Aliphatic Radical Relay Heck Reaction at Unactivated C(sp3)−H Sites of Alcohols

The Mizoroki–Heck reaction is one of the most efficient methods for alkenylation of aryl, vinyl, and alkyl halides. Given its innate nature, this protocol requires the employment of compounds possessing a halogen atom at the site of functionalization. However, the accessibility of organic molecules possessing a halogen atom at a particular site in aliphatic systems is extremely limited. Thus, a protocol that allows a Heck reaction to occur at a specific nonfunctionalized C(sp³)?H site is desirable. Reported here is a radical relay Heck reaction which allows selective remote alkenylation of aliphatic alcohols at unactivated β‐, γ‐, and δ‐C(sp³)?H sites. The use of an easily installed/removed Si‐based auxiliary enables selective I‐atom/radical translocation events at remote C?H sites followed by the Heck reaction. Notably, the reaction proceeds smoothly under mild visible‐light‐mediated conditions at room temperature, producing highly modifiable and valuable alkenol products from readily available alcohols feedstocks.     

Base‐Mediated Defluorosilylation of C(sp2)−F and C(sp3)−F Bonds

The ability to selectively forge C–heteroatom bonds by C?F scission is typically accomplished by metal catalysts, specialized ligands and/or harsh reaction conditions. Described herein is a base‐mediated defluorosilylation of unactivated C(sp²)?F and C(sp³)?F bonds that obviates the need for metal catalysts. This protocol is characterized by its simplicity, mild reaction conditions, and wide scope, even within the context of late‐stage functionalization, constituting a complementary approach to existing C?Si bond‐forming protocols.     

Organocatalytic Enantioselective Functionalization of Unactivated Indole C(sp3)−H Bonds

Described here is a direct catalytic asymmetric functionalization of unactivated alkyl indoles using organocatalysis. In the presence of an effective chiral urea catalyst and a phosphoric acid additive, the intermolecular C?C bond formation between alkyl indoles and trifluoropyruvates proceeded with high efficiency and enantiocontrol. Unlike previous asymmetric C(sp³?H) functionalizations of α‐azaarenes, this process does not require the use of either a strong base or an electron‐deficient substrate. The excellent enantiocontrol is particularly noteworthy in view of the severe background reaction as well as the complete inability of other types of catalysts evaluated. Control experiments, kinetic studies, and DFT calculations provided important insights into the mechanism.     

Intermolecular Amination of Unactivated C(sp3)−H Bonds with Cyclic Alkylamines: Formation of C(sp3)−N Bonds through Copper/Oxygen‐Mediated C(sp3)−H/N−H Activation

The first example of intermolecular amination of unactivated C(sp³)?H bonds by cyclic alkylamines mediated by Cu(OAc)₂/O₂ is reported. This method avoids the use of benzoyloxyamines as the aminating reagent, which are normally prepared from alkylamines in extra steps. A variety of unnatural β^{2, 2}‐amino acid analogues are synthesized by this simple and efficient procedure. This approach offers a solution to the previous unmet challenge of C(sp³)?H/N?H activation for the formation of C(sp³)?N bonds.     

Oxyfunctionalization of the Remote C−H Bonds of Aliphatic Amines by Decatungstate Photocatalysis

Aliphatic amines, oxygenated at remote positions within the molecule, represent an important class of synthetic building blocks to which there are currently no direct means of access. Reported herein is an efficient and scalable solution that relies upon decatungstate photocatalysis under acidic conditions using either H₂O₂ or O₂ as the terminal oxidant. By using these reaction conditions a series of simple and unbiased aliphatic amine starting materials can be oxidized to value‐added ketone products. Lastly, NMR spectroscopy using in situ LED‐irradiated samples was utilized to monitor the kinetics of the reaction, thus enabling direct translation of the reaction into flow.     

Hydroxoiridium‐Catalyzed Hydroalkylation of Terminal Alkenes with Ureas by C(sp3)−H Bond Activation

Direct alkylation of a methyl group, on di‐ and trisubstituted ureas, with terminal alkenes by C(sp³)−H bond activation proceeded in the presence of a hydroxoiridium/bisphosphine catalyst to give high yields of the corresponding addition products. The hydroxoiridium/bisphosphine complex generates an amidoiridium intermediate by reaction with ureas having an N−H bond.     

