Iron porphyrin catalysed light driven C–H bond amination and alkene aziridination with organic azides

Visible light driven nitrene transfer and insertion reactions of organic azides are an attractive strategy for the design of C–N bond formation reactions under mild reaction conditions, the challenge being lack of selectivity as a free nitrene reactive intermediate is usually involved. Herein is described an iron(iii) porphyrin catalysed sp³ C–H amination and alkene aziridination with selectivity by using organic azides as the nitrogen source under blue LED light (469 nm) irradiation. The photochemical reactions display chemo- and regio-selectivity and are effective for the late-stage functionalization of natural and bioactive compounds with complexity. Mechanistic studies revealed that iron porphyrin plays a dual role as a photosensitizer and as a catalyst giving rise to a reactive iron–nitrene intermediate for subsequent C–N bond formation.

An iron(iii) porphyrin catalysed sp³ C–H amination and alkene aziridination with broad substrate scope under mild conditions is conducted, with selectivity through the use of organic azides as the nitrogen source under blue LED light irradiation.     

Photocatalytic C(sp3) radical generation via C–H,C–C,and C–X bond cleavage

C(sp³) radicals (R˙) are of broad research interest and synthetic utility. This review collects some of the most recent advancements in photocatalytic R˙ generation and highlights representative examples in this field. Based on the key bond cleavages that generate R˙, these contributions are divided into C–H, C–C, and C–X bond cleavages. A general mechanistic scenario and key R˙-forming steps are presented and discussed in each section.

C(sp³) radicals (R˙) are of broad research interest and synthetic utility.     

Highly selective α-aryloxyalkyl C–H functionalisation of aryl alkyl ethers

We report highly selective photocatalytic functionalisations of alkyl groups in aryl alkyl ethers with a range of electron-poor alkenes using an acridinium catalyst with a phosphate base and irradiation with visible light (456 nm or 390 nm). Experiments indicate that the reaction operates via direct single-electron oxidation of the arene substrate ArOCHRR′ to its radical cation by the excited state organic photocatalyst; this is followed by deprotonation of the ArOC–H in the radical cation to yield the radical ArOC˙RR′. This radical then attacks the electrophile to form an intermediate alkyl radical that is reduced to complete the photocatalytic cycle. The oxidation step is selective for activated arenes (ArOR) over their non-activated counterparts and the subsequent deprotonation of the methoxy group affords the α-aryloxyalkyl radical that leads to a wide range of functionalised products in good to excellent yield.

We report highly selective photocatalytic functionalisations of alkyl groups in aryl alkyl ethers with a range of electron-poor alkenes using an acridinium catalyst with a phosphate base and irradiation with visible light (456 nm or 390 nm).     

N-Directed fluorination of unactivated Csp3–H bonds

Site-selective fluorination of aliphatic C–H bonds remains synthetically challenging. While directed C–H fluorination represents the most promising approach, the limited work conducted to date has enabled just a few functional groups as the arbiters of direction. Leveraging insights gained from both computations and experimentation, we enabled the use of the ubiquitous amine functional group as a handle for the directed C–H fluorination of Csp³–H bonds. By converting primary amines to adamantoyl-based fluoroamides, site-selective C–H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes. Computational studies revealed a unique reaction coordinate for the catalytic process and offer an explanation for the high site selectivity.

By converting primary amines to adamantoyl-based fluoroamides, site-selective C–H fluorination proceeds under the influence of a simple iron catalyst in 20 minutes.

