Direct synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines from propargyl sulfonylamides and allenamides

Multisubstituted pyrroles are important fragments that appear in many bioactive small molecule scaffolds. Efficient synthesis of multisubstituted pyrroles with different substituents from easily accessible starting materials is challenging. Herein, we describe a metal-free method for the preparation of pentasubstituted pyrroles and hexasubstituted pyrrolines with different substituents and a free amino group by a base-promoted cascade addition–cyclization of propargylamides or allenamides with trimethylsilyl cyanide. This method would complement previous methods and support expansion of the toolbox for the synthesis of valuable, but previously inaccessible, highly substituted pyrroles and pyrrolines. Mechanistic studies to elucidate the reaction pathway have been conducted.

This method is a toolbox for the synthesis of valuable, but previously inaccessible, highly substituted pyrroles and pyrrolines.

Pyrroles are molecules of great interest in a variety of compounds including pharmaceuticals, natural products and other materials. Pyrrole fragments for example are key motifs in bioactive natural molecules, forming the subunit of heme, chlorophyll and bile pigments, and are also found in many clinical drugs, including those in Fig. 1a.¹ Although many classical methods of pyrrole synthesis, including the Paal–Knorr condensation,² the Knorr reaction,³ the Hantzsch reaction,⁴ transition metal-catalyzed reactions,⁵ and multicomponent coupling reactions,⁶ have been developed over many years, the efficient synthesis of multisubstituted pyrroles is still challenging. In condensation syntheses of pyrroles, the major problems lie in the extended syntheses of complex precursors and limited substitution patterns that are allowed. Multicomponent reactions are superior when building pyrrole core structures with more substituents. Among these, the [2+2+1] cycloaddition reaction of alkynes and primary amines is attractive because of the readily available alkyne and amine substrates and the ability to construct fully substituted pyrroles.⁷ However, with the exception of some rare examples,⁸ most [2+2+1] cycloaddition reactions afford pyrroles with two or more identical substituents. The synthesis of multisubstituted pyrroles with all different substituents from simple starting materials therefore remains a major challenge.Open in a separate windowFig. 1Previous reports and this work on propargylamides transformation.Easily accessible propargylamides are classical, privileged building blocks broadly utilized for the synthesis of a large variety of heterocyclic molecules such as pyrroles, pyridines, thiazoles, oxazoles and other relevant organic frameworks.⁹ For example, Looper¹⁰et al. reported the synthesis of 2-aminoimidazoles from propargyl cyanamides and Eycken¹¹ reported a method starting from propargyl guanidines which undergo a 5-exo-dig heterocyclization as shown in Fig. 1b. Subsequently, Wan¹²et al. revealed the cyclization of N-alkenyl propargyl sulfonamides into pyrroles via sulfonyl migration. Inspired by these transformations and multi-substituted pyrrole synthesis, we report herein a direct synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines with all different substituents from propargyl sulfonylamides and allenamides.Previously, Zhu,¹³ Ji¹⁴ and Qiu^13b,15 reported efficient syntheses of 2-aminopyrroles from isocyanides. Ye¹⁶ and Huang¹⁷ independently developed gold-catalyzed syntheses of 2-amino-pentasubstituted pyrroles with ynamides. Despite the many advantages of these methods, they all afford protected amines, rather than free amines. The deprotection of these amines may cause problems in further transformations of the products. Our method delivers pyrroles with an unprotected free amino group and are often complementary to the previously well-developed classical methods.Initially, the cyclization reaction of N-(1,3-diphenylprop-2-yn-1-yl)-N-ethylbenzenesulfonamide (1a) with trimethylsilyl cyanide (TMSCN) was carried out with Ni(PPh₃)₂Cl₂ as a catalyst, a base (Cs₂CO₃) and DMF as a solvent. Different metal catalysts, such as Ni(PPh₃)₂Cl₂, Pd(OAc)₂, Cu(OAc)₂, and Co(OAc)₂ provided the desired product with similar yields (

HydroFlipper membrane tension probes: imaging membrane hydration and mechanical compression simultaneously in living cells

HydroFlippers are introduced as the first fluorescent membrane tension probes that report simultaneously on membrane compression and hydration. The probe design is centered around a sensing cycle that couples the mechanical planarization of twisted push–pull fluorophores with the dynamic covalent hydration of their exocyclic acceptor. In FLIM images of living cells, tension-induced deplanarization is reported as a decrease in fluorescence lifetime of the dehydrated mechanophore. Membrane hydration is reported as the ratio of the photon counts associated to the hydrated and dehydrated mechanophores in reconvoluted lifetime frequency histograms. Trends for tension-induced decompression and hydration of cellular membranes of interest (MOIs) covering plasma membrane, lysosomes, mitochondria, ER, and Golgi are found not to be the same. Tension-induced changes in mechanical compression are rather independent of the nature of the MOI, while the responsiveness to changes in hydration are highly dependent on the intrinsic order of the MOI. These results confirm the mechanical planarization of push–pull probes in the ground state as most robust mechanism to routinely image membrane tension in living cells, while the availability of simultaneous information on membrane hydration will open new perspectives in mechanobiology.

HydroFlippers respond to membrane compression and hydration in the same fluorescence lifetime imaging microscopy histogram: the responses do not correlate.

The detection and study of membrane mechanics in living cells is a topic of current concern.^1–14 To enable this research, appropriate chemistry tools, that is small-molecule fluorescent probes that allow imaging of membrane tension, are needed.¹⁵ With the direct imaging of physical forces being intrinsically impossible, design strategies toward such probes have to focus on the suprastructural changes caused by changes in membrane tension.¹⁵ These suprastructural changes are divers, often interconnected, and vary with the composition of the membrane.^15–25 Beyond the fundamental lipid compression and decompression, they include changes in membrane curvature, from rippling, buckling and budding to tubules extending from the membrane and excess lipid being ejected. Of similar importance are changes in membrane organization, particularly tension-induced phase separation and mixing, i.e. assembly and disassembly of microdomains. Consequences of these suprastructural changes include microdomain strengthening and softening and changes in membrane hydration and viscosity.^16–25The currently most developed fluorescent flipper probes have been introduced^26,27 to image membrane tension by responding to a combination of mechanical compression and microdomain assembly in equilibrium in the ground state.¹⁵ Extensive studies, including computational simulations,²⁸ have shown that flipper probes align non-invasively along the lipid tails of one leaflet and report changes in membrane order and tension as changes in fluorescent lifetimes and shifts of excitation maxima.¹⁵ Among other candidates, solvatochromic probes respond off-equilibrium in the excited state to changes in membrane hydration and have very recently been considered for the imaging of membrane tension in living cells.^29–36 So far not considered to image tension, ESIPT probes also report off equilibrium in the excited state on membrane hydration, but for different reasons.^37,38 Mechanosensitive molecular rotors respond off equilibrium in the excited state to changes in microviscosity.^{17,30,32,39–53} The same principle holds for the planarization of bent, papillon or flapping fluorophores.^54–57 The response of all possible probes to tension can further include less desired changes in positioning and partitioning between different domains, not to speak of more catastrophic probe aggregation, precipitation, disturbance of the surrounding membrane structure, and so on. Although the imaging of membrane tension is conceivable in principle with most of above approaches, the complex combination of parameters that has to be in place can thus far only be identified empirically, followed by much optimization.¹⁵The force-induced suprastructural changes are accompanied by the alteration in several unrelated physical properties of membranes. It is, for instance, well documented that membrane hydration increases with membrane disorder, from solid-ordered (S_o) to liquid-disordered (L_d) phases.^29,58 Increasing cholesterol content decreases membrane hydration in solid- and liquid-ordered membranes.⁵⁹ However, studies in model membranes also indicate that membrane hydration and membrane fluidity do not necessarily correlate.⁵⁹ The dissection of the individual parameters contributing to the response of fluorescent membrane tension probes would be important for probe design and understanding of their responses, but it remains a daunting challenge. In this study, we introduce fluorescent flipper probes that simultaneously report on mechanical membrane compression and membrane hydration at equilibrium in the ground state. Changes of both in response to changes in membrane tension and membrane composition are determined in various organelles in living cells.The dual hydration and membrane tension probes are referred to as HydroFlippers to highlight the newly added responsiveness to membrane hydration. The mechanosensing of lipid compression in bilayer membranes by flipper probes has been explored extensively.¹⁵ Fluorescent flippers²⁷ like 1 are designed as bioinspired⁶⁰ planarizable push–pull probes²⁶ (Fig. 1). They are constructed from two dithienothiophene fluorophores that are twisted out of co-planarity by repulsion of methyls and σ holes on sulfurs^61,62 next to the twistable bond. The push–pull system is constructed first from formal sulfide and sulfone redox bridges in the two twisted dithienothiophenes. These endocyclic donors and acceptors are supported by exocyclic ones, here a trifluoroketone acceptor and a triazole donor.⁶³ To assure stability, these endo- and exocyclic donors are turned off in the twisted ground state because of chalcogen bonding and repulsion, respectively.⁶²Open in a separate windowFig. 1The dual sensing cycle of HydroFlippers 1–5, made to target the indicated MOIs in living cells and responding to membrane compression by planarization and to membrane hydration by dynamic covalent ketone hydration. With indication of excitation maxima (ref. 63) and fluorescence lifetimes (this study).Mechanical planarization of the flipper probe establishes conjugation along the push–pull systems, electrons flow from endocyclic donors to acceptors, which turns on the exocyclic donors and acceptors to finalize the push–pull system.⁶² This elaborate, chalcogen-bonding cascade switch has been described elsewhere in detail, including high-level computational simulations.⁶² The planar high-energy conformer 1dp excels with red shifted excitation and increased quantum yield and lifetime compared to the twisted conformer 1dt because the less twisted Franck-Condon state favors emission through planar intramolecular charge transfer (PICT) over non-radiative decay through twisted ICT, or conical intersections.¹⁵Flipper probe 1 was considered for dual responsiveness to membrane tension and hydration because of the trifluoroketone acceptor.⁶³ Dynamic covalent hydration of 1dt yields hydrate 1ht.^64–76 Blue-shifted excitation and short lifetime of 1ht are not expected to improve much upon planarization because the hydrate is a poor acceptor and thus, the push–pull system in 1hp is weak. The dynamic covalent chemistry of the trifluoroketone acceptor has been characterized in detail in solution and in lipid bilayer membranes.⁶³To explore dual responsiveness to membrane tension in any membrane of interest (MOI) in living cells, HydroFlippers 2–5 were synthesized. While HydroFlipper 1 targets the plasma membrane (PM), HydroFlippers 2–4 were equipped with empirical targeting motifs.⁷⁷ HydroFlipper 5 terminates with a chloroalkane to react with the self-labeling HaloTag protein, which can be expressed in essentially any MOI.⁷⁸ Their substantial multistep synthesis was realized by adapting reported procedures (Schemes S1–S4^†).The MOIs labeling selectivity of HydroFlippers was determined in HeLa Kyoto (HK) cells by confocal laser scanning microscopy. Co-localization experiments of flippers 1–4 with the corresponding trackers gave Pearson correlation coefficients (PCCs) >0.80 for the targeting of mitochondria, lysosomes and the endoplasmic reticulum (ER, Fig. S4–S6^†). HydroFlipper 5 was first tested with stable HGM cells, which express both HaloTag and GFP on mitochondria (referred to as 5_M).^78,79 The well-established chloroalkane penetration assay demonstrated the efficient labeling of HaloTag protein by 5 as previously reported HaloFlippers (Fig. S3^†).⁷⁸ By transient transfection, HydroFlippers 5 were also directed to lysosomes (5_L), Golgi apparatus (GA, 5_G)⁸⁰ and peroxisomes (5_P) with HaloTag and GFP expressed on their surface.⁷⁸ PCCs >0.80 for co-localization of flipper and GFP emission confirmed that MOI labeling with genetically engineered cells was as efficient as with empirical trackers (Fig. S7–S11^†).Dual imaging of membrane compression and hydration was envisioned by analysis of fluorescence lifetime imaging microscopy (FLIM) images using a triexponential model (Fig. 2).⁸¹ FLIM images of ER HydroFlipper 4 in iso-osmotic HK cells were selected to illustrate the concept (Fig. 3a). Contrary to classical flipper probes, the fluorescence decay curve of the total FLIM image (Fig. 2a, grey) showed a poor fit to a biexponential model (Fig. 2a, cyan, b). Consistent with their expected dual sensing mode, a triexponential fit was excellent (Fig. 2a, dark blue, c). Lifetimes τ_1i = 4.3 ns (†) were obtained besides background. This three-component model was then applied to every pixel of FLIM images (Fig. 3c). The resulting reconvoluted FLIM histogram revealed three clearly separated populations for τ₁ (red), τ₂ (green), and background (τ₃, blue, Fig. 2d). Maxima of these three clear peaks were at the lifetimes estimated by triexponential fit of the global decay curve, thus demonstrating the validity of the methodology at necessarily small photon counts. Irreproducible fitting would give randomly scattered data without separated peaks.Open in a separate windowFig. 2(a) Fluorescence decay curve (grey, corresponding to the total image, not to a single pixel) with biexponential (cyan) and triexponential fit (dark blue). (b, c) Residual plots for bi- (b) and triexponential fit (c). (d) Histogram with the intensities associated with the τ₁ (red), τ₂ (green), and τ₃ (blue, background) components obtained by triexponential fit of the fluorescence decay curve of each pixel of the FLIM image, fit to Gaussian function (black solid curves).Open in a separate windowFig. 3FLIM images of HK cells labelled with ER flipper 4 before (a, c) and after (b, d) hyper-osmotic shock, showing average lifetimes τ_av (a, b) and τ₁ (c, d) from triexponential reconvolution; scale bars = 10 μm. (e) Distribution of the photon counts associated with the τ₁ component of 4 in HK cells after triexponential reconvolution of FLIM images before (c, τ_1i) and after (d, τ_1h) hyper-osmotic shock, showing decreasing lifetimes for τ₁ (4d). (f) The dehydration factor dh_i defined as total integrated photon counts for τ₁ (Στ₁) divided by Στ₂ (i.e., dh_i = area Στ_1i/area Στ_2i) for 4 in strongly hydrated ER (dh_i < 2, turquoise) and 1 in weakly hydrated plasma membrane (dh_i > 6, purple) of HK Kyoto cells under iso-osmotic conditions.Dual response of HydroFlippers to changes in membrane tension^a

Polycyclic heteroaromatics via hydrazine-catalyzed ring-closing carbonyl–olefin metathesis

The use of hydrazine-catalyzed ring-closing carbonyl–olefin metathesis (RCCOM) to synthesize polycyclic heteroaromatic (PHA) compounds is described. In particular, substrates bearing Lewis basic functionalities such as pyridine rings and amines, which strongly inhibit acid catalyzed RCCOM reactions, are shown to be compatible with this reaction. Using 5 mol% catalyst loadings, a variety of PHA structures can be synthesized from biaryl alkenyl aldehydes, which themselves are readily prepared by cross-coupling.

Hydrazine catalysis enables the ring-closing carbonyl–olefin metathesis (RCCOM) to form polycyclic heteroaromatics, especially those with basic functionality.

Polycyclic heteroaromatic (PHA) structures comprise the core framework of many valuable compounds with a diverse range of applications (Fig. 1A).¹ For example, polycyclic azines (e.g. quinolines) are embedded in many alkaloid natural products, including diplamine² and eupolauramine³ to name just a few. These types of structures are also of interest for their biological activity, such as with the inhibitor of the Src-SH3 protein–protein interaction shown in Fig. 1A.⁴ Many nitrogenous PHAs are also useful as ligands for transition metal catalysis, as exemplified by the widely used ligand 1,10-phenanthroline.⁵ Meanwhile, chalcogenoarenes⁶ such as dinaphthofuran⁷ and benzodithiophene⁸ have attracted high interest for both their medicinal properties⁹ and especially for their potential use as organic light-emitting diodes (OLEDs), organic photovoltaics (OPVs), and organic field-effect transistors (OFETs).¹⁰ These and numerous other examples have inspired the development of a wide variety of strategies to construct PHAs.^1,11–14 Although these approaches are as varied as the structures they target, the wide range of molecular configurations within PHA chemical space and the challenges inherent in exerting control over heteroatom position and global structure make novel syntheses of these structures a topic of continuing interest.Open in a separate windowFig. 1(A) Examples of PHAs. (B) RCCOM strategy for PHA synthesis. (C) Lewis base inhibition for Lewis acid vs. hydrazine catalyzed RCCOM. (D) Hydrazine-catalyzed RCCOM for PHA synthesis.One potentially advantageous strategy for PHA synthesis is the use of ring-closing carbonyl–olefin metathesis¹⁵ (RCCOM) to forge one of the PHA rings, starting from a suitably disposed alkenyl aldehyde precursor 2 that can be easily assembled by cross-coupling (Fig. 1B). In related work, the application of RCCOM to form polycyclic aromatic hydrocarbons (PAHs) was reported by Schindler in 2017.¹⁶ In this case, 5 mol% FeCl₃ catalyzed the metathesis of substrates to form phenanthrenes and related compounds in high yields at room temperature. This method was highly attractive for its efficiency, its use of an earth-abundant metal catalyst, and the production of benign acetone as the only by-product. Nevertheless, one obvious drawback to the use of Lewis acid activation is that the presence of any functionality that is significantly more Lewis basic than the carbonyl group can be expected to strongly inhibit these reactions (Fig. 1C). Such a limitation thus renders this method incompatible with a wide swath of complex molecules, especially PHAs comprised of azine rings. This logic argues for a mechanistically orthogonal RCCOM approach that allows for the synthesis of PHA products with a broader range of ring systems and functional groups.We have developed an alternative approach to catalytic carbonyl–olefin metathesis that makes use of the condensation of 1,2-dialkylhydrazines 5 with aldehydes to form hydrazonium ions 6 as the key catalyst–substrate association step.^17–19 This interaction has a much broader chemoorthogonality profile than Lewis acid–base interactions and should thus be much less prone to substrate inhibition than acid-catalyzed approaches. In this Communication, we demonstrate that hydrazine-catalyzed RCCOM enables the rapid assembly of PHAs bearing basic functionality (Fig. 1D).For our optimization studies, we chose biaryl pyridine aldehyde 7 as the substrate (20 salt 11 was also productive (entry 2), albeit somewhat less so. Notably, iron(iii) chloride generated no conversion at either ambient or elevated temperatures (entries 3 and 4). Trifluoroacetic acid (TFA) was similarly ineffective (entry 5). Meanwhile, a screen of various solvents revealed that, while the transformation could occur in a range of media (entries 6–9), THF was optimal. Finally, by raising the temperature to 90 °C (entry 10) or 100 °C (entry 11), up to 96% NMR yield (85% isolated yield) of adduct 8 could be obtained in the same time period.Optimization studies^a

Illuminating anti-hydrozirconation: controlled geometric isomerization of an organometallic species

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp₂ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm. Mechanistic delineation of the contra-thermodynamic isomerization step indicates that a minor reaction product functions as an efficient in situ generated photocatalyst. Coupling of the E-vinyl zirconium species with an alkyne unit generates a conjugated diene: this has been leveraged as a selective energy transfer catalyst to enable E → Z isomerization of an organometallic species. Through an Umpolung metal–halogen exchange process (Cl, Br, I), synthetically useful vinyl halides can be generated (up to Z : E = 90 : 10). This enabling platform provides a strategy to access nucleophilic and electrophilic alkene fragments in both geometric forms from simple arylacetylenes.

