Nitrene Insertion Research Articles

β3-Tryptophans by Iron-Catalyzed Enantioselective Amination of 3-Indolepropionic Acids.

A straightforward and general strategy for the catalytic asymmetric synthesis of β3-tryptophans by carboxylic-acid-directed intermolecular C-H amination has been developed. The iron-catalyzed C-H amination of 3-indolepropionic acids with BocNHOMs (Boc, tert-butyloxycarbonyl; OMs, methylsulfonate) in the presence of the base piperidine provides N-Boc-protected β3-tryptophans in a single step with high enantiomeric excess (ee) of up to >99%. Mechanistic experiments and density functional theory calculations support a mechanism through carboxylate-directed iron-mediated C(sp3)-H nitrene insertion. The method incorporates two key sustainability criteria: the use of iron as an abundant, non-toxic, and environmentally benign metal, along with the achievement of streamlined enantioselective C-H functionalization.

Skeletal Editing by Hypervalent Iodine Mediated Nitrogen Insertion.

Hypervalent iodine reagents are versatile and readily accessible reagents that have been extensively applied in contemporary synthesis in modern organic chemistry. Among them, iodonitrene (ArI=NR), is a powerful reactive species, widely used for a single-nitrogen-atom insertion reaction, and skeletal editing to construct N-heterocycles. Skeletal editing with reactive iodonitrene components has recently emerged as an exciting approach in modern chemical transformation. These reagents have been extensively used to produce biologically relevant heterocycles and functionalized molecular architectures. Recently, the insertion of a nitrogen-atom into hydrocarbons to generate N-heterocyclic compounds using hypervalent iodine reagents has been a significant focus in the field of molecular editing reactions. In this review, we discuss the rapidly emerging field of nitrene insertion, including skeletal editing and nitrogen insertion, using hypervalent iodine reagents to access nitrogen-containing heterocycles, and the current mechanistic understanding of these processes.

Optimization of fluorinated phenyl azides as universal photocrosslinkers for semiconducting polymers

Fluorinated phenyl azides (FPA) enable photo-structuring of π-conjugated polymer films for electronic device applications. Despite their potential, FPAs have faced limitations regarding their crosslinking efficiency, and more importantly, their impact on critical semiconductor properties, such as charge-carrier mobility. Here, we report that azide photolysis and photocrosslinking can achieve unity quantum efficiencies for specific FPAs. This suggests preferential nitrene insertion into unactivated C‒H bonds over benzazirine and ketenimine reactions, which we attribute to rapid interconversion between the initially formed hot states. Furthermore, we establish a structure‒activity relationship for carrier mobility quenching. The binding affinity of FPA crosslinker to polymer π-stacks governs its propensity for mobility quenching in both PM6 and PBDB-T used as model conjugated polymers. This binding affinity can be suppressed by FPA ring substitution, but varies in a non-trivial way with π-stack order. Utilizing the optimal FPA, photocrosslinking enables the fabrication of morphology-stabilized, acceptor-infiltrated donor polymer networks (that is, PBDB-T: ITIC and PM6: Y6) for solar cells. Our findings demonstrate the exceptional potential of the FPA photochemistry and offer a promising approach to address the challenges of modelling realistic molecular interactions in complex polymer morphologies, moving beyond the limitations of Flory‒Huggins mean field theory.

Synthesis of α-, β-, and γ-Carbolines via Intramolecular Cyclization of Azidomethyl(indolyl)acrylates Involving PIFA-BF3·OEt2/DBU-Mediated Cyclization as well as Thermolysis Approaches.

In this study, we present our findings on the synthesis of α-, β-, γ-carbolines via PIFA/BF3·OEt2-mediated intramolecular cyclization of isomeric azidomethyl(indolyl)acrylates. Alternately, 1,5,7-triazabicyclo[4.4.0]dec-5-ene/1,8-diazabicyclo(5.4.0)undec-7-ene (TBD/DBU)-mediated Michael addition followed by intramolecular cyclization of isomeric 2/3-(azidomethyl)indol-3/2-yl)acrylates also furnished the respective β- and γ-carboline derivatives. Unexpectedly, the thermolysis of 2-(azidomethyl)-3-(indol-3-yl)acrylates led to the formation of ethyl 5-(2-(phenylsulfonamido)aryl)nicotinates along with γ-carbolines, via nitrene insertion followed by rearrangement and cyclization. The isomeric 2-(azidomethyl)-3-(indol-2-yl)acrylate upon thermolysis led to the expected δ-carboline. Thermal intramolecular nitrene insertion reaction could also be extended for accessing pyrido benzothiophene, pyrido thiophene, and quinoline.