Copper‐Catalyzed Remote C(sp3)−H Trifluoromethylation of Carboxamides and Sulfonamides

Reported herein is an unprecedented protocol for trifluoromethylation of unactivated aliphatic C(sp³)?H bonds. With Cu(OTf)₂ as the catalyst, the reaction of N‐fluoro‐substituted carboxamides (or sulfonamides) with Zn(CF₃)₂ complexes provides the corresponding δ‐trifluoromethylated carboxamides (or sulfonamides) in satisfactory yields under mild reaction conditions. A radical mechanism involving 1,5‐hydrogen atom transfer of N‐radicals followed by CF₃‐transfer from Cu^II?CF₃ complexes to the thus formed alkyl radicals is proposed.     

Ligand‐Enabled Alkynylation of C(sp3)−H Bonds with Palladium(II) Catalysts

The palladium(II)‐catalyzed β‐ and γ‐alkynylation of amide C(sp³)−H bonds is enabled by pyridine‐based ligands. This alkynylation reaction is compatible with substrates containing α‐tertiary or α‐quaternary carbon centers. The β‐methylene C(sp³)−H bonds of various carbocyclic rings were also successfully alkynylated.     

Thioamide‐Directed Cobalt(III)‐Catalyzed Selective Amidation of C(sp3)−H Bonds

A mild, oxidant‐free, and selective Cp*Co^III‐catalyzed amidation of thioamides with robust dioxazolone amidating agents via C(sp³)−H bond activation to generate the desired amidated products is reported. The method is efficient and allows for the C−H amidation of a wide range of functionalized thioamides with aryl‐, heteroaryl‐, and alkyl‐substituted dioxazolones under the Cp*Co^III‐catalyzed conditions. The observed regioselectivity towards primary C(sp³)−H activation is supported by computational studies and the cyclometalation is proposed to proceed by means of an external carboxylate‐assisted concerted metalation/deprotonation mechanism. The reported method is a rare example of the use of a directing group other than the commonly used pyridine and quinolone classes for Cp*Co^III‐catalyzed C(sp³)−H functionalization and the first to exploit thioamides.     

Enantioselective Formal C(sp2)−H Vinylation

An enantioselective formal C(sp²)?H vinylation of prochiral 2,2‐disubstituted cyclopentene‐1,3‐dione is presented. This vinylative desymmetrization is realized by using a two‐step procedure that consists of a catalytic enantioselective vinylogous Michael addition of deconjugated butenolides to cyclopentene‐1,3‐dione and a base‐mediated decarboxylation. The overall process utilizes deconjugated butenolides as the source of the highly substituted vinyl unit. Five‐membered carbocycles containing a remote all‐carbon quaternary stereogenic center are obtained in good yields and with good to high enantioselectivities.     

Stapled Peptides by Late‐Stage C(sp3)−H Activation

Despite the importance of stapled peptides for drug discovery, only few practical processes to prepare cross‐linked peptides have been described; thus the structural diversity of available staple motifs is currently limited. At the same time, C−H activation has emerged as an efficient approach to functionalize complex molecules. Although there are many reports on the C−H functionalization of amino acids, examples of post‐synthetic peptide C−H modification are rare and comprise almost only C(sp²)−H activation. Herein, we report the development of a palladium‐catalyzed late‐stage C(sp³)−H activation method for peptide stapling, affording an unprecedented hydrocarbon cross‐link. This method was first employed to prepare a library of stapled peptides in solution. The compatibility with various amino acids as well as the influence of the size (i ,i +3 and i ,i +4) and length of the staple were investigated. Finally, a simple solid‐phase procedure was also established.     

Catalytic Oxidative Trifluoromethoxylation of Allylic C−H Bonds Using a Palladium Catalyst

A catalytic intermolecular allylic C−H trifluoromethoxylation reaction of alkenes has been developed based on the use of a palladium catalyst, CsOCF₃ as the trifluoromethoxide source, and benzoquinone as the oxidant. This reaction provides an efficient route for directly accessing allylic trifluoromethoxy derivatives with excellent regioselectivities from terminal alkenes via an allylic C−H bond activation process.     