A general strategy to enable the formal anti-hydrozirconation of arylacetylenes is reported that merges cis-hydrometallation using the Schwartz Reagent (Cp₂ZrHCl) with a subsequent light-mediated geometric isomerization at λ = 400 nm.

The venerable Schwartz reagent (Cp₂ZrHCl) is totemic in the field of hydrometallation,¹ where reactivity is dominated by syn-selective M–H addition across the π-bond.^2,3 This mechanistic foundation can be leveraged to generate well-defined organometallic coupling partners that are amenable to stereospecific functionalization. Utilizing terminal alkynes as readily available precursors,⁴ hydrozirconation constitutes a powerful strategy to generate E-configured vinyl nucleophiles that, through metal–halogen exchange, can be converted to vinyl electrophiles in a formal Umpolung process.⁵ Whilst this provides a versatile platform to access the electronic antipodes of the E-isomer, the mechanistic course of addition renders access to the corresponding Z-isomer conspicuously challenging. To reconcile the synthetic importance of this transformation with the intrinsic challenges associated with anti-hydrometallation and metallometallation,⁶ it was envisaged that a platform to facilitate geometric isomerization⁷ would be of value. Moreover, coupling this to a metal–halogen exchange would provide a simple Umpolung matrix to access both stereo-isomers from a common alkyne precursor (Fig. 1).Open in a separate windowFig. 1The stereochemical course of alkyne hydrometallation using the Schwartz reagent and an Umpolung platform to generate both stereo-isomers from a common alkyne precursor.Confidence in this conceptual blueprint stemmed from a report by Erker and co-workers, in which irradiating the vinyl zirconium species derived from phenyl acetylene (0.5 M in benzene) with a mercury lamp (Philips HPK 125 and Pyrex filter) induced geometric isomerization.⁸ Whilst Hg lamps present challenges in terms of safety, temperature regulation, cost and wavelength specificity, advances in LED technology mitigate all of these points. Therefore, a process of reaction development was initiated to generalize the anti-hydrozirconation of arylacetylenes. Crucial to the success of this venture was identifying the light-based activation mode that facilitates alkene isomerization. Specifically, it was necessary to determine whether this process was enabled by direct irradiation of the vinyl zirconium species, or if the E → Z directionality results from a subsequent selective energy transfer process involving a facilitator. Several accounts of the incipient vinyl zirconium species reacting with a second alkyne unit to generate a conjugated diene have been disclosed.^9,10 It was therefore posited that the minor by-product diene may be a crucial determinant in driving this isomerization (Fig. 2).Open in a separate windowFig. 2A working hypothesis for the light-mediated anti-hydrozirconation via selective energy transfer catalysis.To advance this working hypothesis and generalize the formal anti-hydrozirconation process, the reaction of Cp₂ZrHCl with 1-bromo-4-ethynylbenzene (A-1) in CH₂Cl₂ was investigated (‡ for full details). This generates a versatile electrophile for downstream synthetic applications. Gratifyingly, after only 15 minutes, a Z : E-composition of 50 : 50 was reached (entry 1) and, following treatment with NBS, the desired vinyl bromide (Z)-1 was obtained in 76% yield (isomeric mixture) over the two steps. Further increasing the irradiation by 15 minute increments (entries 2–4) revealed that the optimum reaction time for the isomerization is 45 minutes (74%, Z : E = 73 : 27, entry 3). Extending the reaction time to 60 minutes (entry 4, 54%) did not lead to an improvement in selectivity and this was further confirmed by irradiating the reaction mixture for 90 minutes (entry 5). In both cases, a notable drop in yield was observed and therefore the remainder of the study was performed using the conditions described in entry 3. Next, the influence of the irradiation wavelength on the isomerization process was examined (entries 6–11). From a starting wavelength of λ = 369 nm, which gave a Z : E-ratio of 27 : 73 (entry 6), a steady improvement was observed by increasing the wavelength to λ = 374 nm (Z : E = 44 : 56, entry 7) and λ = 383 nm (Z : E = 53 : 47, entry 8). The selectivity reached a plateau at λ = 400 nm, with higher wavelengths proving to be detrimental (Z : E = 60 : 40 at λ = 414 nm, entry 9; Z : E = 26 : 74 at λ = 435 nm, entry 10). It is interesting to note that at λ = 520 nm, Z-1 was not detected by ¹H NMR (entry 11).Reaction optimization^a

Ruthenium pincer complex-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides: substrate keeps the catalyst active

The electron pair of the heteroatom in heterocycles will coordinate with metal catalysts and decrease or even inhibit their catalytic activity consequently. In this work, a pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed. Benefitting from the pincer ligand, a variety of heterocycles, such as thiophenes, morpholine, unprotected indoles, pyrrole, pyridine, pyrimidine, furan, thiazole, pyrazole, benzothiadiazole, and triazole, are compatible here.

A pincer ruthenium-catalyzed heterocycle compatible alkoxycarbonylation of alkyl iodides has been developed.

Since the pioneering work on the catalytic alkoxycarbonylation of unactivated alkyl halides reported by Heck and Breslow in 1963,¹ this transformation has attracted a great deal of interest due to its modularity and the direct employment of CO as a cheap and abundant C1 feedstock.² However, compared with aryl halides, the development of alkoxycarbonylation of alkyl halides has been much more gradual.^2,3 This situation is due to both the slow oxidative addition of C(sp³)–X bonds to the metal center and the easy β-hydride elimination of the alkyl-metal intermediate, particularly in the presence of carbon monoxide.⁴ Several catalytic systems for this process have been successfully developed in recent years (Scheme 1A), such as pure radical-based systems,⁵ palladium-based systems,⁶hν/palladium-based systems,⁷ rhodium-based systems,⁸ copper-based systems,⁹ and other metal carbonyl complex-based systems.¹⁰ Very recently, Neumann, Skrydstrup, and co-workers reported a nickel pincer-mediated alkoxycarbonylation for complete carbon isotope replacement, and this approach provided a procedure for generating carbon-labeled versions of potential simple carboxylate prodrug derivatives (Scheme 1B).¹¹ Besides their advantages, in these cases the heterocycles, particularly those containing multiple N atoms or NH groups, are hardly compatible, which is considered as a remaining challenge. We attribute this to the Lewis-basic atoms in heterocyclic motifs being particularly detrimental to catalyst activity and potentially quenching the radical intermediates.¹² Indeed, the development of heterocycle compatible catalytic systems remains an exciting task in the field of alkoxycarbonylation.Open in a separate windowScheme 1Approaches to alkoxycarbonylation of alkyl halides.On the other hand, heterocycles constitute important structural components of biologically active compounds and are ubiquitous in agrochemical and pharmaceutical industries.¹³ In a recent survey, 88% of small molecule drugs approved by the FDA between 2015 and June 2020 were found to contain at least one N-heterocycle.¹⁴ Specifically, heterocyclic subunits can modify the solubility, lipophilicity, polarity and hydrogen bonding ability of biologically active agents, thereby optimizing the corresponding ADME/Tox (absorption, distribution, metabolism, excretion, and toxicity) properties of drugs or drug candidates.¹⁵ Under this premise, the pursuit of new synthetic methods with good heterocycle compatibility is a worthwhile endeavor.Herein we report a heterocycle compatible catalytic system for alkoxycarbonylation of alkyl iodides. With a ruthenium pincer complex as the catalyst, the tight coordination of the pincer ligand can effectively prevent the ruthenium from deactivation by heterocycle coordination (Scheme 1C). To the best of our knowledge, this is the first example of a ruthenium pincer complex-catalyzed carbonylation reaction.¹⁶ This new catalytic system might lead to novel synthetic routes toward heterocyclic carbonyl-containing compounds.Pincer complexes of ruthenium are among the most effective catalysts for hydrogen transfer reactions between alcohols and unsaturated compounds.¹⁷ We initially used it to attempt the carbonylative coupling of acetophenone with iodobutane, as shown in eqn (1). Although we did not get the desired product I, the ester II could be obtained in 22% yield. By literature survey, we found there was no example showing that alkyl halides could be activated by ruthenium in previous reports on carbonylation reactions.^3,16,18 We thus envisioned that the ruthenium pincer complex played a key role in this transformation.^11,191With this discovery in mind, we started the investigation of this ruthenium-catalyzed alkoxycarbonylation of alkyl halides by examining the reaction of (3-iodopropyl)benzene (1) with isopropanol (2) at 100 °C under a CO atmosphere (10 bar) in the presence of a catalytic amount of various readily available ruthenium pincer complexes (†). The improved yield of the desired product 3 was obtained when utilizing Milstein''s catalyst Ru-2²⁰ (21 were applied in the reaction; however, the selectivity obtained was unsatisfactory (eqn (2), when we removed isopropanol from the reaction, byproduct 2 which was produced by carbonylative homocoupling of the alkyl halide could be obtained in 71% yield.²² However, the reduced conversion and the absence of byproduct 3 implied that the alcohol plays more than a nucleophile role in this reaction. It is important to mention that the addition of water had no effect on the yield of byproduct 2. Concerning the effects from bases, organic bases, such as NEt₃ and DBU, were tested, but no desired ester could be detected. Inorganic bases, including K₂CO₃ and K₃PO₄, were also tested, but very low yield of the ester was obtained. Notably, comparable yield of ester 3 can be obtained when LiO^tBu was used as the base.2Optimization of the alkoxycarbonylation of 1^a

Hypervalent iodine-mediated β-difluoroalkylboron synthesis via an unusual 1,2-hydrogen shift enabled by boron substitution

β-Difluoroalkylborons, featuring functionally important CF₂ moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.

A hypervalent iodine-mediated gem-difluorination allows the facile synthesis of β-difluoroalkylborons. An unusual 1,2-hydrogen migration, triggered by boron substitution, is involved.

Organofluorine compounds have been widely applied in medicinal chemistry and materials science.^1a–d In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.^2a–c Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,^3a,b photoredox difluorination,⁴ radical difluorination,⁵ and cross-coupling reactions with suitable CF₂ carriers^6a–f are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.^7a–i Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).^7a–f Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.^7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.^7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.⁷ⁱOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates^8a–c as starting materials.^9a–e Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.^9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).¹⁰ While extending the scope of our previous work,^9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.^11a–d Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,¹⁰ could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.^12a–dTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et₃N·HF in association with PhI(OAc)₂ (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions

Radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters enabled by a carbon shift from an all-carbon quaternary center

Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes. This reaction allows the expansion of the carbon ring by a carbon shift from an all-carbon quaternary center, and enables further C–C bond formation on the tertiary carbon intermediate with the aim of reconstructing a new all-carbon quaternary center. The good functional group compatibility ensures diverse synthetic transformations of this method. Experimental and theoretical studies reveal that the excellent diastereoselectivity should be attributed to the hydrogen bonding between the substrates and solvent.

Herein, we report an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters to achieve the goal of building molecular complexity via the one-pot multifunctionalization of alkenes.

