A DFT Study on the Conversion of Aryl Iodides to Alkyl Iodides: Reductive Elimination of R−I from Alkylpalladium Iodide Complexes with Accessible β‐Hydrogens

DFT calculations have been performed on the palladium‐catalyzed carboiodination reaction. The reaction involves oxidative addition, alkyne insertion, C?N bond cleavage, and reductive elimination. For the alkylpalladium iodide intermediate, LiOtBu stabilizes the intermediate in non‐polar solvents, thus promoting reductive elimination and preventing β‐hydride elimination. The C?N bond cleavage process was explored and the computations show that PPh₃ is not bound to the Pd center during this step. Experimentally, it was demonstrated that LiOtBu is not necessary for the oxidative addition, alkyne insertion, or C?N bond cleavage steps, lending support to the conclusions from the DFT calculations. The turnover‐limiting steps were found to be C?N bond cleavage and reductive elimination, whereas oxidative addition, alkyne insertion, and formation of the indole ring provide the driving force for the reaction.     

Copper‐Catalyzed S−C/S−N Bond Interconversions

Under an atmosphere of dioxygen, copper‐catalyzed de‐alkylation/amination sequences provide sulfonimidamides from unprotected sulfoximines in moderate to good yields. Mechanistic studies suggest the involvement of radicals in both the C?S bond cleavage and the formation of the new N?S bond.     

Palladium(0)/PAr3‐Catalyzed Intermolecular Amination of C(sp3)H Bonds: Synthesis of β‐Amino Acids

An intermolecular C(sp³)? H amination using a Pd⁰/PAr₃ catalyst was developed. The reaction begins with oxidative addition of R₂N? OBz to a Pd⁰/PAr₃ catalyst and subsequent cleavage of a C(sp³)? H bond by the generated Pd? NR₂ intermediate. The catalytic cycle proceeds without the need for external oxidants in a similar manner to the extensively studied palladium(0)‐catalyzed C? H arylation reactions. The electron‐deficient triarylphosphine ligand is crucial for this C(sp³)? H amination reaction to occur.     

Oxidative Interception of the Hydroamination Pathway: A Gold‐Catalyzed Diamination of Alkenes

A complimentary diamination of alkenes by using homogeneous gold catalysts is described. The reaction is one of very few examples of homogeneous gold oxidation catalysis and proceeds with high selectivity under mild conditions. Individual steps of the suggested catalytic cycle were investigated on isolated model gold complexes, and new pathways for gold‐catalyzed amination reactions were established. The key step is an intramolecular alkyl–nitrogen bond formation from a gold(III) intermediate. This process validates the concept of reductive elimination from high oxidation catalyst states for this type of C? N bond forming reactions.     

Copper‐Catalyzed Oxidative Reaction of β‐Keto Sulfones with Alcohols via C−S Bond Cleavage: Reaction Development and Mechanism Study

A Cu‐catalyzed cascade oxidative radical process of β‐keto sulfones with alcohols has been achieved by using oxygen as an oxidant. In this reaction, β‐keto sulfones were converted into sulfinate esters under the oxidative conditions via cleavage of C?S bond. Experimental and computational studies demonstrate that a new pathway is involved in this reaction, which proceeds through the formation of the key four‐coordinated Cu^II intermediate, O?O bond homolysis induced C?S bond cleavage and Cu‐catalyzed esterification to form the final products. This reaction provides a new strategy to sulfonate esters and enriches the research content of C?S bond cleavage and transformations.     

Direct N‐Methylation Reaction Using DMSO as One‐Carbon Bridge: Convenient Access to Heterocycle‐Containing β‐Amino Ketones

A novel oxidative C? S bond cleavage reaction of DMSO for dual C? C and C? N bond formation is described. A series of acetyl heteroarenes could be selectively converted into the corresponding β‐amino ketones, which are frequently found in biologically active compounds and pharmaceuticals. DMSO acted in this reaction not only as the solvent but also as a one‐carbon bridge.     

