Synthesis of β‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Carbamoylation

A general and user‐friendly synthesis of β‐lactams is reported that makes use of Pd⁰‐catalyzed carbamoylation of C(sp³)−H bonds, and operates under stoichiometric carbon monoxide in a two‐chamber reactor. This reaction is compatible with a range of primary, secondary and activated tertiary C−H bonds, in contrast to previous methods based on C(sp³)−H activation. In addition, the feasibility of an enantioselective version using a chiral phosphonite ligand is demonstrated. Finally, this method can be employed to synthesize valuable enantiopure free β‐lactams and β‐amino acids.     

Silver‐Catalyzed Oxidative C(sp3)−P Bond Formation through C−C and P−H Bond Cleavage

The silver‐catalyzed oxidative C(sp³)−H/P−H cross‐coupling of 1,3‐dicarbonyl compounds with H‐phosphonates, followed by a chemo‐ and regioselective C(sp³)−C(CO) bond‐cleavage step, provided heavily functionalized β‐ketophosphonates. This novel method based on a readily available reaction system exhibits wide scope, high functional‐group tolerance, and exclusive selectivity.     

Ligand-Enabled [3+2] Annulation of Aromatic Acids with Maleimides by C(sp3)−H and C(sp2)−H Bond Activation

A palladium-catalyzed [3+2] annulation of substituted benzoic acids with maleimides leading to tricyclic heterocyclic molecules having a free carboxylic group in a high atom- and step-economical manner is described. The reaction proceeds via a dual C−H bond activation such as C(sp³)−H at the benzylic position and C(sp²)−H bond activation at the meta position of substituted aromatics. An external ligand (MPAA) is crucial for the success of present protocol. Further, the decarboxylation and esterification of the free carboxylic acid group of observed products were carried out.     

BODIPY Peptide Labeling by Late‐Stage C(sp3)−H Activation

Late‐stage BODIPY diversification of structurally complex amino acids and peptides was accomplished by racemization‐free palladium‐catalyzed C(sp³)?H activation. Transformative fluorescence modification proved viable by triazole‐assisted C(sp³)?H arylation in a chemo‐ and site‐selective fashion, providing modular access to novel BODIPY peptide sensors.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

γ‐Functionalizations of Amines through Visible‐Light‐Mediated,Redox‐Neutral C−C Bond Cleavage

Cleavage of unstrained C−C bonds under mild, redox‐neutral conditions represents a challenging endeavor which is accomplished here in the context of a flexible, visible‐light‐mediated, γ‐functionalization of amines. In situ generated C‐centered radicals are harvested in the presence of Michael acceptors, thiols and alkyl halides to efficiently form new C(sp³)−C(sp³), C(sp³)−H and C(sp³)−Br bonds, respectively.     

β- and γ-C(sp3)−H Heteroarylation of Free Carboxylic Acids: A Modular Synthetic Platform for Diverse Quaternary Carbon Centers

Pd^II-catalyzed C(sp³)−H activation of free carboxylic acids represents a significant advance from conventional cyclopalladation initiated reactions. However, developing a modular synthetic platform for diverse quaternary and tertiary carbon centers based on this reactivity, two challenges remain to be addressed: mono-selectivity in each consecutive C−H functionalization step; compatibility with heteroatoms. While the exclusive mono-selectivity was achieved by β-lactonization/nucleophilic attack, the latter limitation remains to be overcome. Herein, we report the Pd^II-catalyzed β- and γ-C(sp³)−H heteroarylation of free carboxylic acids using pyridine-pyridone ligands capable of overcoming these limitations. A sequence of three consecutive C(sp³)−H activation reactions of pivalic acid provides an unique platform for constructing diverse quaternary carbon centers containing heteroaryls which could serve as an enabling tool for escaping the flat land in medicinal chemistry.     

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.     