A Mild Metal‐Free Approach for the Direct Synthesis of Carbamoyl Azides from Carboxylic Acid Redox Active Esters

AbstractCarbamoyl azide is a pivotal compound used in the transformation into urea and amines, as well as in nitrene insertion reactions. In this study, we present a pioneering method for synthesizing carbamoyl azide directly from acid redox active esters without the use of metals or oxidants. This approach demonstrates tolerance for various functional groups, enhancing its applicability. Furthermore, this technique facilitates late‐stage modifications of natural products and pharmaceuticals, thereby accelerating the development and identification of novel drug candidates.

Aminative Suzuki-Miyaura coupling.

The Suzuki-Miyaura and Buchwald-Hartwig coupling reactions are widely used to form carbon-carbon (C-C) and carbon-nitrogen (C-N) bonds, respectively. We report the incorporation of a formal nitrene insertion process into the Suzuki-Miyaura reaction, altering the products from C-C-linked biaryls to C-N-C-linked diaryl amines and thereby joining the Suzuki-Miyaura and Buchwald-Hartwig coupling pathways to the same starting-material classes. A combination of a bulky ancillary phosphine ligand on palladium and a commercially available amination reagent enables efficient reactivity across aryl halides and pseudohalides, boronic acids and esters, and many functional groups and heterocycles. Mechanistic insights reveal flexibility on the order of bond-forming events, suggesting potential for expansion of the aminative cross-coupling concept to encompass diverse nucleophiles and electrophiles as well as four-component variants.

Regiodivergent Synthesis and Biological Activities of Indoloquinoline Based Compounds.

Cryptolepine, neocryptolepine, and isocryptolepine have remained popular synthetic targets ever since their isolation from the aqueous extracts of the West African climbing shrub Cryptolepis sanguinolenta. These natural alkaloids were found to contain significant antimalarial, antiproliferative and antimicrobial activities, making them ideal starting points for the development of novel drug candidates. As natural product synthesis is often plagued with step-heavy procedures and poor atom economy, the discovery of synthetic protocols addressing these concerns are sorely needed. In our laboratories, we have devoted our efforts into the development of regiodivergent synthesis whereby two of the indoloquinoline natural products, namely neocryptolepine and 11H-indolo[3,2-c]quinolines, could be assembled in only a few steps from a common and readily available starting material. Our synthetic endeavors to meet these goals include a cascade palladium-catalyzed Suzuki-Miyuara cross-coupling and intramolecular C-N bond formation and a photochemical nitrene insertion strategy. Furthermore, our methods also allowed for the construction of several diversely functionalized natural product derivatives which were subjected to biological evaluations.

Tailoring C-H amination activity via modification of the triazole-derived carbene ligand.

Two new C,O-bidentate chelating triazolylidene-phenolate ligands were synthesized that feature a diisopropylphenyl (dipp) and an adamantyl (Ad) substituent respectively on the triazole scaffold. Subsequent metalation afforded iron(II) complexes [Fe(C^O)2] that are active catalysts for the intramolecular C-H amination of organic azides. When compared to the parent complex containing a triazolylidene with a mesityl substituent (Mes) the increased steric bulk led to slightly lower activity (TOFmax = 23 h-1vs. 30 h-1), however selectivity towards pyrrolidine formation increases from 92% up to >99%. Kinetic studies indicate that the mechanism is similar in all three complexes and includes a half-order dependence in [Fe(C^O)2], congruent with the involvement of a dimetallic catalyst resting state within this catalyst class. Structural analysis suggests that enhanced bulkiness disfavors N2 loss and nitrene formation, yet shields the nitrene from intermolecular processes and thus favors intramolecular nitrene insertion into the C-H bond. This model rationalizes the high selectivity and the lower reaction rate observed with dipp and with Ad substituents on the ligand.

Avenue to novel o-carboranyl boron compounds - reactivity study of o-carborane-fused aminoborirane towards organic azides.

