Electrochemical Ruthenium-Catalysed Directed C−H Functionalization of Arenes with Boron Reagents

Ortho-directed electrochemical C−H functionalization of aromatics with boron-based coupling partners has been achieved under ruthenium catalysis through an oxidatively induced reductive elimination mechanism. Our method provides a single set of conditions delivering C−H arylation, alkenylation and methylation, yielding ortho-functionalized products with good functional group tolerance, including examples of late-stage functionalization in synthetically useful yields. By harnessing electricity as a ‘green’ oxidant, this method circumvents the need for stoichiometric quantities of chemical oxidants, enhancing our sustainability metrics.     

Palladium‐Catalyzed Intermolecular C‐2 Alkenylation of Indoles Using Oxygen as the Oxidant

A general and efficient palladium‐catalyzed intermolecular direct C‐2 alkenylation of indoles using oxygen as the oxidant has been developed. The reaction is of complete regio‐ and stereoselectivity. All products are E‐isomers at the C‐2‐position with no Z‐isomers and 3‐substituted products were detected.

     

Rhodium(III)‐Catalyzed Regioselective Direct C‐2 Alkenylation of Indoles Assisted by the Removable N‐(2‐Pyrimidyl) Group

The C‐2‐alkenylindole unit is a key component of numerous natural products and pharmacophores. However, the intermolecular direct construction of the core structural motif remains challenging in organic synthesis. Here we report a new, efficient, and versatile methodology for the synthesis of C‐2‐alkenylindoles through rhodium(III)‐catalyzed direct C H functionalization of indoles with acrylates under air by employing a metal‐directing group strategy. This strategy gives a rare selectivity for the alkenylation N‐(2‐pyrimidyl)indoles at the C‐2 position and provides the functionalized C‐2‐ alkenylindoles under mild conditions with broad substrate tolerance. An expansion of the methodology has also been demonstrated to, for example, the direct alkenylation of pyrrole and facile deprotection of the pyrimidyl group. All the results suggest that this methodology could be served as a highly attractive alternative for the direct construction of biologically important C‐2‐alkenylindoles.

     

Enantioselective Synthesis of Alkyl Allyl Ethers via Palladium-Catalyzed Redox-Relay Heck Alkenylation of O-Alkyl Enol Ethers

Herein we report a transformation that generates an array of enantiomerically enriched, alkyl allyl ethers. Cyclic, acyclic, and heteroatom-bearing alkenyl triflates undergo an enantioselective, palladium-catalyzed C−C bond formation with diverse acyclic O-alkyl enol ethers in good yields and excellent enantioselectivities.     

Cross-coupling of C(sp)-H Bonds with Organometallic Reagents via Pd(II)/Pd(0) Catalysis**

Palladium-catalyzed C-H activation/C-C bond-forming reactions have emerged as a promising class of synthetic tools in organic chemistry. Among the many different means of forging C-C bonds using Pd-mediated C-H activation, a new horizon in this field is Pd(II)-catalyzed cross-coupling of C-H bonds with organometallic reagents via a Pd(II)/Pd(0) catalytic cycle. While this type of reaction has proven to be effective for the selective functionalization of aryl C(sp(2))-H bonds, the focus of this review is on Pd(II)-catalyzed C(sp(3))-H activation/C-C cross-coupling, a topic of particular importance because reactions of this type enable fundamentally new methods for bond construction. Since our laboratory's initial report on cross-coupling of C-H bonds in 2006, this area has expanded rapidly, and the unique ability of Pd(II) catalysts to cleave and functionalize alkyl C(sp(3))-H bonds has been exploited to develop protocols for forming an array of C(sp(3))-C(sp(2)) and C(sp(3))-C(sp(3)) bonds. Furthermore, enantioselective C(sp(3))-H activation/C-C cross-coupling has been achieved through the use of chiral amino acid-derived ligands, offering a novel technique for producing enantioenriched molecules. Although this nascent field remains at an early stage of development, further investigations hold the potential to revolutionalize the way in which chiral molecules are synthesized in industrial and academic laboratories.     

