Construction of vicinal 4°/3°-carbons via reductive Cope rearrangement

Herein reported is a strategy for constructing vicinal 4°/3° carbons via reductive Cope rearrangement. Substrates have been designed which exhibit Cope rearrangement kinetic barriers of ∼23 kcal mol⁻¹ with isoenergetic favorability (ΔG ∼ 0). These fluxional/shape-shifting molecules can be driven forward by chemoselective reduction to useful polyfunctionalized building blocks.

Herein reported is a strategy for constructing vicinal 4°/3° carbons via reductive Cope rearrangement.

Constructing sterically congested vicinal quaternary–tertiary carbons (4°/3° carbons) via Cope rearrangement is currently quite limited with only a handful of papers on the subject published over the past 40 years. This stands in stark contrast to the plethora of other methods for establishing sterically congested vicinal carbons.^1–5 Central to the challenge are kinetic and thermodynamic issues associated with the transformation. In the simplest sense, Cope rearrangements proceed in the direction that results in highest alkene substitution (Fig. 1).^6,7 To forge 4°/3° motifs by Cope rearrangement, additional driving forces must be introduced to reverse the [3,3] directionality and compensate for the energetic penalty associated with the steric and torsional strain of the targeted vicinal 4°/3° motif. With limited reports in all cases, oxy-Cope substrates (Scheme 1, eqn (1)),^8–14 divinylcyclopropanes (Scheme 1, eqn (2)),^15–20 and vinylidenecyclopropane-based 1,5-dienes²¹ (Scheme 1, eqn (3)) have demonstrated favourability for constructing vicinal 4°/3° carbons. Malachowski et al. put forth a series of studies on the construction of quaternary centers via Cope rearrangement driven forward by a conjugation event (Scheme 1, eqn (4)).^22–25 In their work, a single example related to the construction of vicinal 4°/3° centers was disclosed, though kinetic (180 °C) and thermodynamic (equilibrium mixtures) challenges are also observed.²³ And of particular relevance to this work, Wigfield et al. demonstrated that 3,3-dicyano-1,5-dienes with the potential to generate vicinal 4°/3° carbons instead react via an ionic mechanism yielding the less congested products (Scheme 1, eqn (5)).²⁶Open in a separate windowFig. 1Cope equilibrium of 1,1,6-trisubstituted 1,5-dienes.Open in a separate windowScheme 1(A) Cope rearrangements for constructing vicinal 4°/3°-centers (B) this report.Our group has been examining strategies to decrease kinetic barriers and increase the thermodynamic favourability of 3,3-dicyano-1,5-diene-based Cope substrates.^27–31 Beyond the simplest, unsubstituted variants, this class of 1,5-diene is not particularly reactive in both a kinetic and thermodynamic sense (e.g.Scheme 1, eqn (5)).^26,32 Reactivity issues aside, these substrates are attractive building blocks for two main reasons: (1) they have straightforward accessibility from alkylidenemalononitriles and allylic electrophiles by deconjugative allylic alkylation.³³ (2) The 1,5-diene termini are substantially different (malononitrile vs. simple alkene) thus allowing for orthogonal functional group interconversion facilitating target and analogue synthesis.³⁴ Herein we report that a combination of 1,5-diene structural engineering^28,31 and reductive conditions (the reductive Cope rearrangement^29,30) can result in the synthesis of building blocks containing vicinal gem-dimethyl 4°/3° carbons along with orthogonal malononitrile and styrene functional groups for interconversion (Scheme 1B). On this line, malononitrile can be directly converted to amides³⁴ yielding functionally dense β-gem-dimethylamides, important pharmaceutical scaffolds.³⁵This project began during the Covid-19 pandemic lockdown (ca. March–May 2020). As such, we were not permitted to use our laboratory out of an abundance of caution. We took this opportunity to first computationally investigate a Cope rearrangement that could result in vicinal 4°/3° carbons (Scheme 2). Then, when permitted to safely return to the lab, we would experimentally validate our findings (vide infra). From our previous work, it is known that by adding either a 4-aromatic group²⁸ or a 4-methyl group³¹ to a 3,3-dicyano-1,5-diene, low barrier (rt – 80 °C) diastereoselective Cope rearrangements can occur. Notably, the 4-substituent was found to destabilize the starting material (weaken the C3–C4 bond, conformationally bias the substrate for [3,3]), and stabilize the product side of the equilibrium via resonance (phenyl group) or hyperconjugation (methyl group). In this study, we modelled substrates 1, 3, and 5 that have variable 4-substitution and would result in vicinal gem-dimethyl- and phenyl-containing 4°/3° carbons upon Cope rearrangement to 2, 4, or 6, respectively. We chose to target this motif due to likely synthetic accessibility from simple starting materials but also because of the important and profound impact that gem-dimethyl groups impart on pharmaceuticals.³⁵ Substrate 1 lacking 4-substitution had an extremely unfavourable kinetic and thermodynamic profile (ΔG^‡ = 31.6; ΔG = +5.3 kcal mol⁻¹). When a 4-methyl group was added, the kinetic barrier (ΔG^‡) dropped appreciably to 28.2 kcal mol; however, the thermodynamics were still quite endergonic (ΔG = +4.4 kcal mol⁻¹). Most excitingly, it was uncovered that the 4-phenyl group dramatically impacted the kinetics and thermodynamics: the [3,3] has a barrier of 22.9 kcal mol⁻¹ (ΔG^‡) and is ∼isoenergetic (ΔG = +0.17 kcal mol⁻¹). Thus, the reaction appears to be fluxional/shape-shifting at room temperature.^36–40 For this substrate, we also modelled the dissociative pathway (Scheme 2D). It was found that bond breakage to two allylic radical intermediates is a higher energy process than the concerted transition state (Scheme 2Cvs.Scheme 2D). Specifically, the dissociative pathway was found to be kinetically less favourable (ΔG^‡ ∼ 27.6 kcal mol; ΔG = 26.2 kcal mol⁻¹) than the concerted process (ΔG^‡ = 22.9 kcal mol⁻¹). While the dissociative pathway is less favourable than the concerted transformation, we surmised that the two-step process becomes accessible at elevated temperature (vide infra). Finally, the ionic pathway was calculated to be significantly higher for this substrate (see the ESI^†).Open in a separate windowScheme 2Computational analysis of 3,3-dicyano-1,5-diene that in theory could result in vicinal 4°/3° carbons. (A) 4-Unsubstituted 3,3-dicyano-1,5-diene. (B) 4-Methyl 3,3-dicyano-1,5-diene. (C) 4-Phenyl 3,3-dicyano-1,5-diene. (D) The dissociative mechanism for substrate 5 is higher than the closed transition state. (E) visualization of the kinetic- and thermodynamic differences of transformations (A–D).The class of substrate uncovered from our computational investigation could be accessed from γ,γ-dimethyl-alkylidenemalononitrile (7a) and 1,3-diarylallyl electrophiles (such as 8a) by Pd-catalyzed deconjugative allylic alkylation (Scheme 3A).³³ As such, model 1,5-diene 5a was prepared to verify the computational results. It was found that upon synthesis of 5a, an inseparable 21 : 79 mixture of 1,5-diene 5a and the 1,5-diene 6a was observed. The predicted ratio of 5a to 6a was 57 : 43 (Scheme 2C). These two results are within the error of the calculations (predicted; slightly endergonic, observed; slightly exergonic). To determine whether the transformation was progressing through the predicted concerted pathway (Scheme 2C) over the dissociative pathway (Scheme 2D), substrate 5b was prepared by an analogous deconjugative allylic alkylation reaction. Similarly, two Cope equilibrium isomers 5b and 6b are observed at room temperature in a 12 : 88 ratio. Upon heating at 100 °C for 3 h, the 1,5-dienes “scramble” (e.g. iso-6b is observed; 0.2 : 1.0 : 1.5 ratio of 5b : 6b : iso-6b) indicating that the dissociative pathway is only accessible at elevated temperature. This is all in good agreement with the calculated kinetics and thermodynamics of this system (Scheme 2).Open in a separate windowScheme 3(A) Observation of fluxional [3,3] and confirmation of calculated predictions. (B) Optimization of a reductive Cope rearrangement protocol for constructing vicinal 4°/3° centers. (C) The Pd-catalyzed deconjugative allylic alkylation must be regioselective.With respect to the synthetic methodology, we aimed to increase the overall efficiency and applicability of the sequence (Scheme 3B). Specifically, we wanted to avoid [3,3] equilibrium mixtures and sensitive/unstable substates and intermediates. It was found that the direct coupling of 7a with diphenylallyl alcohol 9a could take place in the presence of DMAP, Ac₂O, and Pd(PPh₃)₄. When the coupling was complete, methanol and NaBH₄ were added to drive the Cope equilibrium forward, yielding the reduced Cope rearrangement product 10a in 76% isolated yield. In terms of practicality and efficiency, this method utilizes diphenylallyl alcohols, which are more stable and synthetically accessible than their respective acetates, and the [3,3] equilibrium mixture can be directly converted dynamically to a single reduced product.With an efficient protocol in hand for constructing malononitrile–styrene-tethered building blocks featuring central vicinal 4°/3° carbons, we next examined the scope of the transformation (Scheme 4). We chose diarylallyl alcohols with the propensity to react regioselectively via an electronic bias (Scheme 3C).^41,42 The combination of p-nitrophenyl and phenyl (10b) or p-methoxyphenyl (10c) yielded regioselective outcomes with the electron-deficient arene at the allylic position. This is consistent with the expected regiochemical outcome where the nucleophile reacts preferentially at the α-position and the electrophile reacts at the allylic position bearing the donor-arene (Scheme 3C).^41,42 Then, reductive Cope rearrangement occurs to position the electron-deficient arene adjacent to the gem-dimethyl quaternary center. This is an exciting outcome as many pharmaceutically relevant (hetero)arenes are electron deficient. Thus, fluorinated arenes were installed at the allylic position of products 10d–10k. While the phenyl group resulted in poor regioselectivity (1 : 1–3 : 1), the p-methoxyphenyl group enhanced the regiomeric ratios in all cases (3 : 1–15 : 1). The degree of selectivity is correlated with the number and position of fluorine atoms. N-Heterocycles could be incorporated with excellent regioselectivity, generally speaking (10l–10q). For example, 3-chloro-4-pyridyl (10l/10m) groups were installed at the allylic position with >20 : 1 rr. 4-Chloro-3-pyridyl was poorly regioselective (10n), but the combination of 4-trifluomethyl-3-pyridyl/p-methoxyphenyl (10o) gave good regioselectivity of 11 : 1. 2-Pyridyl/p-methoxyphenyl (10q) was also a regioselective combination. We also examined a few other heterocycles including quinoline (10s) and thiazole (10t and 10u) with excellent and modest regioselectivity observed, respectively. As a general trend, when the arenes on the allylic electrophile become less polarized, poor regioselectivity is observed in the Pd-catalyzed allylic alkylation. For example, the combination of p-chlorophenyl and p-methoxyphenyl (10v) or phenyl (10w) yields regioisomeric mixtures of products. This can be circumvented by utilizing symmetric electrophiles (to 10x).Open in a separate windowScheme 4Scope of the 4°/3°-center-generating reductive Cope rearrangement.The phenyl or the p-methoxyphenyl group is necessary to achieve the 4°/3° carbon-generating Cope rearrangement: it functions as an “activator” by lowering the kinetic barrier and increasing thermodynamic favourability. These activating groups can be removed through alkene C C cleavage reactions (e.g. metathesis (Scheme 5) and ozonolysis (Scheme 6B)). In this regard, highly substituted cycloheptenes 11 were prepared by allylation and metathesis (Scheme 4).^28,43 The yields were modest to excellent over this two-step sequence. In many cases, where 10 exists as a mixture of regioisomers, the major allylation/RCM products 11 could be chromatographically separated from their minor constituents. As shown in Scheme 6A, the malononitrile can be transformed via oxidative amidation³⁴ to products 12 containing a dense array of pharmaceutically relevant functionalities (amides, gem-dimethyl, fluoroaromatics, and heteroaromatics). Following this transformation, ozonolysis terminated with a NaBH₄ quench installs an alcohol moiety on small molecule 13a.Open in a separate windowScheme 5Removal of the “activating group” by ring-closing metathesis.Open in a separate windowScheme 6(A) oxidative amidation of malononitrile. (B) Removal of “activating group” by ozonolysis.These first computational and experimental studies utilizing 3,3-dicyano-1,5-dienes as substrates for constructing vicinal 4°/3° centers sets the stage for much further examination and application. For example, while we focused our efforts on gem-dimethyl-based quaternary carbons, it is likely that other functionality can be installed at this position. For example, while unoptimized, it appears the protocol is reasonably effective at incorporating a piperidine moiety in addition to heteroarenes from the allylic electrophile (7b + 9f → 14a; Scheme 7A). Similar functional group interconversion chemistry as described in Schemes 5 and ​and66 can thus yield functionally dense building blocks 15 and 16 in good yields.Open in a separate windowScheme 7(A) The construction of 4/3° centres on piperidines. (B) Promoting endergonic [3,3] rearrangements is possible, assuming the [3,3] kinetic barrier is sufficiently low.While the 4,6-diaryl-3,3-dicyano-1,5-dienes offered the most attractive energetic profile (low kinetic barrier, isoenergetic [3,3] equillibrium; Scheme 2C), the 4-methyl analogue is also intriguing to consider as a viable substrate class for reductive Cope rearrangement (Scheme 2B). The challenge here is that the kinetics and thermodynamics are quite unfavourable (not observable by NMR), but potentially not prohibitively so. It is extremely exciting to find that Cope equilibria that are significantly endergonic in the desired, forward direction (e.g.3a to 4a) can be promoted by a related reductive protocol (Scheme 7B). While unoptimized, we were able to isolate product 17 in xx% yield by heating at 90 °C in the presence of Hantzsch ester in DMF.     

Correction: Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling

Correction for ‘Hydrogen-activation mechanism of [Fe] hydrogenase revealed by multi-scale modeling’ by Arndt Robert Finkelmann et al., Chem. Sci., 2014, 5, 4474–4482, DOI: 10.1039/C4SC01605J.

The authors regret that there were minor typographical errors in two figures. In Fig. 9 and ​and11,11, the internuclear distances were swapped. The Fe-bound hydrogen atoms are affected, where H_p is the hydrogen atom proximal to the oxypyridine ligand and H_d is the hydrogen atom distal to the oxypyridine ligand. In Fig. 9, left panel, the distance between H_p and the oxypyridine O atom was given as 1.82 Å and the distance between H_p and the Fe atom was given as 1.7 Å. However, it should read 1.82 Å between H_p and Fe and 1.70 Å between H_p and the oxypyridine O atom. In Fig. 11, top left panel, the distance between H_p and Fe was shown to be 1.70 Å and the distance between H_d and Fe was given as 1.73 Å. However, it should read 1.73 Å between H_p and Fe and 1.70 Å between H_d and Fe. The correct versions of these figures are given below. The results and conclusions are not affected by these typographical errors.Open in a separate windowFig. 9QM/MM-optimized reactant (left) and product (right) structures of the H₂ cleavage reaction for the scenario with oxypyridine ligand. Distances are given in Å.Open in a separate windowFig. 11Top row: structures of the H₂ adduct for the second scenario with neutral pyridinol; the pyridinol OH can be oriented away from Fe (top left) or towards Fe (top right). Bottom row: products of H₂ cleavage, with the proton transferred to the thiolate; with the hydroxyl oriented away from Fe (bottom left) and towards Fe (bottom right). Distances are given in Å; relative energies with respect to the favoured adduct are indicated in red in kcal mol⁻¹.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Correction: Highly selective acid-catalyzed olefin isomerization of limonene to terpinolene by kinetic suppression of overreactions in a confined space of porous metal–macrocycle frameworks

Correction for ‘Highly selective acid-catalyzed olefin isomerization of limonene to terpinolene by kinetic suppression of overreactions in a confined space of porous metal–macrocycle frameworks’ by Wei He et al., Chem. Sci., 2022, 13, 8752–8758, https://doi.org/10.1039/d2sc01561g.