Herein we report the reactivity study of o-carborane-fused bis(trimethylsilyl)aminoborirane towards three different types of organic azides, i.e., aryl, alkyl, and silyl azides. The reaction with ArN3 (Ar = 2,6-iPr2C6H4, 2,6-C6H3Cl2, 2,4,6-C6H2Br3, C6F5) resulted in the cycloaddition of ArN3 to the borirane BN unit accompanied by silyl migration. Conversely, in the reaction with BnN3, only the BnN3 : borirane 1 : 2 ring expansion product was obtained. Finally, the reaction with Me3SiN3 resulted in a formal nitrene insertion product under thermal conditions. All of the newly obtained o-carborane-fused BN-containing heterocycles were fully characterized, and the mechanism of these substituent-dependent reactions was studied using DFT calculations.

Synthesis of phenanthrylboroles and formal nitrene insertion to access azaborapyrenes.

Extended conjugation has been introduced into boroles but only on the 2,3- or 4,5-positions of the central BC4 core. In this work we synthesize phenanthrylboroles that also have conjugation on the 3,4-positions and demonstrate their insertion reactivity with azides to furnish B,N-analogues of pyrene.

Facile preparation of azido functionalized polyvinyl chloride (PVC) nanofiber (NF) membrane for various applications

Polyvinyl chloride (PVC) nanofiber (NF) membrane functionalized with azido groups (Az-PVC NF) was prepared using various techniques with the aim of enhancing azide substitution of chlorine in the PVC backbone. Azidation strategies that were investigated include: (1) catalyst-assisted azidation in organic solvent, (2) phase transfer catalyzed azidation in aqueous media, (3) phase transfer catalyzed azidation in aqueous media using pre-iodinated membrane, and (4) phase transfer catalyzed azidation in aqueous media of electrospun pre-iodinated PVC granules prepared via Finkelstein reaction. Results showed that azidation was greatly enhanced when PVC NF membrane or PVC powder underwent pre-iodination prior to azidation. As far as it is known, this is the first time that preparation techniques for azidized PVC NF membrane in aqueous media that involve halogen exchange have been studied. Hence, the optimized conditions for the preparation of azidized PVC NF membranes and the resulting membrane properties are hereby reported. Furthermore, the utility of Az-PVC NF in the development of water treatment technologies was demonstrated with successful grafting of cucurbiturils via nitrene insertion.

Biocatalytic Construction of Chiral Pyrrolidines and Indolines via Intramolecular C(sp3)-H Amination.

Nature harnesses exquisite enzymatic cascades to construct N-heterocycles and further uses these building blocks to assemble the molecules of life. Here we report an enzymatic platform to construct important chiral N-heterocyclic products, pyrrolidines and indolines, via abiological intramolecular C(sp3)-H amination of organic azides. Directed evolution of cytochrome P411 (a P450 enzyme with serine as the heme-ligating residue) yielded variant P411-PYS-5149, capable of catalyzing the insertion of alkyl nitrene into C(sp3)-H bonds to build pyrrolidine derivatives with good enantioselectivity and catalytic efficiency. Further evolution of activity on aryl azide substrates yielded variant P411-INS-5151 that catalyzes intramolecular C(sp3)-H amination to afford chiral indolines. In addition, we show that these enzymatic aminations can be coupled with a P411-based carbene transferase or a tryptophan synthase to generate an α-amino lactone or a noncanonical amino acid, respectively, underscoring the power of new-to-nature biocatalysis in complexity-building chemical synthesis.

Deciphering Iron-Catalyzed C-H Amination with Organic Azides: N2 Cleavage from a Stable Organoazide Complex.

Catalytic C-N bond formation by direct activation of C-H bonds offers wide synthetic potential. En route to C-H amination, complexes with organic azides are critical precursors towards the reactive nitrene intermediate. Despite their relevance, α-N coordinated organoazide complexes are scarce in general, and elusive with iron, although iron complexes are by far the most active catalysts for C-H amination with organoazides. Herein, we report the synthesis of a stable iron α-N coordinated organoazide complex from [Fe(N(SiMe3 )2 )2 ] and AdN3 (Ad=1-adamantyl) and its crystallographic, IR, NMR and zero-field 57 Fe Mössbauer spectroscopic characterization. These analyses revealed that the organoazide is in fast equilibrium between the free and coordinated state (Keq =62). Photo-crystallography experiments showed gradual dissociation of N2 , which imparted an Fe-N bond shortening and correspond to structural snapshots of the formation of an iron imido/nitrene complex. Reactivity of the organoazide complex in solution showed complete loss of N2 , and subsequent formation of a C-H aminated product via nitrene insertion into a C-H bond of the N(SiMe3 )2 ligand. Monitoring this reaction by 1 H NMR spectroscopy indicates the transient formation of the imido/nitrene intermediate, which was supported by Mössbauer spectroscopy in frozen solution.

