Synthesis of Chiral β‐Lactams by Pd‐Catalyzed Enantioselective Amidation of Methylene C(sp3)–H Bonds Enabled by a 2‐Pyridylisopropyl Auxiliary†

Qiang Yue, Xu Yang, Meng‐Xue Jiang, Bing‐Feng Shi, Tao Zhou, Yi Ding and Ye‐Qiang Han (from left to right). Mr. Tao Zhou is currently a postdoctoral fellow in the group of Prof. Bing‐Feng Shi in Zhejiang University. Mr. Ye‐Qiang Han is currently a fourth‐year PhD student in the group of Prof. Bing‐Feng Shi in Zhejiang University.     

Selective Palladium(II)‐Catalyzed Carbonylation of Methylene β‐C−H Bonds in Aliphatic Amines

Palladium(II)‐catalyzed C−H carbonylation reactions of methylene C−H bonds in secondary aliphatic amines lead to the formation of trans ‐disubstituted β‐lactams in excellent yields and selectivities. The generality of the C−H carbonylation process is aided by the action of xantphos‐based ligands and is important in securing good yields for the β‐lactam products.     

Synthesis of Strained γ‐Lactams by Palladium(0)‐Catalyzed C(sp3)−H Alkenylation and Application to Alkaloid Synthesis

A variety of strained α‐alkylidene‐γ‐lactams were synthesized by palladium(0)‐catalyzed intramolecular C(sp³)?H alkenylation from easily accessible acyclic and monocyclic bromoalkene precursors. These lactams are valuable intermediates for accessing various classes of mono‐ and bicylic alkaloids containing a pyrrolidine ring, as illustrated with the synthesis of an advanced model of the marine natural product plakoridine A and of the indolizidine alkaloid δ‐coniceine.     

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.     

Ligand‐Enabled PdII‐Catalyzed Iterative γ‐C(sp3)−H Arylation of Free Aliphatic Acid

C?H functionalization of aliphatic carboxylic acids without attaching exogenous auxiliary has been so far limited at the proximal β‐position. In this work, we demonstrate a ligand enabled palladium catalyzed first regioselective distal γ‐C(sp3)?H functionalization of aliphatic carboxylic acids without incorporating an exogenous directing group. Aryl iodides containing versatile functional groups including complex organic molecules are well tolerated with good to excellent yields during the γ‐C(sp3)?H arylation reaction. Interestingly, weak coordination of carboxylate group can be further extended for sequential hetero di‐arylation. Application of the protocol has been showcased by synthesizing substituted α‐tetralone. Mechanistic investigations have been carried out to shed light on the reaction pathway.     

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.     

Nickel,Cobalt and Palladium Catalysed C−H Functionalization of Un‐Activated C(sp3)−H Bond

This review represents nickel, cobalt and palladium catalyzed C?H activation of sp³ carbon, with special emphasis on methyl C?H activation. The importance of directing group assistance and effect of ligand on β‐ or γ‐ C(sp³)?H activation is summarized in this review. The mechanistic study for Ni, Co and Pd catalyzed sp³ C?H bond functionalization also discussed in detail.     

Reductive C−C Coupling from α,β‐Unsaturated Nitriles by Intercepting Keteniminates

We present an atom‐economic strategy to catalytically generate and intercept nitrile anion equivalents using hydrogen transfer catalysis. Addition of α,β‐unsaturated nitriles to a pincer‐based Ru?H complex affords structurally characterized κ‐N‐coordinated keteniminates by selective 1,4‐hydride transfer. When generated in situ under catalytic hydrogenation conditions, electrophilic addition to the keteniminate was achieved using anhydrides to provide α‐cyanoacetates in high yields. This work represents a new application of hydrogen transfer catalysis using α,β‐unsaturated nitriles for reductive C?C coupling reactions.     

Palladium‐Catalyzed Pyrazole‐Directed sp3 C−H Bond Arylation for the Synthesis of β‐Phenethylamines

We have developed a method for palladium‐catalyzed, pyrazole‐directed sp³ C−H bond arylation by aryl iodides. The reaction employs a Pd(OAc)₂ catalyst at 5–10 mol % loading and silver(I) oxide as a halide‐removal agent, and it proceeds in acetic acid or acetic acid/hexafluoroisopropanol solvent. Ozonolysis of the pyrazole moiety affords pharmaceutically important β‐phenethylamines.     