The authors regret that there were errors in Fig. 2, Fig. 5 and Fig. 6 in the original article and Fig. S18 of the ESI. The stereochemistry of the chemical structural formulas for (−)-α-pinene (6) and (−)-β-pinene (7) was incorrectly reversed. The correct versions of the figures are shown below, and in the updated version of the ESI.Open in a separate windowFig. 2Metal–macrocycle framework (MMF). (a) Self-assembly of asymmetrically twisted Pd^II-macrocycles into (b) a porous crystal MMF (sticks model) with five enantiomeric pairs of binding pockets (surface model). (c) Previously reported site-selective adsorption of (−)-α-pinene (6) (space-filling model) on the channel surface of the MMF.¹ Blue, yellow, red, or black dashed circles indicate the ceiling-, side-, bottom-, or tubular-pockets of the MMF, respectively. MMF: Pd, yellow; Cl, green; N, blue; C, grey. 6: C, pink; H, white. Hydrogen atoms attached to the MMF were omitted for clarity. Green or blue surface represents exposed Cl or N–H groups of the MMF, respectively.Open in a separate windowFig. 5Investigation of the inhibitory effects of additives on the isomerization reaction of 2 using 2-NBSA@MMF at 25 °C for 102 h.Open in a separate windowFig. 6Crystallographic study of MMFs soaked in (a) a CHCl₃ solution containing 1 (1.0 M), (b) a CHCl₃ solution containing 2 (1.0 M), and (c) a CH₃CN solution containing 7 (1.0 M). MMF: stick model or surface model; 1 and 7: space-filling model; water and CHCl₃: stick model. Red dashed circles indicate the bottom pocket of the MMF. MMF: Pd, yellow; Cl, green; N, blue; C, grey. 1: C, yellow; H, white. 7: C, pink; H, white. Water and CHCl₃: O, red; H, white; C, grey; Cl, green. Hydrogen atoms attached to the MMF were omitted for clarity. Green and blue surface represents exposed Cl and N–H groups of the MMF, respectively.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Correction: Suppressing carboxylate nucleophilicity with inorganic salts enables selective electrocarboxylation without sacrificial anodes

Correction for ‘Suppressing carboxylate nucleophilicity with inorganic salts enables selective electrocarboxylation without sacrificial anodes’ by Nathan Corbin et al., Chem. Sci., 2021, DOI: 10.1039/D1SC02413B.

We regret that there was a minor error in the structure of the benzyl chloride in Scheme 2, Fig. 2 and the ESI. The structure of the benzyl chloride should be 4-methyl benzyl chloride but was instead given as 3-methyl benzyl. The correct figure and scheme are shown below, and the ESI has been updated.Open in a separate windowFig. 2(A) Comparison of acid yields for non-sacrificial-anode and sacrificial-anode carboxylation of various substrates. (B) Ratio of carboxylic acid to nucleophilic side products (ester + carbonate + alcohol) for various systems and substrates. Effect of adding MgBr₂ to the sacrificial-anode system on the (C) acid yield and (D) ratio of acid to S_N2 side products for benzyl bromide. Acid yields are tabulated in Table S6.† ND: acid not detected (acid-to-S_N2 ratio <0.1).Open in a separate windowScheme 2Substrate scope for the sacrificial-anode-free electrochemical carboxylation of organic halides. ^aStandard reaction conditions: 100 mM electrolyte, 100 mM substrate, 100 mM MgBr₂, silver cathode, platinum anode, 20 sccm CO₂, 2.2 mL DMF, −20 mA cm⁻² for 3.5 h. TBA-Br was used for chlorinated substrates because bromide oxidizes more readily than chloride, and only a small amount of chloride was replaced by bromide (<1% for the alkyl chloride, ∼4% for the benzylic chloride). Yields are referenced to the initial amount of substrate and were calculated from ¹H NMR spectroscopy using either 1,3,5-trimethoxybenzene or ethylene carbonate as internal standards. ^b−15 mA cm⁻² instead of −20 mA cm⁻². ^c150 mM MgBr₂ instead of 100 mM MgBr₂.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Regioselective catalytic carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones

A new Pd/Cu-catalyzed carbonylation and borylation of alkynes with aryldiazonium salts toward α-unsubstituted β-boryl ketones with complete regioselectivity has been developed. This transformation shows broad substrate scope and excellent functional-group tolerance. Moreover, the obtained 1,2-carbonylboration products provide substantial opportunities for further transformations which cannot be obtained by known carbonylation procedures. Preliminary mechanistic studies indicate that the three hydrogen atoms of the products originated from ethyl acetate.

A multi-component procedure on the carbonylative and hydroborative synthesis of β-boryl ketones has been developed with alkynes, B₂pin₂ and aryldiazonium salts as the substrates and using ethyl acetate as the reagent and solvent.

Construction of boro-containing organic molecules remains an important and hot research field due to their wide applications in materials science,¹ pharmaceuticals² and organic chemistry.³ A multitude of methods have been developed for the synthesis of organoboron compounds over the past decades.⁴ Among these methods, transition-metal-catalyzed borofunctionalization of alkynes is a powerful synthetic strategy due to its high selectivity and efficiency.⁵ For example, the use of copper as a precatalyst for the borylation of alkynes has generated renewed interest in the area. The β-borylalkenylcopper intermediates obtained via syn addition of borylcopper to alkynes can electrophilically trap various electrophiles to form different alkenylboronates (Scheme 1, 1). The classical approach of this type of transformation is alkyne hydroboration (Scheme 1, 1a).⁶ Subsequently, with vinylcopper species as the proposed key intermediates, their further reactions with halogen substitutes (Scheme 1, 1b),⁷ CO₂ (Scheme 1, 1c),⁸ allyl phosphates (Scheme 1, 1d),⁹ and tin alkoxides (Scheme 1, 1e)¹⁰ to give the corresponding alkenylboronates were reported. More recently, Mankad and Cheng reported their achievements on the direct efficient synthesis of tetrasubstituted β-borylenones using a copper-catalyzed four-component coupling reaction of simple chemical feedstocks: internal alkynes, alkyl halides, bis(pinacolato)diboron (B₂pin₂) and CO (Scheme 1, 1f).¹¹ Inspired by their achievements and considering the advantage of a multicomponent borocarbonylation reaction, we developed a new Pd/Cu-catalyzed multi-component carbonylation and borylation reaction of alkynes, aryldiazonium salts, B₂Pin₂, ethyl acetate and CO to obtain saturated β-boryl ketones (Scheme 1, ​,3).3). In addition, this new catalyst system can catalyze the regioselective functionalization of alkynes to obtain 2,1-carbonylboration products that are different from the 1,2-products by known transition-metal-catalyzed borylacylation (Scheme 1, ​,2a)2a) and borocarbonylation (Scheme 1, ​,2b)2b) of alkenes.¹² Nevertheless, the carbonylative and hydroborative coupling of alkynes with aryldiazonium salts to obtain saturated β-boryl ketones is still a challenge and has never been reported.Open in a separate windowScheme 1Strategies for borofunctionalization.Open in a separate windowScheme 2Scope of alkynes. Reaction conditions: 1 (0.1 mmol, 1 equiv.), B₂pin₂ (0.2 mmol, 2 equiv.), 2a (0.1 mmol, 1 equiv.), Pd(acac)₂ (5 mol%), CuI (10 mol%), PPh₃ (20 mol%), Na₂CO₃ (0.4 mmol, 4 equiv.), CO (20 bar), EA (with molecular sieves, water ≤ 50 ppm, 2 mL), stirred at 110 °C for 12 h, isolated yields.Open in a separate windowScheme 3Scope of aryldiazonium salts. Reaction conditions: 1a (0.1 mmol, 1 equiv.), B₂pin₂ (0.2 mmol, 2 equiv.), 2 (0.1 mmol, 1 equiv.), Pd(acac)₂ (5 mol%), CuI (10 mol%), PPh₃ (20 mol%), Na₂CO₃ (0.4 mmol, 4 equiv.), CO (20 bar), EA (with molecular sieves, water ≤ 50 ppm, 2 mL), stirred at 110 °C for 12 h, isolated yields.Initially, we tested various reaction conditions using phenyl acetylene (1a), 4-methoxybenzenediazonium tetrafluoroborate (2a) and bis(pinacolato)diboron as the reaction partners. To our delight, by using Pd(acac)₂ and CuI as the cooperative precatalyst, PPh₃ as the ligand, Na₂CO₃ as the base and ethyl acetate (EA) as the solvent at 110 °C under a CO atmosphere (20 bar) with 12 h reaction time, the desired borocarbonylative coupling product (3aa) was obtained in a good GC yield of 78% (

Selective radical cascade (4+2) annulation with olefins towards the synthesis of chroman derivatives via organo-photoredox catalysis

Due to the importance of chroman frameworks in medicinal chemistry, the development of novel synthetic methods for these structures is gaining increasing interest of chemists. Reported here is a new (4 + 2) radical annulation approach for the construction of these functional six-membered frameworks via photocatalysis. Featuring mild reaction conditions, the protocol allows readily available N-hydroxyphthalimide esters and electron-deficient olefins to be converted into a wide range of valuable chromans in a highly selective manner. Moreover, the present strategy can be used in the late-stage functionalization of natural product derivatives and biologically active compounds, which demonstrated the potential application. This method is complementary to the traditional Diels–Alder [4 + 2] cycloaddition reaction of ortho-quinone methides and electron-rich dienophiles, since electron-deficient dienophiles were smoothly transformed into the desired chromans.

We have developed a (4 + 2) radical annulation approach for the synthesis of diverse chromans. This method is complementary to the traditional Diels–Alder [4 + 2] annulation of ortho-quinone methides and electron-rich dienophiles.

Chroman moieties frequently exist as the key subunit in a wide array of natural products, pharmaceuticals, and bioactive molecules.¹ For example, vitamin E,² centchroman,² cromakalim³ and rubioncolin B⁴ are well-known active pharmaceutical ingredients in various therapeutic areas (Scheme 1a). Due to their significant importance in medicinal chemistry, developing new methods towards the synthesis of chromans and the installation of a variety of the functional groups in chroman frameworks are gaining increasing attention of the chemical community.⁵Open in a separate windowScheme 1Selected bioactive molecules and the synthetic methods of chromans.In the past few decades, a great deal of methods have been developed for the assembly of substituted chromans, and among them, the Diels–Alder [4 + 2] cycloaddition reaction provides a highly efficient synthetic platform in the construction of these functional six-membered frameworks.⁶ Extensive work has been done with this strategy, resulting in a lot of significant progress. The ortho-quinone methides (o-QMs) are generally essential dienes for the Diels–Alder reaction towards the synthesis of chromans, as they are highly reactive for rapid rearomatization via Michael addition of nucleophiles, cycloaddition with a dienophile of 2π partners or 6π-electrocyclization (Scheme 1b).⁷ Herein, although various valuable chromans have been successfully synthesized with the Diels–Alder [4 + 2] cycloaddition reaction, the use of o-QMs may lead to several potential limitations in some cases. One of the potential limitations is that o-QMs are used mainly as Michael acceptor and electron-deficient dienes to react only with nucleophiles and electron-rich dienophiles. In these considerations, the evolution of synthetic methods for chromans is very important and highly desirable. In particular, novel (4 + 2) cycloaddition strategies capable of synthesizing chromans with the use of easily available materials and electron-deficient dienophiles are of utmost interest.On the basis of retrosynthetic analysis of chroman shown in Scheme 1c, (4 + 2) radical annulation of the corresponding carbon-centered radical R with olefin would be an alternative route, which is able to overcome the above-mentioned potential limitations. Considering that radical species R is normally nucleophilic, thus, it could react with electron-deficient olefins affording chroman products that generally can''t be synthesized by the traditional Diels–Alder [4 + 2] cycloaddition reaction involving o-QMs. Herein, we reported a highly selective (4 + 2) radical–annulation reaction to construct the chroman framework with the use of easily available NHPI ester as the radical precursor and olefin as the radical acceptor under mild conditions.Compared with other alkyl radical precursors, the redox-active N-(acyloxy)phthalimides (NHPI esters) come to the fore, since they are cheap, stable, readily available, and non-toxic.⁸ Bearing above hypothesis in mind, we commenced to investigate the (4 + 2) annulation reaction by utilizing readily available N-hydroxyphthalimide ester A′ and commercially available ethyl acrylate as model substrates. After a great deal of screening on the reaction parameters, only a trace amount of the target product was detected by GC-MS. In contrast, the main product is anisole, which may result from a rapid hydrogen abstraction reaction of the unstable primary alkyl radical intermediate. To restrain the formation of this by-product, we designed N-hydroxyphthalimide esters A and A′′, which could produce more stable tertiary radicals, for the target (4 + 2) annulation reaction instead of A′ (9 74% yield of ethyl-2,2-dimethylchromane-4-carboxylate upon 1 was selectively obtained after irradiation of the reaction system under blue LEDs at room temperature for 12 h, despite a little by-product ( EntryVariation from standard conditionsYield/%1None742No lightn.d3No EYn.d44-CzIPNn.d5Ru(bpy)₃(PF₆)₂366MeCN347DCEn.d8Air39Open in a separate window^aStandard conditions: A (0.2 mmol), ethyl acrylate (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield; n.d. = not detected.In order to explore the substrate scope of the (4 + 2) annulation reaction, we commenced to scrutinize the generality and selectivity with respect to N-hydroxyphthalimide esters. The functional group applicability of N-hydroxyphthalimide esters was investigated by the examination of various electron donating/withdrawing substituents at the varying positions, as illustrated in Scheme 2. Gratifyingly, we found that substances bearing electron-donating substituents (Me, OMe, ^tBu, SMe, OPh, OBn, and Ph) at the para-position could smoothly be transformed into the corresponding chromans with satisfactory yields (2–8). N-Hydroxyphthalimide esters with halogen substituents, such as fluoride, chloride, bromide and iodide are suitable to produce the corresponding chromans in satisfactory yields, which enable potential application in further functionalization (9–12). Surprisingly, electron-withdrawing substituents, such as MeCO, OCF₃, and CF₃, were also tolerated under standard conditions (13–15). This reaction could proceed effectively with N-hydroxyphthalimide esters containing one group or multiple groups in different positions, which delivered a variety of chroman compounds in moderate to good yields (16–19, 21–23). The annulation reaction is not limited to the construction of benzene compounds, as ethyl-3,3-dimethyl-2,3-dihydro-1H-benzo[f]chromene-1-carboxylate was also obtained in 68% yield (20). After the simple esterification, drug molecules, such as clofibric acid, fenofibric acid and ciprofibrate, could be transformed into the corresponding N-hydroxyphthalimide esters, further engaging with ethyl acrylate (10 and 24–25), which highlighted the synthetic applicability of this protocol.Open in a separate windowScheme 2Reactions of NHPI esters with ethyl acrylate. Standard conditions: NHPI ester (0.2 mmol), ethyl acrylate (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield.Next, we shifted attention to the scope with respect to a wide range of acrylates, as shown in Scheme 3. Methyl acrylate and butyl acrylate were well amenable with N-hydroxyphthalimide esters (26–27). Other acrylates, such as cyclohexyl, tert-butyl and phenyl, were also competent reaction partners with a satisfactory efficiency (28–30). Ethyl (E)-but-2-enoate was tolerant to afford the desired chroman product, albeit in 29% yield (31). It is particularly noteworthy that dimethyl maleate was demonstrated to be a suitable substrate, leading to the formation of sterically hindered product (32). The sensitive benzylic C–H bond and the fragile furan and thiophene moieties could be retained in the radical cascade reaction, providing a series of functionalized chromans (33–35). Alkoxy and aligned alkoxy on substances did not reduce the reaction efficacy (36–37). Chromans possessing various subtle trimethylsilyl, hydroxyl, primary/secondary bromoalkene, cyano and thiomethylene were accessed in reasonable yields, which provided the basis for late-stage derivatization of products (38–41, 43). Owing to the superiority of lipophilicity, permeability and metabolism, we tried to introduce trifluoromethyl into chroman skeletons. To our delight, 2,2,2-trifluoroethyl acrylate gave rise to the corresponding chromans with 52% yield (42). The unactivated alkynyl moiety and alkenyl moiety survived in the photoredox catalysis (44–46).Open in a separate windowScheme 3Reactions of A with various olefins. Standard conditions: A (0.2 mmol), olefin (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield.It is well-known notorious that compounds possessing nitrogen atoms are a very important class of biologically active and functional molecules. Thus, we turned our attention from acrylates to acrylamide derivatives. We were delighted to find that N,N-dimethylacrylamide was a suitable radical receptor to give the target molecule in moderate yield (47). Similarly, a series of chroman products were obtained with cyclic and acyclic acrylamides (48–51). Subsequently, we continued to investigate the reaction of different secondary acrylamides with N-hydroxyphthalimide ester A. These secondary acrylamides bearing NH-isopropyl, -cylopropyl, -benzyl, -phenylethyl and -aryl functionalities, could smoothly be transformed into the desired (4 + 2) annulation products under standard conditions (52–57). Besides acrylates and acrylamides, this method was successfully applied to other Michael acceptors resulting in the synthesis of various functionalized chromans (58–61). In order to demonstrate the potential applicability of this methodology, a variety of natural products, their derivatives and functional molecules, such as isoborneol (62), cedrol (63), citronellol (64), cholesterol (65), and dehydroabietylamine (66), were examined, and all these structures could be embedded into target products in 56–70% yields.The (4 + 2) annulation protocol is not limited to the synthesis of chromans. Under standard conditions, the thiochromane derivative could be formed, although less efficiently (Scheme 4a). With curiosity, we tried to use the commercially available pinacol vinylboronate instead of acrylates for this transformation because of the widespread use of organoboron compounds in organic synthesis. The target compound 2-(2,2-dimethylchroman-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, which is a versatile building block in functionalization of chromans, was obtained in 48% yield under the slightly revised conditions (Scheme 4b). It is noting that the reaction could be conducted smoothly to afford 60% yield under sunlight irradiation, showing the potential of industrial application (Scheme 4c). Furthermore, the versatility of chroman 1 was also explored. The oxidative dehydrogenation process of 1 led to the formation of value-added ethyl 2,2-dimethyl-2H-chromene-4-carboxylate 69 by using DDQ as the oxidant (Scheme 4d). 1 could also be reduced to (2,2-dimethylchroman-4-yl)methanol 70 with lithium aluminum hydride in ethyl ether (Scheme 4d).Open in a separate windowScheme 4The synthetic applications. (a) The synthesis of thiochromane. (b) Pinacol vinylboronate as a substrate. (c) Sunlight condition. (d) The derivatization of products.To further gain mechanistic insights into this process, a series of experiments were conducted. When the model reaction was performed under standard conditions but in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a radical scavenger, the target product was not detected (Scheme 5a). Notably, when butylated hydroxytoluene (BHT) was added to this reaction system, the annulation reaction was significantly suppressed, meanwhile, a coupling product was detected by GC-MS and HRMS (Scheme 5b). These results indicated a radical-involved pathway for this transformation. Subsequently, the carbon radical was captured by an intramolecular aromatic ring, giving the cyclization product 69 in excellent yield (Scheme 5c). Moreover, the intermolecular kinetic isotope effect (KIE) experiment was carried out by using A and A-d5 as competitive substrates. Under standard conditions, a KIE value of 1.05 was observed, indicating that the cleavage of the aromatic C–H bond might not be the rate-determining step in the transformation (Scheme 5d).Open in a separate windowScheme 5The control experiments. (a) The addition of TEMPO. (b) The addition of BHT. (c) Intramolecular reaction. (d) KIE experiment.On the basis of the above experimental results, we proposed a possible mechanism cycle for the reaction, as shown in Scheme 6. Initially, the photocatalyst Eosin Y (EY) was transformed into the excited species EY* (E_1/2[EY˙⁺/EY*] = −1.1 V vs. SCE) under the irradiation with visible light. As a redox-active species, EY* was able to reduce N-hydroxyphthalimide ester (E_1/2[A/I] = −0.8 V, see the CV in the ESI^†) via a single-electron-transfer (SET) process, generating the EY˙⁺ radical cation and the corresponding N-hydroxyphthalimide ester radical anion I. The intermediate I underwent rapid homolytic fragmentation to generate carbon-centered nucleophilic radical II by releasing the phthalimide anion and carbon dioxide. Subsequently, the carbon radical II was captured by ethyl acrylate to form the electrophilic radical III, which underwent rapid intramolecular radical cyclization to afford aryl radical IV. Then, the intermediate IV was converted into cation Vvia a SET oxidation. On the other hand, the EY˙⁺ radical cation was transformed into Eosin Y to accomplish the photocatalytic cycle. The rapid deprotonation of V leads to the formation of the product 1.Open in a separate windowScheme 6Proposed reaction mechanism.     