Buttressing Salicylaldehydes: A Multipurpose Directing Group for C(sp3)−H Bond Activation

A palladium‐catalyzed reaction of primary amines with iodoarenes produces γ‐arylated primary amines. A bulky salicylaldehyde, which is marked as easily available, installable, removable, and recoverable, plays a key role in directing palladium to site‐selectively activate the C−H bond located γ to the amino group.     

Catalytic Aerobic Oxidation of C(sp3)−H Bonds

Oxidation reactions are a key technology to transform hydrocarbons from petroleum feedstock into chemicals of a higher oxidation state, allowing further chemical transformations. These bulk‐scale oxidation processes usually employ molecular oxygen as the terminal oxidant as at this scale it is typically the only economically viable oxidant. The produced commodity chemicals possess limited functionality and usually show a high degree of symmetry thereby avoiding selectivity issues. In sharp contrast, in the production of fine chemicals preference is still given to classical oxidants. Considering the strive for greener production processes, the use of O₂, the most abundant and greenest oxidant, is a logical choice. Given the rich functionality and complexity of fine chemicals, achieving regio/chemoselectivity is a major challenge. This review presents an overview of the most important catalytic systems recently described for aerobic oxidation, and the current insight in their reaction mechanism.     

Redox‐Neutral Coupling between Two C(sp3)−H Bonds Enabled by 1,4‐Palladium Shift for the Synthesis of Fused Heterocycles

The intramolecular coupling of two C(sp³)?H bonds to forge a C(sp³)?C(sp³) bond is enabled by 1,4‐Pd shift from a trisubstituted aryl bromide. Contrary to most C(sp³)?C(sp³) cross‐dehydrogenative couplings, this reaction operates under redox‐neutral conditions, with the C?Br bond acting as an internal oxidant. Furthermore, it allows the coupling between two moderately acidic primary or secondary C?H bonds, which are adjacent to an oxygen or nitrogen atom on one side, and benzylic or adjacent to a carbonyl group on the other side. A variety of valuable fused heterocycles were obtained from easily accessible ortho‐bromophenol and aniline precursors. The second C?H bond cleavage was successfully replaced with carbonyl insertion to generate other types of C(sp³)‐C(sp³) bonds.     

Copper‐Catalyzed C(sp3)−H/C(sp3)−H Cross‐Dehydrogenative Coupling with Internal Oxidants: Synthesis of 2‐Trifluoromethyl‐Substituted Dihydropyrrol‐2‐ols

The first oxidative C(sp³)−H/C(sp³)−H cross‐dehydrogenative coupling (CDC) reaction promoted by an internal oxidant is reported. This copper‐catalyzed CDC reaction of oxime acetates and trifluoromethyl ketones provides a simple and efficient approach towards 2‐trifluoromethyldihydropyrrol‐2‐ol derivatives in a highly diastereoselective manner by cascade C(sp³)−C(sp³) bond formation and cyclization. These products were further transformed into various significant and useful trifluoromethylated heterocyclic compounds, such as trifluoromethylated furan, thiophene, pyrrole, dihydropyridazine, and pyridazine derivatives. A trifluoromethylated analogue of an Aβ₄₂ lowering agent was also synthesized smoothly. Preliminary mechanistic studies indicated that this reaction involves a copper(I)/copper(III) catalytic cycle with the oxime acetate acting as an internal oxidant.     

Palladium‐Catalyzed Alkylation with Alkyl Halides by C(sp3)−H Activation

Utilizing halogens as traceless directing goups represents an attractive strategy for C−H functionalization. A two C−H alkylation system, initiated by the oxidative addition of organohalides to Pd⁰, has been developed. The first reaction involves an intermolecular alkylation of palladacycles to form C(sp³)−C(sp²) bonds followed by C(sp²)−H activation/cyclization to deliver alkylated benzocyclobutenes as the final products. In the second reaction, two C−C bonds are formed by the reaction of palladacycles with CH₂Br₂, and provides a facile and efficient method for the synthesis of indanes. The alkylated benzocyclobutene products can be transformed into tricyclic hyrocarbons, and the indane derivatives are essential structural motifs in bioactive and odorant molecules.