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: 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.     

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 (

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: 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.     

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.     

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˙⁻.     

Reversing electron transfer in a covalent triazine framework for efficient photocatalytic hydrogen evolution

Covalent triazine-based frameworks (CTFs) have emerged as some of the most important materials for photocatalytic water splitting. However, development of CTF-based photocatalytic systems with non-platinum cocatalysts for highly efficient hydrogen evolution still remains a challenge. Herein, we demonstrated, for the first time, a one-step phosphidation strategy for simultaneously achieving phosphorus atom bonding with the benzene rings of CTFs and the anchoring of well-defined dicobalt phosphide (Co₂P) nanocrystals (∼7 nm). The hydrogen evolution activities of CTFs were significantly enhanced under simulated solar-light (7.6 mmol h⁻¹ g⁻¹), more than 20 times higher than that of the CTF/Co₂P composite. Both comparative experiments and in situ X-ray photoelectron spectroscopy reveal that the strong interfacial P–C bonding and the anchoring of the Co₂P cocatalyst reverse the charge transfer direction from triazine to benzene rings, promote charge separation, and accelerate hydrogen evolution. Thus, the rational anchoring of transition-metal phosphides on conjugated polymers should be a promising approach for developing highly efficient photocatalysts for hydrogen evolution.

Reversing the electron transfer in a covalent triazine-based framework by Co₂P anchoring achieved highly efficient photocatalytic hydrogen evolution from water splitting.