Electrification of a Milstein-type catalyst for alcohol reformation

Novel energy and atom efficiency processes will be keys to develop the sustainable chemical industry of the future. Electrification could play an important role, by allowing to fine-tune energy input and using the ideal redox agent: the electron. Here we demonstrate that a commercially available Milstein ruthenium catalyst (1) can be used to promote the electrochemical oxidation of ethanol to ethyl acetate and acetate, thus demonstrating the four electron oxidation under preparative conditions. Cyclic voltammetry and DFT-calculations are used to devise a possible catalytic cycle based on a thermal chemical step generating the key hydride intermediate. Successful electrification of Milstein-type catalysts opens a pathway to use alcohols as a renewable feedstock for the generation of esters and other key building blocks in organic chemistry, thus contributing to increase energy efficiency in organic redox chemistry.

Electrification of the Milstein catalyst enabled successful molecular electrocatalytic oxidation of ethanol to the four-electron products acetate and ethyl acetate.

In order to achieve the goals of the Sustainable Development Scenario (SDS) of the International Energy Agency, the chemical industry''s emission should decline by around 10% before 2030.^1,2 This could be achieved by increasing energy efficiency and the usage of renewable feedstocks. In this respect, molecular electrocatalytic alcohol oxidation could be powerful tool by potentially providing energy and atom efficiency for organic synthesis and energy applications.^2–7 Besides the use of aminoxyl-derivatives,^8–13 especially the seminal work of Vizza, Bianchini and Grützmacher demonstrated that (transfer)-hydrogenation (TH) catalysts could be activated electrochemically and used in a so-called “organometallic fuel cell”.¹⁴ Other TH systems are however mostly limited to two electron oxidations of secondary or benzylic alcohols (Scheme 1A).^15–21Open in a separate windowScheme 1(A) Advantages/limitation of electrochemical homogeneous alcohol oxidation using well-defined catalysts. (B) Current efforts to electrify acceptor-less alcohol dehydrogenation (AAD) systems due to their large range of application in thermal catalysis.As an exception, Waymouth et al. recently reported an example of the intramolecular coupling of vicinal benzylic alcohols to the corresponding esters.^19,22 In order to extend the range of possible catalysts candidates, the Waymouth group recently also explored the possibility to use an iron-based acceptor-less alcohol dehydrogenation (AAD) catalysts²³ for electrocatalytic alcohol oxidation (Scheme 1B).²⁴ The stability under electrochemical conditions in this case is limited to <2 turnovers, but it opens the door to explore a wide range of AAD reactions under electrochemical conditions. Here, we demonstrate that a commercially available Milstein-type AAD catalyst (1)²⁵ is competent for the electrocatalytic alcohol oxidation of ethanol to ethyl acetate and acetate (Scheme 1B).The cyclic voltammogram (CV) of complex 1 (Fig. 1) shows a quasi-reversible diffusive one electron oxidation wave at 0.2 V (all potentials are referenced vs. Fc⁺/Fc⁰) in 0.2 M NaPF₆ THF/DFB (2 : 1) (DFB = 1,2 difluoro benzene) assigned to the Ru(ii)–Ru(iii) couple (see ESI, section 2.2^†). The addition of 1 to a 10 mM sodium ethoxide (NaOEt) solution in 200 mM ethanol (EtOH) in 0.1 M NaPF₆ (2 : 1 THF/DFB) gives rise to several waves at ca. −0.5, 0.0 and 0.2 V with currents significantly higher than in the absence of catalysts or substrate, indicative of possible catalytic turnover (Fig. 2). Gradual increase of the EtOH concentration from 200 mM to 1 M is accompanied by the disappearance of the first wave at −0.5 V, while a new oxidation wave appears at ca. −0.25 V (Fig. 2, light to dark green traces).Open in a separate windowFig. 1Scan rate dependence of a 1 mM solution of 1 in in 2 : 1 THF/DFB + 0.2 M NaPF6 (from light to dark green: 0.05, 0.1, 0.2, 0.3, 0.4 and 0.5 V s⁻¹, 3 mm GC electrode). Inset: evolution of the peak current as a function of the square root of the scan rate.Open in a separate windowFig. 2CVs of 10 mM NaOEt (grey) and of 5 mM 1 + 5 mM NaOEt with increasing concentrations of EtOH (from light to dark green: 200, 400, 600, 800 and 1000 mM) in 2 : 1 THF/DFB + 0.2 M NaPF₆. Scan rate 0.1 V s⁻¹, electrode: 3 mm diameter GC electrode.Increasing the base loading gradually from 5 to 20 mM yields a stark increase of current at this new wave at ca. −0.25 V (Fig. 3). Using (TBA)PF₆ instead of NaPF₆ (used to avoid Hofmann-elimination²⁶) gave similar results (see ESI, section 2.2–2.5 and section 4^†). In order to assess catalytic turnover under preparative conditions, controlled potential electrolysis (CPE) was performed. CPE experiments were run in pure ethanol (to reduce cell resistance) in the presence of 0.1 M electrolyte of well soluble bases (e.g. NaOEt, LiOH, see ESI section 4^†). CPE in 0.1 M LiOH with 1 mM 1 at E = 0 V vs. Fc^0/+ delivered ca. 15 mM of acetate and 6 mM of ethyl acetate, corresponding to 21 turnovers (per 4 electrons, or 42 turnovers per two electrons) and a faradaic efficiency (FE) of ca. 62% (see ESI section 4.3^†). In the absence of applied potential (OCP, open circuit potential), no ethyl acetate was formed (see ESI, section 4.4^†). Likewise, in the absence of catalyst, the passed charge was significantly lower (7C vs. 40C) with no detected formation of ethyl acetate. The low FE could be due to catalyst degradation, as Ru-nanoparticle formation is observed on the electrode post CPE (confirmed by SEM/Elemental mapping, see ESI section 5^†). Noteworthy, rinse-test CPE and a CPE using a simple Ru-precursor, RuCl₃, did not show any ethyl acetate formation and gave similar results to blank experiments, indicating that Ru-nanoparticles are probably not the active catalyst species and that catalyst instability could be responsible for low FE. Further studies are underway to fully understand catalyst speciation under preparative conditions (see ESI section 4.7^†) the observed catalytic activity of 1 compares well in terms of TON and product selectivity with other molecular homogeneous TH systems, with most systems being limited to the two-electron oxidation of secondary or benzylic alcohols. The Waymouth group reported a NNC ruthenium pincer for the oxidation of isopropanol to acetone with a TON of 4.¹⁸ The same group reported on the usage of phenoxy mediators with an iridium pincer complex, reaching a TON of 8 for the same reaction.²² Bonitatibus and co-workers demonstrated the activity of an iridium-based systems with a TON of 32 for the formation of p-benzaldehyde.¹⁷ Appel and co-workers reported on a nickel (TON = 3.1)¹⁵ and a cobalt triphos systems (TON = 19.9)¹⁶ for benzaldehyde formation from benzyl alcohol. To the best of our knowledge, there is only one acceptor-less alcohol dehydrogenation (AAD) catalyst that has been activated electrochemically so-far,²⁴ generating acetone with a TON <2. Only a handful of molecular systems are known to catalyze the electrochemical four electron alcohol reformation to esters, however at significantly higher potentials (1.15 V vs. Fc⁺/Fc⁰).^2,27,28 Thus, although not designed for electrochemical applications, 1 shows high activity for the challenging 4 electron oxidation of aliphatic substrates.Open in a separate windowFig. 3CV of 5 mM NaOEt (grey), 5 mM of 1 + 1 M EtOH with varying concentrations of base (5, 10, 15, and 20 mM NaOEt, light to dark green) in 2 : 1 THF/DFB + 0.2 M NaPF₆. Scan rate 0.1 V s⁻¹, electrode: 3 mm diameter GC electrode.To achieve the transposition from thermal to electrochemical TH, both Grützmacher et al. and Waymouth took advantage of a fast equilibrium between the alcohol substrate and a metal hydride intermediate that could be readily oxidized. The chemistry of ruthenium pincer AAD systems is well studied (Scheme 2)^25,29–33 and allows for a putative assignment of the observed CV-behavior. In the presence of excess base and alcohol (Fig. 2 and ​and3),3), 1 is expected to yield dearomatized complex 2,²⁵ as well as the alkoxide species 3.^25,32 We might therefore assign the first wave at −0.5 V to the oxidation of dearomatized complex 2 and the wave around 0 V to the oxidation of the alkoxide complex 3. Indeed, independently synthesized samples of 2 and 3 (in the presence of excess ethanol) give rise to oxidation half-waves at −0.45 V and −0.1 V respectively (see ESI, section 3 and 5.2^†). This is also in agreement with the observed behavior upon increasing the alcohol concentration with the expected consumption of dearomatized species 2 and concomitant disappearance of the first oxidation wave at −0.5 V. The equilibrium between 2, 3 and 4 has been reported³² and addition of excess ethanol to 2 is thus not only generating 3, but also is expected to deliver 4 (Scheme 2). The appearance of a new anodic wave at ca. −0.25 V (Fig. 2) is thus attributed to the increasing formation of 4 upon addition of larger amounts of EtOH. Complex 4 is relatively unstable in solution,^25,32,33 and decomposes in the presence of electrolyte (see ESI section 3.1^†). DFT calculations were thus used to predict its oxidation potential (see ESI, section 6^†), which was in reasonable agreement with the observed wave (−0.19 V). The DFT calculations also confirmed the assignment of the other waves related to the dearomatized complex 2 (−0.33 V) and the ethoxide species 3 (−0.1 V). A more detailed mechanistic analysis remains currently hampered by the chemical instability of 4 under the employed reaction conditions, as well as difficulties to isolate 3 in the solid state (limiting kinetic measurements). DFT calculations were thus used to get a better view on possible reaction pathways (Schemes 2, ​,33 and ESI section 6.3^†). The oxidation of 4 at −0.19 V (DFT) yields the radical cation 5, with a calculated pK_a in THF of 8.2. In the presence of NaOEt, 5 should thus deprotonate readily to give radical 6, which has an extremely negative oxidation potential of −2.1 V. At the potential it is generated, 6 should thus directly be oxidized to cationic complex 7. This cationic species 7 has a calculated pK_a of 22.7 in THF, which is in good agreement with experimental data from the Saouma group on a similar system.²⁶ The high pK_a of 7 in THF also validates the need for a strong base (e.g. NaOEt) to reform dearomatized 2. Both Grützmacher and co-workers,¹⁴ as well as Waymouth²⁴ have noted that the accelerating effect during electrocatalysis stems from the oxidation of a metal hydride intermediate that is generated by fast chemical steps. In order to verify this hypothesis and to exclude an electrochemical activation of this hydride formation step, transition state barriers were computed (Scheme 3). Taking the dearomatized complex 2 as a reference point, a first step will form the alkoxide species 3 (TS₀ = 21.2 kcal mol⁻¹). Oxidizing 2 to 8 slows down the formation of the alkoxide species (T_S0^ox = 27.5 kcal mol⁻¹), most-likely due to decreased basicity of the ligand. From the alkoxide species 3 dihydride 4 is formed via a linear, charge-separated transition state TS₁ (15.7 kcal mol⁻¹). The role of such linear transition states was highlighted recently in the case of ruthenium pincer catalysis for alcohol oxidation.^34–37 In principle, it might be envisioned that the oxidation of the metal center could be an additional driving force for this hydride abstraction step. However, after oxidation, the energy span^38,39 rises by about 11 kcal mol⁻¹ (TS₁^ox = 24.7 kcal mol⁻¹). Likewise, a beta-hydride elimination via side-arm opening is not accelerated either by oxidation (TS₂^ox = 37.5 kcal mol⁻¹, see ESI section 6.4^†). It thus seems that the generation of 4 is not accelerated by electron transfer steps and relies on a thermally activated chemical step. Importantly, alkoxide solutions were shown to be excellent hydride donors electrochemically, further corroborating that under the employed basic conditions, generation of 4 from 3 should be fast.⁴⁰ Oxidation of 4 to 5 also doesn''t accelerate thermal intramolecular release of H₂ (TS_3B^ox = 37.5 kcal mol⁻¹), which is significantly higher than neutral thermal H₂-releasing states (TS_3A and TS_3B). The experimentally observed acceleration via electron-transfer is thus proposed to follow a classical ECEC mechanism initiated by the oxidation of 4 to 5 (at roughly −0.19 V (DFT)), followed by deprotonation and re-oxidation as described above, finally delivering 2 at the electrode surface. Importantly, at the electrode surface 2 and 3 should be oxidized at the employed potentials, but based on DFT-calculations, these pathways are thought to be non-productive (Scheme 3) and could explain the low catalyst life-time and degradation under electrochemical conditions.Open in a separate windowScheme 2Reactivity of pyridine-based ruthenium complexes via dearomatization/aromatization, as well as DFT-based.Open in a separate windowScheme 3DFT-calculated energy landscape for the neutral (black dotted lines and bars) and cationic surface (blue dotted lines and bars) of ethanol dehydrogenation starting from 2 or its cationic analogue 8.     