Ligand-Enabled Palladium(II)-Catalyzed Enantioselective β-C(sp3)−H Arylation of Aliphatic Tertiary Amides**

Amide is one of the most widespread functional groups in organic and bioorganic chemistry, and it would be valuable to achieve stereoselective C(sp³)−H functionalization in amide molecules. Palladium(II) catalysis has been prevalently used in the C−H activation chemistry in the past decades, however, due to the weakly-coordinating feature of simple amides, it is challenging to achieve their direct C(sp³)−H functionalization with enantiocontrol by Pd^II catalysis. Our group has developed sulfoxide-2-hydroxypridine (SOHP) ligands, which exhibited remarkable activity in Pd-catalyzed C(sp²)−H activation. In this work, we demonstrate that chiral SOHP ligands served as an ideal solution to enantioselective C(sp³)−H activation in simple amides. Herein, we report an efficient asymmetric Pd^II/SOHP-catalyzed β-C(sp³)−H arylation of aliphatic tertiary amides, in which the SOHP ligand plays a key role in the stereoselective C−H deprotonation-metalation step.     

Copper‐Catalyzed Bromination of C(sp3)−H Bonds Distal to Functional Groups

Selective bromination of γ‐methylene C(sp³)−H bonds of aliphatic amides and δ‐methylene C(sp³)−H bonds of nosyl‐protected alkyl amines are developed using NBS as the brominating reagent and catalytic amount of Cu^II/phenanthroline complexes as the catalyst. Aryl and benzylic C−H bonds at other locations remain intact during this directed radical abstraction reaction.     

Cobalt‐Catalyzed Cross‐Dehydrogenative C(sp2)−C(sp3) Coupling of Oxazole/Thiazole with Ether or Cycloalkane

Direct C5‐alkylation of oxazole/thiazole with ether or cycloalkane has been achieved through a cobalt‐catalyzed cross‐dehydrogenative coupling (CDC) process in moderate to good yields. This transformation represents the first C(sp²)−C(sp³) cross‐coupling at the C5‐position of the oxazole/thiazole via double C−H bond cleavages. Various functional groups on oxazole/thiazole substrates, as well as water and air, are well‐tolerated with this concise and practical protocol, constituting straightforward access to heterocycles with great medicinal significance. A preliminary mechanism involving a radical process has also been proposed.     

Site‐Selective δ‐C(sp3)−H Alkylation of Amino Acids and Peptides with Maleimides via a Six‐Membered Palladacycle

The site‐selective functionalization of unactivated C(sp³)?H bonds remains one of the greatest challenges in organic synthesis. Herein, we report on the site‐selective δ‐C(sp³)?H alkylation of amino acids and peptides with maleimides via a kinetically less favored six‐membered palladacycle in the presence of more accessible γ‐C(sp³)?H bonds. Experimental studies revealed that C?H bond cleavage occurs reversibly and preferentially at γ‐methyl over δ‐methyl C?H bonds while the subsequent alkylation proceeds exclusively at the six‐membered palladacycle that is generated by δ‐C?H activation. The selectivity can be explained by the Curtin–Hammett principle. The exceptional compatibility of this alkylation with various oligopeptides renders this procedure valuable for late‐stage peptide modifications. Notably, this process is also the first palladium(II)‐catalyzed Michael‐type alkylation reaction that proceeds through C(sp³)?H activation.     

Construction of β-Phenylalanine Derivatives through Pd-Catalyzed,C(sp2)−H (ortho) Functionalization

This paper describes the Pd(II)-catalyzed, picolinamide-directing-group-aided C(sp²)−H (ortho) functionalization of racemic and enantiopure β-phenylalanines and 3-amino-3-phenylpropanols (1,3-amino alcohols). The C(sp²)−H (ortho) functionalizations including arylation, bromination, iodination, and alkoxylation were attempted. The C(sp²)−H (ortho) arylation reactions gave biaryl or terphenyl-type β-phenylalanine scaffolds, halogenation and methoxylation reactions gave ortho C−H halogenated or methoxylated β-phenylalanines. Additionally, the C−H arylation of an ortho-methyl substituted β-phenylalanine containing both C(sp²)−H and remote C(sp³)−H bonds was investigated. β-Phenylalanine is an arylated β-amino acid motif present in various natural products, bioactive molecules, and β-peptides and it is a precursor to medicinally active compounds. Accordingly, this work contributes to the expansion of the library of unnatural β-phenylalanine (β-amino acid) derivatives through site-selective C−H functionalization.     

