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6.

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

Chaohai Wang Hongyu Wang Jongbeom Na Yiyuan Yao Alowasheeir Azhar Xin Yan Junwen Qi Yusuke Yamauchi Jiansheng Li 《Chemical science》2021,12(46):15418

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 window Fig. 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 window Fig. 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 window Fig. 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.³⁴ Open in a separate window Fig. 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˙⁻. 相似文献

7.

Development of an enolate alkynylation approach towards the synthesis of the taiwanschirin natural products

Maxwell B. Haughey Kirsten E. Christensen Darren L. Poole Timothy J. Donohoe 《Chemical science》2021,12(40):13392

相似文献

8.

Do carbon nanotubes catalyse bromine/bromide redox chemistry?

Archana Kaliyaraj Selva Kumar Ruiyang Miao Danlei Li Richard G. Compton 《Chemical science》2021,12(32):10878

The redox chemistries of both the bromide oxidation and bromine reduction reactions are studied at single multi-walled carbon nanotubes (MWCNTs) as a function of their electrical potential allowing inference of the electron transfer kinetics of the Br₂/Br⁻ redox couple, widely used in batteries. The nanotubes are shown to be mildly catalytic compared to a glassy carbon surface but much less as inferred from conventional voltammetry on porous ensembles of MWCNTs where the mixed transport regime masks the true catalytic response.

Schematic of a carbon nanotube impact in bromide solution.

