Nitrene Insertion Research Articles

Introducing the Catalytic Amination of Silanes via Nitrene Insertion.

The direct functionalization of Si–H bonds by the nitrene insertion methodology is described. A copper(I) complex bearing a trispyrazolylborate ligand catalyzes the transfer of a nitrene group from PhI=NTs to the Si–H bond of silanes, disilanes, and siloxanes, leading to the exclusive formation of Si–NH moieties in the first example of this transformation. The process tolerates other functionalities in the substrate such as several C–H bonds and alkyne and alkene moieties directly bonded to the silicon center. Density functional theory (DFT) calculations provide a mechanistic interpretation consisting of a Si–H homolytic cleavage and subsequent rebound to the Si-centered radical.

Biocatalytic Platform for Intermolecular Propargylic C–H Amination

Key words nitrene insertion - amination - propargylic amines - enzyme engineering

The effect of zero‐point energy in simulating organic reactions with post‐transition state bifurcation

AbstractAmbimodal reactions involve a single transition state leading to multiple products. To assess the ratio of the bifurcation products, quasiclassical trajectories (QCTs) are initiated from transition state geometries that are randomly sampled using the zero‐point energy (ZPE) plus thermal energy of a molecule's vibrational modes. However, in the QCTs, the influence of ZPE percentage in the resulting bifurcation ratio and time gap between formation of bonds is not well understood. To benchmark the effect of varying the percentage of the molecules' inherent ZPE used in the simulation, three organic reactions with distinct mechanisms that all display post‐transition state bifurcation were selected. The three reactions studied include an intramolecular [6 + 4]/[4 + 2] cycloaddition, an asynchronous nitrene insertion, and an SN2/addition to a carbonyl on an α‐bromoketone. These reactions encompass various modes of bond formation and cleavage, offering a broad view of the influence of ZPE scaling in evaluating the product ratio resulted from post‐transition state bifurcation. Exploring means of tuning selectivity in simulation enables development of more accurate organic reaction modeling for synthetic prediction. This work will establish a basis for future QCT studies of organic reactions.

An Isolable Gallium-Substituted Nitrilimine and its Reactivity with B-H, Si-H and B-B Bonds.

Reaction of the Ga(I) compound NacNacGa (9) with the diazo compound N2 CHSiMe3 affords the nitrilimine compound NacNacGa(N-NCSiMe3 )(CH2 SiMe3 ) (10). Carrying out this reaction in the presence of pyridine does not lead to C-H activation on the transient alkylidene NacNacGa=CHSiMe3 but generates a metallated diazo species NacNacGa(NHN=CHSiMe3 )(CN2 SiMe3 ) (13) that further rearranges into the isonitrile compound NacNacGa(NHN=CHSiMe3 )(N(NC)SiMe3 ) (15). Reactions of 10 with the silane H3 SiPh and the borane HBcat furnished products of 1,3 addition to the nitrilimine moiety NacNacGa{N(ERn )NCSiMe3 }(CH2 SiMe3 ), whereas reaction with the diborane B2 cat2 gave the product of formal nitrene insertion into the B-B bond. DFT calculations suggest that the interaction of 9 with N2 CHSiMe3 proceeds through intermediate formation of an alkylidene compound that undergoes CH activation with a second molecule of N2 CHSiMe3 . Insertion into the B-B bond likely proceeds through an initial 1,3-addition of the diborane, followed by boryl migration to the former nitrene center.

Enzymatic Nitrene Insertion into C–H Bonds for Synthesis of Enantioenriched Amides

Enzymatic Nitrene Insertion into C–H Bonds for Synthesis of Enantioenriched Amides

Rhodium-Catalyzed Sulfimidation Reactions: A Computational Study

The rhodium-catalyzed sulfimidation of thioethers using N-mesyloxycarbamates is a powerful tool to access chiral sulfilimines. 4-Dimethylaminopyridine (DMAP) and bis-(DMAP)CH2Cl2 additives were found to be crucial to achieving high yields and selectivities. Experimental studies have suggested that the reaction mechanism would involve a rhodium/nitrenoid complex rather than a rhodium/nitrene species. A density functional theory (DFT) study to investigate rhodium-catalyzed sulfimidation reactions is reported herein. Both rhodium nitrene and rhodium nitrenoid species were proposed as key intermediates for the amination reaction. The role of additives was investigated, showing that the apical DMAP ligand was crucial to stabilize the rhodium nitrene intermediate. Furthermore, adding bis-(DMAP)CH2Cl2 diverges the reaction mechanism from a rhodium nitrene insertion to a substitution-like reaction of the rhodium nitrenoid complex. This deviation was demonstrated to be substrate-dependent, which is in agreement with the experimental Hammett study.

