Copper‐Catalyzed Aerobic Oxidations of 3‐N‐Hydoxyaminoprop‐1‐ynes to Form 3‐Substituted 3‐Amino‐2‐en‐1‐ones: Oxidative Mannich Reactions with a Skeletal Rearrangement

Cu‐catalyzed aerobic oxidations of readily available 3‐N‐hydroxyaminopro‐1‐ynes with water, alcohols, or thiols to form diverse 3‐substituted 3‐amino‐2‐en‐1‐ones are described. The utility of this catalysis is manifested by a wide scope of applicable N‐hydroxyl propargylamines and nucleophiles, thus enabling the design of one‐pot cascade or two‐step sequential reactions. Besides synthetic significances, such oxidative Mannich reactions are mechanistically interesting because structurally reorganized products were obtained. Our mechanistic studies reveal that the aerobic oxidations involve initial formation of nitrone intermediates, followed by the attack of nucleophiles. Herein, water and MeOH implement the conversion of nitrone intermediates to reaction products in two distinct pathways.     

Gold‐Catalyzed Synthesis of Iodofulvenes

We report the gold‐catalyzed synthesis of highly functionalized iodofulvenes from iododialkynes under mild conditions. The catalytic cycle involves the formation of gold acetylides and vinylgold intermediates. These intermediates can then undergo an unprecedented iodine/gold exchange. This new pathway for catalyst transfer in dual gold catalysis opens up the possibility of highly regioselective transformations directed by the gold in the organogold intermediates. The resulting products are well suited for further metal‐mediated coupling reactions, allowing the synthesis of extended π‐systems.     

Study of the Transient Reactive Pd(IV) Intermediate in the Pd(OAc)2‐Catalyzed Oxidative Coupling Reaction System by Electrospray Ionization Tandem Mass Spectrometry

Pd‐catalyzed oxidative coupling reaction was of great importance in the aromatic C? H activation and the formation of new C? O and C? C bonds. Sanford has pioneered practical, directed C? H activation reactions employing Pd(OAc)₂ as catalyst since 2004. However, until now, the speculated reactive Pd(IV) transient intermediates in these reactions have not been isolated or directly detected from reaction solution. Electrospray ionization tandem mass spectrometry (ESI‐MS/MS) was used to intercept and characterize the reactive Pd(IV) transient intermediates in the solutions of Pd(OAc)₂‐catalyzed oxidative coupling reactions. In this study, the Pd(IV) transient intermediates were detected from the solution of Pd(OAc)₂‐catalyzed oxidative coupling reactions by ESI‐MS and the MS/MS of the intercepted Pd(IV) transient intermediate in reaction system was the same with the synthesized authentic Pd(IV) complex. Our ESI‐MS(/MS) studies confirmed the presence of Pd(IV) reaction transient intermediates. Most interestingly, the MS/MS of Pd(IV) transient intermediates showed the reductive elimination reactivity to Pd(II) complexes with new C? O bond formation into product in gas phase, which was consistent with the proposed reactivity of the Pd(IV) transient intermediates in solution.     

Reductive Amination by Photoredox Catalysis and Polarity‐Matched Hydrogen Atom Transfer

The excitation of a Ru^II photosensitizer in the presence of ascorbic acid leads to the reduction of iminium ions to electron‐rich α‐aminoalkyl radical intermediates, which are rapidly converted into reductive amination products by thiol‐mediated hydrogen atom transfer (HAT). As a result, the reductive amination of carbonyl compounds with amines by photoredox catalysis proceeds in good to excellent yields and with broad substrate scope and good functional group tolerance. The three key features of this work are 1) the rapid interception of electron‐rich α‐aminoalkyl radical intermediates by polarity‐matched HAT in a photoredox reaction, 2) the method of reductive amination by photoredox catalysis itself, and 3) the application of this new method for temporally and spatially controlled reactions on a solid support, as demonstrated by the attachment of a fluorescent dye on an activated cellulose support by photoredox‐catalyzed reductive amination.     