The bromine–bromide redox couple plays an essential role in diverse energy storage devices including hydrogen–bromine, zinc–bromine, quinone–bromine, vanadium–bromide and bromide–polysulphide flow batteries.^1–5 The Br₂/Br⁻ redox couple is attractive as a cathode reaction due to its high standard potential, large solubility of both reagents, high power density and cost efficiency.⁶ The performance of such devices is generically limited by the thermodynamics and kinetics of the redox couple comprising the battery with fast (‘reversible’) electron transfer is essential. In many cases, including the Br₂/Br⁻ couple the electrode reaction involves more than one electron as given in the stoichiometric reaction:2Br⁻ − 2e⁻ ⇄ Br₂; E⁰ = 1.08 V vs. SHEwith, at high bromide concentrations, the possibility of the follow up chemical reaction⁷Br₂ + Br⁻ ⇄ Br₃⁻Since electrons are usually transferred sequentially this implies that the mechanism is multistep with any of the individual mechanistic steps in principle being rate limiting. For this reason catalysts are commonly required to enhance the electrode kinetics at otherwise favourable electrode materials. One type of catalyst which has seen wide usage, including for the Br₂/Br⁻ couple^8,9 are carbon nanotubes (CNTs) with suggested advantages which include high surface area and the inherent porosity of CNT composites.¹⁰ The deployment of CNTs as a porous composite presents a further level of complexity to the electrode reaction beyond its multistep character because of the ill-defined mass transport within the porous layer. In particular ascertaining the intrinsic electron transfer kinetics and hence the level of catalysis, if any, is essentially impossible since these are masked in the voltammetric response by diffusional mass transport effects.^11–14 Specifically the transport within the porous structure of CNT layers is dominated by thin-layer and other^15,16 effects which give the illusion of electrochemical reversibility. In order to unscramble possible electro-catalysis of the bromine/bromide couple a different approach is needed.In the following we study both the electro-oxidation of bromide (BOR) and the electro-reduction of bromine (BRR) at single MWCNTs via ‘nano-impact (aka ‘single entity’) electrochemistry’^17–20 in aqueous solution. In this approach a micro-wire electrode at a fixed potential is inserted in a suspension of CNTs in the solution of interest. From time to time a single CNT impacts the electrode, adopts the potential of the latter for the duration of the impact which in the case of CNTs can vary from 1–100 of seconds^21–23 and sustained catalytic currents flow if the oxidation/reduction of interest is faster at the nanotube in comparison with the micro-wire electrode. The catalytic currents are studied as a function of potential revealing the electron transfer kinetics. Fig. 1 shows the concept of the experiment.Open in a separate window Fig. 1Schematic representation of ‘nano-impact’ electrochemistry on a carbon micro wire electrode for the oxidation of aqueous bromide from which the kinetics of the BOR are inferred. Analogous experiments but showing negative impact currents allow the inference of the kinetics of the BRR.The BOR and BRR were studied first, however, voltammetrically at an unmodified glassy carbon (GC) electrode as shown in Fig. 2 (black line) using 5.0 mM solutions of either NaBr or Br₂ in 0.1 M HNO₃. The midpoint potential was 0.82 V versus the saturated calomel electrode (SCE) consistent with the literature values for the formal potential of the Br₂/Br⁻ couple.²⁴ The voltammograms were analysed to give transfer coefficients of 0.45 ± 0.01 and 0.33 ± 0.01 (ESI, Section 2^†) for the BOR and BRR respectively. Both processes were inferred to be diffusional and the diffusion coefficients D_Br⁻ and D_Br2 were calculated to be 2.05 (±0.04) × 10⁻⁵ cm² s⁻¹ and 1.50 (±0.04) × 10⁻⁵ cm² s⁻¹ (ESI, Section 3^†) using the Randles–Ševčík equation for an irreversible reaction the values are consistent with literature reports.²⁴ Then the electrodes were modified with 30 μg of MWCNTs consisting of ca. 125 monolayers (the calculation is given in the ESI, Section 9^†) of MWCNTs assuming that they are closely packed across the area of the GC electrode, and the resulting voltammograms are shown in Fig. 2 (red line). In comparison with the unmodified electrode, enhanced currents are seen for the Br₂/Br⁻ couple which partly reflects the enhanced capacitance of the interface reflecting in turn the large surface area of the deposited nanotubes (ca. 60–120 cm²). Larger signals are also seen indicating a thin layer contribution from the material occluded within the porous layer which also leads to the apparently quasi-reversible shape of the voltammograms obtained for both reactions. A log–log plot of peak current (I_p) vs. scan rate (ν) showed a gradient value of 0.68 (±0.01) and 0.66 (±0.03) for the BOR and BRR (ESI, Section 4^†) confirming a mixed mass transport regime^12,14 with a combination of semi-infinite diffusion and thin layer behaviour. The transition from the fully irreversible to the apparent quasi-reversible character is sometimes confused with electro-catalysis attributed to the CNTs rather than thin-layer diffusion. In order to ascertain the true catalytic response, single entity electrochemistry was measured to obtain the BOR and BRR responses at single CNTs.Open in a separate window Fig. 2Cyclic voltammograms at pristine GC (black line) and 30 μg MWCNTs dropcast on GC (red line) at a scan rate of 0.05 V s⁻¹ (a) for the bromide oxidation reaction (BOR) in 5.0 mM NaBr in 0.1 M HNO₃, (b) for the bromine reduction reaction (BRR) in 5.0 mM bromine in 0.1 M HNO₃.For single entity measurements, a clean carbon wire (CWE, length 1 mm and diameter 7 μm) working electrode was used. Chronoamperograms were recorded at a constant applied potential of 0.2 V vs. SCE and 1.3 V vs. SCE for the BOR and BRR respectively (5.0 mM solutions). These values were selected in the light of Fig. 2 to provide a large overpotential for each reaction. Clear oxidative and reductive current steps were observed (Fig. 3). These were ascribed to the arrival of a MWCNT at the electrode surface and the resulting catalytic electron transfer for the duration of the impact. No steps were observed in the absence of MWCNTs (ESI, Fig. S4^†). The average residence time of the MWCNT was 1.2 (±0.5) seconds and the frequency of the collisions was 0.3 (±0.1) impacts per second. The average impact current for the BOR at 1.3 V vs. SCE was 2.8 (±0.2) nA (65 impacts) and for the BRR at 0.2 V vs. SCE it was 3.8 (±0.1) nA (70 impacts). The impact currents were assumed to be entirely faradaic since control experiments in 0.1 M HNO₃ solution in the presence of 100 μg of MWCNTs (in the absence of Br⁻ and Br₂) showed no obvious impacts as shown in ESI Section 10.