Microtubing‐Reactor‐Assisted Aliphatic C−H Functionalization with HCl as a Hydrogen‐Atom‐Transfer Catalyst Precursor in Conjunction with an Organic Photoredox Catalyst

Chlorine radical, which is classically generated by the homolysis of Cl₂ under UV irradiation, can abstract a hydrogen atom from an unactivated C(sp³)?H bond. We herein demonstrate the use of HCl as an effective hydrogen‐atom‐transfer catalyst precursor activated by an organic acridinium photoredox catalyst under visible‐light irradiation for C?H alkylation and allylation. The key to success relied on the utilization of microtubing reactors to maintain the volatile HCl catalyst. This photomediated chlorine‐based C?H activation protocol is effective for a variety of unactivated C(sp³)?H bond patterns, even with primary C(sp³)?H bonds, as in ethane. The merit of this strategy is illustrated by rapid access to several pharmaceutical drugs from abundant unfunctionalized alkane feedstocks.     

Regioselective Vinylation of Remote Unactivated C(sp3)−H Bonds: Access to Complex Fluoroalkylated Alkenes

Regioselective incorporation of a particular functional group into aliphatic sites by direct activation of unreactive C?H bonds is of great synthetic value. Despite advances in radical‐mediated functionalization of C(sp³)?H bonds by a hydrogen‐atom transfer process, the site‐selective vinylation of remote C(sp³)?H bonds still remains underexplored. Reported herein is a new protocol for the regioselective vinylation of unactivated C(sp³)?H bonds. The remote C(sp³)?H activation is promoted by a C‐centered radical instead of the commonly used N and O radicals. The reaction possesses high product diversity and synthetic efficiency, furnishing a plethora of synthetically valuable E alkenes bearing tri‐/di‐/mono‐fluoromethyl and perfluoroalkyl groups.     

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.     

Dehydrative Direct CH Allylation with Allylic Alcohols under [Cp*CoIII] Catalysis

The unique reactivity of [Cp*Co^III] over [Cp*Rh^III] was demonstrated. A cationic [Cp*Co^III] catalyst promoted direct dehydrative C? H allylation with non‐activated allyl alcohols, thus giving C2‐allylated indoles, pyrrole, and phenyl‐pyrazole in good yields, while analogous [Cp*Rh^III] catalysts were not effective. The high γ‐selectivity and C2‐selectivity indicated that the reaction proceeded by directing‐group‐assisted C? H metalation. DFT calculations suggested that the γ‐selective substitution reaction proceeded by C? H metalation and insertion of a C? C double bond, with subsequent β‐hydroxide elimination. The [Cp*Co^III] catalyst favored β‐hydroxide elimination over β‐hydride elimination.     

Iron(II)‐Catalyzed Site‐Selective Functionalization of Unactivated C(sp3)−H Bonds Guided by Alkoxyl Radicals

An alkoxyl radical guided strategy for site‐selective functionalization of unactivated methylene and methine C?H bonds enabled by an Fe^II‐catalyzed redox process is described. The mild, expeditious, and modular protocol allows efficient remote aliphatic fluorination, chlorination, amination, and alkynylation of structurally and electronically varied primary, secondary, and tertiary hydroperoxides with excellent functional‐group tolerance. The application for one‐pot 1,4‐hydroxyl functionalization of non‐oxygenated alkane substrates initiated by aerobic C?H oxygenation is also demonstrated.     

Copper‐Catalyzed 8‐Amido Chelation‐Induced Remote C−H Amination of Quinolines

A copper‐catalyzed 8‐amide chelation‐induced remote C?H amination of quinolines has been developed. This direct amination with readily available azodicarboxylates proceeded with perfect C5‐regioselectivity offering amino‐substituted 8‐aminoquinolines, important bioactive molecular scaffolds, in very high yields (up to 96 %). A single‐electron transfer (SET)‐mediated mechanism with k_H/k_D=1.1 was proposed after trapping of the radical intermediate.     