Nitrene Cyclization of 2-(Trichloromethyl)-5-phenylpyrimidines: Application to the Synthesis of 2-(Trichloromethyl)pyrimido[4,5-b]indoles and Related Heterocycles

AbstractAn aromatic C–H nitrene insertion of 2-(trichloromethyl)pyrimidines bearing a phenyl substituent at the C-5 position is described. Treatment of 4-chloro-5-phenyl-2-(trichloromethyl)pyrimidines with sodium azide in DMF or the reflux of 4-azido-5-phenyl-2-(trichloromethyl)pyrimidines in toluene provided 2-(trichloromethyl)pyrimido[4,5-b]indole derivatives in moderate yields. Excellent yields of this heterocyclic system were obtained through the aromatic C–H insertion with the Du Bois catalyst. This is an attractive approach for synthesizing pyrimido[4,5-b]indoles with a trichloromethyl substituent in the pyrimidine moiety.

Artificial Metalloenzyme-Catalyzed Enantioselective Amidation via Nitrene Insertion in Unactivated C(sp3)-H Bonds.

Enantioselective C-H amidation offers attractive means to assemble C-N bonds to synthesize high-added value, nitrogen-containing molecules. In recent decades, complementary enzymatic and homogeneous-catalytic strategies for C-H amidation have been reported. Herein, we report on an artificial metalloenzyme (ArM) resulting from anchoring a biotinylated Ir-complex within streptavidin (Sav). The resulting ArM catalyzes the enantioselective amidation of unactivated C(sp3)-H bonds. Chemogenetic optimization of the Ir cofactor and Sav led to significant improvement in both the activity and enantioselectivity. Up to >700 TON and 92% ee for the amidation of unactivated C(sp3)-H bonds was achieved. The single crystal X-ray analysis of the artificial nitrene insertase (ANIase) combined with quantum mechanics-molecular mechanics (QM-MM) calculations sheds light on critical second coordination sphere contacts leading to improved catalytic performance.

Recent Progress in Transition Metal Catalyzed C(sp3)—H Nitrene Insertion Reactions Assisted by Directing Groups

Recent Progress in Transition Metal Catalyzed C(sp³)—H Nitrene Insertion Reactions Assisted by Directing Groups

Formal Nitrene Insertion into the β-Vinyl C-H Bond of Acroleins: Synthesis of Enaminals.

An efficient formal nitrene insertion reaction into the β-vinyl C-H bond of acroleins with an electron-rich organic azide was developed. The reaction protocol can produce secondary enaminals in high yield with a broad substrate scope. In the reaction, acid mediated [3 + 2] cycloaddition of organic azides with an acrolein generated intermediate protonated triazolines, which were selectively decomposed into enaminals with addition of a weakly Brønsted basic reagent such as methanol. The resulting secondary enaminal could be easily reduced into a γ-amino alcohol under mild hydrogenation conditions.

Transition Metal-Catalyzed Regioselective Direct C-H Amidation: Interplay between Inner- and Outer-Sphere Pathways for Nitrene Cross-Coupling Reactions.