Decoded fingerprints of hyperresponsive,expanding product space: polyether cascade cyclizations as tools to elucidate supramolecular catalysis

Simple enough to be understood and complex enough to be revealing, cascade cyclizations of diepoxides are introduced as new tools to characterize supramolecular catalysis. Decoded product fingerprints are provided for a consistent set of substrate stereoisomers, and shown to report on chemo-, diastereo- and enantioselectivity, mechanism and even autocatalysis. Application of the new tool to representative supramolecular systems reveals, for instance, that pnictogen-bonding catalysis is not only best in breaking the Baldwin rules but also converts substrate diastereomers into completely different products. Within supramolecular capsules, new cyclic hemiacetals from House–Meinwald rearrangements are identified, and autocatalysis on anion–π catalysts is found to be independent of substrate stereochemistry. Decoded product fingerprints further support that the involved epoxide-opening polyether cascade cyclizations are directional, racemization-free, and interconnected, at least partially. The discovery of unique characteristics for all catalysts tested would not have been possible without decoded cascade cyclization fingerprints, thus validating the existence and significance of privileged platforms to elucidate supramolecular catalysis. Once decoded, cascade cyclization fingerprints are easily and broadly applicable, ready for use in the community.

Hyperresponsive XL product space identifies polyether cascade fingerprinting as an attractive tool to elucidate supramolecular catalysis, including pnictogen-bonding, capsule and anion–π catalysts.

One general expectation from supramolecular catalysis^1–10 is that new ways to interact will provide new ways to transform on the molecular level. This translates to access to new reactivity and products, at best contributing to new solutions for otherwise persistent challenges in science and society. While these high expectations are attracting attention to the development of supramolecular catalysts, their systematic characterization is much less advanced. Most classical and modern benchmark reactions^1,9 are limited to one mechanism and cover little product space, also concerning chemo- and stereochemistry. To maximize the comparability of supramolecular catalysts, the ideal reaction would respond to as many parameters as possible at still manageable complexity. Epoxide opening polyether cascade cyclizations^10–13 promise to meet these requirements for a privileged platform to evaluate supramolecular catalysts. Charismatic in chemistry and biology, they have attracted the attention of many giants in the field.¹¹ They afford the largest polycyclic natural products, regularly featuring more than 10 rings made in one cascade. While product diversity of longer cascades is too complex and single cyclizations are too simple, minimalist cascades from diepoxide substrates such as 1 cover large structural space at tractable complexity (Fig. 1). In substrate 1, supramolecular catalysts can activate nucleophile, electrophile and leaving group, and stabilize cationic and anionic transition states and reactive intermediates (Fig. 1a). Cyclizations can follow either the 5-exo-tet selectivity predicted by the Baldwin rules (B) or anti-Baldwin (A) 6-endo-tet selectivity, leading to the four constitutional isomers 2–5 (Fig. 1a and ​and2).2). They can occur with normal or reverse directionally,¹² forming ring 1 or ring 2 first, respectively (Fig. 1b). They can operate with pseudo S_N2, S_N1, or mixed mechanisms, and can integrate contributions from autocatalysis.^10,13 The stereochemistry covers cis–trans isomers at epoxide 1 and syn–anti isomers with regard to the two epoxides (Fig. 1c). This translates to the stereochemistry of products such as 2–5 at the ring junction and the exocyclic substituents of ring 2. Besides this expected diversity, the product space of the privileged substrate 1 further expands into structures that remain to be discovered, as demonstrated with two new products reported in this study.Open in a separate windowFig. 1(a) Epoxide-opening ether cascade cyclizations from diepoxide 1 as privileged platform to elaborate on supramolecular catalysis, with indication of possible contributions from electron-donating (red) and electron-accepting catalyst motifs (blue), exo-tet Baldwin (B) or endo-tet anti-Baldwin (A) chemoselectivity, (b) normal and reverse directionality, and (c) stereochemistry in selected substrates and products.Open in a separate windowFig. 2(a) Decoded product fingerprints for selected catalysts: Color-coded pie charts for products 2 (red), 3 (yellow), 4 (green), 5 (blue), 6 and 7 (teal) obtained from stereoisomers of cis and trans substrate isomers 1 with representative supramolecular catalysts 8–10 compared to general Brønsted acid (AcOH); results for cis,anti and trans,syn isomers of 1 are calculated (from data for the other diastereomer and the mixture of diastereomers in the respective series); estimated errors ± 5%. (b) Experimental results for cis,anti-1 cyclized with catalyst 9. (c) Selected X-ray structures from the BA series (p-bromobenzoyl derivatives). (d) Structure of catalysts, with indication of selected π-basic surfaces and hydrogen-bond donors on capsule 8 assembled from monomers 11, the cyclopean σ hole of pnictogen-bonding catalyst 9, and the π-acidic surface on anion–π catalyst 10.So far, substrate 1 has been used as a mixture of stereoisomers to characterize supramolecular catalysts.¹³ While results were intriguing, they could not be rationalized. Overlap of different trends obscured the key information and made product fingerprints dependent on the composition of the substrate mixtures. However, the observed hyperresponsiveness of the large product space suggested that decoded product fingerprints could provide a general tool to elucidate supramolecular catalysis.To assess the possibly privileged nature of diepoxide 1 as unifying substrate for supramolecular catalysis, we decided to synthesize and evaluate the necessary stereoisomers separately. The stereoisomers cis-1 and trans-1 were prepared by oxidation of the respective silyl protected cis- and trans-olefins with m-CPBA (meta-chloroperoxybenzoic acid), followed by deprotection (Fig. 2, Schemes S1 and S2^†). They were obtained as roughly equimolar mixtures of syn- and anti-diastereomers (cis-1: dr 54 : 46, trans-1: dr 50 : 50). Shi epoxidation¹⁴ in place of m-CPBA afforded enantioenriched cis,syn-1 (dr 89 : 11; dr 20 : 1 after purification) and trans,anti-1 (dr 82 : 18; dr 20 : 1 after purification) accordingly with unknown absolute configuration. These four substrates were sufficient to realize the complete analysis of the system because the product fingerprints for the remaining diastereomers cis,anti-1 and trans,syn-1 could be obtained from the difference of cis,syn-1 and trans,anti-1 and the respective mixture of diastereomers cis-1 and trans-1 (Fig. 2).To decode product fingerprints from different catalysts in their respective color-coded pie charts, all individual products were isolated and the diagnostic regions of their ¹H NMR spectra and chiral GC traces were assembled for direct comparison (Fig. 3). In most GC traces, the two peaks were well resolved for each pair of enantiomers, confirming access to nearly all stereochemical information. The resulting unified fingerprint of the complete system then allowed to rapidly assign products obtained from different catalysts down to the level of enantiomers. The validity of most structures was confirmed by X-ray crystallography (Fig. 2c and S78–S83^†). If necessary, derivatives were prepared to facilitate the growth of single crystals.Open in a separate windowFig. 3Decoded product fingerprints: Diagnostic regions of ¹H NMR spectra (a and b) and chiral GC (c and d) of purified cascade cyclization products from cis (a and c) and trans (b and d) substrate isomers 1 above representative examples of mixtures produced by AcOH and 9 combined (a and c), and by 8 (b and d).With the analytics in place, product fingerprints were recorded for representative supramolecular catalysts 8–10 in comparison to general Brønsted acid catalysis (Fig. 2). In the cis series, the product mixtures obtained from different catalysts contained all four constitutional isomers expected from Baldwin and anti-Baldwin cyclizations, that is cis-(BB)-2, cis-(BA)-3, cis-(AB)-4 and cis-(AA)-5 (Fig. 2a and ​and3a).3a). In contrast, trans-(AB)-4 was absent in the trans series, and two new products 6 and 7 were found instead (vide infra, Fig. 2a and ​and3b3b).In both the cis and the trans series, general Brønsted acid catalysis with AcOH was confirmed to follow the Baldwin rules almost exclusively, affording mostly (BB)-2 (Fig. 2). In the cis series, the supramolecular capsules 8 violated the Baldwin rules significantly (Fig. 2a). Capsules 8 self-assemble from resorcinarenes 11 and water (Fig. 2d).^3,4 Their internal surface offers hydrogen-bond donors and π-basic aromatic planes for catalysis within their confined interior.^3,4 Unique selectivities have been reported, also for bioinspired terpene cyclizations, for instance.⁴ From cascade cyclization with the mixture of cis-1 diastereomers in capsules 8, cis-(BA)-3 was obtained as the main product besides the still preferred cis-(BB)-2 (Fig. 2a). The pure cis,syn-1 showed a clearly different product distribution, characterized by an increased power to violate the Baldwin rule in cycle 2, affording cis-(BA)-3 as the main product. The calculated fingerprint for the products of cis,anti-1 gave the complementary dominance of the Baldwin conformant cis-(BB)-2 instead.Differences in selectivity for the syn- and anti-diastereomers in the cis series were most spectacular with the pnictogen-bonding catalyst 9 (Fig. 2a). Pnictogen-bonding catalysis has been introduced recently^5–7 for consideration as the non-covalent counterpart of Lewis acid catalysis, analogous to hydrogen-bonding catalysis as non-covalent counterpart of Brønsted acid catalysis.⁷ Catalyst 9 is centered around an antimony V with one deep σ hole acting as pnictogen-bond donor to initiate catalysis.⁷ Catalyst 9 has been shown previously to efficiently break the Baldwin rules in polyether cyclizations.^7,13 In the newly devised pie chart fingerprint, orthodox cis-(BB)-2 was indeed essentially absent (Fig. 2a). The mixture of diastereomers cis-1 afforded cis-(BA)-3 and cis-(AB)-4 as main products. In sharp contrast, diastereo-pure cis,syn-1 gave mostly cis,syn-(BA)-3. As a consequence, the calculated product fingerprint of cis,anti-1 showed the highly selective formation of cis,anti-(AB)-4.Selective access to cis,anti-(AB)-4 with pnictogen-bonding catalyst 9 was remarkable because none of the other stereoisomers of (AB)-4 were observed throughout the study (Fig. 3a and ​and4a).4a). Exclusive access to cis,anti-(AB)-4 from cis,anti-1 was understandable considering cascade cyclization with normal directionality (Fig. 1). Namely, the endo-tet cyclization of ring 1 will afford the reactive intermediate III (Fig. 4b). From this intermediate III, the exo-tet Baldwin conformant formation of ring 2 is possibly supported by an intramolecular hydrogen bond (Fig. 4b and c, arrows), which activates the nucleophile and places an epoxide in an equatorial position.Open in a separate windowFig. 4(a) The formation of only one out of four possible (AB) isomers 4 and (b) the origin of the selectivity and products found in the anti-Baldwin series with capsule 8 and pnictogen-bonding catalyst 9, with (c) selected X-ray structures.These favorable conditions to access cis,anti-(AB)-4 from cis,anti-1 contrasted sharply with the situation with all other diastereomers. In the cis series, access to the complementary cis,syn-(AB)-4 from cis,syn-1 is disfavored although the nucleophile in the reactive intermediate IV remains possibly activated by intramolecular hydrogen bonding. However, the axial orientations of epoxide in intermediate IV and a very bulky tertiary alcohol in product 4 make this reaction unlikely.With cis,syn-(AB)-4 from cis,syn-1 unfavorable, reactive intermediate IV obtained from an anti-Baldwin cyclization of ring 1 needs an alternative solution. An obvious choice is continuation with another endo-tet anti-Baldwin cyclization for ring 2 to result in cis,syn-(AA)-5 with a more flexible cis-fused oxepane ring. This cis,syn-(AA)-5 was indeed part of the product fingerprint of cis,syn-1 cyclized with pnictogen-bonding catalyst 9 (Fig. 2a). The markedly different amounts of cis,syn-(AA)-5 and cis,anti-(AB)-4 obtained from cis,syn-1 and cis,anti-1, respectively (Fig. 2a), would then suggest that normal cascade cyclizations are interconnected, possibly concerted (Fig. 1b).The differences of the selectivity of the cascade cyclization of cis,syn-1 and cis,anti-1 with pnictogen-bonding catalyst 9 (Fig. 2a) and the importance of the implications called for the experimental validation of the calculated results for cis,anti-1. Therefore, pure diastereomer cis,anti-1 was prepared and cyclized using catalyst 9. The experimental product fingerprint was very similar to the calculated one, confirming the unique cis,anti-(AB)-4 as the main product of the reaction (Fig. 2b). This results also validated the use of calculated data to decode complex product fingerprints completely.In the trans series, pnictogen-bonding catalyst 9 again broke the Baldwin rules most efficiently (Fig. 2a). For all diastereomers, trans-(AA)-5 was observed as the main product with more than 75% yield. This exceptional selectivity was understandable considering the reactive intermediates V and VI after the endo-tet cyclization of ring 1 (Fig. 4b). Contrary to intermediates III and IV in the cis series, the methyl substituent at the ring junction is in axial position also with regard to ring 2. 1,3-Diaxial interactions of the approaching electrophile with this methyl thus hinder the formation of this ring 2 by an exo-tet cyclization. Presumably for this reason, the trans-fused bis-oxane products trans,anti-(AB)-4 and trans,syn-(AB)-4 were not observed. With Baldwin cyclizations hindered, endo-tet anti-Baldwin cyclizations occurred instead to afford the respective trans,anti-(AA)-5 and trans,syn-(AA)-5 with very high selectivity (Fig. 2a).The supramolecular capsules 8 applied to the trans series yielded two new products 6 and 7 (Fig. 2). Product 6 was identified by 2D NMR spectroscopy to be a hemiacetal cyclized on an anti-Baldwin ring 1 (Fig. S72^†). It exists in equilibrium with the open ketone form 12, which results in dynamic epimerization at the “anomeric center” (Fig. 2 and ​and4).4). Derivatization of hemiacetal 6 with aromatic hydrazines gave the respective hydrazones (Fig. S76 and S77^†). Product 7 was identified as an acyclic allyl alcohol extending from an anti-Baldwin ring 1 (Fig. 2 and S73–S75^†). Both new products might originate from intermediate VII, which is generated from substrate 1 by endo-tet cyclization of ring 1 and the opening of epoxide 2 to afford the tertiary carbocation (Fig. 4b). From intermediate VII, the formation of allyl alcohol 7 only requires a proton abstraction from one of the two adjacent methyl groups. Ketone 12 originates from the same intermediate VIIvia House-Meinwald rearrangement,¹⁵ that is a 1,2-hydride shift. Similar processes might occur with trans-diepoxide 1 to give an alternative cationic intermediate VIII, which can proceed through reverse cyclization (Fig. 1b) to give products 6 and 7. Stabilization of carbocations via cation–π interactions is a distinct feature of this type of capsules.^3,4The formation of these two new products in capsule 8 could be understood considering the inaccessibility of both AB products in the trans series, i.e., trans,syn-(AB)-4 and trans,anti-(AB)-4, with the explored catalysts (Fig. 4a). As already mentioned, the anti-Baldwin cyclization from trans,anti-1 and trans,syn-1 into intermediates V and VI with ring 1 is unproblematic, whereas continuation with exo-tet Baldwin cyclization of ring 2 is hindered by an axial methyl and, compared to the cis series, missing intramolecular activation of the nucleophile (Fig. 4b). With pnictogen-bonding catalyst 9, the solution was an alternative endo-tet anti-Baldwin cyclization into the trans-fused AA products 5, as discussed above (Fig. 2a and ​and4b).4b). In capsule 8, this endo-tet anti-Baldwin continuation of the cascade was not favorable. The reason for this distinctive selectivity within capsule 8 remains to be explored. In contrast to the other catalysts, the capsule may be able to stabilize cation VII better due to cation–π stabilization, making this pathway accessible.While the new oxanes 6 and 7 were obtained as main products from trans,anti-1 and trans,syn-1 with similar yields, the composition of the side products differed in the respective fingerprints (Fig. 2a). Cyclization of trans,syn-1 gave trans-(BB)-2 as the main side product, while trans,anti-1 gave trans,anti-(AA)-5 as the main side product. This difference was of interest because it could support that the cascade cyclizations might be interconnected, possibly concerted, at least in the present context.While capsules 8 excelled with access to new products in the trans series and pnictogen-bonding catalysts 9 with unique AB-BA selectivity on the level of diastereomers in the cis series, anion–π catalysts gave mostly Baldwin products like general Brønsted acid catalysis, independent of the stereochemistry of substrate 1 (Fig. 2). The largest deviation from Brønsted acid catalysis occurred with cis,anti-1, which gave a substantial percentage of cis-(BA)-3 and also a small amount of cis-(AB)-4 (Fig. 2a). The same trend, but less pronounced, was noted with the complementary trans,anti-1, which produced also small amounts of trans-(BA)-3 and trans-(AA)-5, formed instead of the inaccessible trans-(AB)-4 (see above, Fig. 2a).After investigation for anion transport, anion–π interactions have been introduced to catalysis in stabilizing anionic transition states on π-acidic surfaces.^8,10 Over the past decade, catalysts from hexafluorobenzene to π-stacked foldamers, fullerenes, carbon nanotubes, artificial enzymes have been applied to many reactions, including enolate, enamine, imine, Diels–Alder chemistry.⁸ Polyether cyclizations have been introduced as a cascade transformation that should benefit best from the delocalized nature of anion–π interactions.¹⁰ On π-acidic surfaces, polyether cyclizations were autocatalytic,¹⁰ a unique emergent property that has not been observed in the many studies with systems without anion–π interactions.¹¹With the privileged probe for supramolecular catalysis envisioned in this study, it was thus most interesting to assess the dependence of autocatalysis on the stereochemistry of the substrate. Significant dependence was conceivable considering the different products obtained from diastereomers of cis-1 with pnictogen-bonding catalyst 9 (Fig. 2a). Kinetics of all four test substrates converted with anion–π catalyst showed autocatalytic behavior (Fig. 5a and b). Moreover, autocatalysis was nearly independent of the stereochemistry of the substrate. This absence of diastereoselective autocatalysis was consistent with the computed model for transition-state stabilization by the product, and could explain why it is so difficult to achieve asymmetric autocatalysis on anion–π catalyst 10.¹³ Control experiments confirmed that general Brønsted acid catalysis does not show autocatalytic behavior, independent of the stereochemistry of substrate 1 (Fig. 5c and d).Open in a separate windowFig. 5Kinetics of the conversion of cis-1 (a and c, circles), cis,syn-1 (a and c, squares), trans-1 (b and d, circles) and trans,anti-1 (b and d, squares) with (a and b) anion–π catalyst 10 (10 mol%, rt) and (c and d) AcOH (500 mol%, 40 °C) in CD₂Cl₂, with hypothetical intermediate IX for autocatalysis on π-acidic surfaces.Taken together, the decoding of product fingerprints for cascade cyclizations that are simple enough to be tractable and complex enough to be interesting affords a privileged platform to characterize supramolecular catalysis. It is highly responsive to as many characteristics as possible, thus reporting on as many distinct advantages of the catalytic system as possible. The minimal substrate toolbox contains cis and trans di-epoxides as mixtures of syn–anti diastereomers, and at least one pure diastereomer. Most pairs of enantiomers are resolved in the chiral GC fingerprints. Applied to three model catalysts in comparison to general Brønsted acid catalysis, distinct fingerprints were found for all catalysts as well as for all different diastereomers of the substrate.In the cis series, most significant selectivity was observed with pnictogen-bonding catalysts, which give the unique AB product for anti and the more frequent BA product for the syn diastereomer of the diepoxide substrate with remarkably high selectivity. In the trans series, pnictogen-bonding catalysts broke the Baldwin rules most efficiently and independent of substrate stereochemistry, while within supramolecular capsules, completely new products were formed, including an interesting House–Meinwald rearrangement leading to cyclic hemiacetals. These distinct selectivities can be understood from the nature of the reactive intermediates. Together with particularly revealing details in the decoded product fingerprints, experimental support is obtained that the cascades are interconnected, possibly concerted. In clear contrast, anion–π catalysts gave mostly Baldwin products with fingerprints similar to general Brønsted acids. However, they showed unique autocatalytic behavior, a distinct emergent property that was independent of the stereochemistry of the substrate. All these distinctive characteristics found for representative supramolecular catalysts would be missed without the availability of decoded product fingerprints.These results thus validate the existence and significance of privileged substrate systems as general chemistry tools to characterize supramolecular catalysis. Once established, decoded polyether cascade fingerprints are very easy to use, ready to serve the community. For a new supramolecular catalyst to be characterized, the decoded fingerprints will reveal unique differences compared to controls. Importantly, because the system is hyperresponsive (Fig. 1a and ​and2a),2a), differences will be magnified. Due to the complexity required for hyperresponsiveness, the correlation of the fingerprint with the reactivity of a new catalyst will be mostly tentative and empirical at this point. For instance, AcOH-like fingerprints should reflect activation of epoxide opening to release the intramolecular leaving group, possibly supported by activation of the nucleophile as for autocatalysis on 10 (Fig. 5, IX). Fingerprints with more or even mostly A products should correlate with increasing S_N1-like behavior. However, the generation of mostly B products with AcOH implies that the activation of epoxide opening needs to be supported by stabilization of the resulting carbocation with, e.g., cation–π interactions to afford A products. With pnictogen-bonding catalyst 9, this would be meaningful on the π-basic tetrachlorocatecholate plane next to the σ hole stabilizing the alcoholate (Fig. 2d). In fingerprints with the new HM-rearrangement products, so far unique for capsules 8, the existence of carbocation intermediates is experimentally confirmed and thus presumably most relevant, due to cation–π interactions, confinement effects, or both. From here, with the system trained with more and more fingerprints, the correlation of fingerprint with mechanism of a new catalyst should become increasingly informative. Sooner or later, this will enable high-level computational simulations at high confidence,⁷ which in turn will enhance the information on reactivity available from fingerprints of new catalysts. According to preliminary results on the difference between pnictogen-bonding and Lewis acid catalysis⁷ and the elucidation of more complex supramolecular systems,¹⁶ these future perspectives are most promising.     