^†Open in a separate window Fig. 3Chronoamperograms showing the impact step current (a) for the BOR in 5.0 mM NaBr in 0.1 M HNO₃ at 1.3 V vs. SCE, (b) for the BRR in 5.0 mM bromine in 0.1 M HNO₃ at 0.2 V vs. SCE.Further, impacts for both the BOR and BRR were observed at various potentials (ESI, Section 11^†) and analysed to obtain the average faradaic current at each potential. The average impact step current was plotted against the applied potential (Fig. 4). Two sigmoidal curves were obtained reflecting the current–potential response for either the bromide oxidation (BOR) or the bromine reduction (BRR). The curves reflect the average voltammograms (current–potential characteristics) for the Br₂/Br⁻ redox reaction at single carbon nanotubes. The shape of the two sigmoidal curves reflects the onset of electrolysis followed by a diffusion controlled plateau at high over-potentials.²⁵ Mass transport corrected Tafel analysis (Fig. 4; inset) showed the transfer coefficients β to be ca. 0.42 and α to be ca. 0.20 from the impacts for the BOR and BRR respectively (ESI, Section 6^†). The length distribution of the MWCNTs was calculated (ESI, Section 6^†) from the currents recorded at potentials corresponding to the plateau in Fig. 4 assuming that the reactions are (Fickian) diffusion controlled at the potentials used and by modelling the CNTs as cylindrical electrodes²¹ assuming a nanotube radius of 15 (±5) nm and the diffusion coefficients reported above. Chronoamperometry was also conducted for the BOR and BRR in the absence of MWCNTs at 1.3 V and 0.2 V vs. SCE respectively to confirm that no impact currents were contributed by the redox species in the electrolyte (ESI, Section 5^†). Alongside, chronoamperograms in 0.1 M HNO₃ and 100 μg show that the impact current was contributed only by the Br⁻ and Br₂ redox reaction and the results are shown in the ESI, Section 10.^†Open in a separate window Fig. 4Average step currents observed as a function of applied potential (a) for the BOR in 5.0 mM NaBr in 0.1 M HNO₃ at, (b) for the BRR in 5.0 mM Bromine in 0.1 M HNO₃; insets in both the cases show mass transport corrected Tafel analyses.The lengths were found to be 5.4 (±3.4) μm (BOR) and 5.9 (±1.3) μm (BRR) and are given in Fig. 5 (see ESI, Section 7^† for calculations). These values were compared with previously reported dark-field optical microscopy data and good agreement was observed with the literature value of 5.3 (±2.1) μm.²⁶ The observed consistency provides strong support for the choice of modelling the single entity voltammetry by analogy with that of a cylindrical electrode.Open in a separate window Fig. 5The length of MWCNTs calculated from the impact currents for the BOR (at 1.3 V vs. SCE) and BRR (at 0.2 V vs. SCE).It is evident that the single entity measurements allow a clear analysis of the catalytic behaviour of the carbon nanotubes by providing a well-defined diffusional regime conducive to the extraction of the electrode kinetics of both the bromide oxidation and the bromine reduction process. In contrast, electrodes were formed by ensembles of carbon nanotubes in the form of a porous layer where the mixed transport regime is not amenable to ready modelling and the dissection of thin-layer effects from the measured voltammetry. The electron transfer kinetics for both the BOR and BRR at single MWCNTs was then obtained via full simulation of the two single entity ‘voltammograms’ using the above measured diffusion coefficients and again treating the impacted MWCNT as a cylindrical electrode with uniform diffusional access and further assuming Butler–Volmer kinetics. For the BOR, one electron transfer was considered as given below,For the BRR the two electron transfer was modelled as,Br₂ + 2e⁻ → 2Br⁻The set of parameters used for the analysis are given in the ESI, Section 8.^† By using the transfer coefficients deduced from Fig. 4, the only unknown is the standard electrochemical rate constant k which is determined by fitting the impact voltammogram measured relative to a formal potential for the Br₂/Br⁻ couple of 0.82 V vs. SCE obtained from the voltammogram at pristine GC. Fig. 6 shows the fitting for the BOR and the BRR with rate constants k_BOR of 1.0 (±0.1) × 10⁻³ cm s⁻¹ and k_BRR of 5.0 (±0.1) × 10⁻⁴ cm s⁻¹ respectively. The transfer coefficients and rate constants obtained from impacts were compared to the voltammograms obtained at pristine GC for the BOR and BRR and are given in Open in a separate window Fig. 6DIGISIM simulated curves (black line) for average impact currents obtained at different potentials (red circles) (a) for the BOR with a rate constant (k_BOR) of 1.0 (±0.1) × 10⁻³ cm s⁻¹; (b) BRR with a k_BRR of 5.0 (±0.1) × 10⁻⁴ cm s⁻¹.Transfer coefficients and rate constants for the BOR in 5.0 mM NaBr in 0.1 M HNO₃ and the BRR in 5.0 mM bromine in 0.1 M HNO₃ obtained at the glassy carbon macroelectrode GC, and single MWCNT impact current

Analysed parameter	Oxidation of bromide	Reduction of bromine
Transfer coefficient (GC)	β = 0.45	α = 0.33
Transfer coefficient (impact current)	β = 0.42	α = 0.20
k_BOR/cm s⁻¹ (GC)	9.5 (±0.1) × 10⁻⁵	2.0 (±0.1) × 10⁻⁵
k_BRR/cm s⁻¹ (impact current)	1.0 (±0.1) × 10⁻³	5.0 (±0.1) × 10⁻⁴

Open in a separate windowIn summary, MWCNTs were studied for their catalytic behaviour towards the Br₂/Br⁻ redox couple. From the drop-cast experiment, the ensemble of MWCNTs showed mixed mass transport behaviour complicating and precluding the elucidation of their catalytic behaviour. In contrast, single nano-impact electrochemistry of MWCNTs shows faster electrochemical rate constants compared to pristine GC. This confirms the catalytic activity of MWCNTs for the Br₂/Br⁻ redox reaction but the values determined are insufficiently enhanced over glassy carbon leaving considerable room for improvement via the use of alternative electrocatalysts to carbon nanotubes. 相似文献

9.