Catalytic C-N bond cross-coupling reactions have been a subject of fundamental importance in synthetic organic and medicinal chemistry because amides and amines are ubiquitous motifs in natural products, functional materials, and pharmaceuticals. Since the pioneering works of Breslow and Mansuy on the metalloporphyrin-catalyzed direct hydrocarbon amidation using sulfonyliminoiodinane reagents, substantial development has been achieved toward practical and selective amination protocols. Notably, Du Bois's group developed the dirhodium(II,II) carboxylate catalytic system for direct C(sp3)-H amidations via Rh-sulfonyl nitrene intermediates. Yet, this protocol suffers from competitive alkene aziridination and is limited to electron-rich tertiary and ethereal C-H bonds; analogous direct amidation of arenes remained ineffective.This Account discusses our early effort to explore cyclopalladated complexes for ortho-selective C(aryl)-H amidations. While Buchwald-Hartwig amination cannot be directly applied to arenes, effective amidation of the 2-arylpyridines occurred when an external oxidant such as K2S2O8 was employed. Preliminary studies suggested that the amidation may proceed through reactive Pd-nitrene intermediates. Aiming to develop more diversified amidation protocols, we employed nosyloxycarbamates as nitrene precursors for the Pd-catalyzed ortho-amidation of N-pivalanilides. Likewise, we developed the ortho-selective amidation of benzoic acids to produce anthranilic acids, which are versatile precursors for many medicinally valuable heterocycles. In an attempt to expand the C(aryl)-N coupling reactions to amines, we studied the d6 piano-stool Cp*Rh(III) systems [Cp* = pentamethylcyclopentadienyl]. Our work established a sound reaction platform based on the electrophilic aminating reagents including N-chloroamines, hydroxyamides, and N-carboxyhydrazides for effective C(aryl)-N bond formation in aryl-metal complexes.Building upon the metal-nitrene reaction platform, we moved forward to examine γ-lactam synthesis by intramolecular carbonyl nitrene C(sp3)-H insertion. Noted that carbonyl nitrenes are prone to undergo Curtius-type rearrangement to form isocyanate; we found that the π-basic Ru(II) center effectively decomposes dioxazolones to afford the carbonyl nitrene for regioselective γ-C(sp3)-H insertion. With chiral diphenylethylenediamines (dpen) as ligands bearing electron-withdrawing arylsulfonyl substituents, the [(p-cymene)Ru(dpen)] complex catalyzed the decomposition of the dioxazolones to afford chiral γ-lactams by formal carbonyl nitrene C(sp3)-H insertion. Enantioselective nitrene insertion to allylic and propargylic C(sp3)-H bonds was also achieved with remarkable tolerance to the C═C and C≡C bonds. Notably, the selectivity of the [(p-cymene)Ru] system switched to C(aryl)-H bonds to give dihydroquinolinones when l-proline was employed as ligand. Recently, we aimed to address the regiocontrolled amidation of unactivated methylene C-H bonds using NiH catalyst. While tertiary and benzyl C-H bonds can be differentiated by their bond dissociation energies and steric properties, methylene groups making up the hydrocarbon skeleton display similar electronic and steric properties. In this context, we exploited the five-membered nickelacycle formation to terminate the NiH-mediated chain-walk isomerization, and the nickelacycle reacted with dioxazolones to furnish the C(sp3)-N bond at the γ-methylene position.This Account summarizes our contribution to the development of C-N bond cross-coupling reactions via C-H activation. By exploiting the inner-sphere and outer-sphere reaction pathways, we successfully developed regioselective protocols that target C(sp3)-H and C(aryl)-H bonds. The mechanistic underpinning of the selectivity of different C-H bonds and related studies on the affiliated catalytic systems will be discussed.

Accessing Boron-Doped Pentaphene Analogues from 12-Boradibenzofluorene.

Borole-doped polycyclic aromatic hydrocarbons (PAHs) have garnered attention in recent years due to their attractive photophysical properties and potential utility in electronic devices. In this work, a borole-doped PAH, 12-boradibenzofluorene, is synthesized and formal intermolecular nitrene and oxygen atom insertion reactions were employed to access 1,2-azaborine- and 1,2-oxaborine-containing analogues of the carbonaceous PAH pentaphene. Iodosobenzene is established as a versatile reagent for oxygen atom insertion reactions into a variety of borole species to access 1,2-oxaborine systems.

Carboxylate-Assisted Iridium (III)-Catalyzed C(sp2)-H Amidation of 2-Aroylimidazoles With Dioxazolones.

The Ir(III)-catalyzed ortho C-H amidation of 2-aroylimidazoles with 3-aryldioxazolones as an amidating reagent is reported. The method provides a broad substrate scope with wide functional group compatibility. Mechanistic studies indicate that C-H bond cleavage is reversible and appears not to be the rate-determining step. The presence of an electron-donating group in the 2-aroylimidazoles and an electron-withdrawing group in the 3-aryldioxazoles significantly accelerates the reaction, suggesting that nitrene insertion is the rate-determining step.