A leading motive for the impressive achievements in the area of assembling molecular complexity is the transformation of simple feedstock chemicals into complex molecular skeletons with superior bioactive properties. In this respect, the direct functionalization of alkenes has been demonstrated as one of the most effective and simple strategies to meet this criterion at a high level. While the difunctionalization of alkenes in a one-pot process is the major theme of considerable interest in this field,¹ the multifunctionalization of alkenes,² for example, a 1,2,3-trifunctionalization of alkenes, has the power to simultaneously incorporate multifunctional groups. Therefore, this multifunctionalization reaction model can be regarded as an efficient and novel strategy to afford molecules with high structural diversity and complexity. However, such methods are elusive.During the last decades, radical alkene functionalizations have been revealed to be a powerful tool for building complex molecular frameworks by employing a radical initiator, a transition metal catalyst, or a photocatalyst.^1f–i However, only several successful methods for the radical multifunctionalization of alkenes have been achieved. For example, the Studer group reported an elegant 1,2-boryl shift-enabled radical 1,2,3-trifunctionalization of allylboronic esters using AIBN as the radical initiator (Fig. 1a).³ Shi et al. disclosed an excellent photocatalytic perfluoroalkylation of a vinyl-substituted all-carbon quaternary center through 1,2-aryl migration (Fig. 1b).⁴ Herein, we report a new one-pot protocol to realize an intermolecular, radical 1,2,3-tricarbofunctionalization of α-vinyl-β-ketoesters through a cascade process of deconstruction–reconstruction of the all-carbon quaternary center (Fig. 1c).⁵Open in a separate windowFig. 1Radical 1,2,3-trifunctionalization of alkenes. (a) Studer''s work; (b) Shi''s work; (c) This work.The direct incorporation of a fluorine atom or fluorinated moieties into organic compounds has been extensively investigated and proved to be an significant synthetic strategy in the field of discovering new pharmaceuticals.⁶ Recently, we are interested in the radical functionalization of alkenes with fluoroalkyl groups,⁷ and we envisioned that, different from the typical Dowd–Beckwith⁸ ring expansion reaction,⁹ the addition of a fluoroalkyl radical to the C C double bond would generate an adduct radical species I, which will transform into the radical intermediate II upon ring expansion (Fig. 1c). Finally, the cascade C–C coupling affords the product with a reconstructed all-carbon quaternary center. However, there are several challenging issues that need to be addressed: (1) the carbon shift from an all-carbon quaternary center to afford a tertiary carbon center which is bulkier than the tertiary carbon center formed in a typical Dowd–Beckwith ring expansion reaction; (2) the reconstruction of all-carbon quaternary center from tertiary carbon radical II will meet the associated conformational restriction and steric congestion; (3) side reactions, such as 1,2-radical addition to the alkenyl group, homolytic couplings of the carbon radical intermediates I and II, and direct H-atom abstraction;¹⁰ (4) how to control the diastereomeric ratio of the products. To meet these challenges, we developed a novel method for the 1,2,3-trifunctionalization of alkenes using alkynyl triflones as both the CF₃ (ref. 6) and alkynyl sources, providing the ring-expanded cyclic β-ketoesters with excellent diastereoselectivity and functional group diversity. In addition, good functional group compatibility of this method was observed, which ensures the diverse synthetic transformations. Moreover, hydrogen bonding between the substrates and 2,2,2-trifluoroethanol solvent was revealed to be the key factor for the excellent diastereoselectivity obtained in this reaction, and this result was confirmed by both experimental and theoretical studies.This study began by surveying radical initiators for 1,2,3-tricarbofunctionalizing α-vinyl-β-ketoester 1a with alkynyl triflone 2a¹¹ (12 (13 dramatically increased the diastereoselectivity and (±)-3a could be obtained in an identical yield with an even higher dr value (dr > 20 : 1) (14 Without the addition of a radical initiator, a reaction did not happen ( EntrySolventYield^b (%)1EA60 (dr = 13 : 1)^c2EA55 (dr = 11 : 1)^d3EA63 (dr = 12 : 1)4MTBE45 (dr = 10 : 1)5DCE63 (dr = 15 : 1)6TolueneTrace7DMFTrace8MeOHTrace9TFE63 (dr > 20 : 1)10^eTFE60 (dr > 20 : 1)11^fTFE56 (dr > 20 : 1)12^gTFE70 (dr > 20 : 1)13^hTFE76 (65)ⁱ (dr > 20 : 1)14^jTFE71 (dr > 20 : 1)15TFETraceOpen in a separate window^aReaction conditions: alkene 1a (0.2 mmol, 1 equiv.), 2a (0.6 mmol, 3.0 equiv.), and AIBN (0.3 equiv.) in 3 mL of solvent at 85 °C for 18 h in a sealed tube under a nitrogen atmosphere.^bCrude yield and crude diastereomeric ratio were determined by ¹⁹F NMR.^cLPO was used as the initiator.^dBPO was used as the initiator.^eThe reaction was performed at 100 °C.^fThe reaction was performed at 120 °C.^gAIBN (60 mol%) was used.^h2a (3.0 equiv.) and AIBN (60 mol%) were added as two equal portions with an interval of 9 h.ⁱIsolated yield in parentheses.^j2a (3.0 equiv.) and AIBN (60 mol%) were added as three equal portions with an interval of 6 h.Under optimal conditions, a diverse array of α-vinyl-β-ketoesters serve as substrates in this metal-free deconstruction–construction of all-carbon quaternary centers for the synthesis of carbon-ring expanded cyclic β-ketoesters (Fig. 2). In most of the cases, excellent diastereoselectivities (dr > 20 : 1) were observed by crude ¹⁹F NMR analysis. Substrates with the substituents at the 5- or 6-position of the α-vinyl-β-ketoesters generally produced the corresponding product (±)-3 in higher yields than those with the substituents at the 4-position. Apart from the carbonyl group and the ester group, functional groups such as chloride ((±)-3b and (±)-3f), fluoride ((±)-3c), a methoxyl group ((±)-3d and (±)-3h), a methyl group ((±)-3e and (±)-3g) and a phenyl group ((±)-3i) can be tolerated under the reaction conditions. Notably, the phenyl ring of the core structure with two substituents reacted smoothly to afford the corresponding products ((±)-3j and (±)-3k). When substrate 1l that lacks the fused benzene ring was used for this carbon-ring expansion reaction, a dramatical loss of diastereoselectivity was detected, presumably because of the feasible interconversion of the boat and chair conformations of the intermediate. Substrates with an ethyl ester or a benzyl ester group, as opposed to a methyl ester group, delivered the corresponding products ((±)-3m and (±)-3n) with moderate yields and excellent diastereoselectivity. When the CH₂ unit of the six membered-ring was replaced by a CMe₂ group, only a trace amount of the desired product (±)-3o was detected. A reaction with the purpose of realizing an extension from the six-membered ring was also carried out and (±)-3p was obtained, although with a low yield and low diastereoselectivity. Notably, the diastereochemistries of products (±)-3e and (±)-3h have been confirmed by X-ray crystallography.Open in a separate windowFig. 2Substrate scope of α-vinyl-β-ketoesters. ^aThe reaction was performed with 1p and 2b.The scope with respect to the alkynyl triflones was also investigated and the results are summarized in Fig. 3. Generally, substituents on the phenyl ring of the arylethynyl moiety have little impact on the yields of the corresponding products. The functional groups at the para-, meta-, or ortho-position of the phenyl ring produced the desired products ((±)-4a–(±)-4k) with excellent diastereoselectivities. Furthermore, the method is compatible with alkynyl triflones that have a thienyl group or a perfluorobutyl group and the reactions afforded the product ((±)-4l or (±)-4m) with an excellent dr value, respectively. However, when the arylethynyl moiety was replaced by an alkylethynyl or a silylethynyl part, the reaction failed to produce the targeted tricarbofunctionalization product ((±)-4n or (±)-4o).¹⁵ Moreover, when triflic azide or (Z)-TolCH CHSO₂CF₃ was used in place of the alkynyl triflone, the desired product was not obtained and most of the starting material was recovered. Notably, the diastereochemistry of product (±)-4a has been confirmed by X-ray crystallography.Open in a separate windowFig. 3Substrate scope of alkynyl triflones.This 1,2,3-trifunctionalization reaction not only allows the deconstruction and reconstruction of all-carbon quaternary centers, but features good functional group tolerance and excellent diastereoselectivity. Regarding the diverse reactivities of these functional groups, many valuable synthetic transformations have been successfully achieved (Fig. 4). For example, the C–C triple bond of (±)-4a can be completely reduced to a CH₂CH₂ unit ((±)-5) in the presence of hydrogen and a Pd/C catalyst,¹⁶ while the selective reduction of (±)-4a gives rise to a Z-alkene (±)-6 when quinoline is added as an additive for the Lindlar reduction.¹⁷ The diastereochemistry of (±)-6 has been confirmed by X-ray crystallography. The selective reducing methods afford formal approaches for radical 1,3-trifluoromethylalkylation and 1,3-trifluoromethylalkenylation of α-vinyl-β-ketoesters, respectively, to produce the corresponding products which are otherwise difficult to obtain. In addition, the C–C triple bond can be oxidized under oxidative conditions with RuCl₃/NaIO₄, and (±)-4a can be smoothly transformed into the trifluoromethylated triketone (±)-7 in 65% yield.¹⁸ With a large excess amount of reducing agent LiAlH₄, the carbonyl group and the ester group, together with the C–C triple bond, can be unexpectedly reduced simultaneously, affording the alkenyl diol (±)-8 in excellent regioselectivity. The hydrolysis process under basic conditions provided a reliable method for access to a free carboxylic acid (±)-9. Interestingly, when the reaction was performed under milder conditions compared to those for the synthesis of (±)-8, (±)-4a was successfully converted into an alkynyl diol (±)-10, which can be cyclized into a spiro compound (±)-11 (ref. 19) and an endocyclic compound (±)-12,²⁰ respectively. Notably, in the majority of these cases, the excellent diastereoselectivity was reserved. These synthetic applications can demonstrate the significant value of this method.Open in a separate windowFig. 4Synthetic transformations.In order to gain some mechanistic insights into this radical cascade reaction, subsequent efforts have been made (Fig. 5). First, the detection of trifluoromethylated toluene (with toluene as the solvent, Fig. 5a, see ESI^† for details). Second, we were curious about the excellent diastereoselectivity associated with the use of TFE as the solvent. As can be seen in Fig. 5b, ¹H NMR titration of 1a with increasing amounts of TFE showed a chemical shift of the resonance signal corresponding to protons. The 2D NOESY spectrum indicates the existence of an interaction between 1a and TFE (Fig. 5c). Moreover, Job plot studies by both ¹H NMR and ¹⁹F NMR imply a 1 : 1.5 stoichiometry of the complex adduct resulting from 1a and TFE (Fig. 5d). These mechanistic studies strongly suggest that the excellent diastereoselectivity of this reaction might be attributed to the hydrogen bonding between TFE and the α-vinyl-β-ketoester.Open in a separate windowFig. 5Mechanism studies. (a) Radical probe; (b) ¹H NMR titration; (c) 2D NOESY; (d) Job plot studies.On the other hand, density functional theory (DFT) calculations have also been performed at the B3LYP-D3(SMD)/Def2-TZVP//B3LYP-D3(SMD)/Def2-SVP level of theory in the TFE solvent model to further investigate the reaction pathways (Fig. 6). On the basis of the experimental results, herein, the radical pathway was considered. Initially, the CF₃ radical addition onto 1a was calculated, and a transition state, TS1, was located with a free energy barrier of 10.9 kcal mol⁻¹ to deliver the radical intermediate int1 with an exergonicity of 20.5 kcal mol⁻¹. Then, a bicyclic transition state, TS2,²¹ with a barrier of 11.0 kcal mol⁻¹ through a concerted 1,2-shift route was found to be the lower barrier TS for int2 formation than that of the addition to 2b for the byproduct (see Fig. S5 in ESI^†), which is consistent with the experimental results of the mainly hexacyclic products. Moreover, the intrinsic reaction coordinate (IRC) calculations and the root mean square (RMS) gradient of the potential energy surface from TS2 suggested that no transition state for the formation of the previously proposed strained alkoxyl radical was found. Next, the radical intermediate int2 attacking 2b was calculated. To understand the diastereoselectivity of this step, the transition states of the addition of 2b onto the Re and Si faces of C3 in int2 were located with barriers of 12.5 and 17.4 kcal mol⁻¹ (TS3 and TS3′), respectively. It is noteworthy that the torsion angle of C1–C2–C3–C4 in TS3′ is −62.3°, larger than that of −40.9° in int2 and −49.0° in TS3, indicating that the distortion factor in TS3′ is large due to the steric effect from the trifluoroethyl group in int2 and, therefore, increases the barrier. The transition states of 2b addition were also optimized in solvents DCE and EA, and the free energy barrier differences between TS3 and TS3′ [ΔG^‡ = G^‡(TS3′) − G^‡(TS3)] are 3.6 and 3.0 kcal mol⁻¹, respectively, in agreement with the experimental observations. Finally, dissociation of a SO₂ molecule with a CF₃ radical from int3 to deliver the product was conducted, and a transition state TS4 with a much lower barrier of only 7.1 kcal mol⁻¹ was located, which led to the major product (±)-4a with a relative free enthalpy of −51.6 kcal mol⁻¹.Open in a separate windowFig. 6Gibbs free energy profile for the synthesis of 4a in the TFE solvent model.     

Ligand-promoted palladium-catalyzed β-methylene C–H arylation of primary aldehydes

The transient directing group (TDG) strategy allowed long awaited access to the direct β-C(sp³)–H functionalization of unmasked aliphatic aldehydes via palladium catalysis. However, the current techniques are restricted to terminal methyl functionalization, limiting their structural scopes and applicability. Herein, we report the development of a direct Pd-catalyzed methylene β-C–H arylation of linear unmasked aldehydes by using 3-amino-3-methylbutanoic acid as a TDG and 2-pyridone as an external ligand. Density functional theory calculations provided insights into the reaction mechanism and shed light on the roles of the external and transient directing ligands in the catalytic transformation.

Aliphatic aldehydes are among the most common structural units in organic and medicinal chemistry research. Direct C–H functionalization has enabled efficient and site-selective derivatization of aliphatic aldehydes.

Simple aliphatic functional groups enrich the skeletal backbones of many natural products, pharmaceuticals, and other industrial materials, influencing the utility and applications of these substances and dictating their reactivity and synthetic modification pathways. Aliphatic aldehydes are some of the most ubiquitous structural units in organic materials.¹ Their relevance in nature and industry alike, combined with their reactivity and synthetic versatility, attracted much attention from the synthetic organic and medicinal chemistry communities over the years (Fig. 1).² Efficient means to the functionalization of these molecules have always been highly sought after.Open in a separate windowFig. 1Select aliphatic aldehyde-containing medicines and biologically active molecules.Traditionally, scientists have utilized the high reactivity of the aldehyde moiety in derivatizing a variety of functional groups by the means of red-ox and nucleophilic addition reactions. The resourceful moiety was also notoriously used to install functional groups at the α-position via condensation and substitution pathways.³ Although β-functionalization is just as robust, it has generally been more restrictive as it often requires the use of α,β-unsaturated aldehydes.^4,5 Hence, transition metal catalysis emerged as a powerful tool to access β-functionalization in saturated aldehydes.⁶ Most original examples of metal-catalyzed β-C–H functionalization of aliphatic aldehydes required the masking of aldehydes into better metal coordinating units since free unmasked aldehydes could not form stable intermediates with metals like palladium on their own.⁷ Although the masking of the aldehyde moiety into an oxime, for example, enabled the formation of stable 5-membered palladacycles, affording β-functionalized products, this system requires the installation of the directing group prior to the functionalization, as well as the subsequent unmasking upon the reaction completion, compromising the step economy and atom efficiency of the overall process.⁸ Besides, some masking and unmasking protocols might not be compatible with select substrates, especially ones rich in functional groups. As a result, the development of a one-step direct approach to the β-C–H functionalization of free aliphatic aldehydes was a demanding target for synthetic chemists.α-Amino acids have been demonstrated as effective transient directing groups (TDGs) in the remote functionalization of o-alkyl benzaldehydes and aliphatic ketones by the Yu group in 2016.⁹ Shortly after, our group disclosed the first report on the direct β-C–H arylation of aliphatic aldehydes using 3-aminopropanoic acid or 3-amino-3-methylbutanoic acid as a TDG.¹⁰ The TDG was found to play a similar role to that of the oxime directing group by binding to the substrate via reversible imine formation, upon which, it assists in the assembly of a stable palladacycle, effectively functionalizing the β-position.¹¹ Since the binding of the TDG is reversible and temporary, it is automatically removed upon functionalization, yielding an efficient and step-economic transformation. This work was succeeded by many other reports that expanded the reaction and the TDG scopes.^12–14 However, this system suffers from a significant restriction that demanded resolution; only substitution of methyl C–H bonds of linear aldehydes was made possible via this approach (Scheme 1a–e). The steric limitations caused by incorporating additional groups at the β-carbon proved to compromise the formation of the palladacycle intermediate, rendering the subsequent functionalization a difficult task.¹²Open in a separate windowScheme 1Pd-catalyzed β-C–H bond functionalization of aliphatic aldehydes enabled by transient directing groups.Encouraged by the recent surge in use of 2-pyridone ligands to stabilize palladacycle intermediates,^15,16 we have successfully developed the first example of TDG-enabled Pd-catalyzed methylene β-C–H arylation in primary aldehydes via the assistance of 2-pyridones as external ligands (Scheme 1f). The incorporation of 2-pyridones proved to lower the activation energy of the C–H bond cleavage, promoting the formation of the intermediate palladacycles even in the presence of relatively bulky β-substituents.¹⁷ This key advancement significantly broadens the structural scopes and applications of this process and promises future asymmetric possibilities, perhaps via the use of a chiral TDG or external ligand or both. Notably, a closely related work from Yu''s group was published at almost the same time.¹⁸We commenced our investigation of the reaction parameters by employing n-pentanal (1a) as an unbiased linear aldehyde and 4-iodoanisole (2a) in the presence of catalytic Pd(OAc)₂ and stoichiometric AgTFA, alongside 3-amino-3-methylbutanoic acid (TDG1) and 3-(trifluoromethyl)-5-nitropyridin-2-ol (L1) at 100 °C (ii) sources proved Pd(OAc)₂ to be the optimal catalyst, while Pd(TFA)₂, PdCl₂ and PdBr₂ provided only moderate yields (entries 10–12). Notably, a significantly lower yield was observed in the absence of the 2-pyridone ligand, and no desired product was isolated altogether in the absence of the TDG (entries 13 and 14). The incorporation of 15 mol% Pd catalyst was deemed necessary after only 55% yield of 3a was obtained when 10 mol% loading of Pd(OAc)₂ was instead used (entry 15).Optimization of reaction conditions^a

Entry	Pd source	L (mol%)	TDG1 (mol%)	Solvent (v/v, mL)	Yield (%)
1	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP	30
2	Pd(OAc)2	L1 (30)	TDG1 (40)	AcOH	<5
3	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 1)	28
4	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (9 : 1)	47
5	Pd(OAc)2	L1 (30)	TDG1 (40)	HFIP/AcOH (1 : 9)	<5
6	Pd(OAc)2	L1 (30)	TDG1 (60)	HFIP/AcOH (9 : 1)	50
7	Pd(OAc)2	L1 (30)	TDG1 (80)	HFIP/AcOH (9 : 1)	25
8	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	70(68)b
9	Pd(OAc)2	L1 (75)	TDG1 (60)	HFIP/AcOH (9 : 1)	51
10	Pd(TFA)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	60
11	PdCl2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	52
12	PdBr2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	54
13	Pd(OAc)2	—	TDG1 (60)	HFIP/AcOH (9 : 1)	9
14	Pd(OAc)2	L1 (60)	—	HFIP/AcOH (9 : 1)	0
15c	Pd(OAc)2	L1 (60)	TDG1 (60)	HFIP/AcOH (9 : 1)	55