Due to the pervasiveness of fluorine atoms in industrially relevant small molecules, all practicing organic chemists appreciate the importance of this element. As a result of its unusual size and electronegativity, fluorine imparts unique physicochemical properties to pendant organic molecules.¹ For example, the strong C–F bond can prevent biological oxidation pathways, thereby thwarting rapid clearance and potentially improving pharmacokinetics of molecules.² Moreover, the installation of fluorine or trifluoromethyl groups, with their strong inductive effects,² can have a profound effect on the pK_a of nearby hydrogen atoms.³ These attributes, among others, have solidified the importance of fluorinated molecules in the medicinal,^1–4 material,⁵ and agrochemical⁶ industries. Yet, the same unique properties that make fluorine atoms attractive chemical modifiers also make their installation difficult. Consequently, new methods for site-selective fluorine incorporation remain highly desirable.⁷Methods to construct Csp²–F bonds traditionally make use of the Balz–Schiemann fluorodediazonization⁸ and halogen exchange (“Halex” process).⁹ Advances in transition metal-mediated fluorination have broadened access to Csp²–F-containing molecules,¹⁰ but methods to access aliphatic fluorides remain limited. Conventional methods to make Csp³–F bonds—such as nucleophilic displacement of alkyl halides¹¹ and deoxyfluorination¹²—can have limited functional group compatibility and unwanted side reactions. A more efficient route to form aliphatic C–F bonds would target the direct fluorination of Csp³–H bonds (Scheme 1).¹³Open in a separate windowScheme 1(a) Previous work on functional-group directed Csp³–H fluorination; (b) our approach to N-directed fluorination.Recent efforts with palladium catalysis employ conventional C–H-metallation strategies to target Csp³–H bonds for fluorination.¹⁴ Alternatively, radical H-atom abstraction can remove the transition metal from the C–H-cleavage step, thereby offering a promising approach for Csp³–H-bond functionalization.¹⁵ With undirected C–H fluorination,¹⁶ however, selectivity remains a challenge in molecules without strength-differentiated Csp³–H bonds.¹⁷ To overcome this, our group pioneered the directed fluorination of benzylic Csp³–H bonds through an iron-catalyzed process that involves 1,5 hydrogen-atom transfer (HAT) to cleave the desired Csp³–H bond.¹⁸ Since this work, other groups have demonstrated directed Csp³–H fluorination based on radical propagation that proceeds through an interrupted Hofmann–Löffler–Freytag (HLF)¹⁹ reaction (Scheme 1a). These examples employ various radical precursors such as enones,²⁰ ketones,²¹ hydroperoxides,²² and carboxamides²³ to direct fluorination to specific Csp³–H bonds. Since amines are ubiquitous in natural products and drugs, we sought to use amines as the building block of our directing group to achieve fluorination of unactivated Csp³–H bonds (Scheme 1b). By using amines as the starting point, one could use the approach in straightforward synthetic planning for the late-stage functionalization of remote C–H bonds.In the design phase of the project, we needed to devise a synthetically tractable N–F system that would enable 1,5-HAT and allow for fluorine transfer (Scheme 1b). To begin, we decided to examine common amine activating groups that would support 1,5-HAT while avoiding undesired radical reactions. The chosen activating group would provide the ideal steric and electronic properties to enable both N–F synthesis and N–F scission for 1,5-HAT. We first examined common acyl groups (e.g., acetyl-, benzoyl, and tosyl-based amides), but these proved unsatisfactory. For example, fluoroamide synthesis was either not achieved or low yielding, and the desired fluorine transfer proceeded with significant side reactions or returned starting material. We then turned our attention to more sterically hindered amides—which allow for higher yielding fluoroamide synthesis. For fluorine transfer, we hypothesized that the increased steric bulk could slow intermolecular H-atom transfer, thereby leading more efficient intramolecular 1,5-HAT. To that end, we were delighted that pivaloyl-based fluoroamide 1a proceeded in 64% yield to form product 2a (Scheme 2a). Interestingly, 7% of 1a underwent fluorination at the tert-butyl group of the pivaloyl—presumably through a 1,4-HAT reaction (2aa, Scheme 2a).