Photocatalytic water splitting into hydrogen fuels has been considered as a promising technique for converting solar energy into chemical energy.^1–3 To achieve this target, it is necessary to design and construct photocatalysts with high solar-to-hydrogen (STH) conversion efficiency.^4,5 Recently, covalent triazine-based frameworks (CTFs),^6,7 as a new class of conjugated polymer materials, have attracted significant attention in the photocatalytic water splitting field owing to their visible-light response, organized architecture, adjustable pore-size, and controllable functionalization.^8–12 However, owing to the high charge recombination and fewer active sites for the hydrogen evolution reaction (HER), the photocatalytic activities of pristine CTFs are very low. To overcome this drawback, noble-metal platinum (Pt) is generally required in CTF-based photocatalytic systems as the HER cocatalyst for promoting charge separation and catalyzing hydrogen generation.^13–15 However, the high cost and scarcity of metallic Pt greatly limit the large-scale commercial applications. Thus, it is highly desirable to explore economical materials as noble-metal substitutes for achieving comparable or even superior hydrogen evolution activities.Recently, transition-metal phosphides (TMPs) have attracted intensive attention as HER cocatalysts for photocatalytic water splitting, owing to their unique structural and electronic properties.^16–20 Up to now, a variety of semiconductor materials, including metal oxides,^21,22 metal sulfides,^23,24 g-C₃N₄,^25,26 MOFs,^27,28etc., decorated with TMPs have been extensively investigated, and the hydrogen generation activity in some reports is even higher than that of Pt cocatalysts. However, related studies about the decoration of TMP cocatalysts on CTF photocatalysts for highly efficient hydrogen generation have not been reported so far. Taking into account the molecular structure of CTFs, the nitrogen sites in the triazine frameworks could easily coordinate with transition metal ions to form nitrogen–metal interactions.^29–31 In contrast, the coordination of TMPs with CTFs is relatively difficult owing to the high electronegativity of P sites which could draw electrons from metal atoms.¹⁷ Moreover, most reported TMPs were fabricated directly from precursor metal salts, oxides, etc.,^32–35 and the resultant large-dimensions usually lead to very limited contact-interface with CTFs, or even a physical mixture form. Accordingly, the charge transfer between TMPs and CTFs is significantly restrained. Thus, effective anchoring of TMPs on CTFs for achieving highly efficient photocatalytic hydrogen evolution still remains a great challenge.Herein, a one-step phosphidation strategy has been developed to achieve phosphorus bonding with the benzene rings of CTFs and the anchoring of well-defined dicobalt phosphide (Co₂P) nanocrystals (∼7 nm). The photocatalytic results clearly reveal that an excellent hydrogen evolution activity (7.6 mmol h⁻¹ g⁻¹) is achieved, which is much higher than that of the CTF/Co₂P composite (0.37 mmol h⁻¹ g⁻¹). More detailed studies confirm that the phosphidation strategy could effectively facilitate the interfacial bonding between CTFs and Co₂P nanocrystals. More importantly, the SI-XPS results clearly suggest that the charge transfer direction in CTFs is completely reversed, and the photo-generated electrons efficiently transferred from the triazine rings to P-bonded benzene rings, where the Co₂P cocatalyst attracted electrons through the interfacial P–C bonds for efficient hydrogen evolution. To our knowledge, this is the first report on incorporating TMPs on a CTF photocatalyst for enhancing the hydrogen evolution activity. Fig. 1A shows the basic procedures for the preparation of CTF polymer anchored Co₂P nanocrystals. Briefly, the CTFs with adsorbed cobalt ions were directly phosphatized by thermal decomposition of NaH₂PO₂ under an Ar atmosphere, which could simultaneously achieve P atom bonding with benzene rings and the anchoring of the Co₂P cocatalyst (marked as P-CTF-Co₂P). Fig. 1B shows the typical transmission electron microscopy (TEM) image of the obtained sample, clearly revealing that well-defined Co₂P nanocrystals with an average diameter of 5∼9 nm were uniformly dispersed on the CTF surface. Furthermore, the high-resolution TEM (HR-TEM) image (Fig. 1C) of the formed nanocrystals exhibited two lattice fringes with d-spacing values of 0.20 and 0.21 nm, respectively, which could be well indexed to the (211) and (121) planes of orthorhombic Co₂P crystals.^36,37Fig. 1D shows the X-ray diffraction (XRD) pattern of the obtained P-CTF-Co₂P sample. For comparison, the pristine CTF, and Co₂P nanocrystals have also been studied. It can be clearly seen that for the P-CTF-Co₂P sample, except for the two broad diffraction peaks at 7.3° and 26.1° attributed to the in-plane (100) facets and interlayer (001) stacking of CTFs,^38,39 the other XRD peaks well matched with those of the Co₂P crystals,^40,41 confirming the successful incorporation of the Co₂P cocatalyst in the CTFs. Furthermore, energy-dispersive X-ray (EDX) elemental mapping (Fig. 1E) clearly reveals the uniform distribution of C, N, Co and P elements in the whole detection region, further confirming the uniform dispersion of Co₂P on CTF polymers.Open in a separate windowFig. 1(A) Basic procedures and the ideal structure scheme for fabricating P-CTF-Co₂P catalysts; (B) TEM image and (C) HR-TEM image of the P-CTF-Co₂P catalyst; (D) XRD patterns of CTFs, Co₂P and P-CTF-Co₂P catalysts; (E) EDX elemental mapping images of the P-CTF-Co₂P catalyst.To further explore the P-bonding sites, high-resolution X-ray photoelectron spectroscopy (XPS) was performed on both P-CTF-Co₂P and pristine CTFs. As shown in Fig. 2A, for pristine CTF samples, the C 1s peak could be well fitted into two peaks located at 284.8 and 286.8 eV, which could be assigned to C–C C and N–C N bonds,^38,39,42 respectively. Notably, after the phosphidation treatment, a new peak at 285.3 eV attributed to P–C bonds was detected in the P-CTF-Co₂P sample,^43–45 and the C–C C to N–C N ratio was significantly decreased from 10.2 (pristine CTFs) to 7.1 (P-CTF-Co₂P). In contrast, compared with the N 1s spectrum of the pristine CTF sample, no evident change of peak shape and intensity could be detected in the P-CTF-Co₂P sample (Fig. 2B). These results clearly reveal that after the phosphidation treatment, P atoms should mainly bond with the carbon sites of the benzene rings in CTFs instead of the triazine rings.