Total Synthesis of Aplydactone by a Conformationally Controlled C−H Functionalization

A concise, protecting-group-free total synthesis of the unusual brominated sesquiterpene aplydactone is described. Our synthesis features a [2+2] photocycloaddition, a Wolff ring contraction, an unusual remote C−H functionalization to establish the highly strained tetracyclic core, and a hydrogen-atom transfer (HAT) reaction to access the bromine-containing stereocenter. A finely tuned conformation of the α-diazoketone precursor is the key for the success of the late-stage transannular C−H insertion to deliver a bridged six-membered ring and a quaternary stereocenter (C6) between two quaternary carbon atoms (C1 and C7).     

Predicting Regioselectivity in Radical C−H Functionalization of Heterocycles through Machine Learning

Radical C−H bond functionalization provides a versatile approach for elaborating heterocyclic compounds. The synthetic design of this transformation relies heavily on the knowledge of regioselectivity, while a quantified and efficient regioselectivity prediction approach is still elusive. Herein, we report the feasibility of using a machine learning model to predict the transition state barrier from the computed properties of isolated reactants. This enables rapid and reliable regioselectivity prediction for radical C−H bond functionalization of heterocycles. The Random Forest model with physical organic features achieved 94.2 % site accuracy and 89.9 % selectivity accuracy in the out-of-sample test set. The prediction performance was further validated by comparing the machine learning results with additional substituents, heteroarene scaffolds and experimental observations. This work revealed that the combination of mechanism-based computational statistics and machine learning model can serve as a useful strategy for selectivity prediction of organic transformations.     

Regioselective C−H Functionalization of Heteroarene N-Oxides Enabled by a Traceless Nucleophile

Although N-alkenoxyheteroarenium salts have been widely used as umpoled synthons with nucleophilic (hetero)arenes, the use of electron-poor heteroarenes has remained unexplored. To overcome the inherent electron deficiency of quinolinium salts, a traceless nucleophile-triggered strategy was designed, wherein the quinolinium segment is converted into a dearomatized intermediate, thereby allowing simultaneous C8-functionalization of quinolines at room temperature. Experimental and computational studies support the traceless operation of a nucleophile, which enables the previously inaccessible transformation of N-alkenoxyheteroarenium salts. Remarkably, the generality of this strategy has been further demonstrated by broad applications in the regioselective C−H functionalization of other electron-deficient heteroarenes such as phenanthridine, isoquinoline, and pyridine N-oxides, offering a practical tool for the late-stage functionalization of complex biorelevant molecules.     

Synthesis of Natural Products by C−H Functionalization of Heterocycless

Total synthesis is considered by many as the finest combination of art and science. During the last decades, several concepts were proposed for achieving the perfect vision of total synthesis, such as atom economy, step economy, or redox economy. In this context, C−H functionalization represents the most powerful platform that has emerged in the last years, empowering rapid synthesis of complex natural products and enabling diversification of bioactive scaffolds based on natural product architectures. In this review, we present an overview of the recent strategies towards the total synthesis of heterocyclic natural products enabled by C−H functionalization. Heterocycles represent the most common motifs in drug discovery and marketed drugs. The implementation of C−H functionalization of heterocycles enables novel tactics in the construction of core architectures, but also changes the logic design of retrosynthetic strategies and permits access to natural product scaffolds with novel and enhanced biological activities.     

Multi C−H Functionalization Reactions of Carbazole Heterocycles via Gold-Catalyzed Carbene Transfer Reactions

Herein we describe a multiple C−H functionalization reaction of carbazole heterocycles with diazoalkanes. We show that gold catalysts play a distinct role in enabling a multiple C−H functionalization reaction to introduce up to six carbene fragments onto molecules containing multiple carbazole units or to link multiple carbazole units into a single molecule. A one-pot stepwise approach enables the introduction of two different carbene fragments to allow orthogonal deprotection and straightforward derivatization.     

Site-Selective C−H Functionalization of Carbazoles

Carbazole alkaloids hold great potential in pharmaceutical and material sciences. However, the current approaches for C1 functionalization of carbazoles rely on the use of a pre-installed directing group, severely limiting their applicability and hindering their overall efficiency. Herein, we report for the first time the development of direct Pd-catalyzed C−H alkylation and acylation of carbazoles assisted by norbornene (NBE) as a transient directing mediator. Notably, the involvement of a six-membered palladacycle intermediate was suggested in this case, representing the first example of such intermediacy within the extensively studied Pd/norbornene reactions realm.     

meta-Selective C−H Functionalization of Pyridines

The pyridine moiety is an important core structure for a variety of drugs, agrochemicals, catalysts, and functional materials. Direct functionalization of C−H bonds in pyridines is a straightforward approach to access valuable substituted pyridines. Compared to the direct ortho- and para-functionalization, meta-selective pyridine C−H functionalization is far more challenging due to the inherent electronic properties of the pyridine entity. This review summarizes currently available methods for pyridine meta-C−H functionalization using a directing group, non-directed metalation, and temporary dearomatization strategies. Recent advances in ligand control and temporary dearomatization are highlighted. We analyze the advantages as well as limitations of current techniques and hope to inspire further developments in this important area.     