²⁴ The problem is further exacerbated when the pivaloyl group is homologated by one methylene—providing only 7% yield of desired 2b with 32% of the fluorination taking place on the iso-pentyl group (2bb, Scheme 2a). In an attempt to “tie back” the pivaloyl group and prevent the undesired fluorination, we employed a cyclopropylmethyl-based fluoroamide but observed no improvement.Open in a separate windowScheme 2(a) The targeted 1,5-fluorination of unactivated aliphatic C–H bonds results in partial fluorination of the amine activating group; (b) DFT studies (uM06/cc-pVTZ(-f)-LACV3P**//uM06/LACVP** level of theory) identified the competing pathways responsible for alternate fluorination; (c) DFT (uM06/cc-pVTZ(-f)-LACV3P**//uM06/LACVP** level of theory) evaluation of adamantoylamides revealed higher transition state energy for 1,4-HAT due to restricted vibrational scissoring (d) adamantoyl-activated octylamine shows no fluorination of the activating group. ^{a 1}H-NMR yield using 1,3,5-trimethoxybenzene as an internal standard. ^{b 19}F-NMR yield using 4-fluorotoluene as an internal standard.At this point, 1a proved most promising for efficient fluorine transfer, as well as being the most synthetically accessible fluoroamide. The increased steric hindrance minimizes N-sulfonylation during fluorination with NFSI, a problem that plagued the synthesis of our previously targeted fluoroamides.¹⁸ Therefore, to further investigate how to improve fluorine transfer from 1a, we decided to model H-abstraction computationally.We hypothesized that the fluorinated side product 2aa was formed after 1,4-HAT. Since 1,4-HAT is rare,²⁴ we employed DFT (see ESI^† for details) to calculate the 5-membered and 6-memebered transition-states for 1,4- and 1,5-HAT, respectively. Surprisingly, we found that the barrier for 1,4 C–H abstraction in 1a was 18.7 kcal mol⁻¹, which was only 2.6 kcal mol⁻¹ higher in energy than the barrier calculated for 1,5 C–H abstraction in the same system (Scheme 2b). This suggested that both processes were competing at room temperature. We attributed the comparable barriers to the flexibility of the tert-butyl group, which undergoes vibrational scissoring to accommodate the C–H abstraction. The transition state distortion is modest and allows the molecule to maintain bond angles close to the ideal 109.5° (Scheme 2b). Based on this insight, we sought to limit the scissoring of the tert-butyl group and prevent the 1,4-HAT that leads to the undesired side product. After investigating several possible candidates, the underutilized adamantoyl group appeared promising. To evaluate the rigidity of adamantane, we calculated the barriers for 1,4- and 1,5-HAT for the adamantoyl-capped octylamine 1c (Scheme 2c). As expected, the barriers for 1,4- and 1,5-HAT differed significantly—with 1,4 C–H abstraction proceeding with a barrier of 25.1 kcal mol⁻¹ and the 1,5-HAT barely changed at 16.4 kcal mol⁻¹—an 8.7 kcal mol⁻¹ difference. Consequently, we synthesized 1c and subjected it to the reaction conditions. Excitingly, the adamantoyl-capped system produced desired product 2c in 75% yield with no fluorination of the adamantyl group (Scheme 2d).Using the newly devised adamantoyl-based fluoroamides, the reaction conditions were optimized. While a range of metal salts, ligands, and radical initiators were evaluated, Fe(OTf)₂ proved unique in catalyzing fluorine transfer with fluoroamides.¹⁸ Catalyst loading of 10 mol% allowed convenient setup and minor deviations above or below this loading had little effect on yield (see ESI^†). Increasing the temperature to 40 °C produced a slight increase in yield (entry 2, Table 1). Likewise, raising the temperature to 80 °C resulted in full conversion of the starting material in 20 minutes with 81% yield of the desired product (entry 3, Table 1). It should be noted that fluorine transfer occurs efficiently at a variety of temperatures with adjustments in reaction time (see ESI^†). Increasing the reaction concentration or changing the solvent resulted in decreased yield (entries 4 and 5, Table 1). Furthermore, the absence of Fe(OTf)₂ leads to no reaction and quantitative recovery of starting material, attesting to the stability of fluoroamides and the effectiveness of Fe(OTf)₂ (entry 6, Table 1).Optimization of pertinent reaction parameters