^46,47 To further confirm this inference, XPS studies on phosphatized CTFs without Co₂P nanocrystals (marked as P-CTFs) were also performed. It can be clearly seen from Fig. S9^† that similar changes for the C 1s and N 1s peaks of P-CTF-Co₂P (Fig. 2A and B) are observed in the P-CTF sample. Moreover, in both P-CTF-Co₂P and P-CTF samples, an evident P 2p peak corresponding to P–C bonds could be observed (Fig. 2C),⁴⁸ further indicating the bonding of P atoms with C atoms on the benzene rings in CTFs after the phosphidation treatment. However, note that the binding energy (BE) position of P–C peaks in P-CTF-Co₂P (133.6 eV) is slightly higher than that of P-CTF (133.2 eV), which should be attributed to the anchoring with Co₂P nanocrystals. In addition to the XPS investigations, solid-state cross-polarization magic angle spinning carbon-13 and phosphorus-31 nuclear magnetic resonance (¹³C-NMR and ³¹P-NMR) spectroscopy studies were further performed to explore the bonding sites of phosphorus atoms in the P-CTF (Fig. S10^†). The Fourier-transformed infrared (FTIR) spectrum was also employed (Fig. 2D). It can be clearly observed that the typical FTIR peaks of the triazine frameworks and the stretching vibrations of carbon–nitrogen (C–N) (1521 cm⁻¹ and 1354 cm⁻¹) in P-CTF-Co₂P are consistent with those of pristine CTFs.^38,39 However, the peaks at 1672 cm⁻¹ and 1014 cm⁻¹ corresponding to the stretching vibrations of C C and C–H in benzene rings were evidently decreased in P-CTF-Co₂P compared with those of pristine CTFs.^49,50 Combining the results of XPS, NMR, and FTIR, it can be concluded that in the obtained P-CTF-Co₂P sample, the carbon sites of the benzene rings in the CTFs were partially bonded with P-atoms, which should anchor Co₂P through P–Co bonding.Open in a separate windowFig. 2High-resolution XPS spectra of (A) C 1, (B) N 1s and (C) P 2p in CTF, P-CTF and P-CTF-Co₂P samples (the insets show the molecular structures); (D) Fourier transform infrared spectroscopy (FT-IR) of CTF and P-CTF-Co₂P samples.Furthermore, the hydrogen evolution activities of the P-CTF-Co₂P (2 wt% Co₂P) sample were evaluated under simulated solar light irradiation. For comparison, the CTF/Co₂P composite and pristine CTFs were also measured under the same conditions. As shown in Fig. 3A, the P-CTF-Co₂P sample exhibits a much higher H₂ evolution activity (15.2 mmol g⁻¹) than the CTF/Co₂P composite (0.7 mmol g⁻¹) at 2 h, while no evident hydrogen generation could be detected in the pristine CTF sample. To further explore the crucial roles of interfacial P-bonding in CTFs and the anchoring of the Co₂P cocatalyst, the hydrogen evolution rates of various samples were calculated and their comparison is shown in Fig. 3B. Obviously, compared with the excellent activity of P-CTF-Co₂P (7.6 mmol h⁻¹ g⁻¹), CTF/Co₂P and P-CTF/Co₂P only exhibit very low hydrogen evolution rates of 0.37 and 0.38 mmol h⁻¹ g⁻¹, respectively, while no evident activity could be detected for CTFs, Co₂P, and P-CTF samples. The above results clearly confirm that the significant enhancement of the hydrogen evolution activity of the P-CTF-Co₂P sample should be mainly attributed to the P-bonding and the anchoring of the Co₂P cocatalyst. Furthermore, the photocatalytic performances of CTFs decorated with Pt nanoparticles were also studied (the inset of Fig. 3B, Fig. S15^†), as Pt is generally recognized as the most active cocatalyst for hydrogen generation. Amazingly, the hydrogen production rates of the Pt cocatalyst at different amounts (1∼5 wt%) were all lower than that of the P-CTF-Co₂P sample, indicating that the rational bonding of the Co₂P cocatalyst on CTFs should be a promising strategy for achieving highly efficient photocatalytic hydrogen evolution.Open in a separate windowFig. 3(A) Photocatalytic H₂ evolution tests of the as-prepared photocatalysts; (B) comparative presentation of the hydrogen evolution rates; (C) ultraviolet-visible diffuse reflectance spectrum of the P-CTF-Co₂P photocatalyst (red solid line) and wavelength-dependent hydrogen production activities of the P-CTF-Co₂P photocatalyst within 2 h; light source: a 300 W Xe lamp equipped with various cut-off filters. (D) The cycling photocatalytic tests of P-CTF-Co₂P and the CTF/Co₂P composite; (E) I–t curves of various catalysts at −0.3 V (vs. SCE); (F) electrochemical impedance spectroscopy under light of the various catalysts. Measurements were conducted in 0.2 mol L⁻¹ Na₂SO₄ electrolyte solution under AM 1.5 G illumination.Furthermore, the relationship between wavelength and the hydrogen evolution activity of the P-CTF-Co₂P photocatalyst was studied and is shown in Fig. 3C. With increasing the wavelength from full-spectrum light irradiation (λ > 300) to 500 nm, the hydrogen evolution rate significantly decreased from 7.6 to 0.06 mmol h⁻¹ g⁻¹, which is generally consistent with their absorption spectrum. The highest value of the apparent quantum yields (AQYs) attained is 31.8% at 365 nm. Moreover, the photocatalytic stability and durability of P-CTF-Co₂P and CTF/Co₂P were examined by cycling experiments. As shown in Fig. 3D, the CTF/Co₂P composite demonstrated relatively poor stability, and there is no evident activity after only one cycling experiment, resulting from the incompact combination between CTFs and Co₂P (Fig. S5^†). In contrast, the P-CTF-Co₂P sample exhibits relatively high stability, and no evident inactivation was detected during the whole test. These results further confirm that in addition to enhancing activities, the interfacial P–C bonds and the anchoring of the Co₂P cocatalyst could also effectively promote the hydrogen evolution stability. To further confirm the efficient charge separation and electron transfer in P-CTF-Co₂P, photoelectrochemical (PEC) tests were performed. As shown in Fig. 3E, the amperometric I–t curves clearly reveal that P-CTF-Co₂P exhibits higher photocurrent density than pristine CTFs and CTF/Co₂P samples, confirming its more efficient charge separation capability. Moreover, electrochemical impedance spectroscopy (EIS) was also performed to explore the interfacial charge transfer process.