Chemically Stable Diazo Peptides as Selective Probes of Cysteine Proteases in Living Cells.

Diazo peptides have been described earlier, however, due to their high reactivity have not been broadly used until today. Here, we report the preparation, properties, and applications of chemically stable internal diazo peptides. Peptidyl phosphoranylidene-esters and amides were found to react with triflyl azide primarily to novel 3,4-disubstituted triazolyl-peptides. Nonaflyl azide instead furnished diazo peptides, which are chemically stable from pH 1-14 as amides and from pH 1-8 as esters. Thus, diazo peptides prepared by solid phase peptide synthesis were stable to final deprotection with 95% trifluoroacetic acid. Diazo peptides with the recognition sequence of caspase-3 were identified as specific, covalent, and irreversible inhibitors of this enzyme at low nanomolar concentrations. A fluorescent diazo peptide entered living cells enabling microscopic imaging and quantification of apoptotic cells via flow cytometry. Thus, internal diazo peptides constitute a novel class of activity-based probes and enzyme inhibitors useful in chemical biology and medicinal chemistry.

Cleavage of Carbodicarbenes with N2O for Accessing Stable Diazoalkenes: Two-fold ligand exchange at a C(0)-atom.

The cleavage of carbophosphinocarbenes and carbodicarbenes with nitrous oxide (N2O) leads to the formation of room-temperature stable diazoalkenes. The utility of Ph3P/N2 and NHC/N2 ligand exchange reactions were demonstrated by accessing novel benzimidazole- and benzothiazole derived diazoalkenes, which are not accessible by the current state-of-the-art methods. The stable diazoalkenes subsequently allow further ligand exchange reactions at C(0) with carbon monoxide, isocyanide, or a diamidocarbene (DAC). Overall, the combination of hitherto unknown NHC/N2 and N2/L (L = DAC, CO, R-NC) ligand exchange reactions at a C(0) center allow the selective functionalization of the carbodicarbene ligand structure which represents a new methodology to rapidly assemble novel carbodicarbenes or cumulenic compounds.

Microwave Promoted Tandem Reaction of Free Primary Arylamines with Diazo Compounds under Metal-Free Condition in Water: Clean Synthesis of 2,2-Disubstituted 3­Oxindoles.

Herein, a microwave promoted tandem reaction of free primary arylamines with diazo compounds in water for clean synthesis of 2,2-disubstituted 3-oxindoles is present. Water plays important roles in the whole cascade process: O-H insertion to diazo, air oxidation, ortho C-H functionalization, cyclization and 1,2-ester migration. In particular, water plays a mediation role in the site selective ortho-C-H addition.

Modular Synthesis of Azines Bearing a Guanidine Core from N-Heterocyclic Carbene (NHC)-Derived Selenoureas and Diazo Reagents.

N-Heterocyclic carbene (NHC)-derived selenoureas comprise a fundamentally important class of NHC derivatives, with key applications in coordination chemistry and the determination of NHC electronic properties. Considering the broad reactivity of chalcogen-containing compounds, it is surprising to note that the use of NHC-derived selenoureas as organic synthons remains essentially unexplored. The present contribution introduces a novel, straightforward transformation leading to azines bearing a guanidine moiety, through the reaction of a wide range of NHC-derived selenoureas with commercially available diazo compounds, in the presence of triphenylphosphine. This transformation offers a new approach to such products, having biological, materials chemistry, and organic synthesis applications. The guanidine-bearing azines are obtained in excellent yields, with all manipulations taking place in air. A reaction mechanism is proposed, based on both experimental mechanistic findings and density functional theory (DFT) calculations. A one-pot, multicomponent transesterification reaction between selenoureas, α-diazoesters, alcohols, and triphenylphosphine was also developed, providing highly functionalized azines.

Polycyclic Pyrazolidines by Tandem Diazomalonate Dipolar Cycloadditions and CpRu-Catalyzed Carbene Additions.