Total syntheses of naturally occurring antiviral indolosesquiterpene alkaloids,xiamycins C–F via Csp3–H functionalization

Concise total syntheses of naturally occurring antiviral indolosesquiterpene alkaloids, xiamycin C (2a), D (2b), E (2c) and F (2d), have been achieved via a late-stage oxidative δ-Csp³–H functionalization of an advanced pentacyclic enone intermediate 8. This strategy takes advantage of ipso-nitration of naturally occurring abietane diterpenoids to synthesize o-bromo nitroarene derivative 11. A Suzuki–Miyaura coupling of 11 with phenylboronic acid followed by Cadogan''s ring closure provided a modular approach to a carbazole ring required for a functionalized pentacyclic core of indolosesquiterpene alkaloids.

Enantioenriched enone 8 was synthesized via three key transformations: ipso-nitration of abietane diterpenoids to furnish o-bromo nitroarene 11, Suzuki coupling with phenylboronic acid, and Cadogan''s reductive ring closure to craft a carbazole ring.     

Metal-free tandem carbene N–H insertions and C–C bond cleavages

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage. Compared to the simple N–H insertion manipulation of diazo, this method elegantly accomplishes a tandem N–H insertion/S_EAr/C–C cleavage/aromatization reaction, and the synthetic utility of this new transformation is exemplified by the succinct syntheses of trisphaeridine and bicolorine alkaloids.

A metal-free C–H [5 + 1] annulation reaction of 2-arylanilines with diazo compounds has been achieved, giving rise to two types of prevalent phenanthridines via highly selective C–C cleavage.     

Visible-light-induced indole synthesis via intramolecular C–N bond formation: desulfonylative C(sp2)–H functionalization

Despite significant advances made on the synthesis of indole derivatives through photochemical strategies during the past several years, the requirement of equivalent amounts of oxidants, bases or other additional additives has limited their practical applications in the synthesis of natural products and pharmaceuticals as environment-friendly processes. Herein, we report LED visible-light-induced redox neutral desulfonylative C(sp²)–H functionalization for the synthesis of N-substituted indoles with a broad scope through γ-fragmentation under mild conditions in the absence of any additional additive. The reaction mechanism paradigm has been investigated on the basis of deuterium labeling experiments, kinetic analysis, Hammett plotting analysis and DFT calculations.

LED visible-light-induced redox neutral desulfonylative C(sp²)–H functionalization for the synthesis of N-substituted indoles in the absence of any additional additive has been established on the basis of KIE, Hammett plotting and DFT calculations.     

Intermolecular CDC amination of remote and proximal unactivated Csp3–H bonds through intrinsic substrate reactivity – expanding towards a traceless directing group

An intermolecular radical based distal selectivity in appended alkyl chains has been developed. The selectivity is maximum when the distal carbon is γ to the appended group and decreases by moving from γ → δ → ε positions. In –COO– linked alkyl chains, the same distal γ-selectivity is observed irrespective of its origin, either from the alkyl carboxy acid or alkyl alcohol. The appended groups include esters, N–H protected amines, phthaloyl, sulfone, sulfinimide, nitrile, phosphite, phosphate and borate esters. In borate esters, boron serves as a traceless directing group, which is hitherto unprecedented for any remote C_sp³–H functionalization. The selectivity order follows the trend: 3° benzylic > 2° benzylic > 3° tertiary > α to keto > distal methylene (γ > δ > ε). Computations predicted the radical stability (thermodynamic factors) and the kinetic barriers as the factors responsible for such trends. Remarkably, this strategy eludes any designer catalysts, and the selectivity is due to the intrinsic substrate reactivity.

An intermolecular amination at the distal methylene carbon has been realized in an appended alkyl chain with electron withdrawing groups. Traceless remote C_sp³–H functionalization has been accomplished using borate esters.     

Functionalisation of ethereal-based saturated heterocycles with concomitant aerobic C–H activation and C–C bond formation

With an ever-growing emphasis on sustainable synthesis, aerobic C–H activation (the use of oxygen in air to activate C–H bonds) represents a highly attractive conduit for the development of novel synthetic methodologies. Herein, we report the air mediated functionalisation of various saturated heterocycles and ethers via aerobically generated radical intermediates to form new C–C bonds using acetylenic and vinyl triflones as radical acceptors. This enables access to a variety of acetylenic and vinyl substituted saturated heterocycles that are rich in synthetic value. Mechanistic studies and control reactions support an aerobic radical-based C–H activation mechanism.