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

Correction: In situ monitoring of functional activity of extracellular matrix stiffness-dependent multidrug resistance protein 1 using scanning electrochemical microscopy

Correction for ‘In situ monitoring of functional activity of extracellular matrix stiffness-dependent multidrug resistance protein 1 using scanning electrochemical microscopy’ by Shuake Kuermanbayi et al., Chem. Sci., 2022, https://doi.org/10.1039/d2sc02708a.

The authors regret that an incorrect version of Fig. 5f was included in the original article. This error does not affect the conclusions of the original article as the correct Fig. 5f also proves that there is no significant difference in the mRNA levels of MRP1 in the MCF-7 cells on the PA gels with three stiffness. The correct version of Fig. 5 is presented below.Open in a separate windowFig. 1(a and b) Immunofluorescence images and (c and d) the normalized total MRP1 intensities of (a and c) MCF cells and (b and d) MDA-MB-231 cells on the PA gels with stiffness of 2.5, 17.1 and 26.2 kPa, respectively (scale bar: 40 μm). (e) Western blot analysis of the MRP1 expressions of the MCF-7 and MDA-MB-231 cells on the PA gels with stiffness of 2.5, 17.1 and 26.2 kPa, respectively. (f and g) The relative MRP1 mRNA expressions in (f) the MCF-7 cells and (g) the MDA-MB-231 cells on the PA gels with stiffness of 2.5, 17.1 and 26.2 kPa, respectively.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

Correction: Biofunctional Janus particles promote phagocytosis of tumor cells by macrophages

Correction for ‘Biofunctional Janus particles promote phagocytosis of tumor cells by macrophages’ by Ya-Ru Zhang et al., Chem. Sci., 2020, 11, 5323–5327, https://doi.org/10.1039/D0SC01146K.

The authors regret an error in Fig. 4a, where two of the panels contain partial overlap.Open in a separate windowFig. 1Tf–SPA3–aSIRPα JMPs promote the interaction and subsequent phagocytosis of B16F10 cells by BMDMs. (A) Representative confocal images of phagocytosis assays treated with different formulations for 2 or 4 h, respectively. (B) Time-dependent of phagocytosis treated with Tf–SPA3–aSirpα JMPs. In (A) and (B), B16F10 cells were labelled with CFSE (green), BMDMs were labelled with eFluor 670 (red) and particles were labelled with RB (blue). Scale bar: 20 μm.The panels for 2 h SPA3 and 2 h Tf + aSIRPα + SPA3 contain overlap, as the wrong data was initially used for 2 h SPA3. An independent expert has viewed the new data and has concluded that it is consistent with the discussions and conclusions presented.The correct Fig. 4 is shown below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.     

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 ( EntryCat.BaseSolventYield1Ni(PPh₃)₂Cl₂Cs₂CO₃DMF67%2Pd(OAc)₂Cs₂CO₃DMF65%3Cu(OAc)₂Cs₂CO₃DMF65%4Co(OAc)₂Cs₂CO₃DMF63%5Cs₂CO₃DMF65%6KFDMFTrace7K₃PO₄DMFTrace8K₂CO₃DMF48%9KOHDMF52%10KO^tBuDMF46%11Et₃NDMFTrace12Cs₂CO₃CH₃CN18%13Cs₂CO₃DME23%14Cs₂CO₃TolueneTrace15Cs₂CO₃DCETrace16Cs₂CO₃DioxaneTraceOpen in a separate window^aReaction conditions: 1a (0.1 mmol, 1 equiv.), TMSCN (0.3 mmol, 3 equiv.), cat. (0 or 10 mol%), base (0.3 mmol, 3 equiv.) and solvent (1 mL), at 80 °C for 10 h; isolated yield.With the optimal reaction conditions in hand, we investigated the scope of this reaction. As shown in Fig. 2, the transformation tolerates a broad variety of substituted propargylamides (1). The R¹ group could be an aryl group containing either electron-donating groups or electron-withdrawing groups, and the corresponding products (2b–2h) were obtained in yields of 62–80%. The substituent R¹ could also be an alkyl group such as 1-hexyl in which case the reaction provided the corresponding pyrrole (2i) in 53% yield. Exploration of the R² substituent was also conducted. Electron-rich and electron-deficient substituents in the aromatic ring of R² gave the desired products (2j–2o) with yields of 70–81%. The product bearing a furyl group (2p) can be produced in 61% yield. However, when R² group is an aliphatic group, the reaction failed to provide the desired product. Substituent groups R³, such as benzyl (2q) or 3,4-dimethoxyphenylethyl (2r) were also compatible in the reaction, providing the corresponding products in moderate yields. Significantly, this method has the potential to produce core structures (for example 2s) similar to that in Atorvastatin. Interestingly, when alkynyl substituted isoquinolines (1t–1v) were used as the substrates, the reactions smoothly afforded fused pyrrolo[2,1-α]isoquinoline derivatives (2t–2v), members of a class of compounds that are found widely in marine alkaloids and exhibit anticancer and antiviral activity.¹⁸Open in a separate windowFig. 2Substrate scope of propargylamides. Reaction conditions: 1 (0.20 mmol, 1 equiv.), TMSCN (0.60 mmol, 3 equiv.), Cs₂CO₃ (0.60 mmol, 3 equiv.) and DMF (2 mL), at 80 °C for 10 h; isolated yield.Allenes are key intermediates in the synthesis of many complex molecules.¹⁹ As a subtype of allenes, allenamines are also useful as reaction intermediates.²⁰ Although the transformation of allenamides to multisubstituted pyrroles has not been previously recorded, this reaction probably goes through the allenamide intermediates which can be derived from propargyl sulfonamides under basic conditions. To verify this hypothesis, the trisubstituted allenamide (3) was synthesized and subjected to the standard reaction conditions. A pyrrole (2a) was isolated in 82% yield from this reaction (Fig. 3). This result confirmed our assumption and raised a new question: is it possible to build hexasubstituted pyrrolines from tetrasubstituted allenamides? A range of tetrasubstituted allenamides²¹ was tested under the standard reaction conditions, and the hexasubstituted pyrrolines were obtained as is shown in Fig. 4. The R¹ group could be an aryl substituent or an alkyl chain, and the corresponding products (5a–5e) were obtained with good yields. Various aryl groups with either electron-donating groups or electron-withdrawing groups in the aromatic ring of R² provided the desired products (5f–5k) in 62–83% yields. In addition, the difluoromethyl group can also be replaced by a phenyl group, and the reaction provided the corresponding product 5l in 82% yield. It is worth noting that these pyrroline products are not easily accessible from other methods.Open in a separate windowFig. 3Synthesis of substituted pyrroles from allenes.Open in a separate windowFig. 4Substrate scope of tetrasubstituted allenamides. Reaction conditions: 4 (0.10 mmol, 1 equiv.), TMSCN (0.30 mmol, 3 equiv.), K₂CO₃ (0.30 mmol, 3 equiv.) and DMF (1 mL), at 80 °C for 10 h, isolated yield.Some synthetic applications of this method are shown in Fig. 5. The amide is a naturally occurring and ubiquitous functional group. When using benzoyl chloride to protect the free amino group of the fully-substituted pyrrole (2a), a bis-dibenzoyl amide (6) was obtained in the presence of a base, triethylamine while the monobenzoyl protected amide (7) was obtained in the presence of pyridine as the base (Fig. 5a). This method also provides a straightforward approach to pyrrole fused lactam structures (Fig. 5b). For examples, a five-membered lactam and a six-membered lactam were generated separately in a one pot reaction, directly from, (8 and 10), respectively. Taking advantage of this method, an analogue of the drug Atorvastatin was synthesized in 5 steps (Fig. 5c), demonstrating the synthetic value of the reaction.Open in a separate windowFig. 5Synthetic applications.Mechanistic experiments were performed (Fig. 6) to explore the mechanism of the reaction. When 3 equivalents of TEMPO were added, the reaction was not inhibited and the desired product (2a) was formed in 62% yield (Fig. 6a). This result suggested that the reaction might not involve a radical process. To probe the reaction further, a kinetic study was conducted (Fig. 6b). According to this study, the propargylamide (1a) was completely converted to an allenamide (3a) in 10 min under the standard conditions. The multi-substituted pyrrole (2a) was then gradually produced from the intermediate allenamide and no other reaction intermediates were observed or identified. On the other hand, DFT calculations of substrates 3b and 4a were carried out at the B3LYP-D3(SMD)/Def2-TZVP//B3LYP-D3/Def2-SVP level of theory to identify the natural bond orbital (NBO) charges on the carbons of the allene moieties. NBO charges on the internal carbon in both 3b and 4a are 0.11 and 0.18, respectively (Fig. 6c) indicating that the nucleophilic addition of cyanide anion onto the internal carbon should be reasonable as opposed to its addition onto the terminal carbon. Pathways of the cyano addition to 3b were also calculated (Fig. 6d). The transition state of cyano addition on the internal carbon (TS1), is indeed much lower than addition on the terminal carbon (TS2). The intermediate of internal carbon addition int1, is more stable than int2, implying that the internal carbon addition pathway is not only kinetically but also thermodynamically favoured.Open in a separate windowFig. 6Mechanistic studies and proposed mechanism.Based on the results of these mechanistic studies, a plausible reaction mechanism for the synthesis of pentasubstituted pyrroles and hexasubstituted pyrrolines is proposed and is shown in Fig. 6e. First, under basic conditions, the propargylamide isomerizes to an intermediate allenamide (A), which can be attacked nucleophilically by the cyanide anion to afford an intermediate imine (B) with release of the sulfonyl group. Then, the second cyanide anion attacks the imine to form an intermediate (C), which can undergo cyclization and protonation to afford the fully substituted pyrrole (2). Similarly, the hexasubstituted pyrroline product (5) can be obtained from double nucleophilic attack of the intermediate (A) by the cyanide ion.     

One step synthesis of unsymmetrical 1,3-disubstituted BCP ketones via nickel/photoredox-catalyzed [1.1.1]propellane multicomponent dicarbofunctionalization

Bicyclo[1.1.1]pentanes (BCPs), utilized as sp³-rich bioisosteres for tert-butyl- and aryl groups as well as internal alkynes, have gained considerable momentum in drug development programs. Although many elegant methods have been developed to access BCP amines and BCP aryls efficiently, the methods used to construct BCP ketones directly are relatively underdeveloped. In particular, the preparation of unsymmetrical 1,3-disubstituted-BCP ketones remains challenging and still requires multiple chemical steps. Herein, a single-step, multi-component approach to versatile disubstituted BCP ketones via nickel/photoredox catalysis is reported. Importantly, installing a boron group at the carbon position adjacent to the BCP structure bypasses the limitation to tertiary BF₃K coupling partners, thus expanding the scope of this paradigm. Further transformation of disubstituted-BCP ketones into a variety of other BCP derivatives demonstrates the synthetic value of this developed method.

Bicyclo[1.1.1]pentanes (BCPs), utilized as sp³-rich bioisosteres for tert-butyl- and aryl groups as well as internal alkynes, have gained considerable momentum in drug development programs.