^51,52 As shown in Fig. 3F, the P-CTF-Co₂P sample with the smallest arc radius revealed remarkably increased interfacial charge transport efficiency. These PEC results clearly demonstrate the highly efficient photogenerated charge separation and transfer in the P-CTF-Co₂P photocatalyst, which are highly consistent with the above photocatalytic hydrogen evolution results.The photo-induced charge separation and transfer in the excited state are crucial processes for determining the photocatalytic activity. Herein, we have demonstrated an in situ irradiation X-ray photoelectron spectroscopy (SI-XPS) technique for exploring the intrinsic charge separation and transfer mechanisms between Co₂P and CTFs. As shown in Fig. S20 and S21,^† no evident binding energy (BE) shift could be observed in both pristine CTF and Co₂P samples, confirming their relatively poor charge separation capability. Amazingly, for the P-CTF-Co₂P sample (Fig. 4), distinct variations for C 1s, N 1s, P 2p, and Co 2p peaks were detected in the excited state. More specifically, the C 1s and N 1s peaks in the CTFs shifted towards the high BE region by 0.3 eV accompanied by the broadening of peak shape (Fig. 4B and C), while the P 2p and Co 2p peaks of the Co₂P cocatalyst shifted towards the low BE direction by 0.3 and 0.4 eV (Fig. 4D and E), respectively.Interestingly, as shown in Fig. 4D, the P 2p peaks attributed to interfacial P–C bonds exhibited no evident BE change under dark and light irradiation. On the basis of the above SI-XPS results, it can be concluded that under light irradiation, the photo-excited electrons effectively transferred from CTFs to Co₂P through the P-bonding sites as well as the interfacial P–C bonds, leading to electron enrichment in Co₂P nanocrystals and hole enrichment in CTFs. To further confirm the crucial roles of interfacial P-bonding in CTFs and the anchoring of the Co₂P cocatalyst in promoting charge separation, SI-XPS studies for the CTF/Co₂P composite were also conducted. As shown in Fig. S22,^† no new peak or shape change of C 1s, N 1s, P 2p, and Co 2p peaks could be detected in CTF/Co₂P compared with pristine CTFs and Co₂P in the ground state, indicating no interfacial bonding in the CTF/Co₂P composite. Furthermore, in the excited state, no evident BE shifts and shape change could be observed, indicating the poor charge-separation capability of CTF/Co₂P, which is highly consistent with its fairly low hydrogen evolution activity. These SI-XPS results further confirm the crucial roles of interfacial P-bonding in CTFs and the anchoring of the Co₂P cocatalyst in efficiently promoting charge separation and enhancing the photocatalytic activity.Open in a separate windowFig. 4(A) Schematic illustration of the SI-XPS technique for direct observation of electron transfer in the excited state. The (B) C 1s, (C) N 1s, (D) P 2p and (E) Co 2p of SI-XPS spectra in the P-CTF-Co₂P sample tested under dark and light illumination.On the basis of the above results, it can be concluded that the P-bonding and Co₂P-cocatalyst anchoring should reverse the photo-induced electron transfer direction from the triazine to benzene rings in CTFs. To further confirm this speculation, the photocatalytic behavior of various CTF-based photocatalysts was studied and their electron transfer directions in excitation states have been proposed (Fig. 5A and B). First, when Co²⁺ ions were further bonded with the N sites of the triazine rings in the P-CTF-Co₂P sample (marked as P-CTF-Co₂P-Co), the hydrogen evolution activity remarkably increased from 7.6 up to 8.4 mmol h⁻¹ g⁻¹. This result clearly reveals that the Co–N bonding in P-CTF-Co₂P could further promote charge separation due to the effective hole trapping on Co sites. In contrast, when the Pt cocatalyst was decorated on the P-CTF-Co₂P sample (marked as P-CTF-Co₂P–Pt) to form Pt–N coordination, the photocatalytic activity significantly decreased to 4.6 mmol h⁻¹ g⁻¹, mainly resulting from the electron transfer competition between Pt and Co₂P. Furthermore, the decoration of the single Pt cocatalyst on CTFs promoted the photo-induced electron transfer from the benzene rings to triazine rings, and the photocatalytic activity achieved was up to 3.8 mmol h⁻¹ g⁻¹. Furthermore, in situ FTIR spectroscopy was performed for exploring the intermediate products in the photocatalytic process of the P-CTF-Co₂P sample with co-adsorption of H₂O vapor (Fig. S27^†), which also demonstrated the direction of electron transfer combined with the in situ XPS results. Accordingly, a possible mechanism has been proposed for clarifying the hydrogen evolution activities of the P-CTF-Co₂P photocatalyst (Fig. 5B). Owing to the P-bonding and the anchoring of Co₂P nanocrystals, the photo-generated electrons could effectively transfer from the triazine rings to benzene rings, where the electrons are trapped by the Co₂P cocatalyst through the interfacial P–C bonds for the hydrogen evolution reaction. Simultaneously, the holes left behind in the CTFs participated in oxidation reactions. More importantly, this mechanism may provide a new insight for understanding the crucial roles of interfacial P-bonding in CTFs and their bonding with Co₂P in promoting the charge separation for efficient hydrogen evolution.Open in a separate windowFig. 5(A) Photocatalytic hydrogen evolution activities of various samples and the scheme of electron-transfer direction in the excited state. (B) The ideal structural illustration of the interfacial bonding and charge transfer of the P-CTF-Co₂P photocatalyst for hydrogen evolution.     