Herein we disclose a novel method for the aerobic C–H activation of ethereal-based heterocycles to generate various α-functionalised building blocks.     

Ni(0)-promoted activation of Csp2–H and Csp2–O bonds

A dinickel(0)–N₂ complex, stabilized with a rigid acridane-based PNP pincer ligand, was studied for its ability to activate C(sp²)–H and C(sp²)–O bonds. Stabilized by a Ni–μ–N₂–Na⁺ interaction, it activates C–H bonds of unfunctionalized arenes, affording nickel–aryl and nickel–hydride products. Concomitantly, two sodium cations get reduced to Na(0), which was identified and quantified by several methods. Our experimental results, including product analysis and kinetic measurements, strongly suggest that this C(sp²)–H activation does not follow the typical oxidative addition mechanism occurring at a low-valent single metal centre. Instead, via a bimolecular pathway, two powerfully reducing nickel ions cooperatively activate an arene C–H bond and concomitantly reduce two Lewis acidic alkali metals under ambient conditions. As a novel synthetic protocol, nickel(ii)–aryl species were directly synthesized from nickel(ii) precursors in benzene or toluene with excess Na under ambient conditions. Furthermore, when the dinickel(0)–N₂ complex is accessed via reduction of the nickel(ii)–phenyl species, the resulting phenyl anion deprotonates a C–H bond of glyme or 15-crown-5 leading to C–O bond cleavage, which produces vinyl ether. The dinickel(0)–N₂ species then cleaves the C(sp²)–O bond of vinyl ether to produce a nickel(ii)–vinyl complex. These results may provide a new strategy for the activation of C–H and C–O bonds mediated by a low valent nickel ion supported by a structurally rigidified ligand scaffold.

A structurally rigidified nickel(0) complex was found to be capable of cleaving both C(sp²)–H and C(sp²)–O bonds.     

Thioether-enabled palladium-catalyzed atroposelective C–H olefination for N–C and C–C axial chirality

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air. Both N–C and C–C axial chiral (hetero)biaryls were successfully constructed, leading to a broad range of axially chiral N-aryl indoles and biaryls with excellent enantioselectivities up to 99% ee. Experimental and computational studies were conducted to unravel the walking mode for the atroposelective C–H olefination. A plausible chiral induction model for the enantioselectivity-determining step was established by detailed DFT calculations.

Thioethers allowed for highly atroposelective C–H olefinations by a palladium/chiral phosphoric acid catalytic system under ambient air.     

A general method for site-selective Csp3–S bond formation via cooperative catalysis

Herein, we report a copper-catalysed site-selective thiolation of Csp³–H bonds of aliphatic amines. The method features a broad substrate scope and good functional group compatibility. Primary, secondary, and tertiary C–H bonds can be converted into C–S bonds with a high efficiency. The late-stage modification of biologically active compounds by this method was also demonstrated. Furthermore, the one-pot preparation of pyrrolidine or piperidine compounds via a domino process was achieved.

A copper-catalyzed site-selective thiolation of Csp³–H bonds of aliphatic amines was developed. The method features a broad substrate scope and good functional group tolerance.     

Nickel-catalyzed C–O/N–H,C–S/N–H,and C–CN/N–H annulation of aromatic amides with alkynes: C–O,C–S,and C–CN activation

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones. The use of a base is essential for the reaction to proceed. The reaction proceeds, even in the absence of a ligand, and under mild reaction conditions (40 °C). An electron-donating group on the aromatic ring facilitates the reaction. The reaction was also applicable to carbamate (C–O bond activation), methylthio (C–S bond activation), and cyano (C–CN bond activation) groups as leaving groups.

The Ni-catalyzed reaction of ortho-phenoxy-substituted aromatic amides with alkynes in the presence of LiO^tBu as a base results in C–O/N–H annulation with the formation of 1(2H)-isoquinolinones.     