Generation of Alkoxyl Radicals by Photoredox Catalysis Enables Selective C(sp3)−H Functionalization under Mild Reaction Conditions

Reported herein is the first visible‐light‐induced formation of alkoxyl radicals from N‐alkoxyphthalimides, and the Hantzsch ester as the reductant is crucial for the reaction. The selective hydrogen atom abstraction by the alkoxyl radical enables C(sp³)?H allylation and alkenylation reactions under mild reaction conditions at room temperature. Broad substrate variations, including a structurally complexed steroid, undergo the C(sp³)?H functionalization reaction effectively with high regio‐ and chemoselectivity.     

Remote Hydroxylation through Radical Translocation and Polar Crossover

Mild conditions are reported for the hydroxylation of aliphatic C? H bonds through radical translocation, oxidation to carbocation, and nucleophilic trapping with H₂O. This remote functionalization employs fac‐[Ir(ppy)₃] together with Tz^o sulfonate esters and sulfonamides to facilitate the site‐selective replacement of relatively inert C? H bonds with the more synthetically useful C? OH group. The hydroxylation of a range of substrates and the methoxylation of two substrates through 1,6‐ and 1,7‐hydrogen‐atom transfer are demonstrated. In addition, a synthesis of the antidepressant fluoxetine using remote hydroxylation as a key step is presented.     

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.     

Allylic Acetals as Acrolein Oxonium Precursors in Tandem C−H Allylation and [3+2] Dipolar Cycloaddition

The ruthenium(II)‐catalyzed C?H functionalization of (hetero)aryl azomethine imines with allylic acetals is described. The initial formation of allylidene(methyl)oxoniums from allylic acetals could trigger C(sp²)?H allylation, and subsequent endo‐type [3+2] dipolar cycloaddition of polar azomethine fragments to deliver valuable indenopyrazolopyrazolones. The utility of this method is showcased by the late‐stage functionalization of bioactive molecules such as estrone and celecoxib. Combined experimental and computational investigations elucidate a plausible mechanism of this new tandem reaction. Notably, the reductive transformation of synthesized compounds into biologically relevant diazocine frameworks highlights the importance of the developed methodology.     

Predictable Selectivity in Remote C−H Oxidation of Steroids: Analysis of Substrate Binding Mode

Predictability is a key requirement to encompass late‐stage C?H functionalization in synthetic routes. However, prediction (and control) of reaction selectivity is usually challenging, especially for complex substrate structures and elusive transformations such as remote C(sp³)?H oxidation, as it requires distinguishing a specific C?H bond from many others with similar reactivity. Developed here is a strategy for predictable, remote C?H oxidation that entails substrate binding to a supramolecular Mn or Fe catalyst followed by elucidation of the conformation of the host‐guest adduct by NMR analysis. These analyses indicate which remote C?H bonds are suitably oriented for the oxidation before carrying out the reaction, enabling prediction of site selectivity. This strategy was applied to late‐stage C(sp³)?H oxidation of amino‐steroids at C15 (or C16) positions, with a selectivity tunable by modification of catalyst chirality and metal.     

N‐Centered Radical Directed Remote C−H Bond Functionalization via Hydrogen Atom Transfer

The N‐centered radical directed remote C?H bond functionalization via hydrogen‐atom‐transfer at distant sites has developed as an enormous potential tool for the organic synthetic chemists. Unactivated and remote secondary and tertiary, as well as selected primary C?H bonds, can be utilized for functionalization by following these methodologies. The synthesis of the heterocyclic scaffolds provides them extra attention for the modern days′ developments in this field of unactivated remote C?H bonds functionalizations.     