Open in a separate window^aReaction conditions: 1a (0.2 mmol), 2a (0.4 mmol), Pd source (15 mol%), AgTFA (0.3 mmol), L1, TDG1, solvent (2.0 mL), 100 °C, 12 h. Yields are based on 1a, determined by ¹H-NMR using dibromomethane as an internal standard.^bIsolated yield.^cPd(OAc)₂ (10 mol%).To advance our optimization of the reaction conditions, a variety of 2-pyridones and TDGs were tested (Scheme 2). Originally, pyridine-2(1H)-one (L2) was examined as the external ligand, but it only yielded the product (3a) in 7% NMR yield. Similarly, other mono- and di-substituted 2-pyridone ligands (L3–L10) also produced low yields, fixating L1 as the optimal external ligand. Next, various α- and β-amino acids (TDG1–10) were evaluated, yet TDG1 persisted as the optimal transient directing group. These amino acid screening results also suggest that a [5,6]-bicyclic palladium species is likely the key intermediate in this protocol since only β-amino acids were found to provide appreciable yields, whereas α-amino acids failed to yield more than trace amounts of the product. The supremacy of TDG1 when compared to other β-amino acids is presumably due to the Thorpe–Ingold effect that perhaps helps facilitate the C–H bond cleavage and stabilize the [5,6]-bicyclic intermediate further.Open in a separate windowScheme 2Optimization of 2-pyridone ligands and transient directing groups.With the optimized reaction conditions in hand, substrate scope study of primary aliphatic aldehydes was subsequently carried out (Scheme 3). A variety of linear primary aliphatic aldehydes bearing different chain lengths provided the corresponding products 3a–e in good yields. Notably, relatively sterically hindered methylene C–H bonds were also functionalized effectively (3f and 3g). Additionally, 4-phenylbutanal gave rise to the desired product 3h in a highly site-selective manner, suggesting that functionalization of the methylene β-C–H bond is predominantly favored over the more labile benzylic C–H bond. It is noteworthy that the amide group was also well-tolerated and the desired product 3j was isolated in 60% yield. As expected, with n-propanal as the substrate, β-mono- (3k1) and β,β-disubstituted products (3k2) were isolated in 22% and 21% yields respectively. However, in the absence of the key external 2-pyridone ligand, β-monosubstituted product (3k1) was obtained exclusively, albeit with a low yield, indicating preference for functionalizing the β-C(sp³)–H bond of the methyl group over the benzylic methylene group.Open in a separate windowScheme 3Scope of primary aliphatic aldehydes. Reaction conditions: 1 (0.2 mmol), 2a (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields. ^aL1 (60 mol%) was absent and yields are given in parentheses.Next, substrate scope study on aryl iodides was surveyed (Scheme 4). Iodobenzenes bearing either an electron-donating or electron-withdrawing group at the para-, meta-, or ortho-position were all found compatible with our catalytic system (3l–3ah). Surprisingly, ortho-methyl- and fluoro-substituted aryl iodides afforded the products in only trace amounts. However, aryl iodide with ortho-methoxy group provided the desired product 3ac in a moderate yield. Notably, a distinctive electronic effect pattern was not observed in the process. It should be mentioned that arylated products bearing halogen, ester, and cyano groups could be readily converted to other molecules, which significantly improves the synthetic applicability of the process. Delightfully, aryl iodide-containing natural products like ketoprofen, fenchol and menthol were proven compatible, supplying the corresponding products in moderate yields. Unfortunately, (hetero)aryl iodides including 2-iodopyridine, 3-iodopyridine, 4-iodopyridine and 4-iodo-2-chloropyridine failed to produce the corresponding products. Although our protocol provides a novel and direct pathway to construct β-arylated primary aliphatic aldehydes, the yields of most examples are modest. The leading reasons for this compromise are the following: (1) aliphatic aldehydes are easily decomposed or oxidized to acids; (2) some of the prepared β-arylated aldehyde products may be further transformed into the corresponding α,β-unsaturated aldehydes.Open in a separate windowScheme 4Scope of aryl iodides. Reaction conditions: 1a (0.2 mmol), 2 (0.4 mmol), Pd(OAc)₂ (15 mol%), AgTFA (0.3 mmol), L1 (60 mol%), TDG1 (60 mol%), HFIP (1.8 mL), HOAc (0.2 mL), 100 °C, 12 h. Isolated yields.Density functional theory (DFT) calculations were performed to help investigate the reaction mechanism and to elucidate the role of the ligand in improving the reactivity (Fig. 2). The condensation of the aliphatic aldehyde 1a with the TDG to form imine-1a was found thermodynamically neutral (ΔG° = −0.1 kcal mol⁻¹). As a result, it was permissible to use imine-1a directly in the calculations. According to the calculations results, the precatalyst [Pd(OAc)₂]₃, a trimeric complex, initially experiences dissociation and ligand metathesis with imine-1a to generate the Pd(ii) intermediate IM1, which is thermodynamically favorable by 21.9 kcal mol⁻¹. Consequently, the deprotonated imine-1a couples to the bidentate ligand to form the stable six-membered chelate complex IM1. Therefore, IM1 is indeed the catalyst resting state and serves as the zero point to the energy profile. We have identified two competitive pathways for the Pd(ii)-catalyzed C–H activation starting from IM1, one of which incorporates L1 and another which does not. On the one hand, an acetate ligand substitutes one imine-1a chelator in IM1 to facilitate the subsequent C–H activation leading to IM2, which undergoes C(sp³)–H activation through concerted metalation-deprotonation (CMD) viaTS1 (ΔG^‡ = 37.4 kcal mol⁻¹). However, this kinetic barrier is thought to be too high to account for the catalytic activity at 100 °C. On the other hand, the chelate imine-1a could be replaced by two N-coordinated ligands (L1) leading to the Pd(ii) complex IM3. This process is endergonic by 6.4 kcal mol⁻¹. To allow the ensuing C–H activation, IM3 dissociates one ligand (L1) producing the active species IM4, which undergoes TS2 to cleave the β-C(sp³)–H bond and form the [5,6]-bicyclic Pd(ii) intermediate IM5. Although this step features an energy barrier of 31.2 kcal mol⁻¹, it is thought to be feasible under the experimental conditions (100 °C). Possessing similar coordination ability to that of pyridine, the ligand (L1) effectively stabilizes the Pd(ii) center in the C–H activation process, indicating that this step most likely involves a manageable kinetic barrier. This result explicates the origin of the ligand-enabled reactivity (TS2vs.TS1). Additionally, we considered the γ-C(sp³)–H activation pathway viaTS2′ which was found to have a barrier of 35.5 kcal mol⁻¹. The higher energy barrier of TS2′ compared to that of TS2 is attributed to its larger ring strain in the [6,6]-bicyclic Pd(ii) transition state, which reveals the motive for the site-selectivity. Reverting back to the supposed pathway, upon the formation of the bicyclic intermediate IM5, it undergoes ligand/substrate replacement to afford intermediate IM6, at which the Ar–I coordinates to the Pd(ii) center to enable oxidative addition viaTS3 (ΔG^‡ = 27.4 kcal mol⁻¹) leading to the five-coordinate Pd(iv) complex IM7. Undergoing direct C–C reductive elimination in IM7 would entail a barrier of 29.6 kcal mol⁻¹ (TS4). Alternatively, iodine abstraction by the silver(i) salt in IM7 is thermodynamically favorable and irreversible, yielding the Pd(iv) intermediate IM8 coordinated to a TFA ligand. Subsequently, C–C reductive coupling viaTS5 generates the Pd(ii) complex IM9 and concludes the arylation process. This step was found both kinetically facile (6.1 kcal mol⁻¹) and thermodynamically favorable (30.7 kcal mol⁻¹). Finally, IM9 reacts with imine-1avia metathesis to regenerate the palladium catalyst IM1 and release imine-3a in a highly exergonic step (21.0 kcal mol⁻¹). Ultimately, imine-3a undergoes hydrolysis to yield the aldehyde product 3a and to release the TDG.Open in a separate windowFig. 2Free energy profiles for the ligand-promoted Pd(ii)-catalyzed site-selective C–H activation and C–C bond formation, alongside the optimized structures of the C–H activation transition states TS1 and TS2 (selected bond distances are labelled in Å). Energies are relative to the complex IM1 and are mass-balanced.     

Three-component 1,2-carboamination of vinyl boronic esters via amidyl radical induced 1,2-migration

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented. Vinylboron ate complexes generated in situ from the boronic ester and an organo lithium reagent are shown to react with readily available N-chloro-carbamates/carboxamides to give valuable 1,2-aminoboronic esters. These cascades proceed in the absence of any catalyst upon simple visible light irradiation. Amidyl radicals add to the vinylboron ate complexes followed by oxidation and 1,2-alkyl/aryl migration from boron to carbon to give the corresponding carboamination products. These practical cascades show high functional group tolerance and accordingly exhibit broad substrate scope. Gram-scale reaction and diverse follow-up transformations convincingly demonstrate the synthetic potential of this method.

Three-component 1,2-carboamination of vinyl boronic esters with alkyl/aryl lithium reagents and N-chloro-carbamates/carboxamides is presented.

Alkenes are important and versatile building blocks in organic synthesis. 1,2-Difunctionalization of alkenes offers a highly valuable synthetic strategy to access 1,2-difunctionalized alkanes by sequentially forming two vicinal σ-bonds.^1a–h Among these vicinal difunctionalizations, the 1,2-carboamination of alkenes, in which a C–N and a C–C bond are formed, provides an attractive route for the straightforward preparation of structurally diverse amine derivatives (Scheme 1a).^2a–c Along these lines, transition-metal-catalyzed or radical 1,2-carboaminations of activated and unactivated alkenes have been reported.^3a–p However, the 1,2-carboamination of vinylboron reagents, a privileged class of olefins,^4a–h to form valuable 1,2-aminoboron compounds which can be readily used in diverse downstream functionalizations,^{5a–c,6a–d} has been rarely investigated. To the best of our knowledge, there are only two reported examples, as shown in Schemes 1b and c. In 2013, Molander disclosed a Rh-catalyzed 1,2-aminoarylation of potassium vinyltrifluoroborate with benzhydroxamates via C–H activation (Scheme 1b).⁷ Thus, the 1,2-carboamination of vinylboron reagents is still underexplored but highly desirable.Open in a separate windowScheme 1Intermolecular 1,2-carboamination of alkenes.1,2-Alkyl/aryl migrations induced by β-addition to vinylboron ate complexes have been shown to be highly reliable for 1,2-difunctionalization of vinylboron reagents (Scheme 1c).^4d–h In 1967, Zweifel''s group developed 1,2-alkyl/aryl migrations of vinylboron ate complexes induced by an electrophilic halogenation.⁸ In 2016, the Morken group reported the electrophilic palladation-induced 1,2-alkyl/aryl migration of vinylboron ate complexes.^9a–k Shortly thereafter, we,^10a–c Aggarwal,^11a–c and Renaud¹² developed alkyl radical induced 1,2-alkyl/aryl migrations of vinylboron ate complexes. In these recent examples, the migration is induced by a C-based radical/electrophile, halogen and chalcogen electrophiles.^13a,bIn contrast, N-reagent-induced migration of vinylboron ate complexes proceeding via β-amination is not well investigated. To our knowledge, as the only example the Aggarwal laboratory described the reaction of a vinylboron ate complex with an aryldiazonium salt as the electrophile, but the desired β-aminated rearrangement product was formed in only 9% NMR yield (Scheme 1c).^13a No doubt, β-amino alkylboronic esters would be valuable intermediates in organic synthesis. Encouraged by our continuous work on amidyl radicals^14a–i and 1,2-migrations of boron ate complexes,^{10a–c,15a–f} we therefore decided to study the amidyl radical-induced carboamination of vinyl boronic esters for the preparation of 1,2-aminoboronic esters. N-chloroamides were chosen as N-radical precursors,^16a–c as these N-chloro compounds can be easily prepared from the corresponding N–H analogues.¹⁷ Herein, we present a catalyst-free three-component 1,2-carboamination of vinyl boronic esters with N-chloroamides and readily available alkyl/aryl lithium reagents (Scheme 1d).We commenced our study by exploring the reaction of the vinylboron ate complex 2a with tert-butyl chloro(methyl)carbamate 3a applying photoredox catalysis. Complex 2a was generated in situ by addition of n-butyllithium to the boronic ester 1a in diethyl ether at 0 °C. After solvent removal, the photocatalyst fac-Ir(ppy)₃ (1 mol%) and THF were added followed by the addition of 3a. Upon blue LED light irradiation, the mixture was stirred at room temperature for 16 hours. To our delight, the desired 1,2-aminoboronic ester 4a was obtained, albeit with low yield (26%, EntryPhotocatalystSolventT (°C)Yield^b (%)1 fac-Ir(ppy)₃THFrt262 fac-Ir(ppy)₃DMSOrt23 fac-Ir(ppy)₃MeCNrt564Ru(bpy)₃Cl₂·6H₂OMeCNrt695Na₂Eosin YMeCNrt696^cNa₂Eosin YMeCNrt707^cNoneMeCNrt458^cNoneMeCN0789^cNoneMeCN−2088 (85)10^c,dNoneMeCN−202Open in a separate window^aReaction conditions: 1a (0.20 mmol), ⁿBuLi (0.22 mmol), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar. After vinylboron ate complex formation, solvent exchange to the selected solvent (2 mL) was performed.^bGC yield using n-C₁₄H₃₀ as an internal standard; yield of isolated product is given in parentheses.^c4 mL MeCN was used.^dReaction carried out in the dark.With optimal conditions in hand, we then investigated the scope of this new 1,2-carboamination protocol keeping 2a as the N-radical acceptor (Scheme 2). This transformation turned out to be compatible with various primary amine reaction partners bearing carbamate (4a, 4b and 4d–4g) or acyl protecting groups (4c) (20–85%). Notably, N-chlorolactams can be used as N-radical precursors, as shown by the successful preparation of 4h (71%). Moreover, Boc-protected ammonia was also tolerated, delivering 4i in an acceptable yield (55%).Open in a separate windowScheme 21,2-Carboamination of 1a with various amidyl radical precursors. Reaction conditions: 1a (0.20 mmol, 1.0 equiv.), ⁿBuLi (0.22 mmol, 1.1 equiv.), in Et₂O (2 mL), 0 °C to rt, 1 h, under Ar; then [N]-Cl (0.24 mmol, 1.2 equiv.), −20 °C, 16 h, in MeCN (4 mL). Yields given correspond to yields of isolated products. ^aA solution of [N]-Cl (0.30 mmol, 1.5 equiv.) in MeCN (1 mL) was used. See the ESI^† for experimental details.We continued the studies by testing a range of vinylboron ate complexes (Scheme 3). To this end, various vinylboron ate complexes were generated by reacting the vinyl boronic ester 1a with methyllithium, n-hexyllithium, isopropyllithium and tert-butyllithium. For the n-alkyl-substituted vinylboron ate complexes, the 1,2-carboamination worked smoothly to afford 4j and 4k in good yields. However, the vinylboron ate complex derived from isopropyllithium addition provided the desired products in much lower yield (4l, 18% yield). When tert-butyllithium was employed, only a trace of the targeted product was detected (see ESI^†). As expected, cascades comprising a 1,2-aryl migration from boron to carbon worked well. Thus, by using PhLi for vinylboron ate complex formation, the 1,2-aminoboronic esters 4m–4o were obtained in 69–73% yields with the Boc (t-BuOCONClMe), ethoxycarbonyl-(EtOCONClMe) and methoxycarbonyl (Moc)-(MeOCONClMe) protected N-chloromethylamines (for the structures of 3, see ESI^†) as radical amination reagents. Keeping 3b as the N-donor, other aryllithiums bearing various functional groups at the para position of the aryl moiety, such as methoxy (4p), trimethylsilyl (4q), methyl (4r), phenyl (4s), trifluoromethoxy (4t), trifluoromethyl (4u), and halides (4v–4x) all reacted well in this transformation. Aryl groups bearing meta substituents are also tolerated, as documented by the preparation of 4y (81%). To our delight, a boron ate complex generated with a 3-pyridyl lithium reagent engaged in the cascade and the carboamination product 4z was isolated in high yield (82%).Open in a separate windowScheme 3Scope of vinylboron ate complexes. Reaction conditions: 1 (0.20 mmol, 1.0 equiv.), R_MLi (0.22 mmol, 1.1 or 1.3 equiv.), Et₂O or THF, under Ar; then [N]-Cl (0.30 mmol, 1.5 equiv.), −20 °C, 16 h, in MeCN. Yields given correspond to yields for isolated products. See the ESI^† for experimental details.The reason for the dramatic reduction in yield when α-branched alkyllithium or electron-rich aryllithium reagents were used might be that the corresponding vinylboron ate complexes could be oxidized by N-chloroamides via a single-electron oxidation process.^18a–e Furthermore, the α-unsubstituted vinyl boronic ester and vinyl boronic ester bearing various α-substituents are suitable N-radical acceptors and the corresponding products 4aa–4ac were obtained in 48–70% yield.To gain insights into the mechanism of this 1,2-carboamination, a control experiment was conducted. The reaction could be nearly fully suppressed when the reaction was carried out in the presence of a typical radical scavenger (2,2-6,6-tetramethyl piperidine-N-oxyl, TEMPO), indicating a radical mechanism (Scheme 4a). Further, considering an ionic process, the N-chloroamides would react as Cl⁺-donors that would lead to Zweifel-type products, which were not observed under the applied conditions. The proposed mechanism is shown in Scheme 4b. As chloroamides have been recently proposed to undergo homolysis under visible light irradiation,^19a,b we propose that initiation proceeds via homolytic N–Cl cleavage generating the electrophilic amidyl radical A, which then adds to the electron-rich vinylboron ate complex 2a to give the adduct boronate radical B. The radical anion B then undergoes single electron transfer (SET) oxidation with 3a in an electron-catalyzed process^20a,b or chloride atom transfer with 3a to provide C or D along with the amidyl radical A, thereby sustaining the radical chain. Intermediates C or D can then react via a boronate 1,2-migration^10c,11c,21 to eventually give the isolated product 4a.Open in a separate windowScheme 4Control experiment and proposed mechanism.To document the synthetic utility of the method, a larger-scale reaction and various follow-up transformations were conducted. Gram-scale reaction of 2a with 3a afforded the desired product 4a in good yield, demonstrating the practicality of this transformation (Scheme 5a). Oxidation of 4a with NaBO₃ provided the β-amino alcohol 5 in 89% yield (Scheme 5b). The N-Boc homoallylic amine 6 was obtained by Zweifel-olefination with a commercially available vinyl Grignard reagent and elemental iodine in good yield (79%).²² Heteroarylation of the C–B bond in 4a was realized by oxidative coupling of 4a with 2-thienyl lithium to provide 7.²³Open in a separate windowScheme 5Gram-scale reaction and follow-up chemistry.In summary, we have described an efficient method for the preparation of 1,2-aminoboronic esters from vinyl boronic esters via catalyst-free three-component radical 1,2-carboamination. Readily available N-chloro-carbamates/carboxamides, which are used as the N-radical precursors, react efficiently with in situ generated vinylboron ate complexes to afford the corresponding valuable 1,2-aminoboronic esters in good yields. The reaction features broad substrate scope and high functional group tolerance. The value of the introduced method was documented by Gram-scale reaction and successful follow-up transformations.     

Organocatalytic discrimination of non-directing aryl and heteroaryl groups: enantioselective synthesis of bioactive indole-containing triarylmethanes

Despite the enormous developments in asymmetric catalysis, the basis for asymmetric induction is largely limited to the spatial interaction between the substrate and catalyst. Consequently, asymmetric discrimination between two sterically similar groups remains a challenge. This is particularly formidable for enantiodifferentiation between two aryl groups without a directing group or electronic manipulation. Here we address this challenge by using a robust organocatalytic system leading to excellent enantioselection between aryl and heteroaryl groups. With versatile 2-indole imine methide as the platform, an excellent combination of a superb chiral phosphoric acid and the optimal hydride source provided efficient access to a range of highly enantioenriched indole-containing triarylmethanes. Control experiments and kinetic studies provided important insights into the mechanism. DFT calculations also indicated that while hydrogen bonding is important for activation, the key interaction for discrimination of the two aryl groups is mainly π–π stacking. Preliminary biological studies also demonstrated the great potential of these triarylmethanes for anticancer and antiviral drug development.

Excellent enantiodiscrimination between aryl and heteroaryl groups without a directing group has been achieved with organocatalysis. The highly enantioenriched triarylmethane products exhibit anticancer and antiviral activities.