Thanks to the ability of diazo derivatives to react either as 1,3-dipoles and as carbenes after dinitrogen extrusion, combinations of oxa or aza benzonorbornadienes and diazomalonates afford polycyclic pyrazolidines via a three-step sequence of (i) a highly diastereoselective [3+2]-cycloaddition, (ii) a CpRu-catalyzed carbene addition, and (iii) a second dipolar cycloaddition. Of importance, step (II) represents a unique access to novel bench-stable N,N-cyclic azomethine imines, which behave as effective 1,3-dipoles in combination with electron-poor dipolarophiles. Each step proceeds efficiently and the 3-step process can be performed in one-pot to yield a polycyclic pyrazolidine in excellent overall yield (90 %).

Stereoselective Synthesis of Polysubstituted Conjugated Dienes Enabled by Photo-Driven Sequential Sigmatropic Rearrangement.

We here reported a highly stereoselective method for the synthesis of polysubstituted conjugated dienes from α-aryl α-diazo alkynyl ketones and pyrazole-substituted unsymmetric aminals under mild conditions, which was promoted by photo-irridation and involved with 1,6-dipolar intermediate and quadruple sigmatropic rearrangements, was successfully developed. In this transformation, the cleavage of four bonds and the recombination of five bonds were implemented in one operational step. This protocol provided a modular tool for constructing dienes from amines, pyrazoles and α-alkynyl-α-diazoketones in one-pot manner. The results of mechanistic investigation indicated that the plausible reaction path underwent the 1,6-sigmatropic rearrangement instead of the 1,5-sigmatropic rearrangement.

Photocatalytic Enantioselective Radical Cascade Multicomponent Minisci Reaction of ß-Carbolines Using Diazo Compounds as Radical Precursors.

Here, a photocatalytic asymmetric multicomponent cascade Minisci reaction of ß-carbolines with enamides and diazo compounds is reported, enabling an effective enantioselective radical C─H functionalization of ß-carbolines with high yields and enantioselectivity (up to 83% yield and 95% ee). This enantioselective multicomponent Minisci protocol exhibits step economy, high chemo-/enantio-selective control, and good functional group tolerance, allowing access to a variety of valuable chiral ß-carbolines. Notably, diazo compounds are suitable radical precursors in enantioselective cascade radical reactions. Moreover, the efficiency and practicality of this approach are demonstrated by the asymmetric synthesis of bioactive compounds and natural products.

Synthesis of Hypervalent Iodine Diazo Compounds and Their Application in Organic Synthesis.

Diazomethyl-substituted iodine(III) compounds with electron-withdrawing groups (EWG) connected to diazo methyl center were a type of donor-acceptor diazo compounds with potential reaction abilities similar to ordinary diazo compounds. Although several diazomethyl-substituted iodine(III) compounds were synthesized and used in the nucleophilic substitution reactions as early as 1994, the synthesis and application of new iodine(III) diazo compounds have only been reported to a certain extent in recent years. In the presence of rhodium catalyst, photocatalyst, or nucleophiles, diazomethyl-substituted iodine(III) compounds can be converted into rhodium-carbenes, diazomethyl radicals, ester radicals or nucleophilic intermediates, which can be used as key intermediates for the formation of chemical bonds. The aim of this review is to give an overview of diazomethyl-substituted iodine(III) compounds in organic synthesis.

Trifluoroethylation and Pentafluoropropylation of C(sp3)-H Bonds.

Polyfluorinated substituents often enhance effectiveness, improve the stability within metabolic processes, and boost the lipophilicity of biologically active compounds. However, methods for their introduction into aliphatic carbon chains remain very limited. A potentially general route to integrate the fluorinated scaffolds into organic molecules involves insertion of fluorine-containing carbenes into C(sp3)-H bonds. The electron-withdrawing characteristics of perfluoroalkyl groups enhances the reactivity of these carbenes which should enable the functionalization of unactivated C(sp3)-H bonds. Curiously, it appears that use of perfluoroalkyl-containing carbenes in alkane C-H functionalization is exceedingly rare. This concept describes photolysis, enzymatic catalysis, and transition metal catalysis as three primary approaches to C(sp3)-H functionalization by trifluoromethylcarbene and its homologues.