N‐Heterocyclic Carbene Iron(III) Porphyrin‐Catalyzed Intramolecular C(sp3)–H Amination of Alkyl Azides

Metal‐catalyzed intramolecular C?H amination of alkyl azides constitutes an appealing approach to alicyclic amines; challenges remain in broadening substrate scope, enhancing regioselectivity, and applying the method to natural product synthesis. Herein we report an iron(III) porphyrin bearing axial N‐heterocyclic carbene ligands which catalyzes the intramolecular C(sp³)–H amination of a wide variety of alkyl azides under microwave‐assisted and thermal conditions, resulting in selective amination of tertiary, benzylic, allylic, secondary, and primary C?H bonds with up to 95 % yield. 14 out of 17 substrates were cyclized selectively at C4 to give pyrrolidines. The regioselectivity at C4 or C5 could be tuned by modifying the reactivity of the C5–H bond. Mechanistic studies revealed a concerted or a fast re‐bound mechanism for the amination reaction. The reaction has been applied to the syntheses of tropane, nicotine, cis‐octahydroindole, and leelamine derivatives.     

1,3‐Diazasilabicyclo[1.1.0]butane with a Long Bridging N−N Bond

A 1,3‐diazasilabicyclo[1.1.0]butane ( 1 ) is synthesized as thermally stable crystals by using the cycloaddition reaction of an isolable dialkylsilylene with aziadamantane. The bridge N?N bond length of 1 (1.70 Å) is the longest among those of known N?N singly‐bonded compounds, including side‐on bridged transition‐metal dinitrogen complexes. The compound 1 is intact in air but moisture sensitive. No reaction occurs with hydrogen, even under pressure at 0.5 MPa. Irradiation of 1 with light gives an isomer quantitatively by N?N and adamantyl C?C bond cleavage. The origin of the remarkable N?N bond elongation is ascribed to significant interaction between a Si?C σ* and Ν?Ν π and σ orbitals as determined by DFT calculations of model compounds.     

Synthesis of N‐Arylated 1,2‐Dihydroheteroaromatics Through the Three‐Component Reaction of Arynes with N‐Heteroaromatics and Terminal Alkynes or Ketones

The reaction of benzynes with N‐heteroaromatics including quinolines, isoquinolines, and pyridines and various terminal alkynes or ketones with an α‐hydrogen in the presence of KF and 18‐crown‐6 in THF at room temperature for 8 h gave various N‐arylated 1,2‐dihydroheteroaromatics in good to moderate yields. Some of these product structures are found in various naturally occurring and biologically active heterocyclic compounds. The reaction involves an unusual multiple construction of new C? C, C? N, and C? H bonds and the cleavage of a C? H bond in one pot. It is likely that the three‐component coupling proceeds through the nucleophilic addition of quinoline to benzyne, which generates a zwitterionic species. The latter then attracts a proton from terminal alkyne (or ketone) to generate an N‐arylated quinolinium cation and an acetylide anion. Further reaction of these two ions provides the final substituted 1,2‐dihydroquinolines. In the reaction, the terminal alkyne acts first as a proton donor and then as a nucleophile. The application of a three‐component coupling reaction product, 1,2‐dihydro‐2‐pyridinyl alkyne in a stereospecific [4+2] Diels–Alder cycloaddition reaction with N‐phenyl maleimide to give an isoquinuclidine derivative, an important core present in various natural products, is demonstrated.     

Ligand‐Promoted Rhodium(III)‐Catalyzed ortho‐C−H Amination with Free Amines

Ligand development for rhodium(III)‐catalyzed C−H activation reactions has largely been limited to cyclopentadienyl (Cp) based scaffolds. 2‐Methylquinoline has now been identified as a feasible ligand that can coordinate to the metal center of Cp*RhCl to accelerate the cleavage of the C−H bond of N ‐pentafluorophenylbenzamides, providing a new structural lead for ligand design. The compatibility of this reaction with secondary free amines and anilines also overcomes the limitations of palladium(II)‐catalyzed C−H amination reactions.     