Asymmetric catalysis has evolved arguably into the most powerful method for the synthesis of enantioenriched molecules.¹ It features high efficiency and atom-economy in principle as compared to other approaches such as chiral resolution and auxiliary-based asymmetric synthesis, thereby enabling increasing applications in industrial synthesis.² In the past few decades, a wide range of chiral catalytic systems with diverse activation modes have been developed. However, the fundamental basis for enantiocontrol remains essentially unchanged, i.e., spatial interaction between the substrate and catalyst.^1,2 For example, in the construction of a tetrahedral C(sp³)-chiral center from a prochiral C(sp²)-based planar substrate (e.g., carbocation, radical, carbonyl, and olefin), a chiral catalyst typically provides enantiodifferentiation by blocking one face of the plane and directing the reaction partner (Y) to approach towards the other face (Scheme 1a). To achieve this, the catalyst must be able to effectively discriminate between the two substituents (R¹ and R²) on the prochiral carbon. Obviously, the larger the difference of these two substituents is, the better enantioselectivity will be expected. Consequently, it has been well-established to achieve high enantioselectivity for cases bearing two sterically different groups (e.g., alkyl/aryl vs. H and large alkyl vs. small alkyl). In contrast, for cases bearing two substituents of a similar size, it remains challenging.¹Open in a separate windowScheme 1Introduction to asymmetric differentiation in C(sp²)-prochiral centers.1,1-Diarylmethinyl stereocenters are a widely prevalent structural motif in various natural products and biologically important molecules.³ Asymmetric addition to the 1,1-diaryl C C and C = X (X = heteroatom) bonds represents one of the most direct approaches for the construction of this unit.^4–8 However, this requires effective discrimination between two (often) sterically similar aryl groups, which represents a notable challenge in asymmetric catalysis (Scheme 1b).⁴ So far, success has mainly relied on the use of a directing group in one aryl group to allow catalyst recognition (e.g., by coordination) or electronic difference by incorporating electron-donating/withdrawing groups.^6,7 Notably, the effective enantiodifferentiation between aryl and heteroaryl groups still remains challenging, particularly in the absence of a directing group.⁸ Moreover, despite the above-mentioned important progress, it is worth noting that almost all these examples relied on metal catalysis, and little success has been achieved by organocatalysis.^4–8 In this context, here we describe organocatalytic discrimination of non-directing aryl and heteroaryl groups, providing access to highly enantioenriched triarylmethanes, and in view of the general diverse biological activities of triarylmethanes,⁹ we have also investigated the anticancer and antiviral activities of these products.Indole imine methides (IIMs) have recently emerged as versatile intermediates for the asymmetric synthesis of enantioenriched indole derivatives, a family of useful units in medicinal chemistry.^10–12 In particular, those with the methide motif adorned in the 2-position of indole are particularly useful to construct indole-fused polyheterocycles via asymmetric annulation processes, as pioneered by Shi and co-workers.^10,11 In continuation of our interest in IIMs,¹² we envisioned that these types of intermediates would be a good platform to study the power of organocatalysis for the challenging discrimination between aryl and heteroaryl groups lacking a directing group (Scheme 1c). However, additional challenges should be expected since this intermediate II is likely generated as a Z/E mixture, typically in equilibrium with carbocation I. Therefore, the equilibrium should be made in synergy with the nucleophilic addition step to allow dynamic asymmetric control in order to achieve high enantioselectivity.To test our hypothesis, we employed racemic tertiary alcohol 1a as the model precursor to the 2-indole imine methide intermediate. Notably, no directing group is incorporated in the two aryl groups (phenyl and thienyl) to be discriminated by the catalyst. Despite the above-mentioned substantial challenges in this asymmetric control, considerable efforts were devoted to condition optimization and ultimately led to excellent reaction efficiency and enantiocontrol (13 With benzothiazoline 2a as the hydride source,¹⁴ the asymmetric reduction proceeded smoothly to form indole-containing triarylmethane 3a under mild conditions in essentially quantitative yield and 95% ee (entry 1, 15 gave drastically low enantiocontrol (entry 8). Other solvents did not provide a better result either (entries 9–11). The reaction was very sensitive to coordinating solvents, such as ether and ethyl acetate, which completely shut down the reaction, presumably due to competing binding with the acid catalyst. Decreasing the reaction temperature to 0 °C maintained high enantioselectivity, but moderately affected the reaction rate (entry 12). Finally, at a higher concentration, slightly lower enantioselectivity was observed (entry 13).Evaluation of the reaction conditions^a

Manganese(i)-catalyzed access to 1,2-bisphosphine ligands

Chiral bisphosphine ligands are of key importance in transition-metal-catalyzed asymmetric synthesis of optically active products. However, the transition metals typically used are scarce and expensive noble metals, while the synthetic routes to access chiral phosphine ligands are cumbersome and lengthy. To make homogeneous catalysis more sustainable, progress must be made on both fronts. Herein, we present the first catalytic asymmetric hydrophosphination of α,β-unsaturated phosphine oxides in the presence of a chiral complex of earth-abundant manganese(i). This catalytic system offers a short two-step, one-pot synthetic sequence to easily accessible and structurally tunable chiral 1,2-bisphosphines in high yields and enantiomeric excess. The resulting bidentate phosphine ligands were successfully used in asymmetric catalysis as part of earth-abundant metal based organometallic catalysts.

Chiral bisphosphine ligands are of key importance in transition-metal-catalyzed asymmetric synthesis of optically active products. Mn(i)-catalyzed hydrophosphination offers a two-step, one-pot synthetic sequence to access chiral 1,2-bisphosphines.

The vast majority of important catalytic transformations make use of very effective catalysts based on scarce, expensive and toxic noble transition metals and phosphine containing ligands that, especially when chiral, are often as expensive as the noble metals themselves due to their cumbersome synthetic accessibility.¹ The past decade has witnessed significant progress towards the development of competitive catalysts that contain earth-abundant transition metals instead. These catalysts, however, still frequently rely on the use of chiral phosphine ligands. Bisphosphine ligands (Scheme 1A) for instance Pyrphos,^2a Chiraphos,^2b as well as Josiphos^2c are among the most successful chiral ligands used in homogeneous catalysis. In recent years, bis(phosphine) monoxide compounds such as Bozphos,^2d and Binap(o)^2e have been shown to be powerful ligands in asymmetric catalysis as well. Unfortunately, the synthesis of these frequently and successfully used chiral phosphine-based ligands often requires stoichiometric amounts of chiral auxiliaries, enantiopure substrates, or separation by resolution to obtain them enantiomerically pure.^1b–fOpen in a separate windowScheme 1(A) Examples of phosphine ligands commonly used in homogeneous catalysis. (B) Catalytic asymmetric hydrophosphination of various Michael acceptors. (C) This work: Mn (i)-catalyzed access to chiral 1,2-bisphosphines.Catalytic asymmetric hydrophosphination is one of the most straightforward approaches for generating optically active P-chiral or C-chiral phosphines, from which chiral ligands can be derived.³ The potential of hydrophosphination reactions to access enantioenriched chiral phosphines catalytically was demonstrated for the first time by Glueck and coworkers in 2001 using a catalytic system based on Pt and the chiral bisphosphine ligand Me-DuPhos.⁴ Following the publication of this initial work, precious noble metal complexes such as chiral Pd or Pt catalysts have been widely used in the field of asymmetric hydrophosphination (Scheme 1B).⁵ Only few examples utilizing earth-abundant metals such as Ni,⁶ Cu⁷ and very recently Mn⁸ have been reported to date for catalytic asymmetric hydrophosphination. Apart from metal based catalytic systems, examples of asymmetric organocatalytic hydrophosphination reactions were also presented in the literature.⁹ So far, all successful methods that rely on the addition of phosphines to α,β-unsaturated conjugated systems provide chiral monophosphines.³ Interestingly, the only reported example of catalytic hydrophosphination that allows access to chiral 1,2-bisphosphine ligands utilizes a Michael acceptor with a P-containing electron-withdrawing group.^7bWhile α,β-unsaturated phosphine oxides are bench stable and readily available Michael acceptors, their application is less common when compared to conventional carbonyl based Michael acceptors, which is in part due to their lower reactivity.¹⁰ Yin and co-workers found an elegant solution to this problem by transforming α,β-unsaturated phosphine oxides into phosphine sulphides. This allows a ‘soft–soft’ interaction to be established between the Cu(i) atom of the chiral Cu(i)-catalyst and the S atom of the phosphine sulphide, enabling catalytic hydrophosphination towards the synthesis of chiral bisphosphines.^7b While successful in applying this strategy for catalytic synthesis of variety of chiral bisphosphines, nevertheless it requires 6-steps synthetic sequence starting from α,β-unsaturated phosphine oxides (Scheme 1C).^7bHerein, we present a highly efficient, short and scalable catalytic protocol for the synthesis of chiral 1,2-bisphosphines from readily available, bench stable α,β-unsaturated phosphine oxides employing Mn(i)-catalyzed hydrophosphination as its core transformation (Scheme 1D).The last five years witnessed remarkable success of Mn(i)-complexes as catalysts for reductive transformations of carbonyl compounds including asymmetric variants.^11–13 Next to these reports, we have recently demonstrated that such complexes are capable of catalytic H–P bond activation of diarylphosphines.⁸ Based on these findings we hypothesised that Mn(i)-complexes should be able to bring the phosphine oxide and the phosphine reagents into closer proximity thus allowing the hydrophosphination reaction to take place directly with α,β-unsaturated phosphine oxides. This approach would avoid the additional synthetic steps and purifications procedures necessitated by the installation and removal of the sulphur atom that are intrinsic to the method utilising phosphine sulphides.At the outset of this work, bench-stable α-substituted α,β-unsaturated phosphine oxide 1a was chosen as the model substrate in the reaction with HPPh₂ (i)-complex, Mn(i)-L, developed by Clark and co-workers13a,d for hydrogenation and transfer hydrogenation of carbonyl compounds, was selected as the chiral catalyst. After extensive optimization, the reaction with 5 mol% t-PentOK, 2.5 mol% Mn(i)-L, 1.05 equiv. of HPPh₂ in toluene at room temperature for 16 hours was found to be optimal. Under these conditions, the product 3aa was obtained with 96% isolated yield and over 99% ee (entry 1).Optimization of the reaction conditions^a

Organocatalytic asymmetric formal oxidative coupling for the construction of all-aryl quaternary stereocenters

A new catalytic asymmetric formal cross dehydrogenative coupling process for the construction of all-aryl quaternary stereocenters is disclosed, which provides access to rarely explored chiral tetraarylmethanes with excellent enantioselectivity. The suitable oxidation conditions and the hydrogen-bond-based organocatalysis have enabled efficient intermolecular C–C bond formation in an overwhelmingly crowded environment under mild conditions. para-Quinone methides bearing an ortho-directing group serve as the key intermediate. The precise loading of DDQ is critical to the high enantioselectivity. The chiral products have also been demonstrated as promising antiviral agents.

A one-pot oxidation of racemic triarylmethanes to form para-quinone methides followed by enantioselective construction of all-aryl quaternary stereocenters has been developed.

Cross dehydrogenative coupling (CDC) is a powerful tool to forge intermolecular C–C bonds from two C–H bonds without prefunctionalization.¹ Specifically, the benzylic C–H bond is relatively prone to oxidation and thus it has evolved into a versatile arena for the implementation of this reaction, leading to efficient construction of various benzylic stereogenic centers. As a result, CDC has proved to be useful for the establishment of a wide range of 1,1-diaryl stereocenters (Scheme 1a).² Recently, Liu and coworkers reported a elegant synthesis of enantioenriched triarylacetonitriles via in situ oxidation of α-diarylacetonitriles to para-quinone methides (p-QMs) followed by asymmetric nucleophilic addition with stereocontrol induced by a chiral phosphoric acid catalyst. This represents a rare example of formal CDC for the synthesis of 1,1,1-triarylalkanes (Scheme 1b).³ However, the establishment of tetraaryl-substituted carbon stereocenters by this approach remains unknown (Scheme 1c).Open in a separate windowScheme 1Catalytic asymmetric synthesis of chiral tetraarylmethanes.Distinct from the asymmetric synthesis of triaryl-substituted stereocenters,⁴ substantial steric hindrance in establishing tetraaryl-substituted quaternary stereocenters poses significant synthetic challenges.^5–8 Indeed, even racemic or achiral syntheses of tetraarylmethanes have been an elusive topic of investigation in organic synthesis.⁶ In this context and in continuation of our effort in the studies of asymmetric reactions of para-quinone methides (p-QMs)^9,10 as well as the synthesis of chiral tetraarylmethanes,⁸ we envisioned that suitable oxidation of racemic triarylmethane 1 is expected to generate triarylmethyl cation IM1 (Scheme 1c). With one aryl group as para-hydroxyphenyl, this cation could be stabilized in the form of p-QM IM2. Subsequent asymmetric nucleophilic addition by another electron-rich arene to the p-QM intermediate is expected to generate chiral tetraarylmethanes 2. The challenges associated with this one-pot process mainly include the compatibility problem between the oxidative condition and the catalytic asymmetric system in order to achieve both high efficiency and enantioselectivity.We commenced our study with racemic triarylmethane 1a as the model substrate. The initial study was directed to the search for a suitable oxidant to mildly generate the p-QM intermediate (11 At room temperature, the use of superstoichiometric amounts of Ag₂O or benzoquinone was completely ineffective (entries 1 and 2). Similarly, the reaction did not proceed using oxygen as the oxidant in combination with catalyst Mn(acac)₃ (entry 3). Subsequently, considerable efforts were devoted to screening many other oxidation systems, almost all of which were completely incapable for this oxidation (entries 4–8). However, eventually we were delighted to identify DDQ as the superior oxidant, leading to complete and clean conversion to the desired QM at room temperature (entry 9). In contrast, a combination of catalytic DDQ with 5 equivalents of MnO₂ gave only 60% conversion (entry 10).Evaluation of oxidants

The underlying mechanism for reduction stability of organic electrolytes in lithium secondary batteries

Many organic solvents have very desirable solution properties, such as wide temperature range, high solubility of Li salts and nonflammability, and should be able but fail in reality to serve as electrolyte solvents for Li-ion or -metal batteries due to their reduction instability. The origin of this interfacial instability remains unsolved and disputed so far. Here, we reveal for the first time the origin of the reduction stability of organic carbonate electrolytes by combining ab initio molecular dynamics (AIMD) simulations, density functional theory (DFT) calculations and electrochemical stability experiments. It is found that with the increase of the molar ratio (MR) of salt to solvent, the anion progressively enters into the solvation shell of Li⁺ to form an anion-induced ion–solvent-coordinated (AI-ISC) structure, leading to a “V-shaped” change of the LUMO energy level of coordinated solvent molecules, whose interfacial stability first decreases and then increases with the increased MRs of salt to solvent. This mechanism perfectly explains the long-standing puzzle about the interfacial compatibility of organic electrolytes with Li or similar low potential anodes and provides a basic understanding and new insights into the rational design of the advanced electrolytes for next generation lithium secondary batteries.

By theoretical and experimental evidence, the underlying mechanism for the enhanced reduction stability of the HMRE is revealed, suggesting that the interfacial stability of the electrolyte can be adjusted through the modulation of the anion-induced ISC structure.

The state-of-the-art electrolytes in Li-ion batteries (LIBs) are mostly based on 1.0 mol L⁻¹ LiPF₆/ethylene carbonate (EC)-based carbonate due to the surface passivation of the graphite anode by forming a stable solid electrolyte interphase (SEI). However, these electrolytes cannot operate well for new electrode materials and battery systems that are expected to have higher voltage, better safety and wider temperature range than current commercial LIBs.^1–3 For example, EC-based carbonate electrolytes are easily oxidized on a high voltage cathode at or above 4.3 V, resulting in depletion of electrolytes, gas evolution and low coulombic efficiency, which reduce the cycle life and create safety hazards for LIBs.⁴ These problems of the conventional electrolyte significantly hinder the development of new generation lithium batteries and limit these batteries for high voltage and/or high capacity applications and operation in a wide temperature range.To overcome these problems, great efforts have been devoted in recent years to the development of new electrolytes, such as solid state electrolytes,⁵ ionic liquids,^6–8 highly-concentrated electrolytes (HCEs),⁹ electrolyte stabilizing additive,^10–13 and so on. Among them, the HCEs or high-molar-ratio electrolytes (HMREs) of salt to solvent have received particular attention, owing to their unusual electrochemical stability, nonflammability, and good compatibility with a wide range of anode and cathode materials.^14–17 These desirable properties are apparently attributed to the solution structure of HCEs, where there exist almost no free solvent molecules, and the parasitic side reactions of solvents are thereby greatly reduced. Due to the lack of solvent molecules in HCEs, anions have to enter into the solvation shell of Li⁺, in order to meet the Li⁺ coordination number of 4–6, to form an ion–solvent-coordinated (ISC) structure.¹⁸ Several studies have shown that the unique ISC structure of HCEs leads to the shift of the lowest unoccupied molecular orbital (LUMO) from solvent to salt, which makes anions preferentially reduced or decomposed to produce a robust anion-derived SEI.^14,19 In recent years, the anion-derived SEI structure has been regarded as the “holy grail” of electrolyte chemistry for understanding the interfacial stability and compatibility of HCEs. However, recent studies have showed that some HCEs containing non-film-forming salts and solvents can still achieve excellent reversible Li⁺ insertion reactions.²⁰ Therefore, an intrinsic origin for the interfacial stability of HCEs still remains unrevealed. In our previous studies on HCEs or HMREs, their interfacial stability was found to depend predominately on the molar ratio (MR) of salt to solvent rather than the molar concentration.^2,21,22 Thus, the HMREs instead of the HCEs in the following study could more clearly describe the nature of electrolyte stability.In this work, we reveal the correlation between the solvation microstructures and the LUMO energy levels of typical ISC structures in the electrolytes at various MRs with non-film-forming lithium salt (LiClO₄) and organic carbonate solvents (PC, DMC, EMC and DEC) by ab initio molecular dynamics (AIMD) simulations and density functional theory (DFT) calculations. The choice of non-film-forming lithium salt and solvent in this study was aimed to exclude the contribution of the formation of the SEI film to the interfacial stability of the electrolytes. It is found from this study that the LUMO energy level of the ISC structure formed at a low MR is lower than that of pure solvent. With the increase of the MR, anions gradually enter into the first solvation shell of Li⁺ to form the anion-induced ISC (AI-ISC) structure, resulting in the increase of the LUMO energy level that enhances the reduction stability of the electrolyte. Also, it is revealed that the LUMO levels of ISC structures at different MRs are always situated at the coordinated solvent molecules, i.e., the strong reduction stability of HMREs is dominated by the modulation of solvent molecules rather than only the formation of the anion-derived SEI. Such a theoretical insight is further unequivocally evidenced by chemical compatibility experiments in this work. These findings reveal the origin of the greatly improved interfacial stability of HMREs and provide a mechanistic insight into the rational design of stable electrolytes for new generation alkali or alkaline metal based batteries.To investigate the specific ISC microstructures of the electrolytes with different MRs, AIMD simulations were first performed (see computational details in the ESI^†). Taking non-film-forming DEC solvent as an example, three types of electrolytes with MRs of LiClO₄ to DEC = 1 : 10, 1 : 5 and 1 : 2 are considered (Table S1^†). After long-time AIMD simulation, the representative images of the equilibrium structures are shown in Fig. 1a–c. To characterize the solution structures, the radial distribution function g(r) of the electrolyte with different MRs is analyzed (Fig. 1e–g), and the changes in the Li⁺ coordination number with the O atoms of solvents and anions are listed in Fig. 1d. In addition, it should be noted that the total coordination number of Li⁺ always remains around 4, which implies that the stable tetragonal solvation shell structure of Li⁺ does not change in the different MR electrolytes; meanwhile, both the coordination numbers of Li⁺ contributed by the solvent and anion change oppositely. This phenomenon can be corroborated experimentally through infrared spectroscopy (IR) because the C O bond of the carbonate group has a strong IR absorption in the carbonyl region (1650–1850 cm⁻¹) and its IR peak position shifts sensitively with its coordination environment. As shown in Fig. 1h, the IR band of carbonyl groups in pure DEC is located at ∼1741 cm⁻¹, which is shifted to ∼1710 cm⁻¹ in a LiClO₄/DEC (MR = 1 : 10) electrolyte due to the coordination of the O atom in C O with Li⁺. With the increase of the MR of Li⁺/DEC, its IR peak at ∼1741 cm⁻¹ gradually disappears, reflecting a gradual decrease in the number of free DEC molecules. In addition, the IR band of free ClO₄⁻ in a LiClO₄/DEC (MR = 1 : 10) electrolyte is located at ∼931 cm⁻¹, which is shifted to ∼942 cm⁻¹ in the 1 : 2 LiClO₄/DEC electrolyte due to the ionic association of Li⁺ and ClO₄⁻ (Fig. S1^†). Combining AIMD simulations and IR experiments, it can be concluded that with the increase of the MR of the electrolyte, the anions gradually enter into the solvation shell of Li⁺, which modulates the chemical stability of the electrolyte.Open in a separate windowFig. 1Snapshots of typical equilibrium trajectories from DFT-MD simulations: (a) 1 : 10 LiClO₄/DEC solution (2-LiClO₄/20-DEC), (b) 1 : 5 LiClO₄/DEC solution (3-LiClO₄/15-DEC) and (c) 1 : 2 LiClO₄/DEC solution (7-LiClO₄/14-DEC). (d) Typical ISC structure extracted from DFT-MD. (e–g) Radial distribution function of lithium–oxygen interaction (short dashed lines) and relationship between the coordination number and bond distances (full lines). (h) FTIR spectra of the carbonyl group in LiClO₄/DEC solution. Atom color: H, white; Li, purple; C, cyan; O, red; Cl, green.Coordination numbers (n(r)) of atom pairs of Li–O(DEC) and Li–O (ClO₄⁻) (cut-off length of r = 2.5 Å)