Synthesis of 1,4-dihydropyrazolo[4,3-b]indoles via intramolecular C(sp2)-N bond formation involving nitrene insertion, DFT study and their anticancer assessment

We herein report a new synthetic route for a series of unreported 1,4-dihydropyrazolo[4,3-b]indoles (6–8) via deoxygenation of o-nitrophenyl-substituted N-aryl pyrazoles and subsequent intramolecular (sp2)-N bond formation under microwave irradiation expedite modified Cadogan condition. This method allows access to NH-free as well as N-substituted fused indoles. DFT study and controlled experiments highlighted the role of nitrene insertion as one of the plausible reaction mechanisms. Furthermore, the target compounds exhibited cytotoxicity at low micromolar concentration against lung (A549), colon (HCT-116), and breast (MDA-MB-231, and MCF-7) cancer cell lines, induced the ROS generation and altered the mitochondrial membrane potential of highly aggressive MDA-MB-231 cells. Further investigations revealed that these compounds were selective Topo I (6h) or Topo II (7a, 7b) inhibitors.

Straightforward Construction and Functionalizations of Nitrogen-Containing Heterocycles Through Migratory Insertion of Metal-Carbenes/Nitrenes.

Nitrogen-containing heterocycles are widely found in various biologically active substrates, pharmaceuticals, natural products and organic materials. Consequently, the continuous effort has been devoted towards the development of straightforward, economical, environmentally acceptable, efficient and ingenious methods for the synthesis of various N-containing heterocycles and their functionalizations. Arguably, one of the most prominent direct strategy is regioselective C-H bond functionalizations which provide the step and atom economical approaches in the presence of suitable coupling partners. In this context, site-selective migratory insertion of metal carbenes/nitrenes to the desired C-H bonds has proven as a useful tool to access various functionalized nitrogen heterocycles. In this personal account, we highlight some of our contemporary development toward constructing N-containing heterocycles and their direct functionalizations via transition metal catalysed C-H bond functionalizations based on migratory insertion of metal-carbenes and nitrenes.

Iron‐Catalyzed Intramolecular C—H Amidation of N‐Benzoyloxyureas

Main observation and conclusionA redox‐neutral Fe‐catalyzed intramolecular C—H amidation of N‐benzoyloxyureas is described. This methodology employs a simple iron complex in situ generated from Fe(OTf)2 and bipyridine as the catalyst and N‐benzoyloxyureas as the nitrene precursors without using exogenous oxidants. An array of cyclic ureas were synthesized via aliphatic C(sp3)—H amidation in excellent yields. In addition, this catalytic system is also amenable to aryl C(sp2)—H nitrene insertion to provide benzimidazolones in moderate yields.

Hydroxylamines as One-Atom Nitrogen Sources for Metal-Catalyzed Cycloadditions

AbstractTransition-metal-catalyzed C–N bond formation is one of the most important pathways to synthesize N-heterocycles. Hydroxylamines can be transformed into a nucleophilic reagent to react with a carbon cation or coordinate with a transition metal; it can also become an electrophilic nitrogen source to react with arenes, alkenes, and alkynes. In this short review, the progress made on transition-metal-catalyzed cycloadditions with hydroxylamines as a nitrogen source is summarized.1 Introduction2 Cycloaddition To Form Aziridine Derivatives2.1 Intramolecular Cycloaddition To Form Aziridine Derivatives2.2 Intermolecular Cycloaddition To Form Aziridine Derivatives3 Cycloaddition To Form Indole Derivatives4 Cycloaddition To Form Other N-Heterocycles4.1 Aza-Heck-Type Amination Reactions4.2 Nitrene Insertion Amination Reactions4.3 Intramolecular Nucleophilic and Electrophilic Amination Reactions5 Conclusion and Outlook

Copper/silver co-mediated three-component bicyclization for accessing indeno[1,2-c]azepine-3,6-diones.