Selective C−H Bond Functionalization of Unprotected Indoles by Donor-Acceptor Carbene Insertion

Copper catalysts containing alkoxydiaminophosphine (ADAP) ligand catalyze the selective C3−H functionalization of unprotected indoles upon carbene transfer from donor-acceptor diazo compounds, the N−H bond remaining unaltered during the transformation. Mechanistic studies, including DFT calculations, allows proposing the existence of two competitive pathways, none of them occurring through the formation of cyclopropane intermediates, at variance with previously reported systems.     

Palladium-Catalysed Amide-Directed Ligand Free C8-Olefination of 1-Naphthamides for the synthesis of 2,3-dihydro-1H-benzo[de]isoquinolin-1-ones

This work describes the palladium(II)-catalyzed regioselective C8-H olefination of 1-naphthamides. Interestingly, naphthamide fused lactam 2,3-dihydro-1H-benzo[de]isoquinolin-1-one derivatives were also synthesized in the case of a particular class of napthamides. This protocol was found well compatible with a diverse range of acrylates and styrenes leading to product formation in good yields along with a wide functional group tolerance. The developed strategy was further applied to the synthesis of different drug derivatives.     

Iron-Catalyzed C−C Bond Formation via Chelation-Assisted C−H Activation

This review provides a brief overview of iron-catalyzed C−C bond forming reactions via heteroatom-assisted C−H bond activation, which have been extensively developed in the last decade. Three major types of reactions are discussed, namely, (1) C−H activation/C−C coupling using organometallic reagents under oxidative conditions, (2) C−H activation/C−C coupling using organic electrophiles under redox-neutral conditions, and (3) C−H activation/C−C coupling using unsaturated hydrocarbons under redox-neutral or oxidative conditions.     

Hydrogen-Atom Transfer Oxidation with H2O2 Catalyzed by [FeII(1,2-bis(2,2′-bipyridyl-6-yl)ethane(H2O)2]2+: Likely Involvement of a (μ-Hydroxo)(μ-1,2-peroxo)diiron(III) Intermediate

The iron(II) triflate complex ( 1 ) of 1,2-bis(2,2′-bipyridyl-6-yl)ethane, with two bipyridine moieties connected by an ethane bridge, was prepared. Addition of aqueous 30 % H₂O₂ to an acetonitrile solution of 1 yielded 2 , a green compound with λ_max=710 nm. Moessbauer measurements on 2 showed a doublet with an isomer shift (δ) of 0.35 mm/s and a quadrupole splitting (ΔE_Q) of 0.86 mm/s, indicative of an antiferromagnetically coupled diferric complex. Resonance Raman spectra showed peaks at 883, 556 and 451 cm⁻¹ that downshifted to 832, 540 and 441 cm⁻¹ when 1 was treated with H₂¹⁸O₂. All the spectroscopic data support the initial formation of a (μ-hydroxo)(μ-1,2-peroxo)diiron(III) complex that oxidizes carbon-hydrogen bonds. At 0 °C 2 reacted with cyclohexene to yield allylic oxidation products but not epoxide. Weak benzylic C−H bonds of alkylarenes were also oxidized. A plot of the logarithms of the second order rate constants versus the bond dissociation energies of the cleaved C−H bond showed an excellent linear correlation. Along with the observation that oxidation of the probe substrate 2,2-dimethyl-1-phenylpropan-1-ol yielded the corresponding ketone but no benzaldehyde, and the kinetic isotope effect, k_H/k_D, of 2.8 found for the oxidation of xanthene, the results support the hypothesis for a metal-based H-atom abstraction mechanism. Complex 2 is a rare example of a (μ-hydroxo)(μ-1,2-peroxo)diiron(III) complex that can elicit the oxidation of carbon-hydrogen bonds.     