Chemo-selective cross reaction of two enals via carbene-catalyzed dual activation

A dual catalytic chemo-selective cross-coupling reaction of two enals is developed. One enal (without α-substitution) is activated by an NHC catalyst to form an acylazolium enolate intermediate that undergoes Michael-type addition to another enal molecule bearing an alkynyl substituent. Mechanistic studies indicate that non-covalent interactions between the alkynyl enal and the NHC·HX catalyst play important roles in substrate activation and enantioselectivity control. Many of the possible side reactions are not observed. Our reaction provides highly chemo- and diastereo-selective access to chiral lactones containing functionalizable 1,3-enyn units with excellent enantioselectivities (95 to >99% ee).

An NHC-catalyzed dual activation of two different enals is disclosed with both covalent and non-covalent activation pathways involved.

The development of chemo-selective reactions of two or more substrates bearing similar functional groups remains a classic challenge in organic synthesis.¹ Enals (α,β-unsaturated aldehydes) are common building blocks that offer multiple useful modes of reactions. For instance, enals are readily used as Michael acceptors in many reactions including organic catalytic reactions mediated by amines.² In the area of N-heterocyclic carbene (NHC) organocatalysis,³ enals are used as precursors of several NHC-bound intermediates, including Breslow acyl anion intermediates,⁴ homoenolate intermediates,⁵ enolate intermediates,⁶ and acylazolium intermediates.⁷ Somewhat surprisingly, on the other hand, there is little success in using enals as Michael acceptors to react with any of these NHC-bound intermediates.⁸ Elegant studies in this direction are from Scheidt, in which they showed that in the presence of an NHC catalyst, a homo coupling reaction of enals (with one enal molecule as the Michael acceptor) occurred effectively (Fig. 1a, top side).^8a,c Berkessel reported an intramolecular reaction of two enal moieties (in one molecule) to form a bicyclic lactone adduct in the presence of an achiral NHC catalyst (Fig. 1a, bottom side).^8b To the best of our knowledge, the intermolecular Michael addition reaction of two different enal substrates mediated by NHC catalysts has not been reported.⁹ Possible reasons for the difficulties of enals to behave as effective Michael acceptors likely include: (a) the relatively low electrophilicity of the α,β-unsaturated bonds of enals under the typical NHC catalytic conditions and (b) the presence of competing reactions involving both the alkene and aldehyde moieties of enals.Open in a separate windowFig. 1NHC-catalyzed reactions (a) with enals as Michael acceptors, (b) via cross intermolecular reactions of two enals, and (c) bio-active molecules bearing alkyne units.Here we disclose the first cross intermolecular reaction of two enals catalyzed by NHC catalysts (Fig. 1b). We envisioned that installation of an alkynyl substituent at the α-position of an enal can likely promote its reactivity as a Michael acceptor.¹⁰ The presence of an α-substituent can interrupt π-conjugations and thus minimize its reactivity via the corresponding enal-derived enolate/homoenolate intermediate formed with NHC, as shown by Bode, Glorius and others.^6b,11 In addition, the alkynyl substituent can promote hydrogen-bonding interactions to increase the electrophilicity of the enal to react as a Michael acceptor, as observed in Jørgensen''s amine-catalyzed reactions.¹² In our present study, a non-linear effect was observed regarding enantiomeric excesses of the NHC catalyst and the catalytic reaction product. The reaction enantioselectivity was also found to be sensitive to solvents and bases. These results suggested that the NHC and its azolium salt pre-catalyst (NHC·HX) played dual roles in our reaction: one is to activate the α-unsubstituted enal via the formation of the NHC-bound enolate intermediate,⁶ the other is to activate the α-alkynyl substituted enal via the acidic proton of the chiral NHC·HX (Fig. 1b, intermediate I & transition state TS-I).¹³ With respect to applications, carbon–carbon triple bonds are found in a good number of bioactive molecules such as cleviolide, (+)-prelaureatin, and oxamflatin (Fig. 1c).¹⁴ We demonstrated that our products containing these alkynyl units could be readily transformed into a diverse set of molecules.Cinnamaldehyde 1a and α-alkynyl enal 2a were chosen as the model substrates to search for suitable cross coupling reaction conditions (Table 1). The reactions were first carried out with Et₃N as the base and THF as the solvent. When aminoindanol derived azoium salt A¹⁵ was used as the NHC pre-catalyst, the desired formal [4 + 2] product (3a) was obtained in a very encouraging yield (52%) with excellent ee and dr values (entry 1). The reactions appeared to be very sensitive to the structure of the NHC pre-catalysts, as similar azolium salts with N-phenyl or N–C₆F₅ substituents (B¹⁶ and C¹⁷) were completely ineffective, leading to no product formation (entries 2 & 3). Additional studies on the NHC pre-catalysts finally revealed that introduction of a Br substituent in the indane phenyl ring of the catalyst (D)¹⁸ led to 3a in 85% yield with 99% ee as nearly a single diastereomer (entry 4). Replacing Et₃N with DIEA led to similar results (entry 5). Very interestingly, when the bases were replaced with DABCO or K₃PO₄, a significant drop in the enantioselectivity was observed (entries 6 & 7; see the ESI^† for more details). Changing the solvent from THF to CHCl₃ or EtOAc has moderate effects on reaction yields (entries 8 & 9).Optimization of reaction conditions^a

Allylic alcohol synthesis by Ni-catalyzed direct and selective coupling of alkynes and methanol

Methanol is an abundant and renewable chemical raw material, but its use as a C1 source in C–C bond coupling reactions still constitutes a big challenge, and the known methods are limited to the use of expensive and noble metal catalysts such as Ru, Rh and Ir. We herein report nickel-catalyzed direct coupling of alkynes and methanol, providing direct access to valuable allylic alcohols in good yields and excellent chemo- and regioselectivity. The approach features a broad substrate scope and high atom-, step- and redox-economy. Moreover, this method was successfully extended to the synthesis of [5,6]-bicyclic hemiacetals through a cascade cyclization reaction of alkynones and methanol.

Methanol is an abundant and renewable chemical raw material, but its use as a C1 source in C–C bond coupling reactions still constitutes a big challenge, and the known methods are limited to the use of expensive and noble metal catalysts such as Ru, Rh and Ir.

To address the sustainability issues in the production of new chemicals, the development of new catalytic processes that are free of by-products and using abundant renewable feedstocks is one of the most important challenges facing chemists today. The simplest alcohol, methanol, is very abundant, with a total annual production capacity of approximately 110 million metric tons per year,¹ and is an important C1-feedstock in the chemical industry. Beller² and Milstein³ made fundamental developments in catalytic dehydrogenation reactions of methanol.⁴ Krische and coworkers pioneered the study of Ir-catalyzed direct C–C coupling of methanol with reactive π-unsaturated reactants (1,3-dienes, 1,3-enynes and allenes).⁵ The groups of Glorius,⁶ Donohoe,⁷ Obora,⁸ Andersson⁹ and others¹⁰ demonstrated the direct methylation of ketones or amines using methanol. Despite these achievements, the catalytic C–C bond coupling reactions with methanol are still extremely rare and are limited to the use of precious and noble metal-catalysts such as Ru, Rh or Ir.¹¹ The development and use of cheap and abundant metal catalysts for methanol activation is uphill and remains an important field that urgently needs to be developed.On the other hand, allylic alcohols are highly versatile building blocks in organic synthesis and the pharmaceutical industry, and much effort has been devoted to their synthesis. Among them, nickel-catalyzed reductive coupling of alkynes and aldehydes represents an effective and powerful method. However, this method generally requires the use of stoichiometric reducing reagents that are air-sensitive, metallic or pyrophoric (e.g. ZnR₂, BEt₃, and R₃SiH, Scheme 1a).¹² The direct cross-coupling of alcohols and alkynes to synthesize allylic alcohols without the use of any reductant or oxidant represents a significant advancement (Scheme 1b).¹³ However, this approach still poses many limitations that will require considerable effort to overcome. (1) Alkynes are limited to dialkyl alkynes, and poor regioselectivities were observed for unsymmetrical alkynes, which greatly limits the scope of application of the reaction. (2) Alcohols are restricted to active benzyl alcohols and higher alcohols. The direct cross-coupling of alkynes with methanol has not yet been reported.Open in a separate windowScheme 1Synthesis of allylic alcohols by Ni-catalyzed coupling reaction with alkynes.Although the alkyne–paraformaldehyde reductive coupling has been developed,¹⁴ the paraformaldehyde was itself prepared from synthesis gas (through methanol). Therefore, the development of a new strategy for the direct coupling of alkynes and methanol without the use of any reductant or oxidant is still of great value, but also extremely challenging: (1) alkynes are reactive and could rapidly dimerize to 1,3-dienes¹⁵ or cyclotrimerize to aromatic ring derivatives in the interaction with nickel.¹⁶ (2) Unsymmetric alkynes could result in a mixture of regioisomers that are difficult to separate. (3) The activation energy of methanol in the dehydrogenation process (ΔH = +84 kJ mol⁻¹) is significantly higher than that of higher alcohols or even ethanol (ΔH = +68 kJ mol⁻¹).¹⁷Herein we report the nickel-catalyzed direct and regioselective hydrohydroxymethylation of alkynes for the first time using methanol as a C1-feedstock, providing a broad and efficient approach for the synthesis of high added-value allylic alcohols in a high atom-, step- and redox-economic manner. In addition, a cascade cyclization reaction of alkynones and methanol has also been developed for the synthesis of [5,6]-bicyclic hemiacetals in good yields and excellent regio- and diastereoselectivity (Scheme 1c).In our initial experiments, we chose unsymmetrical internal alkyne 1a as a model substrate to optimize the reaction conditions (13a Even if the reaction temperature was increased to 100 °C, only a trace amount of allylic alcohol product 2a was observed (entry 2), which indicates that the use of methanol in the catalytic C–C coupling reactions is indeed a big challenge. Various N-heterocyclic carbene ligands (L2–L6) were investigated (entries 3–9). We found that the selectivity of allylic alcohol 2a is challenged by a number of side reactions, such as the hydrogenation (3a), dimerization (4a) and trimerization (5a) of alkyne 1a. L4 is the most effective, providing 2a with the highest yield (40%) and excellent regioselectivity (14/1), but an appreciable quantity of dimerization and trimerization by-products 4a and 5a was still obtained (entry 5). Krische¹⁴ reported that PCy₃ could promote the reductive coupling of alkynes and paraformaldehyde, but we found that it is not effective for alkyne–methanol coupling (entry 8).Optimization of reaction conditions^a

Dirhodium(ii)-catalysed cycloisomerization of azaenyne: rapid assembly of centrally and axially chiral isoindazole frameworks

Described herein is a dirhodium(ii)-catalyzed asymmetric cycloisomerization reaction of azaenyne through a cap-tether synergistic modulation strategy, which represents the first catalytic asymmetric cycloisomerization of azaenyne. This reaction is highly challenging because of its inherent strong background reaction leading to racemate formation and the high capability of coordination of the nitrogen atom resulting in catalyst deactivation. Varieties of centrally chiral isoindazole derivatives could be prepared in up to 99 : 1 d.r., 99 : 1 er and 99% yield and diverse enantiomerically enriched atropisomers bearing two five-membered heteroaryls have been accessed by using an oxidative central-to-axial chirality transfer strategy. The tethered nitrogen atom incorporated into the starting materials enabled easy late-modifications of the centrally and axially chiral products via C–H functionalizations, which further demonstrated the appealing synthetic utilities of this powerful asymmetric cyclization.

Rh(ii)-catalyzed asymmetric cycloisomerization of azaenyne through a cap-tether synergistic modulation strategy was described. Diverse centrally and axially chiral isoindazoles were prepared and directed C–H late-stage modifications were developed.