A new copper/silver-co-mediated three-component bicyclization of benzene-linked 1,6-enynes with ICF2CO2Et with TMSN3 was reported, and used to produce a wide range of hitherto unreported difluorinated tetrahydroindeno[1,2-c]azepine-3,6-diones with moderate to good yields. The mechanistic pathway consists of radical-induced 1,6-addition-cyclization, oxidative addition, reductive elimination, nitrene insertion and N-O cleavage, resulting in continuous multiple bond-forming events including C-C and C-N bonds to build up a 6/5/7 tricyclic framework.

Catalytic enantioselective synthesis of β-amino alcohols by nitrene insertion

Chiral β-amino alcohols are important building blocks for the synthesis of drugs, natural products, chiral auxiliaries, chiral ligands and chiral organocatalysts. The catalytic asymmetric β-amination of alcohols offers a direct strategy to access this class of molecules. Herein, we report a general intramolecular C(sp3)–H nitrene insertion method for the synthesis of chiral oxazolidin-2-ones as precursors of chiral β-amino alcohols. Specifically, the ring-closing C(sp3)–H amination of N -benzoyloxycarbamates with 2 mol% of a chiral ruthenium catalyst provides cyclic carbamates in up to 99% yield and with up to 99% ee. The method is applicable to benzylic, allylic, and propargylic C–H bonds and can even be applied to completely non-activated C(sp3)–H bonds, although with somewhat reduced yields and stereoselectivities. The obtained cyclic carbamates can subsequently be hydrolyzed to obtain chiral β-amino alcohols. The method is very practical as the catalyst can be easily synthesized on a gram scale and can be recycled after the reaction for further use. The synthetic value of the new method is demonstrated with the asymmetric synthesis of a chiral oxazolidin-2-one as intermediate for the synthesis of the natural product aurantioclavine and chiral β-amino alcohols that are intermediates for the synthesis of chiral amino acids, indane-derived chiral Box-ligands, and the natural products dihydrohamacanthin A and dragmacidin A.

Recent Achievements in the Rhodium‐Catalyzed Concise Construction of Medium N‐Heterocycles, Azepines and Azocines

AbstractMedium N‐heterocycles, azepines and azocines, serve as important skeletons that occurred widely in natural products, however, due to the lack of efficient synthetic methodologies, their application potential in biologically active molecules, pharmaceuticals and agrochemicals remained to be explored. In this context, rhodium catalysis in this field featured good reactivity and functional group tolerance, with readily available starting materials, and enabled rapid access to the azepines and azocines. Delightfully, great achievements in the concise construction of these 7 and 8‐membered N‐heterocycles under rhodium catalysis have been made, which mainly included cycloisomerization of unsaturated C−X bonds (which might also combine the ring‐opening strategy on strained rings), metal carbenoid or nitrene insertion involved transformations and direct C−H activation reactions. Considering the great performance of rhodium catalyst in the synthesis of azepines and azocines, herein, we summarized the recent results in this field, and wish to give further insight and inspired more encouraging methodologies and new drug discovery based on these 7 and 8‐membered N‐heterocycles.magnified image

An account of synthetic strategies towards indolocarbazole alkaloids: Arcyriaflavin A and staurosporinone

An account of synthetic methods developed for indolocarbazole alkaloids arcyriaflavin A and staurosporinone is presented. Based on a common pathway or key intermediate involved, all these methods are broadly grouped into four categories: 1) using bisindolyl maleimide/anhydride, 2) from bisindoles, 3) using Fischer indolisation, 4) involving nitrene insertion. This review discusses in detail the strategies involved in the construction of these two molecules. • This review provides a detailed account of all the strategies developed for the synthesis of arcyriaflavin A and staurosporinone. • All these methods have been broadly classified into 4 categories based on a common intermediate or a reaction pathway involved in the construction of these molecules. • Both these alkaloids and their synthetic analogues having substituents on either side of the indole rings have been synthesised providing a library of compounds for biological activity studies.

Metal-free C-H Activation over Graphene Oxide toward Direct Syntheses of Structurally Different Amines and Amides in Water.

Unprecedented metal-free synthesis of a variety of amines and amides is reported via amination of C(sp3)-H and C(sp2)-H bonds. The strategy involves graphene-oxide/I2-catalyzed nitrene insertion using PhINTs as a nitrene (NT) source in water at room temperature. A wide range of structurally different substrates, viz., cyclohexane, cyclic ethers, arenes, alkyl aromatic systems, and aldehydes/ketones, having an α-phenyl ring have been employed successfully to afford the corresponding nitrene insertion product in good yield, albeit low in few cases. The envisaged method has superiority over others in terms of its operational simplicity, metal-free catalysis, use of water as a solvent, ambient reaction conditions, and reusability of the catalyst.