Palladium(II)‐Catalyzed Site‐Selective C(sp3)−H Alkynylation of Oligopeptides: A Linchpin Approach for Oligopeptide–Drug Conjugation

The palladium(II)‐catalyzed C(sp³)−H alkynylation of oligopeptides was developed with tetrabutylammonium acetate as a key additive. Through molecular design, the acetylene motif served as a linchpin to introduce a broad range of carbonyl‐containing pharmacophores onto oligopeptides, thus providing a chemical tool for the synthesis and modification of novel oligopeptide–pharmacophore conjugates by C−H functionalization. Dipeptide conjugates with coprostanol and estradiol were synthesized by this method for potential application in targeted drug delivery to tumor cells with overexpressed nuclear hormone receptors.     

PdII‐Catalyzed Enantioselective C(sp3)−H Activation/Cross‐Coupling Reactions of Free Carboxylic Acids

Pd^II‐catalyzed enantioselective C(sp³)?H cross‐coupling of free carboxylic acids with organoborons has been realized using either mono‐protected amino acid (MPAA) ligands or mono‐protected aminoethyl amine (MPAAM) ligands. A diverse range of aryl‐ and vinyl‐boron reagents can be used as coupling partners to provide chiral carboxylic acids. This reaction provides an alternative approach to the enantioselective synthesis of cyclopropanecarboxylic acids and cyclobutanecarboxylic acids containing α‐chiral tertiary and quaternary stereocenters. The utility of this reaction was further demonstrated by converting the carboxylic acid into cyclopropyl amine without loss of optical activity.     

Utilizing Carbonyl Coordination of Native Amides for Palladium‐Catalyzed C(sp3)−H Olefination

Pd^II‐catalyzed C(sp³)?H olefination of weakly coordinating native amides is reported. Three major drawbacks of previous C(sp³)?H olefination protocols, 1) in situ cyclization of products, 2) incompatibility with α‐H‐containing substrates, and 3) installation of exogenous directing groups, are addressed by harnessing the carbonyl coordination ability of amides to direct C(sp³)?H activation. The method enables direct C(sp³)?H functionalization of a wide range of native amide substrates, including secondary, tertiary, and cyclic amides, for the first time. The utility of this process is demonstrated by diverse transformations of the olefination products.     

Microwave‐Assisted Synthesis of β‐Lactams and Cyclo‐β‐dipeptides

Different cyclo‐β‐dipeptides were prepared from corresponding N‐substituted β‐alanine derivatives under mild conditions using PhPOCl₂ as activating agent in benzene and Et₃N as base. To evaluate β³‐substituent influence, the amino acids 7 – 26 were synthesized, and a β‐lactam formation reaction was carried out instead of cyclo‐β‐dipeptide formation. The crystal structures of three derivatives of cyclo‐β‐peptides and one β‐lactam are presented.     

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.     

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.     

Synthesis of β‐Haloketones by β‐Addition Reactions of α,β‐Unsaturated Ketones with BX3 (X = Br,Cl) as Halide Source

A series of β‐bromoketones and β‐chloroketones were synthesized by the addition reactions of α,β‐unsaturated ketones under BX₃ (X = Br, Cl) and ethylene glycol reaction system. The α,β‐unsaturated ester also was successfully converted to its corresponding β‐bromoester under the reaction condition.     

Palladium‐Catalyzed Intermolecular [4+1] Spiroannulation by C(sp3)−H Activation and Naphthol Dearomatization

A novel palladium‐catalyzed [4+1] spiroannulation was developed by using a C(sp³)?H activation/naphthol dearomatization approach. This bimolecular domino reaction of two aryl halides was realized through a sequence of cyclometallation‐facilitated C(sp³)?H activation, biaryl cross‐coupling, and naphthol dearomatization, thus rendering the rapid assembly of a new class of spirocyclic molecules in good yields with broad functional‐group tolerance. Preliminary mechanistic studies indicate that C?H cleavage is likely involved in the rate‐determining step, and a five‐membered palladacycle was identified as the key intermediate for the intermolecular coupling.