N‐Heterocyclic Carbene Catalysis via Azolium Dienolates: An Efficient Strategy for Remote Enantioselective Functionalizations

N‐heterocyclic carbene (NHC) catalysis has emerged as a powerful strategy in organic synthesis. In recent years a number of reviews have been published on NHC‐catalyzed transformations involving Breslow intermediates, acyl azoliums, α,β‐unsaturated acyl azoliums, homoenolate equivalents, and azolium enolates. However, the azolium dienolate intermediates generated by NHCs have been employed in asymmetric synthesis only very recently, especially in cycloadditions dealing with remote functionalization. This Minireview highlights all the developments and the new advances in NHC‐catalyzed asymmetric cycloaddition reactions involving azolium dienolate intermediates.     

N‐Heterocyclic‐Carbene‐Catalyzed Umpolung of Imines

N‐Heterocyclic carbene (NHC) catalysis has been widely used for the umpolung of aldehydes, and recently for the umpolung of Michael acceptors. Described herein is the umpolung of aldimines catalyzed by NHCs, and the reaction likely proceeds via aza‐Breslow intermediates. The NHC‐catalyzed intramolecular cyclization of aldimines bearing a Michael acceptor resulted in the formation of biologically important 2‐(hetero)aryl indole 3‐acetic‐acid derivatives in moderate to good yields. The carbene generated from the bicyclic triazolium salt was found to be efficient for this transformation.     

Cobalt‐Catalyzed Allylic Alkylation Enabled by Organophotoredox Catalysis

Co‐catalyzed allylic substitution reactions have received little attention, arguably because of the lack of any known advantage of Co catalysis over either Rh or Ir catalysis. Described here is a general and regioselective Co‐catalyzed allylic alkylation using an in situ catalyst activation by organophotoredox catalysis. This noble‐metal‐free catalytic system exhibits unprecedentedly high reactivities and regioselectivities for the allylation with an allyl sulfone, for the first time, representing the unique synthetic utility of the Co‐catalyzed method compared to the related Rh‐ and Ir‐catalyzed reactions.     

Copper‐Catalyzed 1,2‐Addition of α‐Carbonyl Iodides to Alkynes

β,γ‐Unsaturated ketones are an important class of organic molecules. Herein, copper catalysis has been developed for the synthesis of β‐γ‐unsaturated ketones through 1,2‐addition of α‐carbonyl iodides to alkynes. The reactions exhibit wide substrate scope and high functional group tolerance. The reaction products are versatile synthetic intermediates to complex small molecules. The method was applied for the formal synthesis of (±)‐trichostatin A, a histone deacetylase inhibitor.     

Scalable Synthesis of N‐Acetylated α‐Amino Acid‐Derived Oxazoline Ligands

A scalable cost‐effective synthesis of promising α‐amino acid‐derived oxazoline ligands has been developed. The advantage of the reported procedures is the use of crystallization for the purification of key intermediates and final products. The ligands obtained have recently demonstrated remarkable enantioselectivity in Pd (II) catalyzed C─H activation reactions. Hence, more rational synthetic route presented here will contribute to this rapidly growing field of chemistry.     

Gold‐Catalyzed Cascade Reactions for Synthesis of Carbo‐ and Heterocycles: Selectivity and Diversity

This account describes our recent efforts devoted to gold chemistry since 2009. Based on furyl–Au 1,3‐dipole analogues and related gold carbene intermediates, a rich variety of gold‐catalyzed cascade reactions have been developed, which provide facile access to a diverse range of novel carbo‐ and heterocycles. In these reactions, the selectivity can be well controlled by the catalyst (ligand and metal), substrate or reagent. In addition, we have also developed the corresponding enantioselective variants, which are guided by bis(phosphinegold) complexes derived from axially chiral scaffolds and asymmetric gold/chiral Brønsted acid relay catalysis.     