Synthesis of [5,6]-Bicyclic Heterocycles with a Ring-Junction Nitrogen Atom: Rhodium(III)-Catalyzed C−H Functionalization of Alkenyl Azoles

The first syntheses of privileged [5,6]-bicyclic heterocycles, with ring-junction nitrogen atoms, by transition metal catalyzed C−H functionalization of C-alkenyl azoles is disclosed. Several reactions are applied to alkenyl imidazoles, pyrazoles, and triazoles to provide products with nitrogen incorporated at different sites. Alkyne and diazoketone coupling partners give azolopyridines with various substitution patterns. In addition, 1,4,2-dioxazolone coupling partners yield azolopyrimidines. Furthermore, the mechanisms for the reactions are discussed and the utility of the developed approach is demonstrated by iterative application of C−H functionalization for the rapid synthesis of a patented drug candidate.     

Late-Stage Direct o-Alkenylation of Phenols by PdII-Catalyzed C−H Functionalization

o-Alkenylation of unprotected phenols has been developed by direct C−H functionalization catalyzed by Pd^II. This work features phenol group as a directing group and realizes highly site-selective C−H bond functionalization of phenols to achieve the corresponding products in moderate to excellent yields at 60 °C. The advantages of this reaction include unprecedented C−H functionalization using phenol as a directing group, high regioselectivity, good substrate scope, mild reaction conditions, and high efficiency. To the best of our knowledge, this is the first example of a regioselective C−H alkenylation of unprotected phenols utilizing phenolic hydroxyl group as a directing group. The alkenylation of unprotected tyrosine and intramolecular cyclization are also successfully carried out under this catalytic system in good yields. Furthermore, this novel method enables a late-stage modification of complex phenol-containing bioactive molecules toward a diversity-oriented drug discovery.     

Direct C−H Carbamoylation of Nitrogen-Containing Heterocycles

Nucleophilic radical additions at innately electrophilic C(sp²) centers are perfectly suited for the direct functionalization of heterocycles. Using bench stable and commercially available alkyl oxamate and oxamic acid derivatives in combination with photoredox catalysis, a direct carbamoylation of heterocycles yielding amide functionalized pharmacophores in a single step is reported. The reaction conditions reported are compatible with structurally complex heterocyclic substrates of pharmaceutical interest. Notably, derivatives containing functional groups incompatible with standard amidation reactions, such as carboxylic acids and unprotected amines, were found to be amenable to this reaction paradigm.     

Electrophotocatalytic Decarboxylative C−H Functionalization of Heteroarenes

Decarboxylative C−H functionalization reactions are highly attractive methods for forging carbon–carbon bonds considering their inherent step- and atom-economical features and the pervasiveness of carboxylic acids and C−H bonds. An ideal approach to achieve these dehydrogenative transformations is through hydrogen evolution without using any chemical oxidants. However, effective couplings by decarboxylative carbon–carbon bond formation with proton reduction remain an unsolved challenge. Herein, we report an electrophotocatalytic approach that merges organic electrochemistry with photocatalysis to achieve the efficient direct decarboxylative C−H alkylation and carbamoylation of heteroaromatic compounds through hydrogen evolution. This electrophotocatalytic method, which combines the high efficiency and selectivity of photocatalysis in promoting decarboxylation with the superiority of electrochemistry in effecting proton reduction, enables the efficient coupling of a wide range of heteroaromatic bases with a variety of carboxylic acids and oxamic acids. Advantageously, this method is scalable to decagram amounts, and applicable to the late-stage functionalization of drug molecules.     

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.     

Enantioselective Synthesis of N-N Atropisomers by Palladium-Catalyzed C−H Functionalization of Pyrroles

The catalytic asymmetric construction of N−N atropisomeric biaryls remains a formidable challenge. Studies of them lag far behind studies of the more classical carbon-carbon biaryl atropisomers, hampering meaningful development. Herein, the first palladium-catalyzed enantioselective C−H activation of pyrroles for the synthesis of N−N atropisomers is presented. Structurally diverse indole-pyrrole atropisomers possessing a chiral N−N axis were produced with good yields and high enantioselectivities by alkenylation, alkynylation, allylation, or arylation reactions. Furthermore, the kinetic resolution of trisubstituted N−N heterobiaryls with more sterically demanding substituents was also achieved. Importantly, this versatile C−H functionalization strategy enables iterative functionalization of pyrroles with exquisite selectivity, expediting the formation of valuable, complex, N−N atropisomers.     