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

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

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

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

Oxindole synthesis via polar–radical crossover of ketene-derived amide enolates in a formal [3 + 2] cycloaddition

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates. Various easily accessible N-alkyl and N-arylanilines are added to disubstituted ketenes and the resulting amide enolates undergo upon single electron transfer oxidation a homolytic aromatic substitution (HAS) to provide 3,3-disubstituted oxindoles in good to excellent yields. A variety of substituted anilines and a 3-amino pyridine engage in this oxidative formal [3 + 2] cycloaddition and cyclic ketenes provide spirooxindoles. Both substrates and reagents are readily available and tolerance to functional groups is broad.

Herein we introduce a simple, efficient and transition-metal free method for the preparation of valuable and sterically hindered 3,3-disubstituted oxindoles via polar–radical crossover of ketene derived amide enolates.

Oxindoles, in particular the 3,3-disubstituted congeners, are highly valuable substructures in medicinal chemistry. The oxindole core can be found in various biologically active compounds, that are for example used in the treatment of cancer or as antibacterial agents.¹ In addition, the oxindole moiety also occurs in several complex natural products.² The first oxindole synthesis was reported by Baeyer and Knop in 1866.³ That time, isatin was converted by sodium amalgam reduction to the corresponding oxindole. Since then, many methods for the preparation of 3,3-disubstituted oxindoles have been developed that proceed via functionalization of a pre-existing oxindole core.⁴ In addition, methods for the construction of 3,3-disubstituted oxindoles starting from acyclic precursors have also been introduced.^5,6 Along these lines, transition metal-mediated reactions^5,7 or homolytic aromatic substitutions (HAS)^8–14 have found to be highly efficient for the construction of the oxindole core. Focusing on the latter approach, the intramolecular HAS proceeds via α-carbonyl radicals derived from radical addition to N-arylacrylamides,⁸ reduction of α-haloarylamides⁹ or oxidation of the corresponding enolates^10–14 (Scheme 1a).Open in a separate windowScheme 1Selected strategies for the synthesis of oxindoles.In 2017, the group of Taylor developed a transition metal-free enolate oxidation-HAS-approach towards oxindoles at low temperature using elemental iodine as the oxidant and malonic acid derived N-aryl amides as substrates which are readily deprotonated.¹⁴The unique reactivity of ketenes¹⁵ has been explored extensively,¹⁶ especially in [2 + 2]-cycloadditions.¹⁷ Moreover, Staudinger,¹⁸ Lippman¹⁹ and Taylor²⁰ showed that ketenes react with aryl nitrones in a tandem [3 + 2]-cycloaddition-[3,3]-sigmatropic-rearrangement cascade²¹ followed by hydrolysis to provide oxindoles (Scheme 1b). The use of chiral nitrones leads to chirality transfer and enantiomerically enriched oxindoles can be obtained via this approach.^21,22 In contrast to the examples discussed in Scheme 1a, two σ-bonds are formed and the overall sequence can be regarded as a formal [3 + 2] cycloaddition. Despite good yields and high enantiomeric excess, nitrones have to be used as precursors and an aldehyde is formed as the byproduct diminishing reaction economy of these elegant cascades.To address these drawbacks, we decided to use the nucleophilic addition^23–26 of deprotonated anilines to ketenes for the generation of the corresponding amide enolates that should then be oxidized in a single electron transfer process to α-amide radicals which can undergo a homolytic aromatic substitution providing direct access to sterically challenging 3,3-disubstituted oxindoles in a straightforward one-pot sequence (Scheme 1c). This polar–radical crossover reaction shows high atom economy and as the reaction with the nitrones can also be regarded as a formal [3 + 2] cycloaddition.We initiated the optimization study with N-methylaniline 1a and ethyl phenyl ketene 2a, which was prepared in an easy and scalable one-pot protocol starting from the corresponding carboxylic acid, as model substrates. Deprotonation of 1a with n-BuLi in THF and subsequent addition to the ketene 2a led to desired Li-enolate which was confirmed by protonation with water and isolation of the amide 4aa (56%). Pleasingly, addition of ferrocenium hexafluorophosphate (FcPF₆, 2.2 equiv.) at room temperature to the Li-enolate afforded the desired oxindole 3aa in 29% yield (14 Light does not appear to play a crucial role in this transformation, as performing the reaction in the dark does not have a significant effect on the reaction outcome ( EntryBaseConc. (M)Oxidant (equiv.)Yield 3aa (%)^b1 n-BuLi0.1FcPF₆ (2.2)29 (18)^c2^d n-BuLi0.1CuCl₂ (2.2)34^c3 n-BuLi0.1I₂ (2.2)41^c4EtMgBr0.1I₂ (2.2)44^c5EtMgBr0.02I₂ (2.2)78 6 EtMgBr 0.01 I ₂ (2.2) 90 (82) ^c 7EtMgBr0.01I₂ (1.2)258EtMgBr0.01NIS^e (2.2)399EtMgBr0.01I₂ (1.2)^f8010EtMgBr0.01I₂ (2.2)^g8211EtMgBr0.01I₂ (2.2)^h7412EtMgBr0.01I₂ (2.2)ⁱ93Open in a separate window^aReactions (0.20 mmol) were conducted under argon atmosphere.^{b 1}H NMR yield using 1,3,5-trimethoxybenzene as internal standard.^cIsolated yield.^dStep 1 and 2 were conducted at 0 °C.^e N-Iodosuccinimide.^fIodine addition at −78 °C, then slowly allowed to warm to room temperature.^14gIn the dark.^hIrradiation with blue LED (40 W, 467 nm, rt, 8 h).