The Catalytic Mechanism of the Class C Radical S‐Adenosylmethionine Methyltransferase NosN

S ‐Adenosylmethionine (SAM) is one of the most common co‐substrates in enzyme‐catalyzed methylation reactions. Most SAM‐dependent reactions proceed through an S_N2 mechanism, whereas a subset of them involves radical intermediates for methylating non‐nucleophilic substrates. Herein, we report the characterization and mechanistic investigation of NosN, a class C radical SAM methyltransferase involved in the biosynthesis of the thiopeptide antibiotic nosiheptide. We show that, in contrast to all known SAM‐dependent methyltransferases, NosN does not produce S ‐adenosylhomocysteine (SAH) as a co‐product. Instead, NosN converts SAM into 5′‐methylthioadenosine as a direct methyl donor, employing a radical‐based mechanism for methylation and releasing 5′‐thioadenosine as a co‐product. A series of biochemical and computational studies allowed us to propose a comprehensive mechanism for NosN catalysis, which represents a new paradigm for enzyme‐catalyzed methylation reactions.     

One‐Pot Organocatalytic Asymmetric Synthesis of 3‐Nitro‐1,2‐dihydroquinolines by a Dual‐Activation Protocol

Generally, amine‐catalyzed enantioselective transformations rely on chiral enamine or unsaturated iminium intermediates. Herein, we report a protocol involving dual activation by an aromatic iminium and hydrogen‐bonding. An enantioselective aza‐Michael–Henry domino reaction of 2‐aminobenzaldehydes with nitroolefins has been developed through this protocol using primary amine thiourea catalysts to provide a variety of 3‐nitro‐1,2‐dihydroquinolines in moderate yields and with up to 90 % ee. The mechanism for the catalytic enantioselective reaction was confirmed by ESI mass spectrometric detection of the reaction intermediates. The products formed are substructures found in skeletons of important biological and pharmaceutical molecules.     

Ag/CNT‐catalyzed hydroamination of activated alkynes with aromatic amines

As a nanoparticle support material, carbon nanotubes (CNTs) provide a certain potential activation of catalysis in heterogeneous catalytic organic reactions. Herein, an efficient Ag/CNT‐catalyzed synthesis of enamines via hydroamination of activated alkynes with aromatic amines has been described. This catalyst still retains catalytic activity after being recycled and reused three times. In addition, it represents a green and environmentally friendly process for preparation of enamines. Copyright © 2013 John Wiley & Sons, Ltd.     

On‐Line Reaction Monitoring and Mechanistic Studies by Mass Spectrometry: Negishi Cross‐Coupling,Hydrogenolysis, and Reductive Amination

Reaction monitoring using inductive ESI mass spectrometry allows chemical reactions to be tracked in real time, including air‐ and moisture‐sensitive as well as heterogeneous reactions. Highly concentrated solutions can also be monitored for long periods without emitter clogging. Sheath gas assists in nebulization and a sample splitter reduces the delay time and minimizes contamination of the instrument. Short‐lived intermediates (ca. 5 s) were observed in Pd/C‐catalyzed hydrogenolysis, and several intermediates were seen in Negishi cross‐coupling reactions.     

On‐Line Reaction Monitoring and Mechanistic Studies by Mass Spectrometry: Negishi Cross‐Coupling,Hydrogenolysis, and Reductive Amination

Reaction monitoring using inductive ESI mass spectrometry allows chemical reactions to be tracked in real time, including air‐ and moisture‐sensitive as well as heterogeneous reactions. Highly concentrated solutions can also be monitored for long periods without emitter clogging. Sheath gas assists in nebulization and a sample splitter reduces the delay time and minimizes contamination of the instrument. Short‐lived intermediates (ca. 5 s) were observed in Pd/C‐catalyzed hydrogenolysis, and several intermediates were seen in Negishi cross‐coupling reactions.     

Visible‐Light‐Promoted Nickel‐ and Organic‐Dye‐Cocatalyzed Formylation Reaction of Aryl Halides and Triflates and Vinyl Bromides with Diethoxyacetic Acid as a Formyl Equivalent

A simple formylation reaction of aryl halides, aryl triflates, and vinyl bromides under synergistic nickel‐ and organic‐dye‐mediated photoredox catalysis is reported. Distinct from widely used palladium‐catalyzed formylation processes, this reaction proceeds by a two‐step mechanistic sequence involving initial in situ generation of the diethoxymethyl radical from diethoxyacetic acid by a 4CzIPN‐mediated photoredox reaction. The formyl‐radical equivalent then undergoes nickel‐catalyzed substitution reactions with aryl halides and triflates and vinyl bromides to form the corresponding aldehyde products. Significantly, besides aryl bromides, less reactive aryl chlorides and triflates and vinyl halides serve as effective substrates for this process. Since the mild conditions involved in this reaction tolerate a plethora of functional groups, the process can be applied to the efficient preparation of diverse aromatic aldehydes.     