Known as one of the most significant and reliable access methods to chiral heterocycles, asymmetric cycloisomerization of conjugated enyne has caught extensive attention and interest for its wide applications in synthetic route design and mechanistic investigation.¹ Specifically, asymmetric cyclization of conjugated enynone (X = C, Z = O) has been successfully developed and applied to the rapid construction of various chiral furan-containing skeletons with high efficiency in an extremely operationally simple manner (Scheme 1a).² However, compared to the fruitful research with enynone, it is surprising that the analogous asymmetric version of azaenyne (Z = N–R) still remains underdeveloped.³ In fact, no successful example of catalytic asymmetric cyclization of azaenyne has been reported in the literature despite the apparent significance of nitrogen-containing five-membered heterocycles in the synthetic and pharmaceutical community.⁴ In 2004, Haley and Herges reported a detailed experimental and theoretical study of the cyclization reaction of (2-ethynylphenyl)-phenyldiazene, which is a unique azaenyne.⁵ According to the DFT calculations, very close and low activation barriers for 5-exo-dig and 6-endo-dig cyclization pathways under catalyst-free conditions were found, which shed light on the inherent challenges of the asymmetric reaction of azaenyne (Scheme 1b). For instance, there was usually a regioselectivity issue (5-exo and 6-endo) in the cyclization reaction of azaenyne because of their close reaction barriers where the competitive 6-endo-dig cyclization^3a,6 may lead to troublesome side-product formation. In addition, the low activation barrier deriving from the strong N-nucleophilicity of azaenyne may easily lead to self-cyclization which will cause severe background reactions to interfere with the asymmetric process. More troublingly, this transformation might suffer from catalyst deactivation arising from the high coordinating capability of the nitrogen atom in both starting materials and products, which might give more opportunities to the propagation of detrimental background reactions. In some cases, even a super-stoichiometric amount of transition metal has to be used to ensure effective conversion.^3a,7 Therefore, although many nonchiral approaches have been reported,^3,5 catalytic asymmetric cyclization of azaenyne still remains elusive due to the inherent obstacles aforementioned. With our continuous interest in alkyne chemistry,^2a,8 herein we designed a cap-tether synergistic modulation strategy to tackle these challenges, envisioning that modulation of the tethered atom and protecting cap of nitrogen in the azaenyne would intrinsically perturb and alter the reactivity of the starting material, and therefore the azaenyne motif could be effectively harnessed as a promising synthon for asymmetric transformations (Scheme 1c). It should be noted that the obtained centrally chiral product produced from intramolecular C–H insertion of donor-type metal carbene⁹ might be potentially converted into the axially chiral molecule via a central-to-axial chirality conversion strategy.Open in a separate windowScheme 1Development of the asymmetric cyclization reaction of conjugated azaenyne.With this design in mind, different types of azaenynes bearing typical tethering atoms and capping groups were chosen to test our hypothesis and representative results are shown in Scheme 2. First, tBu-capping imine (X = C, R = tBu) was selected as a substrate to test our hypothesis.^6a It was found that the imine exhibited low reactivity and the reaction temperature has to be elevated to 100 °C to initiate the transformation with or without catalyst. Unfortunately, the desired 5-exo-dig cyclization product was not detected, but isoquinoline from 6-endo-dig cyclization was obtained instead (Scheme 2a). To further regulate and control the regioselectivity and reactivity, triazene (X = N, R = N-piperidyl) was then investigated. Similarly, this substrate also showed low reactivity and it is still required to be heated at 100 °C for conversion. In the absence of a metal catalyst, an unexpected alkyne, deriving from the fragmentation of the triazene moiety, was produced in 41% yield. When 2 mol% Rh₂(OPiv)₄ was added as a catalyst, the side reaction could be efficiently suppressed and the reaction selectivity was apparently reversed. In this case, the target C–H insertion dihydrofuran was furnished as the major product in 30% yield but still accompanied by concomitant formation of 12% yield of undesired alkyne (Scheme 2b). The above investigations showed neither the imine nor triazene was an ideal substrate for the asymmetric reaction. Thus, we moved our attention to the diazene substrate (X = N, R = aryl). As demonstrated by Haley''s and Herges'' pioneering work, ortho-alkynyl diazene, compared with imine and triazene, was more unstable and tended to self-cyclization even at room temperature.^5a As shown in Scheme 2c, the ortho-alkynyl diazene degrades and 5-exo-dig cyclization products could be observed even in DCE solvent without any catalyst at room temperature. When the phenyl capping group was installed in the substrate, the reaction furnished 10% yield of isoindazole derivative. The uncatalyzed self-cyclization reaction was obviously accelerated when an electron-rich capping group (4-MeO–C₆H₄–) was introduced, affording the corresponding product in 20% yield. Inspired by these findings, we assumed that installation of an electron deficient group on the capping phenyl would reduce the nucleophilicity of the nitrogen atom and thus the troublesome self-cyclization reaction might be effectively inhibited. To our delight, when a bromo-substituent was introduced onto the phenyl cap, the undesired self-cyclization was almost suppressed. When Rh₂(OPiv)₄ was added as a catalyst, the desired carbene-involved C–H insertion product was furnished in 90% yield at room temperature. Worthy of note was the total absence of any cinnoline formation from 6-endo-dig cyclization.^3a,6b In short, the synthetic challenges associated with regioselectivity (5-exo-dig and 6-endo-dig), strong background reaction and catalyst deactivation could be successfully regulated and controlled via a tether-cap synergistic modulation strategy.Open in a separate windowScheme 2Typical substrate investigation.Encouraged by the above findings, ortho-alkynyl bromodiazene 1a was chosen as a model substrate and different types of chiral dirhodium catalysts¹⁰ were screened in DCE at room temperature for 48 h. As shown in EntryRh(ii)*SolventYield^b [%]er^c1Rh₂(R-DOSP)₄DCE5629 : 712Rh₂(5S-MEPY)₄DCE1750 : 503Rh₂(S-BTPCP)₄DCE618 : 924Rh₂(S-PTPA)₄DCE9191 : 95Rh₂(S-PTTL)₄DCE8697 : 36Rh₂(S-PTAD)₄DCE9394 : 67Rh₂(S-NTTL)₄DCE9296 : 48Rh₂(S-TCPTTL)₄DCE9598 : 2 9 Rh ₂ (S-TFPTTL) ₄ DCE 98 ^d 98 : 210Rh₂(S-TFPTTL)₄DCM8898 : 211Rh₂(S-TFPTTL)₄Toluene9298 : 212Rh₂(S-TFPTTL)₄MeCN1692 : 813Rh₂(S-TFPTTL)₄ n-Hexane9698 : 214^eRh₂(S-TFPTTL)₄DCE65^f96 : 4 Open in a separate window^aUnless otherwise noted, reactions were performed at 0.1 M in DCE using 0.20 mmol substrate and catalyst (2 mol%) under a N₂ atmosphere.^bDetermined by ¹H NMR spectroscopy.^cThe er value of 2a was determined by HPLC using a chiral stationary phase.^dIsolated yields.^e1 mol% catalyst was used.^f25% starting material was recovered.With the optimized reaction conditions in hand (Scheme 3, the catalytic process could be successfully applied to azaenynes 1 bearing different ether side chains. For example, in addition to 1a, various azaenyne derivatives containing benzylic ethers could be efficiently converted into the desired products 2b–i with excellent diastereoselectivities and enantioselectivities (>99 : 1 d.r., 97:3–99 : 1 er). The yields were typically higher than 90% for most substrates. Satisfyingly, the substrates with bulkier aryl groups were well-tolerated to afford the isoindazole products 2j–m in good yields with excellent diastereo- and enantiocontrol (>97 : 3 d.r., > 95 : 5 er). In addition to azaenynes with arylmethyl ether, this protocol was also successfully applied to substrates with allylic ether, propargyl ether and even aliphatic ether to furnish the cyclization products 2n–u in good yields with decent diastereo- and enantioselectivities (>93 : 7 d.r., > 90 : 10 er). In the cases of allylic and propargyl ether, only C–H insertion products (2n–p) were observed though cyclopropanation or cyclopropenation often took place competitively when using the allylic or propargyl substrate to trap the carbene intermediate.¹¹ It was noted that the azaenynes with aliphatic ether, which represent challenging substrates^2a in the asymmetric carbene transfer reactions, also showed good reactivities to afford the corresponding chiral dihydrobenzofurans (2q–u) with excellent diastereoselectivities (>93 : 7 d.r.) and enantioselectivities (>98 : 2 er). Interestingly, when phenyl and methoxyphenyl capping azaenynes, which potentially suffered from the undesired background reactions, were subjected to the standard conditions, chiral products (2v–w) could be obtained with high optical purity (>99 : 1 d.r., > 96 : 4 er) as well. These results might be attributed to the high catalytic activity of Rh₂(S-TFPTTL)₄ in the asymmetric cyclization process, which eventually led to complete suppression of the uncatalyzed self-cyclization. The scopes with respect to the group R¹ on the fused phenyl ring were further investigated. Both electron-rich and -deficient substituents R¹ were well accommodated, with the product yields ranging from 80% to 99%, enantiomeric ratios ranging from 95 : 5 to 97 : 3 and diastereomeric ratios higher than 99 : 1 (2x–z). In addition, azaenyne substituted with an alkyl side chain at the alkynyl carbon atom was also tested, giving tetrahydrofuran (2aa) with excellent diastereoselectivity (>99 : 1 d.r.), good enantioselectivity (90 : 10 er) and moderate yield (43%). In addition to the side chain of ether, this asymmetric protocol could even be extended to the more challenging nitrogen- and thio-tethered analogues, albeit with somewhat lower reactivities (46–65% yields) but good stereoselectivities (93 : 7 er and 84 : 16 d.r. for 2ab; 81 : 19 er and >99 : 1 d.r. for 2ac). Structures of the resulting products were confirmed by X-ray crystallographic analysis of their analogue 2h.Open in a separate windowScheme 3 ^aUnless otherwise noted, the reactions were performed under standard conditions for 48 h or monitored by TLC until the starting material disappeared. ^b5 mol% catalyst was used. ^cReactions were performed in n-hexane, using 2 mol% Rh₂(S-TCPTTL)₄ as the catalyst.The successful preparation of centrally chiral isoindazole through the asymmetric cyclization reaction prompted us to explore the further applications of this protocol. Axially chiral biaryl skeletons are undoubtedly regarded as one of the most prominent structural motifs for their ubiquity in natural products, pharmaceuticals and useful chiral ligands in asymmetric catalysis.¹² Due to the lower rotational barrier, there are only limited examples of the enantioselective synthesis of axially chiral atropisomers featuring a five-membered ring, especially those bearing two pentatomic aromatics.¹³ Compared with the furan analogue, the extending cap in the isoindazole scaffold provides additional ortho steric hindrance making these molecules possible candidates for the preparation of five-five-membered biaryl atropisomers. Considering the unique chiral skeleton of dihydrofuranyl isoindazole 2, we began to explore their potential application in chiral atropisomer synthesis via a central-to-axial chirality transfer strategy. As shown in Scheme 4, oxidative aromatization of representative dihydrofuran candidate 2m furnished two configurationally unstable atropisomers, which might be attributed to their relatively low rotational barriers as five-membered atropisomers especially when the furan ring was incorporated (see ESI^† for details). Therefore, it was hypothesized that extending the fused phenyl to naphthyl might afford stable atropisomers by enhancing the ortho steric hindrance (Scheme 4b).Open in a separate windowScheme 4Investigation of central-to-axial chirality transfer.To our delight, as shown in Scheme 5, naphthyl-fused dihydrofurans 4 could be easily accessed through the above established dirhodium-catalyzed cyclization process and configurationally stable atropisomers 5 could be generated via further oxidative dehydrogenation with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) as the oxidant (see ESI^† for the proposed mechanism). For example, asymmetric cyclization reactions proceeded smoothly to give the centrally chiral compounds 4 in good yields (54–99%) with excellent diastereoselectivities (92 : 8–99 : 1 d.r.) and enantioselectivities (95 : 5–99 : 1 er) under slightly modified reaction conditions. This reaction was compatible with a variety of arylmethyl side chains in azaenynes and well-accommodated with various functional groups (F, Cl, Br, OMe, and –CO₂Me). Additionally, oxidative dehydrogenation of chiral candidates 4 with DDQ smoothly resulted in the formation of axially chiral atropisomers 5 in 90–99% yields with only slight loss of chiral integrity (90 : 10–97 : 3 er). An enantiomerically pure atropisomer could be obtained through a simple recrystallization procedure as exemplified by compound 5g. The structure and absolute configuration of isoindazole 4g and atropisomer 5g were confirmed by their single-crystal X-ray diffraction analysis.Open in a separate windowScheme 5 ^aConditions for cyclization of azaenyne: Rh₂(S-TCPTTL)₄ (2 mol%), n-hexane, rt for 48 h or monitored by TLC until the starting material disappeared; conditions for oxidative chirality transfer: DDQ (2 equiv.), DCE, −20 °C for 48 h or monitored by TLC until the starting material disappeared. ^b45 °C. ^cDDQ (5 equiv.). ^dRoom temperature. ^eAfter one recrystallization.With centrally and axial chiral molecules in hand, further transformations of these compounds were also explored. The tethered nitrogen atom in azaenynes not only showed a synergetic effect with the capping group on promoting asymmetric cyclization but also served as an innate directing group for late-stage modifications via C–H functionalization. As shown in Scheme 6, a variety of functional groups could be directly introduced onto the capping aromatic rings, allowing for rapid build-up of molecular complexity. For example, synthetically valuable alkenyl,¹⁴ allyl¹⁵ and alkynyl¹⁶ groups could be easily incorporated into the final structures, which had wide potential applications in organic synthesis (6a–c). Furthermore, C–H alkylation,¹⁷ amidation¹⁸ and selenylation¹⁹ were performed smoothly to afford the desired products 6d–g. It is noteworthy that unique chiral chelation backbones were constructed by amidation and selenylation of the isoindazole moiety (6e–g). In addition to centrally chiral compounds, axial chiral atropisomers 5 themselves could be efficiently converted to their functionalized scaffolds as well (6h–i) through a similar directed C–H functionalization process.Open in a separate windowScheme 6Late-stage modification of chiral isoindazoles. Reaction conditions: ^a4-octyne, [Rh(Cp*Cl₂)]₂, AgSbF₆, Cu(OAc)₂, DCE, 80 °C. ^bAllyl carbonate, [Rh(Cp*Cl₂)]₂, AgSbF₆, PivOH, PhCl, 40 °C. ^cHypervalent iodine-alkyne, [Rh(Cp*Cl₂)]₂, Zn(OTf)₂, DCE, 80 °C. ^dAlkene, [Rh(Cp*Cl₂)]₂, AgSbF₆, AcOH, 1,4-dioxane, 50 °C. ^e3-Phenyl-1,4,2-dioxazol-5-one, [Cp*Co(MeCN)₃](SbF₆)₂, DCE, 80 °C. ^fPhSeCl, [Rh(Cp*Cl₂)]₂, AgSbF₆, THF, 60 °C.     

Monitoring single Au38 nanocluster reactions via electrochemiluminescence

Herein, we report for the first time single Au₃₈ nanocluster reaction events of highly efficient electrochemiluminescence (ECL) with tri-n-propylamine radicals as a reductive co-reactant at the surface of an ultramicroelectrode (UME). The statistical analyses of individual reactions confirm stochastic single ones influenced by the applied potential.

Herein, we report for the first time single Au₃₈ nanocluster reaction events of highly efficient electrochemiluminescence (ECL) with tri-n-propylamine radicals as a reductive co-reactant at the surface of a Pt ultramicroelectrode (UME).