Recent Progress in Functionalization of the Pyridine Ring through C−S Bond Formation under Transition Metal Catalyst Free Conditions

Pyridines and quinolines substituted with sulfur-containing functional groups are widely used as drugs, drug candidates, organic materials, N,S-ligands and others. Traditional synthetic routes to produce these compounds are based on nucleophilic aromatic substitution reactions and transition metal-catalyzed cross-coupling reactions of (pseudo)halopyridines. While effective in many cases, both approaches are limited due to using forcing conditions and expensive, specifically designed catalytic systems. In the last decade, a number of innovative methods for the functionalization of the pyridine ring via the formation of a C−S bond have been developed. Most of these methods proceed through the direct or indirect C−H functionalization of unfunctionalized pyridines, thus avoiding the use of oftentimes not readily available halopyridines as the starting materials. Deoxygenative C−H functionalization of pyridine-N-oxides and deaminative transformation of aminopyridines have been also employed for the introduction of diverse organosulfur functionality into the pyridine ring. All these processes can be easily performed under mild conditions, typically affording value pyridines and quinolines in good to high yields. Usually being highly chemo- and regioselective, these methods allow the late-stage functionalization of complex molecules including drugs and natural products. In this Review, we summarize the most recent synthetic methods for functionalization of pyridines and fused pyridines with sulfur-containing functional groups reported mostly since 2018. For a better understanding of the processes, the mechanisms of the described reactions are briefly discussed.     

Oxoiron(V) Complexes of Relevance in Oxidation Catalysis of Organic Substrates

The selective oxidation of alkane and olefin moieties are reactions of fundamental importance in both chemical synthesis and biology. Nature efficiently catalyzes the oxidation of hydrocarbons using iron-dependent enzymes, which operate through the mediation of oxoiron(IV) or oxoiron(V) species. In the quest for chemo, regio and stereoselective transformations akin to those taking place in nature, bioinspired iron catalysts have been developed and understanding their mechanism of action has become a particularly relevant area of research. While a prominent advance in the preparation and characterization of oxoiron(IV) species has been accomplished, oxoiron(V) species remain exceedingly rare, presumably because the high reactivity that makes them particularly interesting also makes them difficult to observe. This review summarizes the advances in the field, focusing in synthetic systems for which the oxoiron(V) species relevant in these transformations have been directly detected and spetroscopically characterized.     

Selective C−H Functionalizations by Electrochemical Reactions with Palladium Catalysts

Efficient, selective, transition-metal-catalyzed C−H functionalizations have been widely studied and are recognized as atom- and step-economical tools in organic synthesis. During the past two decades, a variety of catalytic reactions involving C−H bond cleavage have been developed. In this review, we briefly survey studies dealing with transition-metal-catalyzed efficient and selective C−H functionalization by electrochemical reactions.     

Ruthenium(II)‐ or Rhodium(III)‐Catalyzed Grignard‐Type Addition of Indolines and Indoles to Activated Carbonyl Compounds

The ruthenium(II)‐ or rhodium(III)‐catalyzed pyrimidinyl‐directed Grignard‐type C−H additions of N‐heterocycles with activated aldehydes and ketones are described. A cationic ruthenium catalyst and sodium acetate additive in dichloroethane as solvent were found to be optimal catalytic system for the construction of C‐7 alkylated indolines. In sharp contrast, a cationic rhodium complex allows the generation of C‐2 alkylated indoles and pyrroles as well as C‐1 alkylated carbazoles. The site‐selective C−H functionalization of these heterocyclic scaffolds could be an important asset towards the development of novel bioactive compounds.

     

Diversification of NH-Aryl Sulfoximines through Iridium-Catalyzed ortho- and meta-Selective C−H Borylation

Herein, the selective ortho- and meta-C−H bond borylation of NH-aryl sulfoximines is reported. Regioselectivity is achieved by the choice of commercially available ligands giving fast excess to valuable borylated aryl sulfoximine building blogs. The utility of the borylated products is demonstrated for the formation of C−O, C−C, C−N, C−D, and C−I bonds.     