Asymmetric Multicomponent Reactions Based on Trapping of Active Intermediates

Metal carbenes derived from transition metal‐catalyzed decomposition of diazo compounds react with nucleophiles with heteroatoms, such as alcohols and amines, to generate highly active oxonium/ammonium ylides intermediates. These intermediates can be trapped by appropriate electrophiles to provide three‐component products. Based on this novel trapping process, we have developed novel multicomponent reactions (MCRs) of diazo compounds, alcohols/anilines, and electrophiles. The nucleophiles were also extended to electron‐rich heterocycles (indoles and pyrroles)/arenes, in which the resulting zwitterionic intermediates were also trapped by electrophiles. By employing efficient catalysis strategy, the reactions were realized with excellent stereocontrol and wide substrate scope. In this personal account, we introduce our breakthroughs in the development of novel asymmetric MCRs via trapping of the active ylides and zwitterionic intermediates with a number of electrophiles, such as imines, aldehyde, and Michael acceptors, under asymmetric catalysis. Transition metal/chiral Lewis acid catalysis, transition metal/Brønsted acid catalysis, and chiral transition‐metal catalysis, enable excellent stereocontrolled outcomes. The methodologies not only provide experimental evidence to support the existence of protic onium ylides intermediates/zwitterionic intermediates and the stepwise pathways of carbene‐induced O?H, N?H and C?H insertions, but also offer a novel approach for the efficient construction of chiral polyfunctional molecules.     

Cooperative Catalysis for the Highly Diastereo‐ and Enantioselective [4+3]‐Cycloannulation of ortho‐Quinone Methides and Carbonyl Ylides

We describe herein a highly diastereo‐ and enantioselective [4+3]‐cycloannulation of ortho‐quinone methides and carbonyl ylides to furnish functionalized oxa‐bridged dibenzooxacines with excellent yields and stereoselectivity in a single synthetic step. The combination of rhodium and chiral phosphoric acid catalysis working in concert to generate both transient intermediates in situ provides direct access to complex bicyclic products with two quaternary and one tertiary stereogenic centers. The products may be further functionalized into valuable and enantiomerically highly enriched building blocks.     

Gold‐Catalyzed Cycloisomerization of Yne‐Vinylidenecyclopropanes: A Three‐Carbon Synthon for [3+2] Cycloadditions

A novel type of yne‐vinylidenecyclopropanes (VDCPs) has been synthesized and applied in gold‐catalyzed cycloisomerization reactions. It was found that these compounds can undergo an intramolecular cycloisomerization and perform as a three‐carbon synthon for [3+2] cycloaddition under gold catalysis to give fused [4.3.0] and [5.3.0] bicyclic derivatives and VDCP rearranged products in moderated to good yields under mild conditions. The substrate scope of these novel transformations has been explored and plausible reaction mechanisms have been presented on the basis of deuterium labeling experiments and DFT calculations.     

Highly Acidic Conjugate‐Base‐Stabilized Carboxylic Acids Catalyze Enantioselective oxa‐Pictet–Spengler Reactions with Ketals

Acyclic ketone‐derived oxocarbenium ions are involved as intermediates in numerous reactions that provide valuable products, however, they have thus far eluded efforts aimed at asymmetric catalysis. We report that a readily accessible chiral carboxylic acid catalyst exerts control over asymmetric cyclizations of acyclic ketone‐derived trisubstituted oxocarbenium ions, thereby providing access to highly enantioenriched dihydropyran products containing a tetrasubstituted stereogenic center. The high acidity of the carboxylic acid catalyst, which exceeds that of the well‐known chiral phosphoric acid catalyst TRIP, is largely derived from stabilization of the carboxylate conjugate base through intramolecular anion‐binding to a thiourea site.