Intramolecular Cooperative CC Bond Cleavage Reaction of 1,3‐Dicarbonyl Compounds with 2‐Iodoanilines to Give o‐(N‐Acylamino)aryl Ketones and Multisubstituted Indoles

A copper‐catalyzed C?C bond cleavage reaction of 1,3‐dicarbonyl compounds with 2‐iodoanilines was developed. In this process, the ortho effect played an important role in the reactivity and a new reaction pathway that involved a (2‐aminophenyl)‐bis‐(1,3‐dicarbonyl) copper species was clearly observed by a time‐course HRMS analysis of the reaction mixture. Unlike the previous reports, both the nucleophilic and electrophilic parts of the 1,3‐dicarbonyl compound were coupled with 2‐iodoaniline by C?C bond cleavage to form o‐(N‐acylamino)aryl ketones, which could be efficiently converted into multisubstituted indoles.     

Copper‐Catalyzed α‐Amination of Phosphonates and Phosphine Oxides: A Direct Approach to α‐Amino Phosphonic Acids and Derivatives

A direct approach to important α‐amino phosphonic acids and its derivatives has been developed by using copper‐catalyzed electrophilic amination of α‐phosphonate zincates with O‐acyl hydroxylamines. This amination provides the first example of C? N bond formation which directly introduces acyclic and cyclic amines to the α‐position of phosphonates in one step. The reaction is readily promoted at room temperature with as little as 0.5 mol % of catalyst, and demonstrates high efficiency on a broad substrate scope.     

Rapid Assembly of Diversely Functionalized Spiroindenes by a Three‐Component Palladium‐Catalyzed C−H Amination/Phenol Dearomatization Domino Reaction

A novel palladium‐catalyzed three‐component reaction of phenol‐derived biaryls with N‐benzoyloxyamines and norbornadiene (NBD) has been developed for the assembly of highly functionalized spiroindenes. This domino process was realized through NBD‐assisted C−H amination and phenol dearomatization by forming one C−N bond and two C−C bonds in a single step. Preliminary studies indicated that asymmetric control of this transformation was feasible with chiral ligands. Moreover, the potential synthetic utility of this methodology was highlighted by a series of further transformations.     

Transition‐Metal‐Free Activation of Amides by N−C Bond Cleavage

The amide bond N?C activation represents a powerful strategy in organic synthesis to functionalize the historically inert amide linkage. This personal account highlights recent remarkable advances in transition‐metal‐free activation of amides by N?C bond cleavage, focusing on both (1) mechanistic aspects of ground‐state‐destabilization of the amide bond enabling formation of tetrahedral intermediates directly from amides with unprecedented selectivity, and (2) synthetic utility of the developed transformations. Direct nucleophilic addition to amides enables a myriad of powerful methods for the formation of C?C, C?N, C?O and C?S bonds, providing a straightforward and more synthetically useful alternative to acyl‐metals.     

Palladium(0)‐Catalyzed Heck Reaction/CH Activation/Amination Sequence with Diaziridinone: A Facile Approach to Indolines

Indolines are important moieties present in various biologically significant molecules and have attracted considerable attention in synthetic chemistry. This paper describes a Heck reaction/C? H activation/amination sequence for forming indolines using di‐tert‐butyldiaziridinone. The reaction process likely proceeds via a pallada(II)cycle, which is converted into an indoline by oxidative addition to the diaziridinone and two subsequent C? N bond formations.     

Extended Reaction Scope of Thiamine Diphosphate Dependent Cyclohexane‐1,2‐dione Hydrolase: From CC Bond Cleavage to CC Bond Ligation

ThDP‐dependent cyclohexane‐1,2‐dione hydrolase (CDH) catalyzes the C? C bond cleavage of cyclohexane‐1,2‐dione to 6‐oxohexanoate, and the asymmetric benzoin condensation between benzaldehyde and pyruvate. One of the two reactivities of CDH was selectively knocked down by mutation experiments. CDH‐H28A is much less able to catalyze the C? C bond formation, while the ability for C? C bond cleavage is still intact. The double variant CDH‐H28A/N484A shows the opposite behavior and catalyzes the addition of pyruvate to cyclohexane‐1,2‐dione, resulting in the formation of a tertiary alcohol. Several acyloins of tertiary alcohols are formed with 54–94 % enantiomeric excess. In addition to pyruvate, methyl pyruvate and butane‐2,3‐dione are alternative donor substrates for C? C bond formation. Thus, the very rare aldehyde–ketone cross‐benzoin reaction has been solved by design of an enzyme variant.     