Three-dimensional (3D) molecular scaffolds have received considerable attention in drug molecular design to improve physicochemical properties of drug candidates.¹ Among the promising 3D scaffolds in this area are the bicyclo[1.1.1]pentanes (BCPs), which serve as bioisosteres of aromatic rings as well as tert-butyl- and alkyne groups in medicinal chemistry.² In Stepan''s pioneering work,^2a the replacement of the fluorinated aryl ring of a gamma secretase inhibitor with a BCP moiety resulted in improved permeability and kinetic solubility. Since this landmark work, the number of patents published with BCP-containing drugs has skyrocketed. Despite considerable interest from the medicinal chemistry community, the incorporation of BCPs into specific structural classes found in bioactive molecules remains an unsolved challenge.BCP ketones could be considered as bioisosteres of aryl ketones, which widely exist in FDA-approved drugs (Fig. 1A).³ They can also be used as vehicles for the synthesis of other important BCP derivatives, including BCP amides and BCP esters through efficient transformations. Nevertheless, the methods that are used to construct BCP ketones efficiently are relatively underdeveloped, especially compared with well-developed approaches to access amino BCPs and aryl BCPs (Fig. 1B).⁴ Specifically, the Wiberg,^5a Walsh,^5b and Pan^5c groups have reported methods for acylation of [1.1.1]propellane with aldehydes to form monosubstituted-BCP ketones. In contrast, the preparation of unsymmetrically 1,3-disubstituted-BCP ketones remains challenging and still requires multiple chemical steps. For example, Wills and coworkers reported a method for the synthesis of BCP ketones by reacting [1.1.1]propellane and Grignard reagents, followed by addition to an aldehyde and oxidation with MnO₂ (Fig. 2A).^6a This method requires the use of metal reagents and multiple synthesis steps, which are incompatible with the construction of complex targets containing sensitive functional groups. The Knochel group developed a similar two-step strategy to construct 1,3-disubstituted BCP ketones by opening the [1.1.1]propellane with allylzinc halides, followed by addition to acyl chlorides (Fig. 2A).^6b However, this method is only suitable for some special organozinc reagents, which limits the diversity of the BCP ketones. Chemists at SpiroChem also reported a two-step method for construction of 1,3-disubstituted BCP ketones through a process involving radical addition to [1.1.1]propellane, followed by engagement with different arylmetal reagents (Fig. 2A).^6c In this case, the other substituent on the BCP ring is limited to an ester functional group. Furthermore, there are some individual examples showing that disubstituted BCP ketones can be obtained from the corresponding BCP redox active ester. Specifically, the Ohmiya group developed the N-heterocyclic carbene-catalyzed acylation of BCP redox active ester, but the yield was only 20% (Fig. 2A).^6d The Yuan group also conducted the cross-coupling of BCP redox active esters with pyridyl esters to access BCP ketones (Fig. 2A).^6e Considering the five-step synthesis of BCP ketones from [1.1.1]propellane, these methods cannot meet the requirements of rapid synthesis of a library of products in the medicinal chemistry setting. Clearly, the drawbacks of stepwise synthetic approaches to 1,3-disubstituted BCP ketones hamper the broad application of bicyclo[1.1.1]pentanes. Thus, more efficient methods for the preparation of disubstituted BCP ketones are urgently needed.Open in a separate windowFig. 1(A) Examples of bioactive diaryl ketones. (B) Representative BCP derivatives.Open in a separate windowFig. 2(A) Previous strategies to access unsymmetrically 1,3 disubstituted BCP ketones. (B) Research reported herein. HE = Hantzsch ester; RAE = Redox active ester [N-(acyloxy)phthalimide]; NHC = N-heterocyclic carbene; CzIPN = 1,2,3,5-tetrakis(carbazol-9-yl)-4,6-dicyanobenzene.Multicomponent reactions (MCRs) that allow one-step access to complex and diverse disubstituted BCP products are synthetically advantageous to current stepwise approaches to BCP derivatives. However, achieving such a transformation is still challenging because of competing two-component coupling or propellane oligomerization. Uchiyama,^7a MacMillan,^7b and our group^7c,d have successfully developed multi-component approaches to versatile BCP derivatives based on the differentiated reactivity of BCP radicals and substrate alkyl radicals. In our previous report,^7d we successfully took advantage of the slow capture of tertiary radicals by Ni species as a key mechanistic aspect to achieve a one-step, multicomponent reaction for the synthesis of BCP-aryl derivatives. Meanwhile, our group has successfully developed an efficient photoredox/Ni dual catalysis paradigm for transition metal-catalyzed cross-couplings of alkylboron- or alkylsilicon reagents with various electrophiles, including aryl halides, acyl chlorides, alkenyl halides, and isocyanates based on a single-electron transfer (SET) transmetalation pathway.⁸ Inspired by these results, we questioned whether acyl chlorides or other electrophiles could also serve as partners in the three-component radical coupling of [1.1.1]propellane to access a diverse array of BCP derivatives of high importance in the pharmaceutical industry. Herein we report a one-step, three-component radical coupling of [1.1.1]propellane to afford diversely functionalized bicycles using various electrophiles.To determine the chemoselectivity of the proposed MCR pathway, the reactivity of tertiary alkyl and BCP radicals in the nickel/photoredox-catalyzed cross-couplings with acyl chlorides was first examined (Fig. 3). The results indicated that BCP bridgehead radicals engage the nickel catalyst to enter the cross-coupling catalytic cycle, generating the product BCP ketone, while acyclic tertiary radicals do not take part in this catalytic cycle. Encouraged by this promising reactivity pattern, we explored the possibility of achieving a multi-component reaction forging two C–C bonds in a single operation using [1.1.1]propellane.Open in a separate windowFig. 3Control experiments.Initial investigations utilized t-BuBF₃K, [1.1.1]propellane, and benzoyl chloride as a model reaction to optimize the reaction conditions ( EntryDeviation from standard conditionsNMR yield (%) 1 None 63 2No base3230.01 M5240.025 M555427 mm2562 mol% [Ir] cat. 10 mol% [Ni]4972 mol% [Ir] cat. 20 mol% [Ni]588No [Ni] catalyst09No [Ir] catalyst010No light011 t-BuCOOCs, instead of 10Open in a separate window^aOptimization of reaction conditions: 1 (0.15 mmol), 2 (0.3 mmol), 3 (0.10 mmol) under purple Kessil irradiation (λ max = 390 nm) for 16 h at rt; NMR yield was calculated using 1,3,5-trimethoxybenzene as an internal standard (IS) from the crude mixture.With suitable conditions in hand, the generality of this metallaphotoredox protocol with respect to a broad range of aliphatic- and aromatic acyl chlorides was investigated. As summarized in Fig. 4, both electron-rich and electron-poor aromatic acyl chlorides were coupled under the developed reaction conditions with 28−64% yields (4–15). For example, aromatic acyl chlorides containing common functional groups such as ether (5), fluoro (6), chloro (7), trifluoromethoxy (8), cyano (10) and trifluoromethylthio (12) proved to be suitable. Heteroaromatic acyl chlorides (14, 15) also react smoothly to afford the desired product in acceptable yield. Furthermore, the success of the reaction with ethyl succinyl chloride (19), which was not compatible utilizing previous methods employing metal reagents, further demonstrates the functional group compatibility of this protocol. Notably, alkyl bromide or -chloride handles (20, 21) have been incorporated, thus enabling further modification by substitution. Finally, other electrophiles including isocyanates and alkenyl halides (24, 25) have been embedded within the substrates, although the efficiency is not ideal in these cases.Open in a separate windowFig. 4Scope of aliphatic and aromatic acyl chloride substrates. Reaction conditions: acyl chlorides (0.30 mmol, 1.0 equiv.), [1.1.1]propellane (0.90 mmol, 3.0 equiv.), alkyltrifluoroborates (0.45 mmol, 1.5 equiv.), [Ir(dFCF₃ppy)₂dtbbpy]PF₆ (2 mol%, 0.006 mmol), Ni(dtbbpy)Br₂ (20 mol%, 0.06 mmol), Cs₂CO₃ (1.5 equiv., 0.45 mmol), DME (0.05 M), irradiating with purple Kessil irradiation (λ max = 390 nm) for 16 h at rt.To explore the generality of this transformation further, a variety of structurally diverse tertiary- and secondary alkyltrifluoroborates were investigated using the developed conditions. Thanks to the development of powerful synthetic methods, tertiary boronate esters⁹ are quite readily available from diverse feedstocks including carboxylic acids, alkenes, alkyl halides, and ketones.¹⁰ As demonstrated in Fig. 5, ester-, nitrile-, ketone-, alkene-, and even hydroxyl-containing trifluoroborates were incorporated into the established protocol (26–32). These sensitive functional groups would be difficult to integrate within previously reported synthetic methods, especially those using metal reagents as the coupling partner. Additionally, alkyltrifluoroborates possessing various ring sizes reacted smoothly to afford the coupled products (33–39). Interestingly, the secondary radical derived from a benzyltrifluoromethyl-substituted alkyltrifluoroborate was engaged in this MCR process (40), with no evidence for formation of the two-component product. Aliphatic acyl chlorides were also tested and found to be compatible with the reaction conditions, affording the corresponding products 41–43. Finally, we applied this method to the late-stage modification of drug-like molecules. Several alkyltrifluoroborate-containing natural products and drug scaffolds were incorporated under the standard conditions to afford the desired products in moderate to good yields (44–48), demonstrating the applicability of the developed method in complex molecular settings.Open in a separate windowFig. 5Scope of aliphatic- and aromatic acyl chloride substrates. Reaction conditions: acyl chlorides (0.30 mmol, 1.0 equiv.), [1.1.1]propellane (0.90 mmol, 3.0 equiv.), alkyltrifluoroborates (0.45 mmol, 1.5 equiv.), [Ir(dFCF₃ppy)₂dtbbpy]PF₆ (2 mol%, 0.006 mmol), Ni(dtbbpy)Br₂ (20 mol%, 0.06 mmol), Cs₂CO₃ (1.5 equiv., 0.45 mmol), DME (0.05 M), irradiating with purple Kessil irradiation (λ max = 390 nm) for 16 h at rt.Although the established one-step, three-component radical coupling enabled by nickel/photoredox dual catalysis provides an efficient method for rapid construction of disubstituted BCP ketones, this protocol was only applicable to tertiary radicals or a specific secondary radical that limits its generality. To resolve this issue, we examined the feasibility of incorporating a substituent on the carbon adjacent to the BF₃K group that would serve as a versatile surrogate group. As an example, if a Bpin group was installed into this position, it could be proto-deborylated or even further manipulated in downstream transformations, greatly expanding the scope of the overall process. The Masarwa group reported a method for the desymmetrization of gem-diborylalkanes,¹¹ allowing ready access to the requisite trifluoroborates. Gratifyingly, when the desymmetrized 1,1-dibora substrate was subjected to the developed reaction conditions with an aromatic- and aliphatic acyl chloride, the desired products 49 and 50 were formed in good yield (Fig. 6A).Open in a separate windowFig. 6(A) the Synthesis of β-Bpin-substituted BCP ketones. (B) Further transformations.Ketones have long been used as important intermediates to provide access to other functional groups. We have utilized the efficient access to BCP ketones provided by the method developed herein to demonstrate their conversion into a variety of diverse BCP substructures, including carboxylates and amides through classical functional group interconversions (Fig. 6). Considering the lack of efficient methods for synthesis of such building blocks, the current protocol takes on added significance. Reduction of ketones with NaBH₄ produces the corresponding secondary alcohol 51 with a good yield. By using a Baeyer–Villiger oxidation, the corresponding BCP carboxylate 52 was formed. Alternatively, the ketone was further transformed into BCP amide 24via a Beckmann rearrangement. Finally, a BCP ketone was used to generate the corresponding alkene in 75% yield through a Wittig olefination.To gain insights into the reaction mechanism, we conducted a series of control experiments. First, competition experiments demonstrated that a tertiary radical participates in the three-component reaction exclusively, while a secondary radical was only involved in the classical cross-coupling reaction (Fig. 7A). TEMPO trapping experiments showed that the reaction was completely suppressed in the presence of this reagent, and only TEMPO adducts 56 derived from the radical precursors were observed (Fig. 7B). The reaction of the alkyltrifluoroborate generated from verbenone under the standard conditions afforded ring-opened product 58 (Fig. 7C).¹² Therefore, the radical nature of the MCR process was confirmed. Based on these results and previous reports,¹⁰ a plausible reaction mechanism for this dual nickel/photoredox catalyzed three-component cross-coupling is depicted in Fig. 7D. Initially, under light irradiation, the photocatalyst is excited to provide *Ir(iii). The alkyltrifluoroborates reductively quench the excited photocatalyst *Ir(iii) to generate tertiary alkyl radical V. Because the metal–carbon bond between the nickel center and tertiary alkyl group is quite fragile, the acyclic tertiary radical favorably dissociates from the Ni(iii) center to form free alkyl tertiary radicals.¹³ Tertiary alkyl radical V undergoes irreversible radical addition to [1.1.1]propellane, leading to BCP radical VI, which is then trapped by Ni(0), forming an alkyl Ni(i) species VIII. Subsequently, VIII undergoes rapid oxidative addition with acyl chlorides. Alternatively, as shown in blue, BCP radical VI can also be captured by Ni(ii) oxidative addition complex IX. Both pathways lead to Ni(iii) complex X, which subsequently undergoes rapid and productive C–C bond formation to yield the BCP ketone products.Open in a separate windowFig. 7Mechanistic study. (A) Secondary versus tertiary radical competition (the ratio was determined by GC-MS analysis). (B) Radical-trapping experiment. (C) Radical ring-opening reaction. (D) Proposed mechanism.In conclusion, the multi-component radical cross-coupling reaction involving [1.1.1]propellane reported herein enables rapid access to a diverse array of disubstituted BCP ketones and offers an expedient alternative to traditional routes for the synthesis of BCP ketones via pre-functionalization of [1.1.1]propellane. The method exhibits several advantages over previously reported routes, including excellent chemoselectivity, mild reaction conditions, and good functional group tolerance. Importantly, the usefulness of this method is further boosted by installing boronate esters (Bpin) at the carbon adjacent to the BCP substructure, which in principle could be protodeborylated or even further manipulated in downstream transformations. Overall, the reaction described herein enables access to unprecedented BCP structures of interest to the organic chemistry synthetic community, especially in the drug discovery sector.     

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.     

Tuning through-space interactions via the secondary coordination sphere of an artificial metalloenzyme leads to enhanced Rh(iii)-catalysis

We report computationally-guided protein engineering of monomeric streptavidin Rh(iii) artificial metalloenzyme to enhance catalysis of the enantioselective coupling of acrylamide hydroxamate esters and styrenes. Increased TON correlates with calculated distances between the Rh(iii) metal and surrounding residues, underscoring an artificial metalloenzyme''s propensity for additional control in metal-catalyzed transformations by through-space interactions.

We report computationally-guided protein engineering of monomeric streptavidin Rh(iii) artificial metalloenzyme to enhance catalysis of the enantioselective coupling of acrylamide hydroxamate esters and styrenes.