ⁱRefluxing THF for step 3, reaction completed within 2 h.With the optimized reaction conditions in hand, we investigated the scope by first varying the R¹-substituent at the N-atom using the ketene 2a as the reaction partner (Scheme 2). In general, increasing the steric bulk at the nitrogen leads to diminished yields of the targeted oxindoles. The lower yields go along with the formation of a larger amount of the corresponding α,β-unsaturated amide side product 5. Thus, as compared to the parent N-methyl derivative, all other N-alkyl derivatives were formed in lower yields (49%, 3ab; 35%, 3ac; 49%, 3ad). The N-benzyl protected oxindole 3af and the N-phenyl oxindole 3ae were isolated in 54% and 56% yield, respectively. Next, a diastereoselective oxindole synthesis was attempted using chiral anilines 1g and 1h. Surprisingly, despite the bulkiness of these nucleophiles containing styryl-type N-substituents, good yields were obtained for the oxindoles 3ag and 3ah (73–79%). Unfortunately, diastereocontrol was low in both cases (1.9 : 1 d.r. and 1.5 : 1 d.r.). Of note, addition of Mg-1g and Mg-1h to ketene 2a was rather slow under the standard reaction condition and a significant amount of unreacted aniline was recovered. That problem could be solved by prolonging the reaction time of both step 1 (deprotonation) and also step 2 (Mg-enolate formation).Open in a separate windowScheme 2Substrate scope – variation of substituents at the nitrogen. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a For step 1 and 2 reaction time was 1 h.Next, the substrate scope was investigated by using different anilines in combination with the ketene 2a (Scheme 3). N-Methyl-p-toluidine 1i and N-methyl-p-haloanilines 1j–m could be successfully transformed to the corresponding oxindoles 3al–am in moderate to good yields (53–87%). Electron-withdrawing and also electron-donating substituents are tolerated and oxindoles derived from p-cyano- (3an, 92%), p-acetyl- (3ao, 30%), p-methoxycarbonyl- (3ap, 82%) and p-methoxy- (3aq, 71%) anilines were isolated in moderate to excellent yields documenting a high functional group tolerance of this reaction. The meta-methyl aniline afforded oxindole 3ar in 76% yield as a 1.8 : 1 mixture of the two regioisomers (only the major isomer drawn). For the pyridyl derivative 3as, a lower yield was obtained (39%), but reaction occurred with complete regiocontrol. Of note, ortho-methyl N-methylaniline provided the corresponding oxindole only in trace amounts (not shown).Open in a separate windowScheme 3Substrate Scope – variation of anilines and ketenes. Reactions (0.20 mmol) were conducted under argon atmosphere. ^a Isolated as an inseparable mixture (1 : 1.4) with the protonated enolate 4fa (56% combined yield).The ketene component was also varied using N-methylaniline 1a as the reaction partner. The transformation of methyl phenyl ketene 2b provided the oxindole 3ba in 58% yield. p-Bromophenyl ethyl ketene 2c and p-iodophenyl ethyl ketene 2d afforded the oxindoles 3ca and 3da in good yields (70% and 76%). For the ibuprofene-derived ketene 2e a lower yield was obtained (3ea, 40%) and the bulkier phenyl isopropyl congener 3fa was isolated in 27% yield as an inseparable mixture with the protonated enolate 4fa (56% combined yield). In the latter case, increasing the reaction time did neither lead to a higher yield of 3fa nor to a suppression of the formation of 4fa. The lower yield is likely caused by steric effects. Surprisingly, diphenyl ketene 2g delivered the targeted oxindole 3ga in acceptable 55% yield despite the steric demand of the two phenyl groups and the high stability of the corresponding α-amide radical. Spirocyclic oxindoles are of great interest due to their high pharmaceutical potential.²⁷ We were pleased to find that our method also works for the preparation of such spiro compounds as documented by the successful synthesis of 3ha (26%).Mechanistically, we propose initial formation of the enolate A by nucleophilic attack of the deprotonated aniline to the ketene 2, which is then oxidized by elemental iodine to the α-amide radical B (pathway b). The radical nature of the transformation is supported by the fact that electronic effects on the arene show no influence on the efficiency of the cyclization, as would be shown by a conceivable polar aromatic substitution. Radical B readily cyclizes onto the aniline ring to generate the cyclohexadienyl radical D which is oxidatively rearomatized via cationic intermediate E to finally give the oxindole 3 (Scheme 4).^10–14 Alternatively, enolate A can be iodinated with I₂ to give the unstable iodide C which then undergoes C–I bond homolysis to generate the radical B (pathway a). Indeed, Taylor and coworkers¹⁴ observed under similar reaction conditions the decay of α-iodinated compounds of type Cvia C–I homolysis^14,28 to give radicals of type B. Usually, we observed α,β-unsaturated amides analogous to 5aa as by-products. However, the corresponding protonated enolates were detected only in tiny amounts in most of these cases. This strongly suggests that those amides are not formed via disproportionation of radical B. HI-elimination seems more likely, pointing towards the presence of the iodinated species C and thus the contribution of pathway b to product formation. In addition, dimerization of radical B was also not observed.Open in a separate windowScheme 4Suggested mechanism.To further support pathway b, isolation of the iodinated intermediate C was attempted at low temperature. Upon addition of iodine (1.2 equiv.) to the preformed Mg-enolate A derived from aniline 1a and ketene 2a at −78 °C,¹⁴ TLC analysis showed a clean conversion to a single new compound, which was analyzed by rapid ESI-MS analysis and provided evidence for the formation of the iodinated intermediate C (Scheme 5). However, isolation of this highly unstable compound was not possible due to rapid HI-elimination to the amide 5aa. Note that oxindole formation worked well upon I₂-addition at −78 °C and subsequent warming to room temperature (see Scheme 5). This is consistent with the observation from our optimization studies that irradiation with blue light does not contribute to the yield of oxindole 3aa (Open in a separate windowScheme 5Mechanistic experiments. (a) (1) EtMgBr (1.1 equiv.), rt, 30 min, (2) 2a (1.5 equiv.), −78 °C, 30 min, (3) I₂ (1.2 equiv.), −78 °C, 15 min in THF (0.01 M). (b) Warm to room temperature in THF (0.01 M), 18 h. (c) NaI (1.2 equiv.) in acetone (0.77 M), rt, 18 h. (d) Irradiation with blue LED (40 W, 467 nm) in THF (0.01 M), rt, 8 h.     