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

Long Yang Becky Bongsuiru Jei Alexej Scheremetjew Binbin Yuan A. Claudia Stückl Lutz Ackermann 《Chemical science》2021,12(39):12971

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 window Fig. 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.²² Open in a separate window Scheme 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.²² Open in a separate window Scheme 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.²⁰ Open in a separate window Scheme 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 window Fig. 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 window Scheme 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,b Open in a separate window Scheme 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. 相似文献

10.

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

Zhipeng Guan Xingxing Zhong Yayu Ye Xiangwei Li Hengjiang Cong Hong Yi Heng Zhang Zhiliang Huang Aiwen Lei 《Chemical science》2022,13(21):6316

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.⁵ Open in a separate window Scheme 1Selected bioactive molecules and the synthetic methods of chromans.In the past few decades, a great deal of methods have been developed for the assembly of substituted chromans, and among them, the Diels–Alder [4 + 2] cycloaddition reaction provides a highly efficient synthetic platform in the construction of these functional six-membered frameworks.⁶ Extensive work has been done with this strategy, resulting in a lot of significant progress. The ortho-quinone methides (o-QMs) are generally essential dienes for the Diels–Alder reaction towards the synthesis of chromans, as they are highly reactive for rapid rearomatization via Michael addition of nucleophiles, cycloaddition with a dienophile of 2π partners or 6π-electrocyclization (Scheme 1b).⁷ Herein, although various valuable chromans have been successfully synthesized with the Diels–Alder [4 + 2] cycloaddition reaction, the use of o-QMs may lead to several potential limitations in some cases. One of the potential limitations is that o-QMs are used mainly as Michael acceptor and electron-deficient dienes to react only with nucleophiles and electron-rich dienophiles. In these considerations, the evolution of synthetic methods for chromans is very important and highly desirable. In particular, novel (4 + 2) cycloaddition strategies capable of synthesizing chromans with the use of easily available materials and electron-deficient dienophiles are of utmost interest.On the basis of retrosynthetic analysis of chroman shown in Scheme 1c, (4 + 2) radical annulation of the corresponding carbon-centered radical R with olefin would be an alternative route, which is able to overcome the above-mentioned potential limitations. Considering that radical species R is normally nucleophilic, thus, it could react with electron-deficient olefins affording chroman products that generally can''t be synthesized by the traditional Diels–Alder [4 + 2] cycloaddition reaction involving o-QMs. Herein, we reported a highly selective (4 + 2) radical–annulation reaction to construct the chroman framework with the use of easily available NHPI ester as the radical precursor and olefin as the radical acceptor under mild conditions.Compared with other alkyl radical precursors, the redox-active N-(acyloxy)phthalimides (NHPI esters) come to the fore, since they are cheap, stable, readily available, and non-toxic.⁸ Bearing above hypothesis in mind, we commenced to investigate the (4 + 2) annulation reaction by utilizing readily available N-hydroxyphthalimide ester A′ and commercially available ethyl acrylate as model substrates. After a great deal of screening on the reaction parameters, only a trace amount of the target product was detected by GC-MS. In contrast, the main product is anisole, which may result from a rapid hydrogen abstraction reaction of the unstable primary alkyl radical intermediate. To restrain the formation of this by-product, we designed N-hydroxyphthalimide esters A and A′′, which could produce more stable tertiary radicals, for the target (4 + 2) annulation reaction instead of A′ (9 74% yield of ethyl-2,2-dimethylchromane-4-carboxylate upon 1 was selectively obtained after irradiation of the reaction system under blue LEDs at room temperature for 12 h, despite a little by-product ( EntryVariation from standard conditionsYield/%1None742No lightn.d3No EYn.d44-CzIPNn.d5Ru(bpy)₃(PF₆)₂366MeCN347DCEn.d8Air39 Open in a separate window^aStandard conditions: A (0.2 mmol), ethyl acrylate (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield; n.d. = not detected.In order to explore the substrate scope of the (4 + 2) annulation reaction, we commenced to scrutinize the generality and selectivity with respect to N-hydroxyphthalimide esters. The functional group applicability of N-hydroxyphthalimide esters was investigated by the examination of various electron donating/withdrawing substituents at the varying positions, as illustrated in Scheme 2. Gratifyingly, we found that substances bearing electron-donating substituents (Me, OMe, ^tBu, SMe, OPh, OBn, and Ph) at the para-position could smoothly be transformed into the corresponding chromans with satisfactory yields (2–8). N-Hydroxyphthalimide esters with halogen substituents, such as fluoride, chloride, bromide and iodide are suitable to produce the corresponding chromans in satisfactory yields, which enable potential application in further functionalization (9–12). Surprisingly, electron-withdrawing substituents, such as MeCO, OCF₃, and CF₃, were also tolerated under standard conditions (13–15). This reaction could proceed effectively with N-hydroxyphthalimide esters containing one group or multiple groups in different positions, which delivered a variety of chroman compounds in moderate to good yields (16–19, 21–23). The annulation reaction is not limited to the construction of benzene compounds, as ethyl-3,3-dimethyl-2,3-dihydro-1H-benzo[f]chromene-1-carboxylate was also obtained in 68% yield (20). After the simple esterification, drug molecules, such as clofibric acid, fenofibric acid and ciprofibrate, could be transformed into the corresponding N-hydroxyphthalimide esters, further engaging with ethyl acrylate (10 and 24–25), which highlighted the synthetic applicability of this protocol.Open in a separate window Scheme 2Reactions of NHPI esters with ethyl acrylate. Standard conditions: NHPI ester (0.2 mmol), ethyl acrylate (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield.Next, we shifted attention to the scope with respect to a wide range of acrylates, as shown in Scheme 3. Methyl acrylate and butyl acrylate were well amenable with N-hydroxyphthalimide esters (26–27). Other acrylates, such as cyclohexyl, tert-butyl and phenyl, were also competent reaction partners with a satisfactory efficiency (28–30). Ethyl (E)-but-2-enoate was tolerant to afford the desired chroman product, albeit in 29% yield (31). It is particularly noteworthy that dimethyl maleate was demonstrated to be a suitable substrate, leading to the formation of sterically hindered product (32). The sensitive benzylic C–H bond and the fragile furan and thiophene moieties could be retained in the radical cascade reaction, providing a series of functionalized chromans (33–35). Alkoxy and aligned alkoxy on substances did not reduce the reaction efficacy (36–37). Chromans possessing various subtle trimethylsilyl, hydroxyl, primary/secondary bromoalkene, cyano and thiomethylene were accessed in reasonable yields, which provided the basis for late-stage derivatization of products (38–41, 43). Owing to the superiority of lipophilicity, permeability and metabolism, we tried to introduce trifluoromethyl into chroman skeletons. To our delight, 2,2,2-trifluoroethyl acrylate gave rise to the corresponding chromans with 52% yield (42). The unactivated alkynyl moiety and alkenyl moiety survived in the photoredox catalysis (44–46).Open in a separate window Scheme 3Reactions of A with various olefins. Standard conditions: A (0.2 mmol), olefin (0.5 mmol), Eosin Y (2 mol%), DMAc (2.0 mL), blue light, N₂, rt, 12 h, isolated yield.It is well-known notorious that compounds possessing nitrogen atoms are a very important class of biologically active and functional molecules. Thus, we turned our attention from acrylates to acrylamide derivatives. We were delighted to find that N,N-dimethylacrylamide was a suitable radical receptor to give the target molecule in moderate yield (47). Similarly, a series of chroman products were obtained with cyclic and acyclic acrylamides (48–51). Subsequently, we continued to investigate the reaction of different secondary acrylamides with N-hydroxyphthalimide ester A. These secondary acrylamides bearing NH-isopropyl, -cylopropyl, -benzyl, -phenylethyl and -aryl functionalities, could smoothly be transformed into the desired (4 + 2) annulation products under standard conditions (52–57). Besides acrylates and acrylamides, this method was successfully applied to other Michael acceptors resulting in the synthesis of various functionalized chromans (58–61). In order to demonstrate the potential applicability of this methodology, a variety of natural products, their derivatives and functional molecules, such as isoborneol (62), cedrol (63), citronellol (64), cholesterol (65), and dehydroabietylamine (66), were examined, and all these structures could be embedded into target products in 56–70% yields.The (4 + 2) annulation protocol is not limited to the synthesis of chromans. Under standard conditions, the thiochromane derivative could be formed, although less efficiently (Scheme 4a). With curiosity, we tried to use the commercially available pinacol vinylboronate instead of acrylates for this transformation because of the widespread use of organoboron compounds in organic synthesis. The target compound 2-(2,2-dimethylchroman-4-yl)-4,4,5,5-tetramethyl-1,3,2-dioxaborolane, which is a versatile building block in functionalization of chromans, was obtained in 48% yield under the slightly revised conditions (Scheme 4b). It is noting that the reaction could be conducted smoothly to afford 60% yield under sunlight irradiation, showing the potential of industrial application (Scheme 4c). Furthermore, the versatility of chroman 1 was also explored. The oxidative dehydrogenation process of 1 led to the formation of value-added ethyl 2,2-dimethyl-2H-chromene-4-carboxylate 69 by using DDQ as the oxidant (Scheme 4d). 1 could also be reduced to (2,2-dimethylchroman-4-yl)methanol 70 with lithium aluminum hydride in ethyl ether (Scheme 4d).Open in a separate window Scheme 4The synthetic applications. (a) The synthesis of thiochromane. (b) Pinacol vinylboronate as a substrate. (c) Sunlight condition. (d) The derivatization of products.To further gain mechanistic insights into this process, a series of experiments were conducted. When the model reaction was performed under standard conditions but in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) as a radical scavenger, the target product was not detected (Scheme 5a). Notably, when butylated hydroxytoluene (BHT) was added to this reaction system, the annulation reaction was significantly suppressed, meanwhile, a coupling product was detected by GC-MS and HRMS (Scheme 5b). These results indicated a radical-involved pathway for this transformation. Subsequently, the carbon radical was captured by an intramolecular aromatic ring, giving the cyclization product 69 in excellent yield (Scheme 5c). Moreover, the intermolecular kinetic isotope effect (KIE) experiment was carried out by using A and A-d5 as competitive substrates. Under standard conditions, a KIE value of 1.05 was observed, indicating that the cleavage of the aromatic C–H bond might not be the rate-determining step in the transformation (Scheme 5d).Open in a separate window Scheme 5The control experiments. (a) The addition of TEMPO. (b) The addition of BHT. (c) Intramolecular reaction. (d) KIE experiment.On the basis of the above experimental results, we proposed a possible mechanism cycle for the reaction, as shown in Scheme 6. Initially, the photocatalyst Eosin Y (EY) was transformed into the excited species EY* (E_1/2[EY˙⁺/EY*] = −1.1 V vs. SCE) under the irradiation with visible light. As a redox-active species, EY* was able to reduce N-hydroxyphthalimide ester (E_1/2[A/I] = −0.8 V, see the CV in the ESI^†) via a single-electron-transfer (SET) process, generating the EY˙⁺ radical cation and the corresponding N-hydroxyphthalimide ester radical anion I. The intermediate I underwent rapid homolytic fragmentation to generate carbon-centered nucleophilic radical II by releasing the phthalimide anion and carbon dioxide. Subsequently, the carbon radical II was captured by ethyl acrylate to form the electrophilic radical III, which underwent rapid intramolecular radical cyclization to afford aryl radical IV. Then, the intermediate IV was converted into cation Vvia a SET oxidation. On the other hand, the EY˙⁺ radical cation was transformed into Eosin Y to accomplish the photocatalytic cycle. The rapid deprotonation of V leads to the formation of the product 1.Open in a separate window Scheme 6Proposed reaction mechanism. 相似文献