催化在有机合成中的新进展

近年来,过渡金属催化的卤代芳烃与各种亲核试剂的偶联反应已成为构筑C―C或C―杂原子键的有效手段,例如著名的Suzuki、Kumada、Stille、Negishi等生成C―C键的偶联反应等。最近,C―H键的直接活化及功能化方面有了一些突破。介绍了这一领域的新进展。     

Biosynthesis of the Fungal Organophosphonate Fosfonochlorin Involves an Iron(II) and 2-(Oxo)glutarate Dependent Oxacyclase

The fungal metabolite Fosfonochlorin features a chloroacetyl moiety that is unusual within known phosphonate natural product biochemistry. Putative biosynthetic genes encoding Fosfonochlorin in Fusarium and Talaromyces spp. were investigated through reactions of encoded enzymes with synthetic substrates and isotope labelling studies. We show that the early biosynthetic steps for Fosfonochlorin involve the reduction of phosphonoacetaldehyde to form 2-hydroxyethylphosphonic acid, followed by oxidative intramolecular cyclization of the resulting alcohol to form (S)-epoxyethylphosphonic acid. The latter reaction is catalyzed by FfnD, a rare example of a non-heme iron/2-(oxo)glutarate dependent oxacyclase. In contrast, FfnD behaves as a more typical oxygenase with ethylphosphonic acid, producing (S)-1-hydroxyethylphosphonic acid. FfnD thus represents a new example of a ferryl generating enzyme that can suppress the typical oxygen rebound reaction that follows abstraction of a substrate hydrogen by a ferryl oxygen, thereby directing the substrate radical towards a fate other than hydroxylation.     

Ruthenium(II)-Catalyzed Selective C(sp2)−H Acyloxylation of 2-Aroyl-Pyridine Derivatives with Sodium Carboxylate

A ruthenium-catalyzed C(sp²)−H acyloxylation of 2-aroyl pyridine derivatives with simple sodium carboxylate utilizing transformable directing groups is described. This protocol features broad functional group tolerance and chemo- and regio-selectivity, providing the acyloxylation products in 45%-84%yield. Furthermore, the synthetic utility of this protocol was demonstrated by the late-stage functionalization of pharmaceutical compounds. Notably, the acyloxylation products could be further transformed into a variety of useful heterocycles under mild conditions.     

Directed Evolution of a Cp*RhIII-Linked Biohybrid Catalyst Based on a Screening Platform with Affinity Purification

Directed evolution of Cp*Rh^III-linked nitrobindin (NB), a biohybrid catalyst, was performed based on an in vitro screening approach. A key aspect of this effort was the establishment of a high-throughput screening (HTS) platform that involves an affinity purification step employing a starch-agarose resin for a maltose binding protein (MBP) tag. The HTS platform enables efficient preparation of the purified MBP-tagged biohybrid catalysts in a 96-well format and eliminates background influence of the host E. coli cells. Three rounds of directed evolution and screening of more than 4000 clones yielded a Cp*Rh^III-linked NB(T98H/L100K/K127E) variant with a 4.9-fold enhanced activity for the cycloaddition of acetophenone oximes with alkynes. It is confirmed that this HTS platform for directed evolution provides an efficient strategy for generating highly active biohybrid catalysts incorporating a synthetic metal cofactor.     

Pyrrole Functionalization by Copper-Catalyzed Nitrene Transfer Reactions

The catalytic functionalization of pyrroles by incorporation of a nitrene group is reported. The Cα-H bond of 1H-pyrrole is amidated upon the formal insertion of the NTs (Ts=p-toluenesulfonyl) group catalyzed by Tp^Br3Cu(NCMe) (Tp^Br3=hydrotris(3,4,5-tribromo-pyrazolyl)borate). N-substituted pyrroles also verify the same transformation. The mechanism proposal is similar to that previously described for benzene amidation with the same catalyst and PhI=NTs, which takes place through aziridine formation, ring opening and 1,2-hydrogen shift. A cascade reaction involving the coupling of 2,5-dimethylfuran, 1,2,3-trimethyl-pyrrole and a nitrene NTs group is also described, leading to a 1,2-dihydropyridine-imine compound.     

Nickel-Catalyzed Benzylation of C−H Bonds in Aromatic Amides with Benzyltrimethylammonium Halides

Nickel-catalyzed benzylation reactions of C−H bonds in aromatic amides with benzyltrimethylammonium halides are developed by using a 5-chloro-8-aminoquinoline derivative as a bidentate directing group. Benzylation occurs selectively at the ortho-C−H bonds in aromatic amides, and no methylation was detected. The presence of a 5-chloro-8-aminoquinoline moiety is essential for the success of this reaction, in which a variety of functional groups can be tolerated.