Synthesis of Cyclic Peptides by Photochemical Decarboxylation of N‐Phthaloyl Peptides in Aqueous Solution

The synthesis of a variety of cyclic peptides from N‐phthaloyl‐protected di‐, tri‐, tetra‐, and pentapeptides with different aminocarboxylic acid tethers by photodecarboxylation – initiated by intramolecular electron transfer – has been explored in aqueous media. The progress and the chemoselectivity of the follow‐up processes after CO₂ extrusion were traced by the respective pH/time‐profiles, as well as by the overall change in pH after completion of the reaction. The competition between cyclization and simple oxidative decarboxylation depends on spacer length and geometry, H‐bonding interaction between the electron accepting phthalimide C?O groups and amide H‐atoms, as well as the geometric reorganization coupled with the radical combination step and the formation of the lactam rings. With progressing reaction, hydrolysis of the phthalimide chromophore becomes an increasingly important side reaction due to the constant increase in pH. The use of phosphate‐buffered aqueous media consequently improved the cyclization yields. The ground‐state interactions between amide groups and the terminal COO^? group with the imide C?O groups were studied for the model system [N‐(phthaloyl)glycyl]sarcosine ( 1 ) by NMR spectroscopy where the amide (E/Z)‐equilibrium depends on the presence of carboxylate vs. free carboxylic acid, demonstrating the role of H‐bonding and metal coordination.     

Palladium‐Catalyzed Asymmetric C(sp3)−H Allylation of 2‐Alkylpyridines

The palladium‐catalyzed asymmetric side‐chain C(α)‐allylation of 2‐alkylpyridines, without using an external base, was developed. The high linear selectivities and enantioselectivities were achieved using new chiral diamidophosphite monodentate ligands. Given that the reaction conditions do not require an external base, this catalyst system enabled chemoselective C(α)‐allylation of 2‐alkylpyridines containing α‐carbonyl C?H bonds, which are more acidic than α‐pyridyl C?H bonds.     

Hydrogen‐Bond Cooperativity in Formamide2–Water: A Model for Water‐Mediated Interactions

The rotational spectrum of formamide₂–H₂O formed in a supersonic jet has been characterized by Fourier‐transform microwave spectroscopy. This adduct provides a simple model of water‐mediated interaction involving the amide linkages, as occur in protein folding or amide‐association processes, showing the interplay between self‐association and solvation. Mono‐substituted ¹³C, ¹⁵N, ¹⁸O, and ²H isotopologues have been observed and their data used to investigate the structure. The adduct forms an almost planar three‐body sequential cycle. The two formamide molecules link on one side through an N?H???O hydrogen bond and on the other side through a water‐mediated interaction with the formation of C=O???H?O and O???H?N hydrogen bonds. The analysis of the quadrupole coupling effects of two ¹⁴N‐nuclei reveals the subtle inductive forces associated to cooperative hydrogen bonding. These forces are involved in the changes in the C=O and C?N bond lengths with respect to pure formamide.     

Chiral Counteranion Strategy for Asymmetric Oxidative C(sp3)H/C(sp3)H Coupling: Enantioselective α‐Allylation of Aldehydes with Terminal Alkenes

The first enantioselective α‐allylation of aldehydes with terminal alkenes has been realized by combining asymmetric counteranion catalysis and palladium‐catalyzed allylic C? H activation. This method can tolerate a wide scope of α‐branched aromatic aldehydes and terminal alkenes, thus affording allylation products in high yields and with good to excellent levels of enantioselectivity. Importantly, the findings suggest a new strategy for the future creation of enantioselective C? H/C? H coupling reactions.     

The Fluorination of C−H Bonds: Developments and Perspectives

This Review summarizes advances in fluorination by C(sp²)?H and C(sp³)?H activation. Transition‐metal‐catalyzed approaches championed by palladium have allowed the installation of a fluorine substituent at C(sp²) and C(sp³) sites, exploiting the reactivity of high‐oxidation‐state transition‐metal fluoride complexes combined with the use of directing groups (some transient) to control site and stereoselectivity. The large majority of known methods employ electrophilic fluorination reagents, but methods combining a nucleophilic fluoride source with an oxidant have appeared. External ligands have proven to be effective for C(sp³)?H fluorination directed by weakly coordinating auxiliaries, thereby enabling control over reactivity. Methods relying on the formation of radical intermediates are complementary to transition‐metal‐catalyzed processes as they allow for undirected C(sp³)?H fluorination. To date, radical C?H fluorinations mainly employ electrophilic N?F fluorination reagents but a unique Mn^III‐catalyzed oxidative C?H fluorination using fluoride has been developed. Overall, the field of late‐stage nucleophilic C?H fluorination has progressed much more slowly, a state of play explaining why C?H ¹⁸F‐fluorination is still in its infancy.     