Stereoretentive and regioselective selenium-catalyzed intermolecular propargylic C–H amination of alkynes

Herein we report an intermolecular propargylic C–H amination of alkynes. This reaction is operationally convenient and requires no transition metal catalysts or additives. Terminal, silyl, and internal alkynes bearing a wide range of functional groups can be aminated in high yields. The regioselectivity of amination for unsymmetrical internal alkynes is strongly influenced by substitution pattern (tertiary > secondary > primary) and by relatively remote heteroatomic substituents. We demonstrate that amination of alkynes bearing α-stereocenters occurs with retention of configuration at the newly-formed C–N bond. Competition experiments between alkynes, kinetic isotope effects, and DFT calculations are performed to confirm the mechanistic hypothesis that initial ene reaction of a selenium bis(imide) species is the rate- and product-determining step. This ene reaction has a transition state that results in substantial partial positive charge development at the carbon atom closer to the amination position. Inductive and/or hyperconjugative stabilization or destabilization of this positive charge explains the observed regioselectivities.

Selenium catalysis enables a general intermolecular propargylic C–H amination of alkynes. The concerted mechanism gives rise to high regioselectivity for the more electron-rich end of the alkyne and retention of the C–H propargylic stereocenter.     

Organophotoredox/palladium dual catalytic decarboxylative Csp3–Csp3 coupling of carboxylic acids and π-electrophiles

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed. The new process is mild, operationally simple, and has greatly improved upon the efficiency and generality of previous methodology. In addition, new insights into the reaction mechanism have been realized and provide further understanding of the harnessed reactivity.

A dual catalytic decarboxylative allylation and benzylation method for the construction of new C(sp³)–C(sp³) bonds between readily available carboxylic acids and functionally diverse carbonate electrophiles has been developed.     

Copper catalyzed borocarbonylation of benzylidenecyclopropanes through selective proximal C–C bond cleavage: synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds

A copper catalyzed borocarbonylation of BCPs via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed. Using substituted benzylidenecyclopropanes (BCPs) and chloroformates as starting material, a broad range of γ-boryl-γ,δ-unsaturated esters were prepared in moderate to excellent yields with excellent regio- and stereoselectivity. Besides, when aliphatic acid chlorides were used in this reaction, γ-boryl-γ,δ-unsaturated ketones could be produced in excellent yields. When substituted BCPs were used as substrates, the borocarbonylation occurred predominantly at the proximal C–C bond trans to the phenyl group in a regio- and stereoselective manner, which leads to the Z-isomers as the products. This efficient methodology involves the cleavage of a C–C bond and the formation of a C–C bond as well as a C–B bond, and provides a new method for the proximal C–C bond difunctionalization of BCPs.

A copper catalyzed borocarbonylation of benzylidenecyclopropanes (BCPs) via proximal C–C bond cleavage for the synthesis of γ-boryl-γ,δ-unsaturated carbonyl compounds has been developed.     

Temperature-modulated selective C(sp3)–H or C(sp2)–H arylation through palladium catalysis

Transition metal-catalysed C–H bond functionalisations have been extensively developed in organic and medicinal chemistry. Among these catalytic approaches, the selective activation of C(sp³)–H and C(sp²)–H bonds is particularly appealing for its remarkable synthetic versatility, yet it remains highly challenging. Herein, we demonstrate the first example of temperature-dependent selective C–H functionalisation of unactivated C(sp³)–H or C(sp²)–H bonds at remote positions through palladium catalysis using 7-pyridyl-pyrazolo[1,5-a]pyrimidine as a new directing group. At 120 °C, C(sp³)–H arylation was triggered by the chelation of a rare [6,5]-fused palladacycle, whereas at 140 °C, C(sp²)–H arylation proceeded instead through the formation of a 16-membered tetramer containing four 7-pyridyl-pyrazolo[1,5-a]pyrimidine–palladium chelation units. The subsequent mechanistic study revealed that both C–H activations shared a common 6-membered palladacycle intermediate, which was then directly transformed to either the [6,5]-fused palladacycle for C(sp³)–H activation at 120 °C or the tetramer for C(sp²)–H arylation at 140 °C with catalytic amounts of Pd(OAc)₂ and AcOH. Raising the temperature from 120 °C to 140 °C can also convert the [6,5]-fused palladacycle to the tetramer with the above-mentioned catalysts, hence completing the C(sp²)–H arylation ultimately.