Visible-Light-Enabled C−H Functionalization by a Direct Hydrogen Atom Transfer Uranyl Photocatalyst

The development of the uranyl cation as a powerful photocatalyst is seriously delayed in comparison with the advances in its fundamental and structural chemistry. However, its characteristic high oxidative capability in the excited state ([UO₂]²⁺* (+2.6 V vs. SHE; SHE=standard hydrogen electrode) combined with blue-light absorption (hv=380 – 500 nm) and a long-lived fluorescence lifetime up to microseconds have reveals that the uranyl cation approaches an ideal photocatalyst for visible-light-driven organic transformations. Described herein is the successful use of uranyl nitrate as a photocatalyst to enable C(sp³)−H activation and C−C bond formation through hydrogen atom transfer (HAT) under blue-light irradiation. In particular, this operationally simple strategy provides an appropriate approach to the synthesis of diverse and valuable diarylmethane motifs. Mechanistic studies and DFT calculations have provided insights into the detailed mechanism of the photoinduced HAT pathway. This research suggests a general platform that could popularize promising uranyl photocatalytic performance.     

Chemical Upcycling of Polyolefins through C−H Functionalization

Polyolefins consist of abundant hydrophobic C−C and C−H bonds, and are considered as immensely potential untapped resources. Chemical upcycling offers a convenient and promising recycling strategy of polyolefins to produce newly-functionalized polymeric materials, and high-value added chemicals. The significant progress made in C−H functionalization reactions of alkane molecules provides new opportunities for improving polyolefin treatments. This review focuses on recent advancements in post-modification routes, specifically the introduction of C−C and C−X (X=O, N, S, halogens and etc.) bonds onto polyolefin chain backbones, as well as degradation models involving homogeneous C−H functionalization. By emphasizing these developments, we aim to highlight the potential of chemical upcycling for enhancing the treatment of polyolefins.     

Photochemical Functionalization of Heterocycles with EBX Reagents: C−H Alkynylation versus Deconstructive Ring Cleavage**

The development of novel methodologies for the functionalization of saturated heterocycles is highly desirable. Herein, we report a cheap and efficient photochemical method for the C−H functionalization of saturated O-heterocycles, as well as the deconstructive ring-cleavage of S-heterocycles, employing hypervalent iodine alkynylation reagents (ethynylbenziodoxolones, EBX). This photochemical alkynylation is performed utilizing phenylglyoxylic acid as the photoinitiator, leading to the corresponding products in good to high yields, under household fluorescent light bulb irradiation. When O-heterocycles were employed, the expected α-C−H alkynylation took place. In contrast, oxidative ring-opening to form a thioalkyne and an aldehyde was observed with S-heterocycles. Preliminary mechanistic experiments are presented to give first insights into this puzzling divergent reactivity.     

Transition Metal-Catalyzed Enantioselective C−H Functionalization via Chiral Transient Directing Group Strategies

Transition metal-catalyzed enantioselective functionalization of C−H bond, the most abundant functionality in organic molecules, has emerged as an expedient synthetic approach to streamline the synthesis of complex chiral molecules. Despite significant progress, traditional directing group-enabled strategies require additional steps for the installation and removal of directing groups from the target molecule. The recently developed asymmetric C−H functionalization using chiral transient directing groups (cTDGs) offers a promising alternative that can circumvent this obstacle and therefore simplify the process. In this Minireview, we briefly discuss the advent and recent advances of this emerging concept, with an emphasis on discussing the creation of various stereogenic centers and the developments of cTDGs. Applications in natural product synthesis and ligand derivatizations are also discussed. We hope this Minireview will highlight the great potential of this strategy and help to inspire further endeavors.     

Electrochemical C−H Functionalization of (Hetero)Arenes—Optimized by DoE

A novel approach towards the activation of different arenes and purines including caffeine and theophylline is presented. The simple, safe and scalable electrochemical synthesis of 1,1,1,3,3,3-hexafluoroisopropanol (HFIP) aryl ethers was conducted using an easy electrolysis setup with boron-doped diamond (BDD) electrodes. Good yields up to 59 % were achieved. Triethylamine was used as a base as it forms a highly conductive media with HFIP, making additional supporting electrolytes superfluous. The synthesis was optimized using Design of Experiment (DoE) techniques giving a detailed insight to the significance of the reaction parameters. The mechanism was investigated by cyclic voltammetry (CV). Subsequent transition metal-catalyzed as well as metal-free functionalization led to interesting motifs in excellent yields up to 94 %.     

Synthesis of β-Diamine Building Blocks by Photocatalytic Hydroamination of Enecarbamates with Amines,Ammonia and N−H Heterocycles

3-Amino-substituted saturated nitrogen heterocycles are an important subclass of β-diamines, appearing in a number of clinical agents. Herein, we report a unified approach to these products based upon the regioselective photoredox-mediated hydroamination of enecarbamates. The amine coupling partner can encompass diverse amine types under a single set of reaction conditions, including primary alkyl amines, ammonia, aryl and heteroaryl amines, and N−H heterocycles. The method enables the synthesis of a wide range of pharmaceutically relevant building blocks.