Iridium(III)‐Catalyzed Intermolecular C(sp3)−H Insertion Reaction of Quinoid Carbene: A Radical Mechanism

Described herein is an Ir^III/porphyrin‐catalyzed intermolecular C(sp³)?H insertion reaction of a quinoid carbene (QC). The reaction was designed by harnessing the hydrogen‐atom transfer (HAT) reactivity of a metal‐QC species with aliphatic substrates followed by a radical rebound process to afford C?H arylation products. This methodology is efficient for the arylation of activated hydrocarbons such as 1,4‐cyclohexadienes (down to 40 min reaction time, up to 99 % yield, up to 1.0 g scale). It features unique regioselectivity, which is mainly governed by steric effects, as the insertion into primary C?H bonds is favored over secondary and/or tertiary C?H bonds in the substituted cyclohexene substrates. Mechanistic studies revealed a radical mechanism for the reaction.     

Photocatalytic Sulfonylcarbocyclization of Alkynes Using SEt as a Traceless Directing Group: Access to Cyclopentenes and Indenes

Cyclopentenes and indenes are important structural scaffolds in synthetic, medical, and material chemistry. Cyclization of alkynes via remote C?H functionalization is an appealing approach to construct these motifs due to its high efficiency and step-economy. Herein, a traceless directing group strategy was designed to reverse the regioselectivity of radical addition which enabled an unprecedented photocatalytic sulfonylcarbocyclization of terminal alkynes by forming C?C bond on inert C(sp³)?H bond. It offers a facile access to decorated cyclopentenes and indenes under mild conditions. The resultant products could be converted into a set of valuable molecular scaffolds, including a key intermediate of AM-6226. Mechanistic experiments suggest a radical cascade pathway comprising a Markovnikov-type sulfonylation, 1,5-hydrogen atom transfer, 5-endo-trig cyclization, and β-elimination. This study lays further groundwork for the use of anti-Baldwin 5-endo-trig radical cyclization in rapidly assembling five-membered carbocycles.     

Electron predators are hydrogen atom traps. Effects of aryl groups on N—Cα bond dissociations of peptide radicals

Effects of substituted aryl groups on dissociations of peptide aminoketyl radicals were studied computationally for model tetrapeptide intermediates GXD^?G where X was a cysteine residue that was derivatized by S‐(3‐nitrobenzyl), S‐(3‐cyanobenzyl), S‐(3,5‐dicyanobenzyl), S‐(2,3,4,5,6‐pentafluorobenzyl), and S‐benzyl groups. The aminoketyl radical was placed within the Asp amide group. Aminoketyl radicals having the S‐(3‐nitrobenzyl) group were found to undergo spontaneous and highly exothermic migration of the hydroxyl hydrogen atom onto the nitro group in conformers allowing interaction between these groups. Competing reaction channels were investigated for aminoketyl radicals having the S‐(3‐cyanobenzyl) and S‐(3,5‐dicyanobenzyl) groups, e.g. H‐atom migration to the C and N atoms of the C≡N group, migration to the C‐4 position of the phenyl ring, and dissociation of the radical‐activated N? C_α bond between the Asp and Gly residues. RRKM kinetic analysis on the combined B3LYP and ROMP2/6‐311++G(2d,p) potential energy surface indicated > 99% H‐atom transfer to the C≡N group forming a stable iminyl intermediate. The N? C_α bond dissociation was negligible. In contrast, peptides with the S‐(2,3,4,5,6‐pentafluorobenzyl) and S‐benzyl groups showed preferential N? C_α bond dissociation that outcompeted H‐atom migration to the C‐4 position and fluorine substituents in the phenyl ring. These computational results are used to suggest an alternative mechanism for the quenching effect on electron‐based peptide backbone dissociations of benzyl groups with electron‐withdrawing substitutents, as reported recently. Copyright © 2010 John Wiley & Sons, Ltd.