Recent Synthetic Advances on the Use of Diazo Compounds Catalyzed by Metalloporphyrins.

Diazo compounds are organic substances that are often used as precursors in organic synthesis like cyclization reactions, olefinations, cyclopropanations, cyclopropenations, rearrangements, and carbene or metallocarbene insertions into C-H, N-H, O-H, S-H, and Si-H bonds. Typically, reactions from diazo compounds are catalyzed by transition metals with various ligands that modulate the capacity and selectivity of the catalyst. These ligands can modify and enhance chemoselectivity in the substrate, regioselectivity and enantioselectivity by reflecting these preferences in the products. Porphyrins have been used as catalysts in several important reactions for organic synthesis and also in several medicinal applications. In the chemistry of diazo compounds, porphyrins are very efficient as catalysts when complexed with low-cost metals (e.g., Fe and Co) and, therefore, in recent years, this has been the subject of significant research. This review will summarize the advances in the studies involving the field of diazo compounds catalyzed by metalloporphyrins (M-Porph, M = Fe, Ru, Os, Co, Rh, Ir) in the last five years to provide a clear overview and possible opportunities for future applications. Also, at the end of this review, the properties of artificial metalloenzymes and hemoproteins as biocatalysts for a broad range of applications, namely those concerning carbene-transfer reactions, will be considered.

Pyrazoline and Analogs: Substrate-Based Synthetic Strategies.

Among the many reports published on strategies applicable to synthesizing pyrazolines and its analogs, The 1,3-dipolar cycloaddition offers a remarkably wide range of utility. Many 1,3-dipolar cycloaddition reactions used for the synthesis of pyrazolines provide better selectivity, eco-friendly, and less expensive chemical processes. In the presented study, we have reviewed various recently adopted strategies for the synthesis of pyrazoline, which followed the 1,3-dipolar cycloaddition reactions mechanism and classified them based on starting materials such as nitrile imines, diazo compounds, different zwitter ions, chalcones, and isoprene units. The manuscript also focused on the synthesis of pyrazolines starting from Seyferth-Gilbert reagents (SGR) and Psilostachyin (PSH) reagents. We hope this work will help those engaged or have plans to research pyrazoline or its analogs, as synthetic protocols based on starting material are rarely available for pyrazolines. Thus, this article holds a valuable complement to the development of newer pyrazoline and its derivatives.

Thermal/Blue Light Induced Cross-Linking of Acrylic Coatings with Diazo Compounds.

The thermal curing of industrial coatings (e.g., car painting and metal coil coatings) is accompanied by a substantial energy consumption due to the intrinsically high temperatures required during the curing process. Therefore, the development of new photochemical curing processes-preferably using visible light-is in high demand. This work describes new diazo-based cross-linkers that can be used to photocure acrylic coatings using blue light. This work demonstrates that the structure of the tethered diazo compounds influences the cross-linking efficiency, finding that side reactions are suppressed upon engineering greater molecular flexibility. Importantly, this work shows that these diazo compounds can be employed as either thermal or photochemical cross-linkers, exhibiting identical crosslinking performances. The performance of diazo-cross-linked coatings is evaluated to reveal excellent water resistance and demonstrably similar material properties to UV-cured acrylates. These studies pave the way for further usage of diazo-functionalized cross-linkers in the curing of paints and coatings.

Chemical Synthesis with Gaseous Molecular Ions: Harvesting [B12 Br11 N2 ]- from a Mass Spectrometer.