Ligand-dependent,palladium-catalyzed stereodivergent synthesis of chiral tetrahydroquinolines

The most fundamental tasks in asymmetric synthesis are the development of fully stereodivergent strategies to access the full complement of stereoisomers of products bearing multiple stereocenters. Although great progress has been made in the past few decades, developing general and practical strategies that allow selective generation of any diastereomer of a reaction product bearing multiple stereocentres through switching distinct chiral catalysts is a significant challenge. Here, attaining precise switching of the product stereochemistry, we develop a novel P-chirogenic ligand, i.e.YuePhos, which can be easily derived from inexpensive and commercially available starting materials in four chemical operations. Through switching of three chiral ligands, an unprecedented ligand-dependent diastereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-arylidene succinimides was developed. This novel method provides an efficient route for the stereodivergent synthesis of six stereoisomers of pyrrolidines bearing up to three adjacent stereocenters (one quaternary center). Despite the anticipated challenges associated with controlling stereoselectivity in such a complex system, the products are obtained in enantiomeric excesses ranging up to 98% ee. In addition, the synthetic utilities of optically active hexahydrocarbazoles are also shown.

An unprecedented ligand-dependent stereodivergent Pd-catalyzed asymmetric intermolecular [4 + 2] cycloaddition reaction of vinyl benzoxazinanone with α-aryliene succinimides was developed.

