoparticles (NPs) can abstract hydrogen from the C(sp³)−H bond of the C_α atom of an alkyl aryl ether β-O-4 linkage. The intense electromagnetic near-field generated at the illuminated plasmonic NPs promotes chemisorption of the β-O-4 compound and the transfer of photo-generated hot electrons from the NPs to the adsorbed molecules leads to hydrogen abstraction and direct cleavage of the unreactive ether C_β−O bond under moderate reaction conditions (≈90 °C). The plasmon-driven process has certain exceptional features: enabling hydrogen abstraction from a specific C(sp³)−H bond, along with precise scission of the targeted C−O bond to form aromatic compounds containing unsaturated, substituted groups in excellent yields.     

Continuous Flow Electrochemistry Enables Practical and Site-Selective C−H Oxidation

The selective oxygenation of ubiquitous C(sp³)−H bonds remains a highly sought-after method in both academia and the chemical industry for constructing functionalized organic molecules. However, it is extremely challenging to selectively oxidize a certain C(sp³)−H bond to afford alcohols due to the presence of multiple C(sp³)−H bonds with similar strength and steric environment in organic molecules, and the alcohol products being prone to further oxidation. Herein, we present a practical and cost-efficient electrochemical method for the highly selective monooxygenation of benzylic C(sp³)−H bonds using continuous flow reactors. The electrochemical reactions produce trifluoroacetate esters that are resistant to further oxidation but undergo facile hydrolysis during aqueous workup to form benzylic alcohols. The method exhibits a broad scope and exceptional site selectivity and requires no catalysts or chemical oxidants. Furthermore, the electrochemical method demonstrates excellent scalability by producing 115 g of one of the alcohol products. The high site selectivity of the electrochemical method originates from its unique mechanism to cleave benzylic C(sp³)−H bonds through sequential electron/proton transfer, rather than the commonly employed hydrogen atom transfer (HAT).     

Synergistic Catalysis for the Umpolung Trifluoromethylthiolation of Tertiary Ethers

The first transition‐metal‐free, site‐specific umpolung trifluoromethylthiolation of tertiary alkyl ethers has been developed, achieving the challenging tertiary C(sp³)–SCF₃ coupling under redox‐neutral conditions. The synergism of organophotocatalyst 4CzIPN and BINOL‐based phosphorothiols can site‐selectively cleave tertiary sp³ C(sp³)–O ether bonds in complex molecules initiated by a polarity‐matching hydrogen‐atom‐transfer (HAT) event. The incorporation of several competing benzylic and methine C(sp³)?H bonds in alkyl ethers has little influence on the regioselectivity. Selective difluoromethylthiolation of C?O bonds has also been achieved. This represents not only an important step forward in trifluoromethylthiolation but also a promising means for site‐selective C?O bond functionalization of unsymmetrical tertiary alkyl ethers.