Mass spectrometry frequently reveals the existence of transient gas phase ions that have not been synthesized in solution or in bulk. These elusive ions are, therefore, often considered to be primarily of analytical value in fundamental gas phase studies. Here, we provide proof-of-concept that the products of ion-molecule reactions in mass spectrometers may be collected on surfaces to generate condensed matter and thus serve as building blocks to synthesize new compounds. The highly reactive fragment anion [B12 Br11 ]- was generated in a mass spectrometer and converted to [B12 Br11 N2 ]- in the presence of molecular nitrogen followed by its mass-selection and soft-landing on surfaces. The molecular structure of [B12 Br11 N2 ]- , which has not been synthetically obtained before, was confirmed by conventional methods of molecular analysis, including nuclear magnetic resonance and infrared spectroscopy. The [B12 Br11 N2 ]- ion is stable on surfaces and in solution at room temperature, but thermal annealing induces elimination of N2 and provides access to the highly reactive intermediate [B12 Br11 ]- in the condensed phase, which can be further used as a reagent, for example, for electrophilic aromatic substitutions. Thus, isolation of [B12 Br11 N2 ]- expands the repertoire of the available diazo ions that can be employed as versatile intermediates in various chemical transformations.

Carbene Formation or Reduction of the Diazo Functional Group? An Unexpected Solvent-Dependent Reactivity of Cyclic Diazo Imides.

The control of the reactivity of diazo compounds is commonly achieved by the choice of a suitable catalyst, e.g. via stabilization of singlet carbenes or radical intermediates. Herein, we report on the light-promoted reactivity of cyclic diazo imides with thiols, where the choice of solvent results in two fundamentally different reaction pathways. In dichloromethane (DCM), a carbene is formed initially and engages in a cascade C-H functionalization/thiolation reaction to deliver indane-fused pyrrolidines in good to excellent yields. When switching to acetonitrile solvent, the carbene pathway is shut down and an unusual reduction of the diazo compound occurs under otherwise identical reaction conditions, where the aryl thiol acts as reductant. A combined set of experimental and computational studies was carried out to obtain mechanistic understanding and to support that indane formation proceeds via the insertion of a triplet carbene, while the reduction of diazo imides proceeds via an electron transfer process.

Cooperative Bimetallic Catalysis via One-Metal/Two-Ligands: Mechanistic Insights of Polyfluoroarylation-Allylation of Diazo Compounds.

Metal/ligand in situ assembly is crucial for tailoring the reactivity & selectivity in transition metal catalysis. Cooperative catalysis via a single metal/two ligands is still underdeveloped, since it is rather challenging to harness the distinct reactivity profiles of the species generated by self-assembly of a single metal precursor with a mixture of different ligands. Herein, we report a catalytic system composed of a single metal/two ligands for a three-component reaction of polyfluoroarene, α-diazo ester, and allylic electrophile, leading to highly efficient construction of densely functionalized quaternary carbon centers, that are otherwise hardly accessible. Mechanistic studies suggest this reaction follows a cooperative bimetallic pathway via two catalysts with distinct reactivity profiles, which are assembled in situ from a single metal precursor and two ligands and work in concert to escort the transformation.

Synthesis and Reactivity of a Zinc Diazoalkyl Complex: [3+2] Cycloaddition Reaction with Carbon Monoxide.

This work reports the synthesis, characterization, and reactivity of the first example of a well-defined zinc α-diazoalkyl complex. Treatment of zinc(I)-zinc(I) bonded compound L2 Zn2 [L=CH3 C(2,6-i Pr2 C6 H3 N)CHC(CH3 )(NCH2 CH2 PPh2 )] or zinc(II) hydride LZnH with trimethylsilyldiazomethane affords zinc diazoalkyl complex LZnC(N2 )SiMe3 . This complex liberates N2 in the presence of a nickel catalyst to form an α-zincated phosphorus ylide by reacting with the pendant phosphine. It selectively undergoes formal [3+2] cycloaddition with CO2 or CO to form the corresponding product with a five-membered heterocyclic core. Notably, the use of CO in such a [3+2] cycloaddition reaction is unprecedented, reflecting a novel CO reaction mode.