The chirality of a biologically active molecule can alter its physiological properties. Therefore, highly efficient access to and fully characterizing all possible stereoisomers of a chiral molecule is one of the fundamental challenges in organic synthesis, drug discovery and development processes. However, most asymmetric catalytic transformations afford products enantioselectively and diastereoselectively and only form one of the stereoisomers containing multiple stereocenters. Stereodivergent access to all possible stereoisomers of the products is incredibly difficult because diastereochemical preference is largely dominated by the inherent structural and stereoelectronic characteristics of substrates, while absolute conformation can be dictated by the choice of the chiral catalyst.¹ In 2013, Carreira and co-workers addressed this limitation by introducing the concept of stereodivergent dual-catalytic synthesis, reporting the allylation of aldehydes in a diastereodivergent fashion by the synergistic reactivity of iridium and amine catalysts under acidic conditions.² Soon after, Carreira,³ Zhang,⁴ Hartwig,⁵ Dong,⁶ Wang,⁷ Zi,⁸ Lee,⁹ and other groups¹⁰ reported using an appropriate combination of dual chiral catalysts in a series of elegant studies (Scheme 1A). Recently, chemists found, in some cases, that tuning non-chiral parameters, including solvents or additives, also controlled the stereochemical outcomes through subtle perturbation of the key diastereomeric transition states.¹¹ In 2018, You and co-workers reported a solvent-controlled palladium-catalyzed enantioselective dearomative formal [3 + 2] cycloaddition, affording stereodivergent synthesis of two diastereomeric tetrahydrofuroindoles.¹² However, a rapid and predictable way to access complete stereoisomers of products bearing multiple stereocentres (for example, three contiguous stereocentres) remains an unsolved challenge through switching of ligands. To the best of our knowledge, only two successful examples were reported by Buchwald and Zhang, in which eight stereoisomers were obtained through tuning catalysts and reactive substrates (Scheme 1B).^4a,13Open in a separate windowScheme 1Strategy for stereodivergent synthesis of different stereoisomers.In metal-catalyzed reactions, ligands can manipulate the reactivity and selectivity by affecting the steric and electronic properties of metal catalysts. Therefore, the design and development of new ligands to improve the utility, activity and selectivity of their related metal catalysts are greatly desired by organic chemists. Recently, our groups have synthesized a new and promising class of P-chiral ligands ZD-Phos (including Ganphos and Jiaphos), and their conformational rigidity and chemical robustness have endowed the structure and its variants with outstanding activity and selectivity as well as excellent stereocontrol features essential to asymmetric cycloaddition reactions.¹⁴ Inspired by these advances, we are interested in continuing the development of P-chiral ligands with new structural motifs in the search for new reactivity and selectivity to tackle current synthetic challenges. More recently, Sadphos has emerged as another superior chiral skeleton, owing to the pioneering contributions by Zhang.¹⁵ Thus its aminophosphine scaffold is envisaged to be introduced into our 1-phosphanorbornene framework (ZD-Phos).¹⁶ We aim to combine the advantages of the aforementioned two types of chiral motifs, thus developing a novel P,P-bidentate ligand. Thus the novel P-chiral ligands, called Yuephos, may show unique stereoselectivity in a metal-catalyzed asymmetric cycloaddition reaction (Fig. 1).Open in a separate windowFig. 1Design of the Yuephos framework.Tetrahydroquinolines are important molecular skeletons that widely occur in natural molecules, pharmaceuticals, and functional materials. For this reason, realizing stereodivergent synthesis of all stereoisomers of fully substituted tetrahydroquinolines has been an important and challenging task in organic synthesis. However, to date, full control of absolute and relative stereochemical configuration of these molecules has remained an unmet synthetic challenge. Considering the potentiality of fully substituted chiral tetrahydroquinolines in drug discovery and stereodivergent synthesis,¹⁷ we envisioned that using our new palladium/ZD-Phos catalytic system may offer an efficient strategy for overcoming the challenges related to regio-, enantio-, and diastereo-selectivity. Herein, we report our studies on the unexplored stereodivergent synthesis of fully substituted tetrahydroquinolines through ligand-controlled, metal-catalyzed asymmetric annulation. Six possible stereoisomers bearing two tertiary and one quaternary stereocenters were easily synthesized in good yields with high enantio- and diastereo-selectivities from the same starting materials (Scheme 1C).The new bisphosphorus ligands we report herein can be easily synthesized by a two-pot method with good yields (Scheme 2). Starting from the corresponding aldehyde¹⁸ and commercially available chiral amine, one-pot sequential reaction gave diastereomers Y1 and Y1′ with 1 : 1 dr, which could be straightforwardly separated by column chromatography. The subsequent reduction using Raney Ni produced the final Yuephos in good yields. The absolute configuration of Yue-1′ was established by single crystal X-ray diffraction.¹⁹ Importantly, the ligands Yuephos can remain stable in air and moisture for more than one year.Open in a separate windowScheme 2Synthesis of Yuephos ligands.With new Yuephos ligands in hand, we began our study by choosing vinyl benzoxazinanone 1a with α-phenylidene succinimide 2a as the model substrate, combined with the Pd₂dba₃·CHCl₃/L complex as the catalyst. Details of [Pd] source and solvent screening can be found in the ESI (Table S1 and S2^†). Notably, using Pd₂dba₃·CHCl₃/Yuephos as the catalyst in ethyl acetate, the reaction proceeded smoothly, affording the desired product 3a in 69% yield with 96% ee and >20 : 1 dr (entry 1). It should be noted that Yuephos ligands were found to be efficient for this reaction, and the product 3a was obtained in good enantioselectivity with seemingly irregular yields and diastereoselectivities (entries 2–6). Trost''s ligand (L1) and chiral diphosphine ligand (L2) promoted the reaction with good diastereoselectivity but in a low yield and poor enantioselectivity (entries 7–8). However, (R)-SegPhos (L3) failed to afford the desired product (entry 9). To our surprise, when the phosphoramidite ligand (L4) was used, the diastereoselectivity was reversed compared to that in Yuephos (entry 10). Thus, a diastereodivergent phenomenon induced by the chiral ligand was discovered. To further improve the yield and selectivity, various solvents and [Pd] sources were screened (Table S3 and S4 in the ESI^†), and an obvious improvement in the enantioselectivity and diastereoselectivity was observed when using DCM as the solvent (entries 10 vs. 11). The reaction enantioselectivity was further increased to 92% with good yield (85%) when the reaction temperature was reduced to −20 °C (entries 12–14).With the optimal conditions established for (S, R, S)-3a (20Optimization of reaction conditions^a

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

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

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

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

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

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

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

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