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.     

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.     

Visible‐Light‐Mediated Remote Aliphatic C−H Functionalizations through a 1,5‐Hydrogen Transfer Cascade

A redox‐neutral, light‐mediated functionalization of unactivated C(sp³)−H bonds via iminyl radicals is presented here. A 1,5‐H transfer followed by the functionalization of a C(sp²)−H bond takes place in aqueous media producing a variety of elaborated fused ketones. Mechanistic investigations have revealed 1,5‐H transfer as the reversible, rate‐determining step in this transformation. Divergent scaffolds are also accessible via C(sp³)−N bond formation upon a careful choice of the reaction additives.     

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.     

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.     

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.     

Photoinduced Remote Functionalisations by Iminyl Radical Promoted C−C and C−H Bond Cleavage Cascades

A photoinduced cascade strategy leading to a variety of differentially functionalised nitriles and ketones has been developed. These reactions rely on the oxidative generation of iminyl radicals from simple oximes. Radical transposition by C(sp³)−(sp³) and C(sp³)−H bond cleavage gives access to distal carbon radicals that undergo S_H2 functionalisations. These mild, visible‐light‐mediated procedures can be used for remote fluorination, chlorination, and azidation, and were applied to the modification of bioactive and structurally complex molecules.     

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.     

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.     

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.     

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.     

Asymmetric Synthesis of Spiropyrazolones by Rhodium‐Catalyzed C(sp2)−H Functionalization/Annulation Reactions

Rhodium‐catalyzed C(sp²)−H functionalization reactions of 4‐aryl‐5‐pyrazolones followed by [3+2] annulation reactions with alkynes provide rapid access to highly enantioenriched five‐membered‐ring 4‐spiro‐5‐pyrazolones. The use of a chiral SCpRh catalyst enabled the synthesis of a large range of spiropyrazolones with all‐carbon quaternary stereogenic centers in up to 99 % yield and 98 % ee from readily available substrates.     

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.     

Non‐empirical calculations of NMR indirect carbon‐carbon coupling constants. Part 5: Bridged bicycloalkanes

All possible J(C,C) of the bicarbocyclic frameworks together with J(C,H) and J(H,H) at bridgeheads in the series of six bridged bicycloalkanes, bicyclo[1.1.0]butane, bicyclo[2.1.0]pentane, bicyclo[3.1.0]hexane, bicyclo[2.2.0]hexane, bicyclo[3.2.0]heptane and bicyclo[3.3.0]octane, were calculated at the SOPPA level with correlation consistent Dunning sets cc‐pVTZ‐Cs augmented with inner core s‐functions and locally dense Sauer sets aug‐cc‐pVTZ‐J augmented with tight s‐functions and rationalized in terms of the multipath coupling mechanism and hybridization effects explaining many interesting structural trends. Copyright © 2003 John Wiley & Sons, Ltd.     

Fulvene Synthesis by Rhodium(I)‐Catalyzed [2+2+1] Cycloaddition: Synthesis and Catalytic Activity of Tunable Cyclopentadienyl Rhodium(III) Complexes with Pendant Amides

It has been established that a Rh^I+/segphos complex catalyzes the [2+2+1] cycloaddition of 1,6‐diynes with cyclopropylideneacetamides to give substituted fulvenes in good yields. The reductive complexation of the product fulvenes with RhCl₃ in EtOH furnished the corresponding dinuclear cyclopentadienyl Rh^III complexes bearing a pendant amide moiety. These Rh^III complexes were highly active catalysts for oxidative annulation and cyclization through C(sp²)−H and C(sp³)−H functionalization.     

Visible‐Light‐Driven Palladium‐Catalyzed Radical Alkylation of C−H Bonds with Unactivated Alkyl Bromides

Reported herein is a novel visible‐light photoredox system with Pd(PPh₃)₄ as the sole catalyst for the realization of the first direct cross‐coupling of C(sp³)−H bonds in N‐aryl tetrahydroisoquinolines with unactivated alkyl bromides. Moreover, intra‐ and intermolecular alkylations of heteroarenes were also developed under mild reaction conditions. A variety of tertiary, secondary, and primary alkyl bromides undergo reaction to generate C(sp³)−C(sp³) and C(sp²)−C(sp³) bonds in moderate to excellent yields. These redox‐neutral reactions feature broad substrate scope (>60 examples), good functional‐group tolerance, and facile generation of quaternary centers. Mechanistic studies indicate that the simple palladium complex acts as the visible‐light photocatalyst and radicals are involved in the process.     