Ruthenium(II)‐Catalyzed C−H Activation of Imidamides and Divergent Couplings with Diazo Compounds: Substrate‐Controlled Synthesis of Indoles and 3H‐Indoles

Indoles are an important structural motif that is commonly found in biologically active molecules. In this work, conditions for divergent couplings between imidamides and acceptor–acceptor diazo compounds were developed that afforded NH indoles and 3H‐indoles under ruthenium catalysis. The coupling of α‐diazoketoesters afforded NH indoles by cleavage of the C(N₂)?C(acyl) bond whereas α‐diazomalonates gave 3H‐indoles by C?N bond cleavage. This reaction constitutes the first intermolecular coupling of diazo substrates with arenes by ruthenium‐catalyzed C?H activation.     

Total Syntheses of Echitamine,Akuammiline, Rhazicine,and Pseudoakuammigine

Echitamine ( 1 ) and akuammiline ( 2 ) are representative members of a fascinating class of monoterpenoid indole alkaloids. We report the syntheses of 2 and its congener deacetylakuammiline ( 3 ). The azabicyclo[3.3.1]nonane motif was assembled through silver‐catalyzed internal alkyne cyclization, and one‐pot C?O bond cleavage/C?N bond formation furnished the pentacyclic scaffold. Compound 3 then served as a common intermediate for preparing a series of structurally diverse and synthetically challenging congeners including 1 . A position‐selective Polonovski–Potier reaction followed by formal N‐4 migration built the core of N‐demethylechitamine ( 4 ) and 1 . An alternative route featuring Meisenheimer rearrangement gave 4 as well. Oxidation of the alcohol within 3 gave rhazimal ( 5 ), which underwent tandem indolenine hydrolysis, hemiaminalization, and hemiketalization to form rhazicine ( 6 ). A sequence of N,O‐ketalization and reductive amination secured the chemoselectivity of N‐methylation, leading to pseudoakuammigine ( 7 ).     

Total Syntheses of Echitamine,Akuammiline, Rhazicine,and Pseudoakuammigine

Echitamine ( 1 ) and akuammiline ( 2 ) are representative members of a fascinating class of monoterpenoid indole alkaloids. We report the syntheses of 2 and its congener deacetylakuammiline ( 3 ). The azabicyclo[3.3.1]nonane motif was assembled through silver‐catalyzed internal alkyne cyclization, and one‐pot C?O bond cleavage/C?N bond formation furnished the pentacyclic scaffold. Compound 3 then served as a common intermediate for preparing a series of structurally diverse and synthetically challenging congeners including 1 . A position‐selective Polonovski–Potier reaction followed by formal N‐4 migration built the core of N‐demethylechitamine ( 4 ) and 1 . An alternative route featuring Meisenheimer rearrangement gave 4 as well. Oxidation of the alcohol within 3 gave rhazimal ( 5 ), which underwent tandem indolenine hydrolysis, hemiaminalization, and hemiketalization to form rhazicine ( 6 ). A sequence of N,O‐ketalization and reductive amination secured the chemoselectivity of N‐methylation, leading to pseudoakuammigine ( 7 ).     

Bottom‐up Construction of π‐Extended Arenes by a Palladium‐Catalyzed Annulative Dimerization of o‐Iodobiaryl Compounds

A straightforward method was developed for construction of aromatic compounds with a triphenylene core. The method involves Pd‐catalyzed annulative dimerization of o‐iodobiaryl compounds by double C?I and C?H bond cleavage steps. Simple reaction conditions are needed, requiring neither a ligand nor an oxidant, and the reaction tolerates a wide range of coupling partners without compromising efficiency or scalability. Significantly, the tetrachloro‐substituted synthon, 1,6,11‐trichloro‐4‐(4‐chlorophenyl)triphenylene, can be generated and used to prepare a series of fully fused, small graphene nanoribbons by a late‐stage arylation with arylboronic acids and a subsequent Scholl reaction. The synthetic strategy enables bottom‐up access to extended π‐systems in a controlled manner.