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 %).

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.

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.

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.

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.

"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.

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.

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.

[3+3]-Annulation of Cyclic Nitronates with Vinyl Diazoacetates: Diastereoselective Synthesis of Partially Saturated [1,2]Oxazino[2,3-b][1,2]oxazines and Their Base-Promoted Ring Contraction to Pyrrolo[1,2-b][1,2]oxazine Derivatives.

A rhodium(II)-catalyzed reaction of cyclic nitronates (5,6-dihydro-4H-1,2-oxazine N-oxides) with vinyl diazoacetates proceeds as a [3+3]-annulation producing bicyclic unsaturated nitroso acetals (4a,5,6,7-tetrahydro-2H-[1,2]oxazino[2,3-b][1,2]oxazines). Optimization of reaction conditions revealed the use of Rh(II) octanoate as the preferred catalyst in THF at room temperature, which allows the preparation of target products in good yields and excellent diastereoselectivity. Under basic conditions, namely, the combined action of DBU and alcohol, these nitroso acetals undergo ring contraction of an unsaturated oxazine ring into the corresponding pyrrole. Both transformations can be performed in a one-pot fashion, thus constituting a quick approach to oxazine-annulated pyrroles from available starting materials, such as nitroalkenes, olefins, and diazo compounds.

Theoretical Study on the Copper-Catalyzed ortho-Selective C-H Functionalization of Naphthols with α-Phenyl-α-Diazoesters.

The aromatic C(sp2)-H functionalization of unprotected naphthols with α-phenyl-α-diazoesters under mild conditions catalyzed by CuCl and CuCl2 exhibits high efficiency and unique ortho-selectivity. In this study, the combination of density functional theory (DFT) calculations and experiments is employed to investigate the mechanism of C-H functionalization, which reveals the fundamental origin of the site-selectivity. It explains that CuCl-catalyzed ortho-selective C-H functionlization is due to the bimetallic carbene, which differs from the reaction catalyzed by CuCl2 via monometallic carbene. The results demonstrate the function of favourable H-bond interactions on the site- and chemo-selectivity of reaction through stabilizing the rate-determining transition states in proton (1,3)-migration.

A Photoenzymatic Strategy for Radical-Mediated Stereoselective Hydroalkylation with Diazo Compounds.

Carbene insertion reactions initiated with diazo compounds have been widely used to develop unnatural enzymatic reactions. However, alternative functionalization of diazo compounds in enzymatic processes has been unexploited. Herein, we describe a photoenzymatic strategy for radical-mediated stereoselective hydroalkylation with diazo compounds. This method generates carbon-centered radicals through an ene reductase catalyzed photoinduced electron transfer process from diazo compounds, enabling the synthesis of γ-stereogenic carbonyl compounds in good yields and stereoselectivities. This study further expands the possible reaction patterns in photo-biocatalysis and offers a new approach to solving the selectivity challenges of radical-mediated reactions.

Copper Complexes with Diazoolefin Ligands and their Photochemical Conversion into Alkenylidene Complexes.

Homometallic copper complexes with alkenylidene ligands are discussed as intermediates in catalysis but the isolation of such complexes has remained elusive. Herein, we report the structural characterization of copper complexes with bridging and terminal alkenylidene ligands. The compounds were obtained by irradiation of CuI complexes with N-heterocyclic diazoolefin ligands. The complex with a terminal alkenylidene ligand required isolation in a crystalline matrix, and its structural characterization was enabled by in crystallo photolysis at low temperature.

Chemoselective Caging of Carboxyl Groups for On-Demand Protein Activation with Small Molecules.

Tools for on-demand protein activation enable impactful gain-of-function studies in biological settings. Thus far, however, proteins have been chemically caged at primarily Lys, Tyr, and Sec, typically through the genetic encoding of unnatural amino acids. Herein, we report that the preferential reactivity of diazo compounds with protonated acids can be used to expand this toolbox to solvent-accessible carboxyl groups with an elevated pKa value. As a model protein, we employed lysozyme (Lyz), which has an active-site Glu35 residue with a pKa value of 6.2. A diazo compound with a bioorthogonal self-immolative handle esterified Glu35 selectively, inactivating Lyz. The hydrolytic activity of the caged Lyz on bacterial cell walls was restored with two small-molecule triggers. The decaging was more efficient by small molecules than by esterases. This simple chemical strategy was also applied to a hemeprotein and an aspartyl protease, setting the stage for broad applicability.

Diazoalkenes: From an Elusive Intermediate to a Stable Substance Class in Organic Chemistry.

Over decades diazoalkenes (R2 C=C=N2 ) were postulated as reactive intermediates in organic chemistry even though their direct spectroscopic detection proved very challenging. In the 1970/80ies several groups probed their existence mainly indirectly by trapping experiments or directly by matrix-isolation studies. In 2021, our group and the Severin group reported independently the synthesis and characterization of the first room-temperature stable diazoalkenes, which initiated a rapidly expanding research field. Up to now four different classes of N-heterocyclic substituted room-temperature stable diazoalkenes have been reported. Their properties and unique reactivity, such as N2 /CO exchange or utilization as vinylidene precursors in organic and transition metal chemistry are presented. This review summarizes the early discoveries of diazoalkenes from their initial postulation as transient, elusive species up to the recent findings of the room-temperature stable derivatives.

Room-Temperature-Stable Diazoalkenes by Diazo Transfer from Azides: Pyridine-Derived Diazoalkenes.

Recently, stable diazoalkenes have received significant attention as a new substance class in organic chemistry. While their previous synthetic access was exclusively limited to the activation of nitrous oxide, we here establish a much more general synthetic approach utilizing a Regitz-type diazo transfer with azides. Importantly, this approach is also applicable to weakly polarized olefins such as 2-pyridine olefins. The new pyridine diazoalkenes are not accessible by the activation of nitrous oxide, allowing for a considerable extension of the scope of this only recently accessed functional group. The new diazoalkene class has properties distinct from the previously reported classes, such as photochemically triggered loss of dinitrogen affording cumulenes and not C-H insertion products. Pyridine-derived diazoalkenes represent the so far least polarized stable diazoalkene class reported.

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.

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.

A Convergent, Modular Approach to Trifluoromethyl-Bearing 5-Membered Rings via Catalytic C(sp3 )-H Activation.

Trifluoromethyl-bearing 5-membered rings are prevalent in bioactive molecules, but modular approaches to these compounds by functionalization of robust C(sp3 )-H bonds in a direct and selective manner are extremely challenging. Herein we report the rhodium-catalyzed α-CF3 -α-alkyl carbene insertion into C(sp3 )-H bonds of a broad range of substrates to access 7 types of CF3 -bearing saturated 5-membered carbo- and heterocycles. The reaction is particularly effective for benzylic C-H insertion exerting good site-, diastereo- and enantiocontrol, and applicable to the synthesis of chiral CF3 analogues of bioactive molecules. Ruthenium α-CF3 -α-alkyl carbene complexes underwent stoichiometric reactions to give C-H insertion products, lending evidence for the involvement of metal α-CF3 -α-alkyl carbene species in the catalytic cycle. DFT calculations revealed that the π⋅⋅⋅π attraction and intra-carbene C-H⋅⋅⋅F hydrogen bond elucidate the origin of selectivity of the benzylic C-H insertion reactions.

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.