Copper (I)-BOX Catalyzed Asymmetric 3-Component Reaction for the Synthesis of Trifluoromethylated Propargylic Ethers and Anilines.

An asymmetric 3-component reaction between EthynylBenziodoXoles (EBXs), 2,2,2-trifluorodiazoethane and nucleophiles catalyzed by a CuI -BOX (Bisoxazoline) catalyst is described. This protocol gives access to chiral trifluoromethylated propargyl ethers and anilines, which are valuable building blocks in synthetic and medicinal chemistry. The reaction proceeds with high enantioselectivity and yield with different nucleophiles such as primary, secondary and tertiary alcohols, as well as both electron-rich and electron-poor anilines. Aryl-, alkyl- and silyl-substituted alkynes can be successfully introduced as electrophiles. In case of chiral substrates, high catalyst control was observed, leading to good diastereoselectivity.

Robust Sub-5 Nanometer bis(Diarylcarbene)-Based Thin Film for Molecular Electronics and Plasmonics.

In miniaturized electronic and optoelectronic circuits, molecular tunnel junctions have attracted enormous research interest due to their small footprint, low power consumption, and rich molecular functions. However, the most popular building blocks used in contemporary molecular tunnel junctions are thiol molecules, which attach to electrode surfaces via a metal-thiolate (MS) bond, showing low stability and usually quick degradation within several days. To pave the way for more widely applicable and stable molecular tunnel junctions, there is a need to develop new molecular anchoring groups. Here, this work demonstrates robust and air-stable molecular tunnel junctions with a sub-5 nanometer bis(diarylcarbene)-based thin film as the tunneling barrier, which anchors to the electrode surface via a AuC bond. The bis(diarylcarbene)-based molecular tunnel junctions exhibit high thermal stability against heating up to 200 °C and long storage lifetime over 5 months in an ambient environment. Both electrical and optical performance of these bis(diarylcarbene)-based molecular junctions are characterized systematically, showing similar behaviors to thiol-based junctions as well as largely improved emission stability. This research highlights the excellent performance of bis(diarylcarbene)-based molecular tunnel junctions, which could be useful for applications in molecular electronics and plasmonics.

"Sandwich" Diimine-Copper Catalyzed Trifluoroethylation and Pentafluoropropylation of Unactivated C(sp3 )-H Bonds by Carbene Insertion.

We report here "sandwich"-diimine copper complex-catalyzed trifluoroethylation and pentafluoropropylation of unactivated C(sp3 )-H bonds in alkyl esters, halides, and protected amines by employing CF3 CHN2 and CF3 CF2 CHN2 reagents. Reactions proceed in dichloromethane solvent at room temperature. Identical C-H functionalization conditions and stoichiometries are employed for generality and convenience. Selectivities for C-H insertions are higher for compounds possessing stronger electron-withdrawing substituents. Preliminary mechanistic studies point to a mechanism involving a pre-equilibrium forming a "sandwich"-diimine copper-CF3 CHN2 complex followed by rate-determining loss of nitrogen affording the reactive copper carbene. It reacts with trifluoromethyldiazomethane about 6.5 times faster than with 1-fluoroadamantane explaining the need for slow addition of the diazo compound.

Access to cyclopropanes with geminal trifluoromethyl and difluoromethylphosphonate groups.

A synthetic route to the bench-stable fluorinated masked carbene reagent diethyl 2-diazo-1,1,3,3,3-pentafluoropropylphosphonate, bearing a trifluoromethyl and a difluoromethyl group is reported for the first time. Its application in CuI-catalyzed cyclopropanation reactions with aromatic and aliphatic terminal alkenes under mild reaction conditions is demonstrated. In total, sixteen new cyclopropanes were synthesized in good to very good yields.