11.

Correction: Site-specific DNA functionalization through the tetrazene-forming reaction in ionic liquids

Seiya Ishizawa Munkhtuya Tumurkhuu Elizabeth J. Gross Jun Ohata 《Chemical science》2022,13(22):6749

相似文献

12.

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

Han-Jun Ai Yang Yuan Xiao-Feng Wu 《Chemical science》2022,13(8):2481

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 window Scheme 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


Entry	[Ru]	Conv.^b (%)	Yield^b (%)
1	Ru(acac)₃	60	15
2	RuH(Cl)(CO)(PPh₃)₃	21	11
3	Ru-1	100	24
4	Ru-2	93	41
5	Ru-3	53	4
6	Ru-4	49	5
7	Ru-5	100	32
8	Ru-6	100	38
9	Ru-7	100	81
10	Ru-7	100	63^c
11	Ru-7	100	82^d
12	Ru-7	100	72^e
13	Ru-7	100	86^d^,^f

Open in a separate window^aReaction conditions: 1 (0.2 mmol), 2 (0.6 mmol), [Ru] (5 mol%), Cs₂CO₃ (0.6 mmol), toluene (0.5 mL), CO (10 bar), 100 °C, 12 h.^bDetermined by GC with hexadecane as the internal standard.^cCO (1 bar), N₂ (9 bar).^d[Ru] (2.5 mol%) was used.^e[Ru] (1 mol%) was used.^f90 °C, average yield of two independent reactions.We next turned our attention to study the scope and the limitation of this transformation, as shown in Fig. 1. At the first stage, a variety of alcohols containing different functional groups and structural blocks were tested. In general, moderate to excellent yields were obtained under the standard conditions. For primary alcohols, the length of the carbon chain did not affect the good yield (4–7). The reaction tolerated the presence of ethers (8, 9), thioether (10), alkene (11), chlorine (12), trimethylsilyl (13), and amide (21). Benzyl alcohols and secondary alcohols were afterwards tested in this system and successfully transformed into the corresponding esters in good yields (14–17). With the further increase of the steric hindrance, tertiary alcohols hardly provided the desired products (18, 19). Phenol was also employed as the substrate in our attempt, and not surprisingly, phenyl 3-phenylpropyl ether (S_N reaction product) was isolated as the main product (20).²³ Interestingly, ethylene glycol could be converted to diester 22 in 83% yield, and no monocarbonylation product was detected, even though the alcohol was three equivalents. This suggests an interaction between the alcohol and the catalytic center, resulting in a higher rate of intramolecular reaction than intermolecular reaction. Subsequently, the excellent heterocycle compatibility of the method is nicely illustrated by the fact that thiophenes (23, 27), morpholine (24), unprotected indoles (25, 26), pyrrole (27), pyridine (28), pyrimidine (29), furan (30), thiazole (31), pyrazole (32), benzothiadiazole (33), and triazole (34) were perfectly tolerated under our protocol. The broad synthetic applicability of the reaction was also reflected in the successful alkoxycarbonylation of various primary iodides (35–44), secondary iodides (45–47), and even sterically hindered tertiary iodides (48–50).Open in a separate window Fig. 1Scope of Ru pincer complex-catalyzed alkoxycarbonylation. Reactions run with 0.2 mmol of alkyl iodide and 3 equiv. of alcohol. Yield of the isolated product. ^aTogether with a 68% yield of the S_N reaction product (phenyl 3-phenylpropyl ether). ^bEthylene glycol (3 equiv.) was used. ^cReduced yield of the isolated product because of the volatility of the product.In particular, the secondary iodides generated the corresponding esters in near quantitative yields. We also evaluated a substrate containing the C(sp²)–I bond to probe the chemoselectivity of our process (41). No trace of arylate was detected in the crude mixture by GC-MS, hence illustrating the good chemoselectivity of this catalytic system and offering opportunities for further structure modification. While this new methodology allows for the formation of a wide range of heterocycle-containing esters, some limitations still remain in terms of substrate scope. Bromoalkanes and chloroalkanes cannot be successfully converted under these conditions, even with the addition of equivalent amounts of NaI.The alkoxycarbonylation could be applied to late-stage modification of a range of drugs and natural products, as shown in Fig. 2. trans-Sobrerol, a mucolytic, was successfully transformed, while the tertiary C–OH group was retained (51). A weak androgen, epiandrosterone, which is widely recognized to inhibit the pentose phosphate pathway and to decrease intracellular NADPH levels, provided 52 in 93% yield. Derivatives of estrone, cholesterol, and vitamin E also delivered the corresponding esters 53–55 in moderate to good yields. Common alcohol natural products, such as crotonyl alcohol, piperonyl alcohol, (−)-perillyl alcohol, (−)-borneol, (−)-menthol, and nerol, were tested as well and applicable to the reaction (56–61), which illustrated the utility of this method.Open in a separate window Fig. 2Modification of drugs and natural products. Reactions run with 0.2 mmol of alkyl iodide and 3 equiv. of alcohol. Yield of the isolated product.To gain more mechanistic insight into the reaction pathway, several experiments were conducted (Scheme 2). Under the standard conditions, the addition of TEMPO (radical capture agent) to the reaction led to the termination of the target reaction; meanwhile, the intermediate was captured (62) in 91% isolated yield (Scheme 2A, middle). In the control experiment, only limited conversion and no 62 was observed in the absence of the pincer catalyst (Scheme 2A, top), thus suggesting that the pincer/Ru activates the alkyl iodides to radicals. To ensure the radical pathway, we subsequently conducted radical inhibition experiments with BHT (butylated hydroxytoluene) as the radical inhibitor (Scheme 2B) and radical clock experiments (Scheme 2C). The model reaction was gradually suppressed with the addition of BHT. Furthermore, (iodomethyl)cyclopropane and 6-iodohex-1-ene under our optimized reaction conditions provided the corresponding ring-opening expansion product 64 and the cyclization product 65, respectively, with high selectivity.²⁴ Open in a separate window Scheme 2Mechanism studies.Based on the above results, we believe that the reaction involves a radical intermediate. In addition to this, as noted earlier, the alcohol appears to interact with the catalytic center and plays a role in promoting the activation of the alkyl halide. To probe this hypothesis, we removed the isopropanol from the reaction and utilized TEMPO to capture the radical intermediate (Scheme 2A, below). Compared with the reaction in the middle of Scheme 2A, the conversion and the yield of 62 significantly decreased in the absence of isopropanol. We explained that the (PNP)Ru(CO)X₂ type complex is the catalyst resting state, and the alcohol may help it to return to the active state by hydrodehalogenation (Scheme 2D).²⁵ Moreover, we could observe acetone during the optimization process, and when we subjected isopropanol alone to our optimized conditions, 57% yield of acetone could be detected,²⁶ which suggests that (PNP)Ru(CO)HX can also undergo hydrodehalogenation to form (PNP)Ru(CO)H₂.Based on the above results and previous reports,^16–18 a plausible mechanism is proposed (Scheme 3). Initially, the active 16 electron ruthenium complex A will be formed under the assistance of the base. Through a SET process, alkyl iodide will be activated and a 17 electron ruthenium complex B will be formed together with the corresponding alkyl radical which will immediately react with B to give 18 electron ruthenium complex C. The acylruthenium complex D will be produced after a CO insertion step. The possibility that the acylruthenium complex D might also be produced from complex B and the in situ formed acyl radical cannot be excluded. After X ligand exchange, ruthenium complex E will be formed which will provide the final ester product after a reductive elimination step and regenerate the active ruthenium catalyst A to finish the catalyst cycle. Alternatively, the direct nucleophilic attack at the acyl carbonyl of complex D by alcohol to give the ester product and complex F is also possible. Then complex F will be transformed into complex A under the assistance of the base.Open in a separate window Scheme 3Proposed mechanism. 相似文献

13.

Simplifying and expanding the scope of boron imidazolate framework (BIF) synthesis using mechanochemistry

Cameron B. Lennox Jean-Louis Do Joshua G. Crew Mihails Arhangelskis Hatem M. Titi Ashlee J. Howarth Omar K. Farha Tomislav Fri&#x; i&#x; 《Chemical science》2021,12(43):14499

Mechanochemistry enables rapid access to boron imidazolate frameworks (BIFs), including ultralight materials based on Li and Cu(i) nodes, as well as new, previously unexplored systems based on Ag(i) nodes. Compared to solution methods, mechanochemistry is faster, provides materials with improved porosity, and replaces harsh reactants (e.g. n-butylithium) with simpler and safer oxides, carbonates or hydroxides. Periodic density-functional theory (DFT) calculations on polymorphic pairs of BIFs based on Li⁺, Cu⁺ and Ag⁺ nodes reveals that heavy-atom nodes increase the stability of the open SOD-framework relative to the non-porous dia-polymorph.