Artificial metalloenzymes (ArMs) can be made by anchoring a non-natural (metal) cofactor into a protein scaffold, with the goal of imbuing new-to-nature reactivity.¹ One of the most common ArM platforms is the biotin-tetrameric(strept)avidin (biotin-tSav) system pioneered by Whitesides and Ward.^2,3 These ArMs utilize high-affinity (up to K_D ∼10⁻¹⁴ M) interactions between tSav and biotin–metal conjugates. tSav-based ArMs have appeared in an increasing number of transition-metal catalyzed transformations.^4–6 In collaboration with the Ward group, we have previously described a tetrameric streptavidin (tSav) system containing a biotinylated Rh(iii) cofactor for the asymmetric synthesis of dihydroisoquinolones using benzhydroxamate esters and acrylate partners.⁷ Monomeric streptavidin (mSav), a streptavidin/rhizavidin hybrid designed to resist tetramerization, retains its high affinity for biotin (K_D ∼10⁻⁹ M).^8,9 We recently described the use of mSav as a new ArM,¹⁰ whose simpler topology encourages protein engineering via a site-directed mutagenesis approach.Traditional manipulation of a metal''s reactivity has been accomplished by modification of the electronic and steric properties of the bound ligands (Fig. 1a).^11,12 For example, we have documented and parsed the impact of Cp electronics and sterics on a number of Rh(iii) catalyzed transformations, by structural changes to the ligand in the primary coordination sphere of Rh.¹³ On the other hand, ArMs have traditionally been used as modifiers of a metal''s steric environment largely focusing on inducing asymmetry in the bond-forming events. Less broadly appreciated is the fact that any mutations in residues proximal to the active site may also impact the metal''s electronic properties via changes to the secondary coordination sphere (Fig. 1b), with the prospect of delivering more active catalysts for a given transformation.Open in a separate windowFig. 1Methods to modify the (a) primary and (b) secondary coordination sphere of a Rh(iii) catalyst.Previously, we described a mSav·Rh(iii) catalyst and demonstrated its use in the direct enantioselective coupling of acrylamide hydroxamate esters and styrenes.¹⁰ The reaction allows rapid access to piperidines – the most common N-heterocycle found in FDA-approved pharmaceuticals.¹⁴ One of the most interesting aspects of this reaction was our observation of a 7-fold increase in turnover number (TON) by embedding the cofactor into mSav''s active site.¹⁵ It has been a long-standing goal of ArMs to not only enable new-to-nature reactivity, but also for them to achieve the stellar kinetics of a native metalloenzyme. As these systems lack the evolutionary privilege of a natural metalloenzyme, extensive mutation of the protein scaffold may be required to find the optimal environment of the metal cofactor.Predicting the effects of specific mutations can prove very challenging, as any alterations to the protein conformation and charge distribution can impact reactivity regardless of the mutation''s distance from the active site.^16–19 In order to design a better mutant, we embarked on a collaborative experimental and computational study to define the role of the protein scaffold and how single point mutations affect reactivity. We identified two key residues that play a pivotal role in mSav·Rh(iii) ArM''s secondary coordination sphere, and have used this insight to design a more active mutant.For the purposes of this study, we focused on the mSav·Rh(iii) ArM-catalyzed coupling of methacrylamide with 4-methoxystyrene as our model reaction (Fig. 2a). Using a small model of the catalyst, the lowest energy pathway of this reaction''s proposed mechanism was generated (Fig. S9^†). The calculations were performed in Turbomole^20–32 with the M06 density functional.³³ Geometries were optimized with the def2-SVP basis set, and final electronic energies were calculated with the def2-TZVP basis set.³⁴ The conductor-like screening model (COSMO)³⁵ was used as implicit solvent with a dielectric of 80 to simulate water. These calculations predicted similar barriers for the N–H activation, the C–H activation, and the migratory insertion (differences less than 3 kcal mol⁻¹). Isotope-exchange experiments revealed that the C–H activation step is reversible, implicating the migratory insertion step as turnover-limiting.¹⁰Open in a separate windowFig. 2(a) Model transformation. (b) Snapshot of the transition state for alkene insertion illustrating key nearby residues Y112 (red), E124 (blue), and S119 (purple). (c) Computed barrier to alkene insertion in the presence and absence of phenol and acetate (shown in blue).The Cp* moiety of the Cp*^biotinRhX₂ cofactor is non-covalently localized in the active site likely due to a π–π stacking interaction with Y112 (Fig. 2b). This assignment is supported by the observation that mutant Y112A leads to lower yield and enantioselectivity.¹⁰ We hypothesized that we could further manipulate both the sterics and electronics of the Cp* moiety by either directly mutating Y112 or indirectly by mutating other residues that affect the Y112-Cp* interaction.To generate a model of mSav''s protein scaffold and active-site we used QM/DMD³⁶ – a hybrid quantum mechanics/molecular mechanics method that simulates proteins piecewise. Discrete molecular dynamics (DMD) equilibrates the entire system except for the metal and part of the substrate.³⁶ After a trajectory of ∼0.5 ns, quantum mechanics (QM) is used to optimize the metal region plus sidechains and residues immediately surrounding it. This process is repeated, providing efficient sampling of the entire protein scaffold while treating the metal environment quantum-mechanically. For this study, the migratory insertion transition state was modeled in WT by freezing the coordinates of the rhodium atom and the two carbon atoms forming a bond. For each system, five replicate simulations were run for ∼20 ns each.Residues E124 and S119 both hydrogen bond to Y112 and are in close proximity to the RhCp* catalytic site (Fig. 2b).³⁷ To estimate the electronic effects of these three residues on the reaction, an acetate ion, methanol molecule, and 4-methylphenol (p-cresol) molecule were added to a small catalyst model without constraints but initially positioned to mimic the sidechains of these residues (Fig. 2c). The migratory insertion energy barrier decreases by 2 kcal mol⁻¹ with incorporation of the three residues. However, this energy barrier decreases by an additional 3 kcal mol⁻¹ upon the deletion of the methanol molecule representing S119. Not only does this imply that these amino acid sidechains may be the primary reason for the increased activity of the protein-installed catalyst, but also suggest that a longer Y112–S119 distance is favorable, so long as no water can insert in this region and replace S119 in its H-bond with Y112. We hypothesize that the carboxylate group of E124 acts as a hydrogen bond acceptor, donating electron density to the Y112 phenol ring, which in turn donates electron density to the catalyst via π–π charge transfer. This could enhance the electron donation of the metal and decrease the energy barrier to the migratory insertion step. On the other hand, S119 acts as a hydrogen bond donor which would remove electron density from Y112 and subsequently the Rh(iii) moiety.Unfortunately, mutation of Y112 (Y112F and Y112W) results in negligible protein yields. We thus identified three flanking residues (T111, E113, H87) that may be expected to have a significant impact on Y112''s position, and one distal (T32) residue, chosen as distal mutations sometimes have significant impact (Fig. 3). Through this subset of mutants, we attempted to increase TON and establish a correlation between the Y112–Rh distance and Y112–S119 distance of the mutants and their reactivities.Open in a separate windowFig. 3Structure of mSav from two different views highlighting some of the mutated residues including their TON and enantioselectivity.We used QM/DMD to simulate a representative set of these mutants spanning a wide range of TONs measured in the experiment. The Y112–Rh and Y112–S119 distances were measured every ∼0.5 ps for every simulation. The results can be represented by a 3-dimensional plot with Y112–Rh distance on the X axis, Y112–S119 distance on the Y axis, and probability density on the Z axis (Fig. 4). We find the best correlation between TON and probability density in the conformational region where the Y112–Rh distance is the shortest and the Y112–S119 interaction is not energetically relevant.³⁸Open in a separate windowFig. 4Three-dimensional probability distributions from select mutants by simultaneous sampling of Rh–Y112 and S119–Y112 distances. Probabilities for the outlined regions are also shown.To clarify this correlation, we calculated the probability of having a Y112–S119 distance between 3.5–6 Å and a Y112–Rh distance less than 5.65 Å. This Y112–S119 distance corresponds to negligible hydrogen bonding.³⁹ Additionally, we constrained the small model catalyst shown in Fig. 5b (ref. 40) and calculated the corresponding energy barriers at different Y112–Rh distances (Fig. 5a). Since rate increases exponentially as the barrier decreases,³⁵ differences in probabilities in the region where the Y112–Rh distance is between 5.4–5.65 Å have the greatest impact on the relative TONs of our model methacrylamide styrene coupling. We conclude that mutants with increasing probability in this region provide increasing TON.Open in a separate windowFig. 5a) Theoretical dependence of migratory insertion barrier on Rh-phenol distance. (b) Small-model catalyst.Theoretically, a shorter Y112–Rh distance relative to WT would result in increased reactivity. Residue G49 is located under the Rh(iii) moiety (Fig. 6). We hypothesize that by mutating the glycine into an alanine, steric congestion would force the biotinylated Rh(iii) cofactor to shift upwards closer to the electron donating phenol side chain of residue Y112. Analyzing the critical portions of the Y112–Rh and Y112–S119 distances in tandem reveals that G49A has the highest probability density in this region (Fig. 4). Indeed, experimentally, this mutant gives 97 TON and 91% ee (Fig. 6). The combination of a short Y112–Rh distance and long Y112–S119 distance leads to an increase in reactivity. This is an approximate 3-fold improvement in the TON relative to WT. The G49A mutant serves as an experimental proof of concept that a computational analysis of an ArMs secondary coordination sphere can lead to the design of a more efficient ArM.Open in a separate windowFig. 6Snapshot of the transition state for alkene insertion highlighting the position of G49 (purple) relative to Rh. Y112 is shown in red and E124 is shown in blue.In summary, we have identified three key residues that contribute to accelerating the rate of a Rh(iii)-catalyzed reaction by electronic communication to the metal via the secondary coordination sphere. E124 hydrogen bonds to Y112 transferring electron density via π–π charge transfer, an effect that is attenuated by hydrogen bonding from S119. Optimal interaction of these residues can be described computationally by finding mutants that have multiple conformations bearing short Y112–Rh distances coupled with negligible bonding between Y112 and S119. This hypothesis was experimentally verified by a mutant that enforces a closer Y112–Rh distance leading to improved TON. This result demonstrates the use of a hypothesis-based site-directed mutagenesis of the secondary sphere residues, to optimize the metal''s electronic environment within the protein scaffold and enhance an ArM''s activity.     

Electrooxidative o-carborane chalcogenations without directing groups: cage activation by copper catalysis at room temperature

Copper-catalyzed electrochemical direct chalcogenations of o-carboranes was established at room temperature. Thereby, a series of cage C-sulfenylated and C-selenylated o-carboranes anchored with valuable functional groups was accessed with high levels of position- and chemo-selectivity control. The cupraelectrocatalysis provided efficient means to activate otherwise inert cage C–H bonds for the late-stage diversification of o-carboranes.

Copper-catalyzed electrochemical cage C–H chalcogenation of o-carboranes has been realized to enable the synthesis of various cage C-sulfenylated and C-selenylated o-carboranes.

Carboranes are polyhedral molecular boron–carbon clusters, which display unique properties, such as a boron enriched content, icosahedron geometry and three-dimensional electronic delocalization.¹ These features render carboranes as valuable building blocks for applications to optoelectronics,² as nanomaterials, in supramolecular design,³ organometallic coordination chemistry,⁴ and boron neutron capture therapy (BNCT) agents.⁵ As a consequence, considerable progress has been witnessed in transition metal-catalyzed regioselective cage B–H functionalization of o-carboranes⁶ and different functional motifs have been incorporated into the cage boron vertices.^7–10 However, progress in this research arena continues to be considerably limited by the shortage of robust and efficient methods to access carborane-functionalized molecules. While C–S bonds are important structural motifs in various biologically active molecules and functional materials,¹¹ strategies for the assembly of chalcogen-substituted carboranes continue to be scarce. A major challenge is hence represented by the strong coordination abilities of thiols to most transition metals, which often lead to catalyst deactivation.¹² While copper-catalyzed B(4,5)–H disulfenylation of o-carboranes was achieved,^7e elevated reaction temperature was required, and 8-aminoquinoline was necessary as bidentate directing group. The bidentate directing group¹³ needs to be installed and removed, which jeopardizes the overall efficacy. Likewise, an organometallic strategy was recently devised for cysteine borylation with a stoichiometric platinum(ii)-based carboranes.¹⁴ Meanwhile, oxidative cage B/C–H functionalizations largely call for noble transition metal catalysts¹⁵ and stoichiometric amounts of chemical oxidants, such as expensive silver(i) salts.¹⁶In recent years, electricity has been identified as an increasingly viable, sustainable redox equivalent for environmentally-benign molecular synthesis.^17,18 While significant advances have been realized by the merger of electrocatalysis with organometallic bond activation,¹⁹ electrochemical carborane functionalizations continue unfortunately to be underdevelopment. In sharp contrast, we have now devised a strategy for unprecedented copper-catalyzed electrochemical cage C–H chalcogenations of o-carboranes in a dehydrogenative manner, assembling a variety of C-sulfenylated and C-selenylated o-carboranes (Fig. 1a). It is noteworthy that our electrochemical cage C–S/Se modification approach is devoid of chemical oxidants, and does not need any directing groups, operative at room temperature.Open in a separate windowFig. 1Electrochemical diversification of o-carboranes and optimization of reaction conditions. ^aReaction conditions: procedure A: 1a (0.10 mmol), 2a (0.3 mmol), CuOAc (15 mol%), 2-PhPy (15 mol%), LiOtBu (0.2 mmol), TBAI (2.0 equiv.), solvent (3 mL), platinum cathode (10 mm × 15 mm × 0.25 mm), graphite felt (GF) anode (10 mm × 15 mm × 6 mm), 2 mA, under air, r.t., 16 h. ^bYield was determined by ¹H NMR with CH₂Br₂ as the internal standard. ^cIsolated yields in parenthesis. ^dKI (1.0 equiv.) as additive. ^eProcedure B: 2 (0.3 mmol), LiOtBu (0.2 mmol), TBAI (2.0 equiv.), solvent (3.0 mL), 2 mA, r.t., 3 h, then adding 1a (0.10 mmol), 2-PhPy (15 mol%), CuOAc (15 mol%), 2 mA, rt, 16 h. ^f2b (0.3 mmol), LiOtBu (0.2 mmol), KI (1.0 equiv.), TBAI (2.0 equiv.), solvent (3.0 mL), 2 mA, r.t., 3 h, then adding 1a (0.10 mmol), 2-PhPy (15 mol%), CuOAc (15 mol%), r.t., 16 h. TBAI = tetrabutylammonium iodide, TBAPF₆ = tetrabutylammonium hexafluorophosphate. DCE = 1,2-dichloroethane, THF = tetrahydrofuran.We commenced our studies by probing various reaction conditions for the envisioned copper-catalyzed cage C–H thiolation of o-carborane in an operationally simple undivided cell setup equipped with a GF (graphite felt) anode and a Pt cathode (Fig. 1b and Table S1^†). After extensive experimentation, we observed that the thiolation of substrate 1 proceeded efficiently with catalytic amounts of CuOAc and 2-phenylpyridine, albeit in the presence of 2 equivalents LiOtBu as the base, and 2 equivalents n-Bu₄NI as the electrolyte at room temperature under a constant current of 2 mA (entry 1). The yield was reduced when other copper sources or additives were used (entries 2–5). Surprisingly, n-Bu₄NPF₆ as the electrolyte failed to facilitate the carborane modification, indicating that n-Bu₄NI operates not only as electrolyte, but also as a redox mediator (entry 6). Altering the stoichiometry of the electrolyte or using KI did not improve the performance (entries 7–8). Product formation was not observed, when the reaction was conducted with DCE as the solvent, while CH₃CN resulted in a drop of the catalytic performance (entries 9–10). Control experiments confirmed the essential role of the electricity and the catalyst (entries 11–12), while a sequential procedure was found to be beneficial (entries 13–15).With the optimized reaction conditions in hand, we explored the versatility of the cage C–H thiolation of o-carborane 1a with different thiols 2 (Scheme 1). Electron-rich as well as electron-deficient substituents on the arenes were found to be amenable to the electrocatalyzed C–H activation, providing the corresponding thiolation products 3aa–3ao in good to excellent yields. Thereby, a variety of synthetically useful functional groups, such as fluoro (3ae, 3am), chloro (3af, 3ak, 3an) and bromo (3ag, 3al), were fully tolerated, which should prove instrumental for further late-stage manipulations. Various disubstituted aromatic and heterocyclic thiols afforded the corresponding cage C–S modified products 3ap–3as. Notably, aliphatic thiols efficiently underwent the electrochemical transformation to provide the corresponding cage alkylthiolated products 3at–3au. Notably, the halogen-containing thiols (2e–2f, 2k–2n and 2q) reacted selectively with o-carboranes to deliver the desired products without halide coupling byproducts being observed. The connectivity of the products 3aa, 3am and 3ao was unambiguously verified by X-ray single crystal diffraction analysis.²²Open in a separate windowScheme 1Electrochemical C–H thiolation of o-carborane 1a. (a) Procedure B. (b) KI (1 equiv.). (c) Cul as the catalyst.Encouraged by the efficiency of the cupraelectro-oxidative cage C–H thiolation, we became intrigued to explore the chalcogenantion of differently-decorated o-carboranes 1 (Scheme 2). Electronically diverse carboranes 1 served as competent coupling partners, giving the corresponding thiolation products 4bo–4do with high levels of efficacy in position-selective manner. The strategy was not restricted to phenyl-substituted o-carboranes. Indeed, substrates bearing benzyl and even alkyl groups also performed well to deliver the desired products 4eo–4ga. It is noteworthy that the C–H activation approach was also compatible with selenols to give the o-carboranes 4av–4fv. The molecular structures of the carborane 4br and 4av were unambiguously verified by single-crystal X-ray diffraction.²²Open in a separate windowScheme 2Electrochemical cage C–H chalcogenation of o-carboranes. (a) Procedure B. (b) KI (1 equiv.).Scaffold functionalization of the thus obtained carborane 3ag provided the alkynylated derivative 5a and amine 5b (Scheme 3), giving access to carborane-based host materials of relevant to phosphorescent organic light-emitting diodes.²⁰Open in a separate windowScheme 3Late-stage diversification.Next, we became attracted to delineating the mode of the cupraelectro-catalyzed cage C–H chalcogenation. To this end, control experiments were performed (Scheme 4a). First, electrocatalysis in the presence of TEMPO or Ph₂C CH₂ gave the desired product 3aa. EPR studies of thiol 2a, LiOtBu and THF under the electrochemical conditions showed a small radical signal, which might be attributed to a thiol radical.²¹ Second, the cupraelectrocatalysis occurred efficiently in the dark. Third, detailed cyclovoltammetric analysis of the thiol and iodide mediator (Scheme 4b and ESI^†)²¹ revealed an irreversible oxidation of the thiol anion at E_p = −0.62 V vs. Ag/Ag⁺ and two oxidation events for the iodide, including an irreversible oxidation at E_p = 0.12 V vs. Ag/Ag⁺ and a reversible oxidation at E_p = 0.44 V vs. Ag/Ag⁺, which is in good agreement with the literature reported iodide oxidation potentials,^18c,d and is suggestive of the preferential oxidation of the iodide as a redox mediator. In this context, the use of n-Bu₄NI as a redox mediator to achieve copper-catalyzed electrochemical arene C–H aminations had been documented.^18d Furthermore, we calculated the redox potential of complex C by means of DFT calculations at the PW6B95-D4/def2-TZVP + SMD(MeCN)//TPSS-D3BJ/def2-SVP level of theory.²¹ These studies revealed a calculated oxidation half-wave potential for complex C is E^o,calc_1/2 = −0.08 V vs. SCE. Hence, iodide is a competent redox mediator to achieve the transformation from complex C to complex D. Analysis of non-covalent interactions²¹ in complex C (Fig. 2) show the presence of a weak stabilization interaction between the chalcogen''s anisole group and the 2-phenylpyridine. In contrast, in complex D these interactions were found more relevant between the o-carborane phenyl group and the chalcogen aromatic motif.Open in a separate windowFig. 2Non-covalent interaction plots for the complexes C and D. Strong attractive interactions are shown in blue, weak attractive interactions are given in green, while red corresponds to repulsive interactions. Ar = 4-MeOC₆H₄.Open in a separate windowScheme 4Control experiments and cyclic voltammograms.On the basis of the aforementioned findings,¹⁸ a plausible reaction mechanism is proposed in Scheme 5, which commences with an anodic single electron-transfer (SET) oxidation of the thiol anion E to form the sulfur-centered radical F. Subsequently, the copper(i) species A reacts with the sulfur radical F to deliver copper(ii) complex B, which next reacts with o-carborane 1 in the presence of LiOtBu to generate a copper(ii)-o-carborane complex C. Thereafter, the complex C is oxidized by the anodically generated redox mediator I₂ to furnish the copper(iii) species D,^18d which subsequently undergoes reductive elimination, affording the final product and regenerating the catalytically active complex A. Alternatively, the direct oxidation of copper(ii) complex C by electricity to generate copper(iii) species D can not be excluded at this stage.^18a,bOpen in a separate windowScheme 5Proposed reaction mechanism.In conclusion, a sustainable electrocatalytic C–H chalcogenation of o-carboranes with thiols and selenols was realized at room temperature by earth abundant copper catalysis. The C–H activation was characterized by mild reaction conditions and high functional group tolerance, leading to the facile assembly of various o-carboranes. Thereby, a transformative platform for the design of cage C–S and C–Se o-carboranes was established that avoids chemical oxidants by environmentally-sound electricity in the absence of directing groups. A plausible mechanism of paired electrolysis was established by detailed mechanistic studies.     