Pd-Catalyzed Arylation and Benzylation of Tyrosine at the δ−C(sp2)−H and C(2) Positions: Expanding the Library of Unnatural Tyrosines

This paper describes Pd(II)-catalyzed picolinamide-directed intermolecular arylation and benzylation of remote δ−C(sp²)−H bond (C(2) position) of the aryl ring in tyrosine derivatives and expansion of the library of unnatural tyrosine. Various racemic and enantiopure bis C(2) (ortho C−H) arylated and benzylated tyrosine derivatives were assembled in good yields. Removal of the picolinoyl moiety after the C(2)−H arylation and assembling of tyrosine-based peptides using C(2)−H arylated tyrosines were shown. Tyrosine derivatives and biaryl amino acids are vital scaffolds in medicinal chemistry. Correspondingly, this work is a contribution towards the expansion of the unnatural tyrosine library with biaryl- or terphenyl and diarylmethane-based tyrosine scaffolds.     

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.     

Selective Functionalization of Aromatic C(sp2)−H Bonds in the Presence of Benzylic C(sp3)−H Bonds by Electron‐Deficient Carbenoids Generated from 4‐Acyl‐1‐Sulfonyl‐1,2,3‐Triazoles

A rhodium(II)‐catalyzed reaction of newly prepared 4‐acyl‐1‐sulfonyl‐1,2,3‐triazoles with benzene, and its derivatives, is investigated. Acceptor/acceptor carbenoids generated from 4‐acyltriazoles undergo selective insertion at aromatic C(sp²)−H bonds in the presence of benzylic C(sp³)−H bonds to produce N ‐sulfonylenaminones.     

Ruthenium-Catalyzed Remote Difunctionalization of Nonactivated Alkenes for Double meta-C(sp2)−H/C-6(sp3)−H Functionalization

Twofold distal C−H functionalization was accomplished by difunctionalization of nonactivated alkenes to provide rapid access to multifunctionalized molecules. The multicomponent ruthenium-catalyzed remote 1,n-difunctionalization (n=6,7) of nonactivated alkenes with fluoroalkyl halides and heteroarenes in a modular manner is reported. The meta-C(sp²)−H/C-6(sp³)−H distal functionalization featured mild conditions, unique selectivity, and broad substrate scope with a domino process for twofold remote C(sp²)−H/C(sp³)−H activation of the sequential formation of three different carbon-centered radicals. A plausible mechanism was proposed based on detailed experimental and computational studies.     

Synthesis of Bicyclo[n.1.0]alkanes by a Cobalt‐Catalyzed Multiple C(sp3)−H Activation Strategy

A cobalt‐catalyzed dual C(sp³)−H activation strategy has been developed and it provides a novel strategy for the synthesis of bicyclo[4.1.0]heptanes and bicyclo[3.1.0]hexanes. A key to the success of this reaction is the conformation‐induced methylene C(sp³)−H activation of the resulting cobaltabicyclo[4.n.1] intermediate. In addition, the synthesis of bicyclo[3.1.0]hexane from pivalamide, by a triple C(sp³)−H activation, has also been demonstrated.     

C(spn)−X (n=1–3) Bond Activation by Palladium

We have studied the palladium-mediated activation of C(spⁿ)−X bonds (n = 1–3 and X = H, CH₃, Cl) in archetypal model substrates H₃C−CH₂−X, H₂C=CH−X and HC≡C−X by catalysts PdL_n with L_n = no ligand, Cl⁻, and (PH₃)₂, using relativistic density functional theory at ZORA-BLYP/TZ2P. The oxidative addition barrier decreases along this series, even though the strength of the bonds increases going from C(sp³)−X, to C(sp²)−X, to C(sp)−X. Activation strain and matching energy decomposition analyses reveal that the decreased oxidative addition barrier going from sp³, to sp², to sp, originates from a reduction in the destabilizing steric (Pauli) repulsion between catalyst and substrate. This is the direct consequence of the decreasing coordination number of the carbon atom in C(spⁿ)−X, which goes from four, to three, to two along this series. The associated net stabilization of the catalyst–substrate interaction dominates the trend in strain energy which indeed becomes more destabilizing along this same series as the bond becomes stronger from C(sp³)−X to C(sp)−X.     

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.