Controllable Si−C Bond Activation Enables Stereocontrol in the Palladium-Catalyzed [4+2] Annulation of Cyclopropenes with Benzosilacyclobutanes

A novel and unusual palladium-catalyzed [4+2] annulation of cyclopropenes with benzosilacyclobutanes is reported. This reaction occurred through chemoselective Si−C(sp²) bond activation in synergy with ring expansion/insertion of cyclopropenes to form new C(sp²)−C(sp³) and Si−C(sp³) bonds. An array of previously elusive bicyclic skeleton with high strain, silabicyclo[4.1.0]heptanes, were formed in good yields with excellent diastereoselectivity under mild conditions. An asymmetric version of the reaction with a chiral phosphoramidite ligand furnished a variety of chiral bicyclic silaheterocycle derivatives with good enantioselectivity (up to 95.5:4.5 er). Owing to the mild reaction conditions, the good stereoselectivity profile, and the ready availability of the functionalized precursors, this process constitutes a useful and straightforward strategy for the synthesis of densely functionalized silacycles.     

Synthesis of Novel,Chiral Bicyclo[3.1.0]hex‐2‐ene Amino Acid Derivatives as Useful Synthons in Medicinal Chemistry

A short and concise synthesis of novel, chiral bicyclo[3.1.0]hex‐2‐ene amino acid derivatives 13 and 14 has been developed. The key step is a stereo‐ and regioselective allylic amination of exo‐ and endo‐methyl bicyclo[3.1.0]hex‐2‐ene‐6‐carboxylates 8 and 9 , which were prepared from 7,7‐dichlorobicyclo[3.2.0]hept‐2‐en‐6‐one ( 1 ). These amino acid derivatives are useful building blocks in medicinal chemistry and can be prepared as chiral compounds by using either (+)‐ 1 or (?)‐ 1 as starting material.     

Mechanistic Insights into C(sp2)−C(sp)N Reductive Elimination from Gold(III) Cyanide Complexes

A new family of phosphine-ligated dicyanoarylgold(III) complexes has been prepared and their reactivity towards reductive elimination has been studied in detail. Both, a highly positive entropy of activation and a primary ^12/13C KIE suggest a late concerted transition state while Hammett analysis and DFT calculations indicate that the process is asynchronous. As a result, a distinct mechanism involving an asynchronous concerted reductive elimination for the overall C(sp²)−C(sp)N bond forming reaction is characterized herein, for the first time, complementing previous studies reported for C(sp³)−C(sp³), C(sp²)−C(sp²), and C(sp³)−C(sp²) bond formation processes taking place on gold(III) species.     

Theoretical investigation toward organophosphine‐catalyzed [3 + 3] annulation of Morita–Baylis–Hillman carbonates with azomethine imines: Mechanism,origin of stereoselectivity,and role of catalyst

A computational study on the detailed mechanism and stereoselectivity of the chiral phosphine‐catalyzed C(sp²)? H activation/[3 + 3] annulation between Morita–Baylis–Hillman (MBH) carbonates and C,N‐cyclic azomethine imines has been performed. Generally, the catalytic cycle consists of two stages, that is, C(sp²)? H activation companied by the dissociation of the t‐BuO group forming phosphonium enolate, and [3 + 3] cycloaddition process followed by regeneration of the catalyst. The calculated results indicate that C(sp²)? H activation is rate‐determining while [3 + 3] cycloaddition is stereoselectivity‐determining. Furthermore, the advantageous hydrogen bond interactions and less steric hindrance in the RR configurational C? C bond forming transition states should be responsible for the favorability of RR‐configured product among the four possible products. The special role of the organocatalyst was also identified by natural bond orbital (NBO) and global reactivity index (GRI) analyses. The mechanistic insights obtained in the present study should be useful for understanding the novel organocatalytic C(sp²)? H activation and cycloaddition cascade reaction of MBH carbonates, and thus provide valuable clues on rational design of efficient organocatalysts for the C(sp²)? H activation/functionalizations.