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

0D–1D hybrid nanoarchitectonics: tailored design of FeCo@N–C yolk–shell nanoreactors with dual sites for excellent Fenton-like catalysis

Heterogeneous Fenton-like processes are very promising methods of treating organic pollutants through the generation of reactive oxygen containing radicals. Herein, we report novel 0D–1D hybrid nanoarchitectonics (necklace-like structures) consisting of FeCo@N–C yolk–shell nanoreactors as advanced catalysts for Fenton-like reactions. Each FeCo@N–C unit possesses a yolk–shell structure like a nanoreactor, which can accelerate the diffusion of reactive oxygen species and guard the active sites of FeCo. Furthermore, all the nanoreactors are threaded along carbon fibers, providing a highway for electron transport. FeCo@N–C nano-necklaces thereby exhibit excellent performance for pollutant removal via activation of peroxymonosulfate, achieving 100% bisphenol A (k = 0.8308 min⁻¹) degradation in 10 min with good cycling stability. The experiments and density-functional theory calculations reveal that FeCo dual sites are beneficial for activation of O–O, which is crucial for enhancing Fenton-like processes.

Novel 0D–1D hybrid nanoarchitectonics consisting of FeCo@N–C yolk–shell nanoreactors are developed for Fenton-like reaction. With the multilevel advantages of this design, FeCo@N–C nano-necklaces exhibit excellent performance for BPA removal.

Advanced oxidation processes (AOPs) are one of the most promising strategies to eliminate organic contaminants, sustainably generating reactive oxygen species (ROS) to ideally destroy all non-biodegradable, recalcitrant, toxic, or membrane-permeable organic impurities.^1–4 Among these AOPs, sulfate radical (SO₄˙⁻)-based Fenton-like processes have gained increasing attention as a water treatment strategy because of the strong oxidation potential of SO₄˙⁻ (3.1 V vs. normal hydrogen electrode) at wider pH ranges. SO₄˙⁻ is mainly produced by physical or chemical methods for activation of persulfate salts, such as peroxymonosulfate (PMS) and persulfate.^5–9 Over the past two decades, heterogeneous catalysis has emerged as the most effective approach to water treatment, with much effort dedicated to developing better catalysts, including transition metal-based and carbonaceous materials.^10,11 Unfortunately, most metal-based catalysts suffer from leaching of toxic metal ions, which can thwart their practical application,^12,13 and although carbonaceous catalysts produce no secondary pollution, their cycle performance is always depressed.¹⁴ There is therefore an urgent need to find robust catalysts with adequate activity and stability for Fenton-like processes.To achieve superior performance, an ideal Fenton-like catalyst should contain oxidants with favorably reactive centers for cleavage of peroxyl bonds (O–O), have structure optimized for target pollutant attraction, and have chainmail to protect the vulnerable active sites for long periods.^15–17 Recent studies have demonstrated Co–N–C active sites prefer to activate the O–O of PMS.¹⁸ Furthermore, introducing Fe-doping into the Co–N–C system not only suppresses Co²⁺ leaching, but also modulates the pyrrolic-N content, which is the adsorption site for capture of bisphenol A (BPA).¹⁹ We previously discovered that Co@C yolk–shell nanoreactors could enhance the catalytic activity because of the confinement effect in the nano-spaces between the core and shell, while the carbon shell acted like a chainmail protecting the Co active sites, keeping them highly reactive after five cycles.^20,21Combining different kinds of materials to generate novel hybrid material interfaces can enable the creation of new kinds of chemical and physical functionalities that do not currently exist. However, one cannot simply mix these materials in an uncontrolled manner, because the ensemble of interfaces created by random mixing tends to favour thermodynamically stable interfaces that are functionally less active. Therefore, to prepare new materials with high functionality, it is necessary to carefully control the hybridization of components in interfacial regions with nanometric or atomic precision. By further hybridization of different components e.g., zero to one dimension (0D–1D) hybrid structures, we can prepare the structure to increase not only the specific surface area but also the interfacial region between different materials.In this work, we report novel 0D–1D hybrid nanoarchitectonics (necklace-like structures) consisting of FeCo@N–C yolk–shell nanoreactors as a PMS activator for Fenton-like processes. This catalyst has multilevel advantages: (i) each FeCo@N–C unit is a well-formed yolk–shell nanoreactor, which can guarantee sufficient contact of reactants and active sites, as well as defend them for good durability; (ii) all single nanoreactors are threaded along the carbon fibers, providing a highway for electron transport; and (iii) all the carbon fibers constructed into a thin film with macroscopic structure, which overcomes the complex recyclability of powder catalysts. Benefiting from favorable composition and unique structure, the FeCo@N–C catalyst delivers excellent performance for BPA removal via activation of PMS accompanied with good stability.The synthesis processes of necklace-like nanoarchitecture containing FeCo@N–C yolk–shell nanoreactors are illustrated in Fig. 1a. First, uniform Fe–Co Prussian blue analogue (Fe–Co PBA) nanocubes with an average size of 800–900 nm (Fig. 1b) are encapsulated in polyacrylonitrile (PAN) nanofibers by electrospinning. The obtained necklace-like FeCo PBA–PAN fibers (Fig. 1c) are then pyrolyzed at 800 °C in N₂ atmosphere to produce FeCo@N–C nano-necklaces. The scanning electron microscopy (SEM) image (Fig. 1d) of the FeCo@N–C shows this necklace-like morphology with its large aspect ratio, with the FeCo@N–C particles strung along the PAN-derived carbon fibers. A broken particle (Fig. 1e) shows that the FeCo@N–C has a yolk–shell architecture, which is also identified by transmission electron microscopy (TEM). Fig. 1f and g show the well-defined space between the inner yolk and outer shell, which is attributed to the volume shrinkage of the original Fe–Co PBAs. During pyrolysis, Fe–Co PBA is reduced to FeCo (inner yolk) and PAN is carbonized (outer carbon shell), resulting in the unique necklace-like nanoarchitecture.^22–24 The high-resolution TEM in Fig. 1h shows a lattice fringe of 0.20 nm, which matches well with the (110) plane of FeCo alloy.²⁵ The scanning transmission electron microscopy (STEM) image (Fig. 1i) and corresponding elemental map (Fig. 1j) indicate that FeCo nanocrystals are well distributed in the inner core with some small FeCo nanocrystals located on external carbon shells. Furthermore, the control samples of Fe@N–C and Co@N–C nano-necklaces, prepared by only replacing the Fe–Co PBA nanocubes with Fe–Fe PB and Co–Co PBA (Fig. S1^†), also demonstrate the versatility of this synthetic strategy. The formation of hierarchical porous structure, beneficial to the PMS transportation on the surface of catalysts, could be determined by N₂ adsorption–desorption isotherms and corresponding pore volume analysis (Fig. S2 and Table S1^†).Open in a separate windowFig. 1(a) Preparation of FeCo@N–C necklace-like nanoarchitecture. SEM images of (b) Fe–Co PBA cubic particles and (c) the electrospun FeCo PBA–PAN fibers. (d and e) SEM, (f and g) TEM, and (h) high-resolution TEM images of FeCo@N–C nano-necklaces. (i) STEM and (j) the corresponding elemental mappings of C, N, Fe, and Co.The X-ray diffraction patterns of the as-prepared products are depicted in Fig. S3,^† with one prominent diffraction peak centered at 44.8° corresponding to the (110) lattice plane of FeCo alloy. All the products also have a characteristic signal at 26°, implying that graphite carbon is formed during pyrolysis. Raman spectroscopy further analyzed the crystal structures and defects of the FeCo@N–C nano-necklaces (Fig. S4^†), where peaks found at 1349 cm⁻¹ and 1585 cm⁻¹ index the disordered (D band) and graphitic carbon (G band), respectively.²⁶ X-ray photoelectron spectroscopy investigated the composition and valence band spectra of FeCo@N–C nano-necklaces. The survey spectrum (Fig. S5a^†) reveals the presence of Fe (1.4%), Co (1.2%), C (86.4%), N (4.5%), and O (6.5%) in the composite. The high-resolution N 1s spectrum (Fig. S5b^†) exhibits broad peaks at 398.1, 401.1, and 407.4 eV, corresponding to the pyridinic-N, graphitic-N, and σ* excitation of C–N, respectively.²⁷ The high-resolution Fe 2p spectrum (Fig. S5c^†) shows a broad peak at 707.4 eV, attributed to Fe⁰. Similarly, the 777.5 eV peak observed in the Co 2p spectrum (Fig. S5d^†) corresponds to Co⁰, implying that FeCo dual sites have formed.²⁸ The oxidation state of these sites was investigated by ⁵⁷Fe Mössbauer spectroscopy, which found a sextet in the Mössbauer spectrum of the FeCo@N–C nano-necklaces attributed to FeCo dual sites (Fig. 2a and Table S2^†).²⁹ The coordination environment of the FeCo dual sites was also verified by X-ray absorption fine structure (XAFS) spectroscopy. Fig. 2b shows that the X-ray absorption near-edge structure (XANES) spectra of the Fe K-edge, which demonstrates a similar near-edge structure to that of Fe foil, illustrating that the main valence state of Fe in FeCo@N–C nano-necklaces is Fe⁰. Furthermore, the extended-XAFS (EXAFS) spectra (Fig. 2c) displays a peak at 1.7 Å, which is ascribed to the Fe–N bond, and a remarkable peak at approximately 2.25 Å corresponding to the metal–metal band.^10,30 The Co K-edge and EXAFS spectra (Fig. S6^†) also confirm the presence of Co–N and the metal–metal band. These results provide a potential structure of the FeCo dual sites in the FeCo@N–C nano-necklaces, as illustrated in Fig. 2d.Open in a separate windowFig. 2(a) ⁵⁷Fe Mössbauer spectra of FeCo@N–C nano-necklaces at 298 K. (b) Fe K-edge XANES spectra of FeCo@N–C nano-necklaces and Fe foil. (c) Corresponding Fourier transformed k³-weighted of the EXAFS spectra for Fe K-edge. (d) Possible structure of the FeCo dual sites.This dual-metal center and necklace-like structure may be beneficial to enhance catalytic performance. Fig. 3a shows the Fenton-like performance for BPA degradation compared to Fe@N–C nano-necklaces, Co@N–C nano-necklaces, and FeCo@N–C particles (Fe–Co PBA directly carbonized without electrospinning). Here, the FeCo@N–C nano-necklaces display a higher catalytic performance, with BPA completely removed in 7 min. To clearly compare their catalytic behavior, the kinetics of BPA degradation was fitted by the first-order reaction. As shown in Fig. 3b, FeCo@N–C nano-necklaces exhibit the highest apparent rate constant (k = 0.83 min⁻¹), which is approximately 6.4, 2.6, and 1.2 times that of FeCo@N–C particles, Fe@N–C nano-necklaces, and Co@N–C nano-necklaces, respectively. The significantly enhanced performance of FeCo@N–C nano-necklaces suggests that the FeCo dual sites and necklace-like nanoarchitecture are crucial. Furthermore, the concentration of BPA and PMS in the solution is higher than that in yolk–shell nanoreactor, resulting a concentration gradient which helps to accelerate the diffusion rates of reactants (Fig. 3c).^31,32 For these nano-necklaces, the carbon shell acts like a chainmail protecting the FeCo active sites from attack by molecules and ions, and all the nanoreactors are threaded along the carbon fibers, providing a highway for electron transport, which is important for SO₄˙⁻ generation (SO₄˙⁻ production as eqn, HSO₅⁻ + e⁻ → SO₄˙⁻ + OH⁻). Electrochemical impedance spectroscopy further confirms the good conductivity of the FeCo@N–C nano-necklaces (Fig. 3d). In addition, the concentration of metal-ion leaching and cycling performance (Fig. 3e and f) reveal the high reusability of FeCo@N–C nano-necklaces, with 95% BPA removal in 20 min after five cycles, which is also proved by the SEM and TEM characterization (Fig. S7^†). The effect of other reaction parameters on the BPA degradation, such as pH, reaction temperature, PMS or catalysts dosage, and common anions, were investigated in detail (Fig. S8–S11^†). All the results demonstrate that FeCo@N–C nano-necklaces deliver a better performance for PMS catalysis. In addition, the turnover frequency (TOF) value of FeCo@N–C nano-necklaces is 5.5 min⁻¹ for BPA degradation, which is higher than many previously reported catalysts (detailed catalytic performance comparison as shown in Table S3^†).Open in a separate windowFig. 3(a) BPA degradation efficiency in different reaction systems and (b) the corresponding reaction rate constants. (c) Schematic illustration of PMS activation in FeCo@N–C nano-necklaces. (d) Nyquist plots of the catalysts. (e) The metal leaching in different reaction systems. (f) Cycling performance of FeCo@N–C nano-necklaces for BPA removal. Reaction conditions: [catalyst] = 0.15 g L⁻¹, [BPA] = 20 mg L⁻¹, [PMS] = 0.5 g L⁻¹, T = 298 K, and initial pH = 7.0.To examine the enhanced catalytic activity, radical quenching experiments were conducted. As shown in Fig. 4a, when NaN₃ is added to the reaction solution as a scavenger for ¹O₂, there is no significant reduction of BPA decomposition, implying that non-radicals are not the dominant reactive species. By comparison, when tert-butanol (TBA) (radical scavenger for ˙OH) is added, there is a slight (2.8%) decrease in BPA removal. However, if methanol (radical scavenger for SO₄˙⁻ and ˙OH) is added, the efficiency of BPA degradation declines by up to 59.2%, indicating that the major radicals generated from the PMS activation are SO₄˙⁻;³³ the presence of these radicals is also verified by electron paramagnetic resonance (EPR) (Fig. 4b). Furthermore, the significant inhibition ratio can be observed when KI (quencher for the surface) is added, demonstrating that BPA degradation is mainly attributed to reactions with SO₄˙⁻, which is produced by a surface catalytic process.³⁴Open in a separate windowFig. 4(a) Effects of the radical scavengers on BPA degradation. (b) EPR spectra of SO₄˙⁻ and ˙OH. (c) The energy profiles of PMS on FeCo@N–C nano-necklaces surface. (d) Optimized configurations of PMS adsorbed on FeCo@N–C nano-necklaces.Density-functional theory was applied to calculate the surface energy of PMS activation at FeCo dual sites (Fig. 4c, d and S12^†). The dissociation barrier of PMS into SO₄˙⁻ and OH⁻ is −2.25 eV, which is much lower than that on an Fe or Co single site, suggesting that cleavage of O–O bonds of PMS occurs more easily on FeCo dual sites. This is because FeCo dual sites provide two anchoring sites for the dissociated O atoms, leading to more efficient activation of O–O. The FeCo@N–C nano-necklaces can reduce the energy barrier of O–O bond breaking, which results in high activity for PMS activation and thus high productivity of SO₄˙⁻.