Mechanochemistry enables rapid access to boron imidazolate frameworks (BIFs), including ultralight materials based on Li and Cu(i) nodes, as well as new, previously unexplored systems based on Ag(i) nodes.

Mechanochemistry^1–7 has emerged as a versatile methodology for the synthesis and discovery of advanced materials, including nanoparticle systems^8–10 and metal–organic frameworks (MOFs),^11–15 giving rise to materials that are challenging to obtain using conventional solution-based techniques.^16–18 Mechanochemical techniques such as ball milling, twin screw extrusion¹⁹ and acoustic mixing^20,21 have simplified and advanced the synthesis of a wide range of MOFs, permitting the use of simple starting materials such as metal oxides, hydroxides or carbonates,^22,23 at room temperature and without bulk solvents, yielding products of comparable stability and, after activation, higher surface areas than solution-generated counterparts.^24–29 The efficiency of mechanochemistry in MOF synthesis was recently highlighted by accessing zeolitic imidazolate frameworks (ZIFs)^30,31 that were theoretically predicted, but not accessible under conventional solution-based conditions.¹⁷The advantages of mechanochemistry in MOF chemistry led us to address the possibility of synthesizing boron imidazolate frameworks (BIFs),^32–34 an intriguing but poorly developed class of microporous materials analogous to ZIFs, comprising equimolar combinations of tetrahedrally coordinated boron(iii) and monovalent Li⁺ or Cu⁺ cations as nodes (Fig. 1A–C). Although BIFs offer an attractive opportunity to access microporous MOFs with lower molecular weights, particularly in the case of “ultralight” systems based on Li⁺ and B(iii) centers, this family of materials has remained largely unexplored – potentially due to the need for harsh synthetic conditions, including the use of n-butyllithium in a solvothermal environment.^32–34 Open in a separate window Fig. 1Structures of previously reported BIFs with: (A) zni-, (B) dia-, or (C) SOD-topology (M = Li, Cu); (D) tetrakis(imidazolyl)boric acids used herein for mechanochemical BIF synthesis; and (E) schematic representation of the herein developed mechanosynthesis of dia- and SOD BIF polymorphs based on Li, Cu or Ag metal nodes.We now show how switching to the mechanochemical environment enables lithium- and copper(i)-based BIFs to be prepared rapidly (i.e., within 60–90 minutes), without elevated temperatures or bulk solvents, and from readily accessible solid reactants, such as hydroxides and oxides (Fig. 1D and E). While the mechanochemically-prepared BIFs exhibit significantly higher surface areas than the solvothermally-prepared counterparts, mechanochemistry allows for expanding this class of materials towards previously not reported Ag⁺ nodes. The introduction of BIFs isostructural with those based on Li⁺ or Cu⁺ but comprising of Ag⁺ ions, enables a periodic density-functional theory (DFT) evaluation of their stability. This reveals that switching to heavier elements as tetrahedral nodes improves the stability of sodalite topology (SOD) open BIFs with respect to close-packed diamondoid (dia) topology polymorphs.As a first attempt at mechanochemically synthesis of BIFs, we targeted the synthesis of previously reported zni-topology LiB(Im)₄ and CuB(Im)₄ frameworks (Li-BIF-1 and Cu-BIF-1, respectively, Fig. 1A) using a salt exchange reaction between LiCl or CuCl with commercially available sodium tetrakis(imidazolyl)borate (Na[B(Im)₄]) (Fig. 2A). Milling of LiCl and Na[B(Im)₄] in a 1 : 1 stoichiometric ratio for up to 60 minutes led to the appearance of Bragg reflections consistent with the target Li-BIF-1 (CSD MOXJEP) and the anticipated NaCl byproduct. The reaction was, however, incomplete, as seen by X-ray reflections of Na[B(Im)₄] starting material. In order to improve reactant conversion, we explored liquid-assisted grinding (LAG), i.e. milling in the presence of a small amount of a liquid phase (measured by the liquid-to-solid ratio η³⁵ in the range of ca. 0–2 μL mg⁻¹). Using LAG conditions with acetonitrile (MeCN, 120 μL, η = 0.5 μL mg⁻¹) led to the complete disappearance of reactant X-ray reflections, concomitant with the formation of Li-BIF-1 alongside NaCl within 60 minutes.Open in a separate window Fig. 2(A) Reaction scheme for the mechanochemical synthesis of Li-BIF-1 by a salt metathesis strategy. Selected PXRD patterns for: (B) Na[B(Im)₄] (C) LiCl, (D) simulated Li-BIF-1 (CSD MOXJPEP) and (E) synthesized BIF-1-Li by LAG for 60 minutes with MeCN (η = 0.5 μL mg⁻¹), (F) CuCl, (G) simulated Cu-BIF-1 (CSD MOXJIT), and (H) synthesized BIF-1-Cu by LAG for 60 minutes with MeOH (η = 0.50 μL mg⁻¹). Asterisks denote NaCl, a byproduct of the metathesis reaction. (Fig. 2B–E, also see ESI^†). The copper-based zni-CuB(Im)₄ (Cu-BIF-1) was readily obtained from CuCl within 60 minutes using similar LAG conditions. We also explored LAG with methanol (MeOH), revealing that the exchange reaction to form NaCl took place with both LiCl and CuCl starting materials. With LiCl, however, the PXRD pattern of the product could not be matched to known phases involving Li⁺ and B(Im)₄⁻ (see ESI^†). With CuCl as a reactant, LAG with MeOH (η = 0.5 μL mg⁻¹) cleanly produced Cu-BIF-1 alongside NaCl (see ESI^†).Next, we explored an alternative synthesis approach, analogous to that previously used to form ZIFs and other MOFs: an acid–base reaction between a metal oxide or hydroxide and the acid form of the linker: tetrakis(imidazolato)boric acid, HB(Im)₄ (Fig. 3A).