Theoretical Mechanistic Studies of Rh‐Catalyzed C(sp3)—H Amination: A Comparison with Co Analogue and Metal Effects

Summary of main observation and conclusionThe mechanism of Rh‐catalyzed C(sp3)—H amination has been computationally investigated. The reaction mechanism mainly involves sequential C(sp3)—H activation, decarboxylation, nitrene migration insertion, and protonation steps. Competitive concerted metalation deprotonation (CMD) and external base assisted deprotonation (EBAD) pathways are found for the involved C(sp3)—H activation in both Rh and Co analogous systems. This is different from the previously reported C(sp2)—H activation, where the CMD is dominant. The key mechanistic difference between the two systems is found to be in the C(sp3)—H activation step. In comparison with Rh species, the lower activity of Co complex toward the C(sp3)—H activation could be ascribed to smaller atomic size of Co and thus larger steric repulsion between ancillary ligand and substrate along with the CMD pathway. In view of the EBAD pathway, however, the lower activity of Co species could be imputed to the triplet nature of Co center, which is against the electron transfer from the electron‐rich carbon atom of the deprotonating C(sp3)—H bond to the Co center. As to the subsequent decarboxylation and nitrene insertion steps, compared with the Co system, the relatively lower reactivity of Rh species is partially due to the stronger Rh—N bond, and the higher π(Rh—N) and π*(Rh—N) orbital energies of the corresponding transition state structure.

Enantioselective Ring-Closing C–H Amination of Urea Derivatives

Summary An enantioselective intramolecular C(sp3)–H amination of N-benzoyloxyurea by using a chiral-at-metal ruthenium catalyst is reported, providing chiral 2-imidazolidinones in yields of up to 99% and with up to 99% ee. Catalyst loadings down to 0.05 mol % are feasible. Control experiments support a stepwise nitrene insertion mechanism through hydrogen atom transfer of a ruthenium nitrenoid intermediate followed by a radical recombination. Chiral 2-imidazolidinones are prevalent in bioactive compounds and can be converted to chiral vicinal diamines in a single step. The synthetic value of the new method is demonstrated for the synthesis of intermediates of the drugs levamisole and dexamisole, the bisindole alkaloids topsentine D and spongotine A, and a chiral organocatalyst.

Versatile Cp*Co(III)(LX) Catalyst System for Selective Intramolecular C–H Amidation Reactions

Herein, we report the development of a tailored cobalt catalyst system of Cp*Co(III)(LX) toward intramolecular C-H nitrene insertion of azidoformates to afford cyclic carbamates. The cobalt complexes were easy to prepare and bench-stable, thus offering a convenient reaction protocol. The catalytic reactivity was significantly improved by the electronic tuning of the bidentate LX ligands, and the observed regioselectivity was rationalized by the conformational analysis and DFT calculations of the transition states. The superior performance of the newly developed cobalt catalyst system could be broadly applied to both C(sp2)-H and C(sp3)-H carbamation reactions under mild conditions.

Synthesis of Carbazoles and Related Heterocycles from Sulfilimines by Intramolecular C-H Aminations.

While direct nitrene insertions into C−H bonds have become an important tool for building C−N bonds in modern organic chemistry, the generation of nitrene intermediates always requires transition metals, high temperatures, ultraviolet or laser light. We report a mild synthesis of carbazoles and related building blocks through a visible light‐induced intramolecular C−H amination reaction. A striking advantage of this new method is the use of more reactive aryl sulfilimines instead of the corresponding hazardous azides. Different catalysts and divergent light sources were tested. The reaction scope is broad and the product yield is generally high. An efficient gram‐scale synthesis of Clausine C demonstrates the applicability and scalability of this new method.

Front Cover: The TpxM Core in Csp3–H Bond Functionalization Reactions: Comparing Carbene, Nitrene, and Oxo Insertion Processes (Tpx = Scorpionate Ligand; M = Cu, Ag) (Eur. J. Inorg. Chem. 11‐12/2020)

Front Cover: The Tp^xM Core in C_sp³–H Bond Functionalization Reactions: Comparing Carbene, Nitrene, and Oxo Insertion Processes (Tp^x = Scorpionate Ligand; M = Cu, Ag) (Eur. J. Inorg. Chem. 11‐12/2020)