Unprecedented 16-membered tetramer or [6,5]-fused palladacycle, mutually shadowboxing-like transformed from the shared common intermediate, accomplishes the Pd-catalysed temperature-dependent selective arylation of C(sp²)–H or C(sp³)–H.     

Pd-catalyzed cross-electrophile Coupling/C–H alkylation reaction enabled by a mediator generated via C(sp3)–H activation

Transition-metal-catalyzed cross-electrophile C(sp²)–(sp³) coupling and C–H alkylation reactions represent two efficient methods for the incorporation of an alkyl group into aromatic rings. Herein, we report a Pd-catalyzed cascade cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides. Methoxy and benzyloxy groups, which are ubiquitous functional groups and common protecting groups, were utilized as crucial mediators via primary or secondary C(sp³)–H activation. The reaction provides an innovative and convenient access for the synthesis of alkylated phenol derivatives, which are widely found in bioactive compounds and organic functional materials.

A cascade Pd-catalyzed cross-electrophile coupling and C–H alkylation reaction of 2-iodo-alkoxylarenes with alkyl chlorides has been developed by using an ortho-methoxy or benzyloxy group as a mediator via C(sp³)–H activation.     

Synthesis,characterization and C–H amination reactivity of nickel iminyl complexes

Metalation of the deprotonated dipyrrin (^AdFL)Li with NiCl₂(py)₂ afforded the divalent Ni product (^AdFL)NiCl(py)₂ (1) (^AdFL: 1,9-di(1-adamantyl)-5-perfluorophenyldipyrrin; py: pyridine). To generate a reactive synthon on which to explore oxidative group transfer, we used potassium graphite to reduce 1, affording the monovalent Ni synthon (^AdFL)Ni(py) (2) and concomitant production of a stoichiometric equivalent of KCl and pyridine. Slow addition of mesityl- or 1-adamantylazide in benzene to 2 afforded the oxidized Ni complexes (^AdFL)Ni(NMes) (3) and (^AdFL)Ni(NAd) (4), respectively. Both 3 and 4 were characterized by multinuclear NMR, EPR, magnetometry, single-crystal X-ray crystallography, theoretical calculations, and X-ray absorption spectroscopies to provide a detailed electronic structure picture of the nitrenoid adducts. X-ray absorption near edge spectroscopy (XANES) on the Ni reveals higher energy Ni 1s → 3d transitions (3: 8333.2 eV; 4: 8333.4 eV) than Ni^I or unambiguous Ni^II analogues. N K-edge X-ray absorption spectroscopy performed on 3 and 4 reveals a common low-energy absorption present only for 3 and 4 (395.4 eV) that was assigned via TDDFT as an N 1s promotion into a predominantly N-localized, singly occupied orbital, akin to metal-supported iminyl complexes reported for iron. On the continuum of imido (i.e., NR²⁻) to iminyl (i.e., ²NR⁻) formulations, the complexes are best described as Ni^II-bound iminyl species given the N K-edge and TDDFT results. Given the open-shell configuration (S = 1/2) of the iminyl adducts, we then examined their propensity to undergo nitrenoid-group transfer to organic substrates. The adamantyl complex 4 readily consumes 1,4-cyclohexadiene (CHD) via H-atom abstraction to afford the amide (^AdFL)Ni(NHAd) (5), whereas no reaction was observed upon treatment of the mesityl variant 3 with excess amount of CHD over 3 hours. Toluene can be functionalized by 4 at room temperature, exclusively affording the N-1-adamantyl-benzylidene (6). Slow addition of the organoazide substrate (4-azidobutyl)benzene (7) with 2 exclusively forms 4-phenylbutanenitrile (8) as opposed to an intramolecular cyclized pyrrolidine, resulting from facile β-H elimination outcompeting H-atom abstraction from the benzylic position, followed by rapid H₂-elimination from the intermediate Ni hydride ketimide intermediate.

Nickel-supported nitrenoids exhibit iminyl character, as determined by multi-edge XAS and TDDFT analysis, demonstrate efficacy for C–H activation and nitrene transfer chemistry.