^36–40 Neat milling LiOH with one equivalent of HB(Im)₄ in a stainless steel milling assembly led to the partial formation of Li-BIF-1, as evidenced by PXRD analysis (see ESI^†). Complete conversion of reactants into Li-BIF-1 was achieved in 60 minutes by LAG with MeCN (η = 0.25 μL mg⁻¹), as indicated by PXRD analysis (Fig. 3B–E), Fourier transform infrared attenuated total reflectance spectroscopy (FTIR-ATR), thermogravimetric analysis (TGA) in air, and analysis of metal content by inductively-coupled plasma mass spectrometry (ICP-MS) (see ESI^†).Open in a separate window Fig. 3(A) Reaction scheme for the mechanochemical synthesis of Li-BIF-1 using the acid–base strategy. Selected PXRD patterns for: (B) H[B(Im)₄] (C) LiOH, (D) simulated Li-BIF-1 (CSD MOXJPEP), (E) synthesized BIF-1-Li by LAG for 60 minutes with MeCN (η = 0.25 μL mg⁻¹), (F) Cu₂O, (G) simulated Cu-BIF-1 (CSD MOXJIT), and (H) synthesized Cu-BIF-1 by ILAG for 60 minutes with MeOH (η = 0.50 μL mg⁻¹) and NH₄NO₃ additive (5% by weight).Neat milling of HB(Im)₄ with Cu₂O under similar conditions gave a largely non-crystalline material, as evidenced by PXRD (see ESI^†). Switching to the ion- and liquid-assisted grinding (ILAG) methodology, in which the reactivity of a metal oxide is enhanced by a small amount of a weakly acidic ammonium salt, and which was introduced to prepare zinc and cadmium ZIFs from respective oxides,^37–40 enabled the synthesis of Cu-BIF-1 from Cu₂O. Specifically, PXRD analysis revealed complete disappearance of the oxide in samples obtained by ILAG with either MeOH or MeCN (η = 0.5 μL mg⁻¹) in the presence of NH₄NO₃ additive (5% by weight, see ESI^†). Notably, achieving complete disappearance of Cu₂O reactant signals also required switching from stainless steel to a zirconia-based milling assembly, presumably due to more efficient energy delivery.⁴¹ After washing with MeOH, the material was characterized by FTIR-ATR, TGA in air, and analysis of metal content by ICP-MS (see ESI^†).Whereas both the metathesis and acid–base approaches can be used to mechanochemically generate Li- and Cu-BIF-1, the latter approach has a clear advantage of circumventing the formation of the NaCl byproduct. Consequently, in order to further the development of mechanochemical routes to other BIFs, we focused on the acid–base strategy. As next targets, we turned to MOFs based on tetrakis(2-methylimidazole)boric acid H[B(Meim)₄],³⁶ previously reported³² to adopt either a non-porous diamondoid (dia) topology (BIF-2) or a microporous sodalite (SOD) topology (BIF-3) with either Li⁺ or Cu⁺ as nodes (Fig. 4). Attempts to selectively synthesize either Li-BIF-2 or Li-BIF-3 by neat milling or LAG (using MeOH or MeCN as liquid additives) with LiOH and a stoichiometric amount of HB(Meim)₄ were not successful. Exploration of different milling times and η-values produced only mixtures of residual reactants with Li-BIF-2, Li-BIF-3, and/or not yet identified phases (see ESI^†). Consequently, we explored milling in the presence of 2-aminobutanol (amb), which is a ubiquitous component of solvent systems used in the solvothermal syntheses of BIFs.^32,33 Gratifyingly, using a mixture of amb and MeCN in a 1 : 3 ratio by volume as the milling liquid led to an effective strategy for the selective synthesis of both the dia-topology Li-BIF-2 (CSD code MOXKUG), and the SOD-topology Li-BIF-3 (CSD code MUCLOM).^‡ The selective formation of phase-pure samples of Li-BIF-2 and Li-BIF-3 was confirmed by PXRD analysis, which revealed an excellent match to diffractograms simulated based on the previously reported structures (Fig. 4B–G). Systematic exploration of reaction conditions, including time (between 15 and 60 minutes) and η value (between 0.25 and 1 μL mg⁻¹) revealed that the open framework Li-BIF-3 is readily obtained at η either 0.75 or 1 μL mg⁻¹ after milling for 45 minutes or longer (Fig. 4B–G, also see ESI^†).^§ Lower η-values of 0.25 and 0.5 μL mg⁻¹ preferred the formation of the dia-topology Li-BIF-2, which was obtained as a phase-pure material upon 60 minutes milling at η = 0.5 μL mg⁻¹, following the initial appearance of a yet unidentified intermediate. The preferred formation of Li-BIF-2 at lower η-values is consistent with our previous observations that lower amounts of liquid promote mechanochemical formation of denser MOF polymorphs.³⁷ Open in a separate window Fig. 4(A) Reaction scheme for the mechanochemical synthesis of Li-BIF-3. Comparison of selected PXRD patterns for the synthesis of Li-BIF-2 and Li-BIF-3: (B) H[B(Meim)₄] reactant; (C) LiOH reactant; (D) simulated for Li-BIF-3 (CSD MUCLOM); (E) simulated for Li-BIF-2 (CSD MOXKUG); (F) Li-BIF-3 mechanochemically synthesized by LAG for 60 minutes with a 1 : 3 by volume mixture of amb and MeCN (η = 1 μL mg⁻¹); and (G) Li-BIF-2 mechanochemically synthesized by LAG for 60 minutes with a 1 : 3 by volume mixture of amb and MeCN (η = 0.5 μL mg⁻¹). Comparison of selected PXRD patterns for the synthesis of Cu-BIF-2 and Li-BIF-3: (H) Cu₂O; (I) Cu-BIF-3 (CSD MOXJOZ); (J) Cu-BIF-2 (CSD MUCLIG); (K) Cu-BIF-3 mechanochemically synthesised by ILAG for 60 minutes using NH₄NO₃ ionic additive (5% by weight) and MeOH (η = 1 μL mg⁻¹); and (L) mechanochemically synthesised Cu-BIF-2 by ILAG for 90 minutes using NH₄NO₃ ionic additive (5% by weight) and MeOH (η = 0.5 μL mg⁻¹).Samples of both Li-BIF-2 and Li-BIF-3 after washing with MeCN were further characterized by FTIR-ATR, TGA in air, and analysis of metal content by ICP-MS (see ESI^†). Nitrogen sorption measurement on the mechanochemically obtained Li-BIF-3, after washing with MeCN and evacuation at 85 °C, revealed a highly microporous material with a Brunauer–Emmett–Teller (BET) surface area of 1010 m² g⁻¹ (Fig. 5A), which is close to the value expected from the crystal structure of the material (1200 m² g⁻¹, 32 For direct comparison with previous work,³² we also calculated the Langmuir surface area, revealing an almost 40% increase (1060 m² g⁻¹) compared to samples made solvothermally (762.5 m² g⁻¹) (Fig. 5A, inset).Experimental Brunauer–Emmett–Teller (BET) and Langmuir surface area (in m² g⁻¹) of mechanochemically synthesized SOD-topology BIFs, compared to previously measured and theoretically calculated values, along with average particle sizes (in nm) established by SEM and calculated energies (in eV) for all Li-, Cu-, and Ag-BIF polymorphs. The difference between calculated energies for SOD- and dia-polymorphs in each system is given as ΔE (in kJ mol⁻¹)