Single entity measurements have been introduced by Bard and Wightman based on the collisions/reactions of individual nanoparticles and molecules at an ultramicroelectrode (UME).^1–9 Since then, the field of single entity electrochemistry has gradually attracted several research groups and has become a frontier field of nanoelectrochemistry and electroanalytical chemistry.^8,10–14 For instance, it has been shown that the chemistry of the electrode surface plays an important role in the collision/reaction events and the kinetics of reaction processes.^15–21 Dasari et al. reported that hydrazine oxidation and proton reduction can be detected using single Pt nanoparticles on the surface of a mercury or bismuth modified Pt UME, and the material of the electrode was found to affect the shape of current–time transients.^22,23 Fast scan cyclic voltammetry provides better chemical information about transient electrode–nanoparticle interactions, which is otherwise difficult to obtain with constant-potential techniques.²⁴ There are only a few reports on photoelectrochemical systems including semiconductor nanoparticles designed to detect single nanoparticles in the course of photocatalysis processes.^25–28 More importantly, owing to the nature of stochastic processes of single entity reactions, statistical analyses have shown substantial influences on the understanding of the underlying processes.Electrochemiluminescence or electrogenerated chemiluminescence (ECL),²⁹ as a background-free technique,^30–32 was also utilized to detect individual chemical reactions and single Pt nanoparticle collisions based on the reaction between the Ru(bpy)₃²⁺ complex and tri-n-propylamine (TPrA) radicals on the surface of an ITO electrode.^2,33,34 It was found that the size of the nanoparticles, the origin of the interaction between particles and the electrode surface, the concentration of species generation, and the lifetime of individual electrogenerated nanocluster species (i.e., Au₃₈²⁺, Au₃₈³⁺, and Au₃₈⁴⁺) in conjunction with the reactivity of those oxidized species with co-reactant radical intermediates (i.e., TPrA radical) play crucial roles in the frequency of the ECL reaction events leading to individual ECL responses. More strikingly, a higher ECL reaction frequency is directly proportional to the amount of collected ECL light.²¹ Chen and co-workers also employed ECL to study stationary single gold-platinum nanoparticle reactivity on the surface of an ITO electrode.³⁵ Lin and co-workers monitored the hydrogen evolution reaction in the course of “ON” and “OFF” ECL signals.³⁶ Recently, we performed a systematic and mechanistic ECL study of a series of gold nanoclusters, with the general formula of Au_n(SC₂H₄Ph)_m^z (n = 25, 38, 144, m = 18, 24, 60 and z = −1, 0, +1), where near-infrared (NIR) ECL emission was observed.³⁷ There are several enhancement factors, such as catalytic loops^38,39 that improve the signal to noise ratio. The Wightman group was able to report single ECL reactions based on the capability of ECL.⁷ Furthermore, thus far, we have explored ECL mechanisms and reported the ECL efficiency of five different gold nanoclusters i.e., Au₂₅(SR)₁₈¹⁻, Au₂₅(SR)₁₈⁰, Au₂₅(SR)₁₈¹⁺, Au₃₈(SR)₂₄⁰ and Au₁₄₄(SR)₆₀⁰, among which the Au₃₈(SR)₂₄⁰/TPrA system revealed outstanding ECL efficiency, ca. 3.5 times higher than that of Ru(bpy)₃²⁺/TPrA as a gold standard. Therefore, we decided to focus on the Au₃₈ (SR)₂₄⁰/TPrA system. It was discovered that the ECL emission of these nanomaterials can be tuned through varying the applied potential and local concentration of the desired co-reactant.Herein, for the first time we report on ECL via a single Au₃₈(SC₂H₄Ph)₂₄ nanocluster (hereafter denoted as Au₃₈ NC) reaction (eq. (1)) in the vicinity of an UME in the presence of TPrA radicals as a reductive co-reactant.1where x is the oxidation number that can be either 0, 1, 2, 3 or 4. Single ECL spikes (Fig. 1A) along with ECL spectroscopy were used for elucidating individual reaction events. Indeed, each single ECL spike demonstrates a single Au₃₈^(x−1)* reaction product. Au₃₈ NCs were synthesized according to procedures reported by us and others, and fully characterized using UV-Visible-NIR, photoluminescence, ¹HNMR spectroscopy and MALDI mass spectrometry to confirm the Au₃₈ nanocluster synthesis (details are provided in ESI, Sections 1–3, Fig. S1–S4^†).^38,40,41Fig. 2 (left) shows a differential pulse voltammogram (DPV) in an anodic scan of a 2 mm Pt disc electrode immersed in 0.1 mM Au₃₈ acetonitrile/benzene solution containing 0.1 M TBAPF₆ as the supporting electrolyte. There are five discrete electrochemical peaks at which Au₃₈⁰ was oxidized to Au₃₈⁺ (E°′ = 0.39 V), Au₃₈²⁺ (E°′ = 0.60 V), and Au₃₈^3+/4+ (E°′ = 0.99 V) and reduced to Au₃₈⁻ (E°′ = −0.76 V) and Au₃₈²⁻ (E°′ = −1.01 V).^38,40,41Open in a separate windowFig. 1(A) An example of the reaction event transient of 10 μM Au₃₈ in benzene/acetonitrile (1 : 1) containing 0.1 M TBAPF₆ in the presence of 20 mM TPrA at 0.9 V vs. SCE, acquired at 15 ms time intervals using a 10 μm Pt UME. The white dashed-line indicates the threshold to identify single ECL spikes. (B) Illustration of a single nanocluster ECL spike. (C) ECL instrumentation with an inset showing ECL spike generation in the vicinity of the Pt UME.Open in a separate windowFig. 2Anodic DPV for Au₃₈ (left), reaction energy diagram of Au₃₈²⁺ and TPrA· (middle) along with the ECL–voltage curve (right) in an anodic potential scan at a 2 mm Pt disk electrode immersed in a solution of 10 μM Au₃₈ with 20 mM TPrA.The rich electrochemistry of Au₃₈ NCs is well-matched with that of co-reactants such as TPrA to generate near infrared-ECL (NIR-ECL), and the ECL emission efficiency of the Au₃₈/TPrA system is 3.5 times larger than that of the Ru(bpy)₃²⁺/TPrA co-reactant ECL system.²⁷Thus, it is of utmost interest to investigate the ECL generation of the above co-reactant system in single reactions, which improves the ECL signal detection sensitivity. To perform the ECL experiment a solution of 10 μM Au₃₈ NC with 20 mM TPrA was prepared. We first confirmed the ECL light generation of such solution along with its blank solution containing only TPrA using a typical 2 mm diameter Pt disk electrode (Fig. 2, S5 and S6^†).A 10 μm Pt UME electrode, which is electrochemically inert (Fig. S7^†), was utilized to investigate the ECL of single NC reactions under potentiostatic conditions, at which a specific positive bias potential was applied to oxidize both Au₃₈ and TPrA. Fig. 1A shows a typical ECL–time transient current curve (ECL intensity versus time) at 0.90 V vs. SCE, which was acquired using a photomultiplier tube (PMT, R928) for a duration of 1800 s at data acquisition time intervals of 15 ms (Fig. 1C and ESI, Section 3^†). Fig. 1B represents an exemplary event of a single ECL spike with a sharp increase followed by a decay in the ECL intensity. It is observed from the many spikes in Fig. 1B that this process can reoccur with a high probability in the vicinity of the UME, probably due to an electrocatalytic reaction loop (Fig. 1C). Indeed, ECL intensity was enhanced in this way as an already relaxed species, i.e., Au₃₈^z+1*, participates in an oxidation step to regenerate Au₃₈^z+1 to react with the TPrA radical (TPrA˙).Once photons resulting from the excited state relaxation in the vicinity of the UME are captured by the PMT, individual reaction events can be observed (Fig. 1A with the instrumentation schematic shown in Fig. 1C). As shown in Fig. 3A, there are many ECL spikes during 1800 s of measurement, each of which represents an individual ECL generation reaction in the vicinity of the UME surface. It is worth noting that there are several spikes with various intensities. This is most likely due to the Brownian motion which is random movement due to the diffusion of individual nanocluster species such as Au₃₈⁰, Au₃₈¹⁺, Au₃₈²⁺, etc., electrogenerated at the local applied potentials. Long and co-workers⁴² proposed that silver nanoparticle collision on the surface of a gold electrode follows Brownian motion, leading to several types of surface-nanoparticle response peak shapes. In fact, the observed ECL spikes, shown in Fig. 1C, with a rise and an exponential decay suggested that Au₃₈ nanocluster species diffuse directly through the electrode double-layer, move towards the tunneling region of the electrode surface, collide⁴² and become oxidized, react with TPrA radicals thereafter to produce excited states, and emit ECL. It is worth emphasizing that this path could be partially different for each individual nanocluster owing to the angle and direction relative to the electrode surface. The single Au₃₈ NC reaction behaviour at various bias potentials was investigated following the electrochemical energy diagram shown in Fig. 2, middle. For example, at a bias potential of 0.70 V (the green spot on the DPV in Fig. 2), Au₃₈⁰ undergoes two successive oxidation reactions to Au₃₈²⁺ and TPrA oxidation and deprotonation start to generate TPrA·. In fact, at a very close oxidation potential to Au₃₈²⁺, TPrA is also oxidized to its corresponding cation radical (ca. 0.80 V vs. SCE) Fig. S6,^† followed by deprotonation to form the TPrA radical.³⁸ The TPrA· with a very high reduction power (E°′ = −1.7 eV)⁴³ injects one electron to the LUMO orbital of the nanocluster and forms excited state Au₃₈⁺*, as illustrated in the reaction energy diagram in Fig. 2, middle.³⁸ Then, Au₃₈⁺* emits ECL light while relaxing to the ground state. For another instance, at 1.10 V vs. SCE (the red spot on the DPV in Fig. 2), Au₃₈⁰ is oxidized to Au₃₈^3/4+ feasibly. At this potential, the TPrA radical is generated massively in the vicinity of the electrode. The efficient electron transfer between the TPrA radical and Au₃₈^3/4+ generates both Au₃₈²⁺* and Au₃₈³⁺* that emit light at the same wavelength of 930 nm.³⁸ The results of such interactions produced a transient composed of many ECL events (Fig. 3A), which is an indication of bias potential enforcement on the nanocluster light emission.Open in a separate windowFig. 3Single-nanocluster ECL photoelectron spectroscopy of Au₃₈. ECL–time transients (A), statistics of the number of photons (B), histogram of the single reaction time between sequential spikes (C) and accumulated ECL spectrum (D) for a 10 μm Pt UME at 1.1 V immersed in a 10 μM Au₃₈ nanocluster solution in benzene/acetonitrile (1 : 1) containing 0.1 M TBAPF₆ in the presence of 20 mM TPrA. (E)–(H) The counterpart plots to (A)–(D) for the UME biased at 0.7 V. # represents the number.We further tried to collect the current–time traces of such events; however, owing to the high background current originating from the high concentration of TPrA relative to that of the nanocluster, no noticeable spikes in the current were observed.In order to study the photochemistry and understand deeply the single nanocluster reactions, ECL–time transients were collected at different applied potentials (i.e., 0.7, 0.8, 0.9 and 1.1 V vs. SCE) as labelled in green, brown, purple, and red on the DPV in Fig. 2, respectively. The transients were further analysed using our home-written MATLAB algorithm adapted from that for nanopore electrochemistry.⁴⁴ The population of individual events was identified by applying an appropriate threshold to discriminate ECL spikes from the noise as demonstrated in Fig. 1A. In fact, the applied algorithm also assisted us to learn about the raising time and intensity of each spike, as well as photons of individual spikes. For instance, Fig. 3A shows another typical transit for 1800 s at an UME potential bias of 1.1 V for the ECL events. Indeed, the integrated area of each peak, the charge of the photoelectrons at the PMT, is directly proportional to the number of photons emitted from individual reactions (see ESI, Section 5^†). Basically, the PMT amplifies the collected single photon emitted in the course of light-to-photoelectron conversion (see ESI, Section 6 and Fig. S8^†) and translates a single photon into photoelectrons. The extracted charge of each ECL reaction, Q_ECL, was then converted to the corresponding number of photons by dividing by the gain factor, g, which is 1.55 × 10⁶ (Fig. S8^†), following eqn (2):2The histograms of the number of photons show a Gaussian distribution (Fig. 3B) with a reaction frequency of 53.5 ± 2.9 at E = 1.1 V, whereas at a lower potential of 0.7 V the reaction frequency drops to 18.5 ± 1.7 (Fig. 3F). This indicates that there is a three-fold lower reaction occurrence at the lower potential. The integration of the Gaussian fitting at 1.1 V and 0.7 V also reveals a three-fold drop from 3.3 × 10⁵ to 1.2 × 10⁵ photons over 1800 s.To further explore the effect of electrode potential bias on the single Au₃₈ NCs ECL reaction, potentials lower than 1.1 and higher than 0.7 V, ca. 0.8 and 0.9 V (brown and purple labels in Fig. 2), were applied. In fact, the resulting ECL–time transients show a lower population of single spikes (Fig. S12A and ESI,^†). The integrated Gaussian curve values support the ECL–time transient observations with ∼4.1 × 10⁴ and ∼6.5 × 10⁴ photons, respectively. In fact, it is unlikely that the PMT would get more than two events in the duration, owing to the following reasons: (i) it has been shown that only 5.5% of incoming photons can be effectively converted to photoelectron signals by our R928 PMT during our absolute efficiency calibration, ESI Section 6 and Fig. S8–S19^†;⁴⁵ (ii) spherical ECL emission is proven to be detected for a substantial small part upon examination of our detection system for the absolute ECL quantum efficiency;⁴⁵ (iii) Au₃₈ nanocluster ECL emissions occur at 930 nm, which is almost at the wavelength detection limit of our PMT response curve.^38,45In addition, we evaluated the stochastic (a series of random events at various probability distributions) nature of the observed events and extracted the reaction time interval (τ) at various potentials. The resulting graph shows an exponential decay (Fig. 3C) as expressed in eqn (3):3where frequency (λ) gives the mean rate of the event and A represents the fitting amplitude. One can expect to obtain the distribution of the number of emitted photons and spatial brightness function. In fact, the exponential decay is a clear indication of random single reaction events as Whiteman and co-workers described for a 9,10-diphenylanthracene (DPA) ECL system in the annihilation pathway.^7,46 At a potential of 1.1 V, λ and A are found to be 4.98 ± 0.02 ms⁻¹ and 80.4 ± 3.2, whereas at 0.7 V, λ and A turned out to be 32.9 ± 1.6 ms⁻¹ and 9.5 ± 0.1 (Fig. 3C and G). Indeed, the lower potential of 0.70 V vs. SCE is high enough to generate the TPrA radical along with Au₃₈²⁺, thereby leading to excited Au₃₈⁺*, Fig. 3E. One can conclude that at the applied potentials of 0.7 V and 1.1 V, Au₃₈⁰ is oxidized to Au₃₈²⁺ and Au₃₈⁴⁺, resulting in the generation of Au₃₈⁺* and Au₃₈³⁺* under static conditions. Thus, there are higher populations of ECL spikes with no discrepancy in the number of collected photon distributions. However, at two intermediate potentials, i.e., 0.8 and 0.9 V, a dynamic behaviour which is due to the mixed oxidation of Au₃₈ species, in the vicinity of the UME, is observed. In fact, at these two applied potentials, the local concentration of the corresponding gold nanoclusters (i.e., Au₃₈³⁺ and Au₃₈⁴⁺) is not sufficient to produce significant ECL spikes. We also attempted to collect the ECL spectrum using a charge-coupled device (CCD) camera, which is relatively more sensitive in the NIR region (e.g., λ > 900 nm, Fig. S16^†). Fig. 3D and H display an accumulated spectrum at 1.1 and 0.7 V vs. SCE, which is collected for 30 minutes. The fitted accumulated ECL spectrum indicates an ECL peak emission at 930 nm and supports higher reactivity at 1.1 V than that at 0.7 V.³⁸ To confirm that the observed ECL spikes and accumulated spectra are generated based on the oxidation of Au₃₈ nanoclusters in the presence of TPrA radicals, ECL–time transients were recorded upon holding an applied potential at which no faradaic process occurs. Fig. S11^† represents ECL–time curves and accumulated ECL spectra at 0.0 V and 0.4 V. One can notice that no appreciable ECL signal can be observed.In addition, we investigate the Pearson cross-correlation (ρ) between the intensities of ECL spikes with τ as shown in Fig. S14^† in which there is a positive correlation at 0.7 and 1.0 V and a negative correlation at 0.8 and 0.9 V. In fact, ρ evaluates whether there is a stationary random process between the two defined parameters (see ESI, Section 6^†). Interestingly, the frequency of the reaction at different applied potentials revealed decay from 0.7 to 0.8 V, followed by an upward trend to 0.9 and 1.1 V vs. SCE (Fig. S15^†). This could be additional support for the transition stage at 0.8 and 0.9 V, where the applied potential as the major driving force to generate oxidized forms (e.g., Au₃₈³⁺ and Au₃₈⁴⁺) governs the flux of the nanocluster species that reach the vicinity of the electrode. Furthermore, the effectiveness of electron transfer reaction kinetics between the radical species, i.e., Au₃₈^z+1 and TPrA radical, competes with the flow of the incoming nanoclusters. It is worth mentioning that each of the ECL single event experiments was repeated three times, and very similar results were obtained. Moreover, lower (5 μM) and higher (20 μM) concentrations of Au₃₈ in the presence of 20 mM were tested. In fact, the former shows a smaller number of single reactions; however the later revealed a larger number of multiple reactions (Fig. S13^†).In summary, in this communication we demonstrated that Au₃₈ NC ECL at the single reaction level can be monitored using a simple photoelectrochemical setup following a straightforward protocol. Indeed, we have rich basic knowledge about the ECL mechanisms of various gold nanoclusters with different charge states (Au₂₅(SR)₁₈¹⁺, Au₂₅(SR)₁₈⁰, Au₂₅(SR)₁₈¹⁻) and various sizes (Au₂₅(SR)₁₈⁰, Au₃₈(SR)₂₄⁰, Au₁₄₄(SR)₆₀⁰) in fine detail. Thus, the ECL emission mechanisms of gold clusters, including the contribution of each charge state and influence of various concentrations of co-reactants, are well known. For instance, in our previous studies^{38,39,47–49} we clearly identified three charge states of an Au₂₅(SR)₁₈¹⁻/TPrA system and we discovered that at a high concentration of TPrA the reduction in the bulk solution of gold nanoclusters influences the ECL emission wavelength. We also have learnt that the Au₃₈/TPrA system is a co-reactant independent of co-reactant concentration. Furthermore, an extensively higher concentration of TPrA provides a dominant reaction over any unknown decomposition reaction at higher oxidation states of Au₃₈. It was discovered that the population of ECL reactions is directly governed by the applied bias potential on a Pt UME. This work is a strong indication of the high sensitivity of the ECL technique in detecting single ECL reactions in a simple solution, which complements those reported by the Bard group using rubrene, for instance, embedded in an organic emulsion in the presence of TPrA or oxalate as a co-reactant.^50,51 These systems needed a substantial ECL enhancement in the presence of an ionic liquid as the supporting electrolyte and emulsifier. The current approach can be further extended to investigate other molecules and nanomaterials'' electrocatalytic processes at the single reaction level.     

Hydroxy-directed fluorination of remote unactivated C(sp3)–H bonds: a new age of diastereoselective radical fluorination

We report a photochemically induced, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity in this burgeoning field. Numerous simple and complex motifs showcase a spectrum of regio- and stereochemical outcomes based on the configuration of the hydroxy group. Notable examples include a long-sought switch in the selectivity of the refractory sclareolide core, an override of benzylic fluorination, and a rare case of 3,3′-difluorination. Furthermore, calculations illuminate a low barrier transition state for fluorination, supporting our notion that alcohols are engaged in coordinated reagent direction. A hydrogen bonding interaction between the innate hydroxy directing group and fluorine is also highlighted for several substrates with ¹⁹F–¹H HOESY experiments, calculations, and more.

We report a photochemical, hydroxy-directed fluorination that addresses the prevailing challenge of high diastereoselectivity. Numerous motifs showcase a range of regio- and stereochemical outcomes based on the configuration of the hydroxy group.

The hydroxy (OH) group is treasured and versatile in chemistry and biology.¹ Its ubiquity in nature and broad spectrum of chemical properties make it an attractive source as a potential directing group.² The exploitation of the mild Lewis basicity exhibited by alcohols has afforded several elegant pathways for selective functionalization (e.g., Sharpless epoxidation,³ homogeneous hydrogenation,⁴ cross-coupling reactions,⁵ among others⁶). Recently, we reported a photochemically promoted carbonyl-directed aliphatic fluorination, and most notably, established the key role that C–H⋯O hydrogen bonds play in the success of the reaction.⁷ Our detailed mechanistic investigations prompt us to postulate that other Lewis basic functional groups (such as –OH) can direct fluorination in highly complementary ways.⁸ In this communication, we report a hydroxy-directed aliphatic fluorination method that exhibits unique directing properties and greatly expands the domain of radical fluorination into the less established realm governing high diastereoselectivity.⁹Our first inclination that functional groups other than carbonyls may influence fluorination regiochemical outcomes was obtained while screening substrates for our published ketone-directed radical-based method (Scheme 1).^8a In this example, we surmised that oxidation of the tertiary hydroxy group on substrate 1 cannot occur and would demonstrate functional group tolerance (directing to C11, compound 2). Surprisingly, the two major regioisomers (products 3 and 4) are derivatized by Selectfluor (SF) on C12 and C16 – indicative of the freely rotating hydroxyl directing fluorination. Without an obvious explanation of how these groups could be involved in dictating regiochemistry, we continued the mechanistic study of carbonyl-directed fluorination (Scheme 2A). We established that the regioselective coordinated hydrogen atom abstraction occurs by hydrogen bonding between a strategically placed carbonyl and Selectfluor radical dication (SRD).⁷ However, we noted that the subsequent radical fluorination is not diastereoselective due to the locally planar nature of carbonyl groups. Thus, we posed the question: are there other directing groups that can provide both regio- and diastereoselectivity? Such a group would optimally be attached to a sp³ hybridized carbon; thus the “three dimensional” hydroxy carbon logically comes to mind as an attractive choice, and Scheme 1 illustrates the first positive hint.Open in a separate windowScheme 1Observed products for the fluorination of compound 1.Open in a separate windowScheme 2(A) Proposed mechanism, (B) β-caryophyllene alcohol hypochlorite derivative synthetic probe, (C) isodesmic relation of transition states showing the general importance of the hydroxy group to reactivity (ωB97xd/6-31+G*), and (D) ¹H NMR experiment with Selectfluor and various additives at different concentrations.We began our detailed study with a simple substrate that contains a tertiary hydroxyl group. Alcohol 5 was synthesized stereoselectively by the reaction of 3-methylcyclohexanone, FeCl₃, and 4-chlorophenylmagnesium bromide;¹⁰ the 4-chlorophenyl substituent allows for an uncomplicated product identification and isolation (aromatic chromophore). We sought to determine optimal reaction conditions by examination of numerous photosensitizers, bases, solvents, and light sources (7 Although we utilize cool blue LEDs (sharp cutoff ca. 400 nm), CFLs (small amount of UVB (280–315 nm) and UVA (315–400 nm)) are useable as well.¹¹ A mild base additive was also found to neutralize adventitious HF and improve yields in the substrates indicated ( EntrySensitizer ¹⁹F yield1None0% 2 Benzil 83% 3Benzil, no base63%4Benzil, K₂CO₃68%5Benzil, CFL light source75%65-Dibenzosuberenone15%74,4′-Difluorobenzil63%89,10-Phenantherenequinone71%9Perylene8%10Methyl benzoylformate42%Open in a separate window^aUnless stated otherwise: substrate (0.25 mmol, 1.0 equiv.), Selectfluor (0.50 mmol, 2.0 equiv.), NaHCO₃ (0.25 mmol, 1.0 equiv.), and sensitizer (0.025 mmol, 10 mol%) were dissolved in MeCN (4.0 mL) and irradiated with cool white LEDs for 14 h.Substrate scope^a