Material	Surface area (m² g⁻¹)				Particle size^b (nm)	Electronic energy per formula unit (eV)	ΔE (kJ mol⁻¹)
Material	Mechanochemical, BET	Mechanochemical, Langmuir	Prior work, Langmuir ³²	Theoretical^a	Particle size^b (nm)	Electronic energy per formula unit (eV)	ΔE (kJ mol⁻¹)
dia-Li-BIF-2	—	—	—	—	—	−2679.174	14.25
SOD-Li-BIF-3	1010	1060	762.5	1200	217 (n = 24)	−2679.026	14.25
dia-Cu-BIF-2	—	—	—	—	—	−3417.091	9.67
SOD-Cu-BIF-3	935	1196	182.3	1100	611 (n = 500)	−3416.991	9.67
dia-Ag-BIF-2	—	—	—	—	—	−4738.959	8.66
SOD-Ag-BIF-3	1020	1205	—	1170	500 (n = 25)	−4738.869	8.66

Open in a separate window^aCalculated using MOF Explorer (see ESI).^bDetermined from SEM measurements, where n corresponds to number of particles observed.Open in a separate window Fig. 5BET adsorption plots for: (A) Li-BIF-3, showing a surface area of 1010 m² g⁻¹ and (B) Cu-BIF-3, showing a surface area of 935 m² g⁻¹. The insets in (A) and (B) are representative SEM images of the mechanochemically prepared BIF samples, with scale bars corresponding to 4 μm and 5 μm shown in white.The analogous copper(i)-based BIF-2 and BIF-3 frameworks were readily accessible by ILAG, by controlling the volume of the liquid additive and milling time (Fig. 4H–L, also see ESI^†). Similarly to our previous studies of ZIFs,^17,24,37,39 increased milling times preferred the formation of the close-packed polymorph, dia-topology Cu-BIF-2. While the PXRD pattern of the reaction mixture after 60 minutes ILAG with MeOH (η = 0.5 μL mg⁻¹) and NH₄NO₃ (5% wt/wt) indicated the presence of the SOD-topology Cu-BIF-3, longer milling led to the appearance of the dia-phase (see ESI^†). The materials were identified through comparison of experimental PXRD patterns to those simulated from published structures (CSD codes MUCLIG and MOXJOZ for Cu-BIF-2 and Cu-BIF-3, respectively).³² Quantitative synthesis of Cu-BIF-2 from Cu₂O was readily accomplished by ILAG for 90 minutes (Fig. 4H–L). Following washing and drying, the products were characterized by PXRD, FTIR-ATR, TGA in air and ICP-MS elemental analysis of metal content.In order to achieve the synthesis of phase-pure microporous Cu-BIF-3, reaction conditions were modified by increasing η to 1 μL mg⁻¹. This modification enabled the reproducible and quantitative synthesis of Cu-BIF-3 in 60 minutes milling (Fig. 4H–L), confirmed by PXRD, FTIR-ATR, TGA and elemental analysis of metal content (see ESI^†). Analyses by SEM and nitrogen sorption were performed on the mechanochemical product after washing and drying in vacuo at 85 °C, revealing that the sample consists of sub-micron particles and exhibits a high BET surface area of 935 m² g⁻¹, which is close to the theoretically expected value of 1100 m² g⁻¹ (Fig. 5B). To enable direct comparison with previously reported work,³² we also calculated the Langmuir surface area, revealing a 7-fold increase (1196 m² g⁻¹) compared to samples made solvothermally (182.3 m² g⁻¹) (†), i.e. 34% lower compared to the mechanochemically synthesized sample, illustrating a clear benefit of mechanochemistry in providing a simpler, more efficient synthesis, as well as materials of improved porosity.^32,42The mechanochemical approaches to Li- and Cu-based BIFs are surprisingly simple compared to previously reported solvothermal methods,^32,33,42 not only avoiding bulk solvents and high temperatures (85 °C for Li-based, 120 °C for Cu-based BIFs), but also enabling the use of simple, easily handled solids LiOH and Cu₂O as starting materials compared to, for example, n-BuLi.⁴² Notably, while the reported solvothermal synthesis of these materials also requires the use of amb for the preparation of both Li- and Cu-BIFs, the use mechanochemical conditions enabled amb-free synthesis of copper-based BIFs. Such simplifications of the synthetic procedure encouraged us to explore the possibility to extend this family of materials towards previously not reported silver(i) derivatives.As a starting material for the synthesis of Ag(i)-based BIFs we focused on Ag₂CO₃, generated in situ from readily accessible AgNO₃ and K₂CO₃. One-pot milling reaction of HB(Meim)₄, AgNO₃, and K₂CO₃ in the respective stoichiometric ratios 1 : 1 : 1/2, using MeCN as the milling additive (η = 0.25 μL mg⁻¹) readily produced the targeted AgB(Meim)₄ material along with the side product KNO₃ (Fig. 5, also see ESI^†). Specifically, analysis of the reaction mixtures by PXRD revealed that, similar to the lithium and copper(i) analogues,³² the silver-based BIF appears in two polymorphs which could be selectively synthesized by varying the milling time. The BIF products were readily separated from the KNO₃ by-product after sequential washing with cold MeOH and acetone, and their respective structures were further validated by structure determination from PXRD data measured on washed and dried materials.Specifically, milling for 30 minutes led to the formation of a material (Ag-BIF-3) which, based on PXRD analysis, was isostructural to the SOD-topology Li-BIF-3 and Cu-BIF-3. Consequently, the crystal structure of Ag-BIF-3 (Fig. 5A) was determined through Rietveld refinement of a structural model based on the Cu-BIF-3 structure, in which the copper(i) sites have been replaced by Ag(i), giving rise to a cubic unit cell (space group P

\bar{4}

3n as in the analogous Cu-BIF-3 and Li-BIF-3 structures) with a = 16.6659(3) Å. Composition of Ag-BIF-3 was verified by TGA/DSC and elemental analysis of metal content (see ESI^†). The microporous nature of the material was confirmed by N₂ sorption analysis, which revealed a high BET surface area of 1020 m² g⁻¹. Sample analysis by SEM revealed dense aggregates of particles, with sizes below 100 nm (Fig. 5). The ¹³C cross-polarisation magic angle spinning (CP-MAS) solid-state nuclear magnetic resonance (ssNMR) spectrum of Ag-BIF-3 was consistent with the crystal structure, revealing three signals in the imidazolate region 100–160 ppm and the –CH₃ group signal at ∼16 ppm (Fig. 6).Open in a separate window Fig. 6(A) Rietveld refinement of Ag-BIF-3 with difference plot shown in grey. (B) Rietveld refinement of Ag-BIF-2 with difference plot shown in grey. (C) BET adsorption plot Ag-BIF-3 showing a surface area of 1020 m² g⁻¹ and a SEM image of a representative sample (scale-bar 1 μm). Comparison of measured and simulated ¹³C CP-MA ssNMR spectra for silver-based BIFs: (D) calculated for Ag-BIF-3, (E) measured for Ag-BIF-3, (F) calculated for Ag-BIF-2 and (G) measured for Ag-BIF-2.Milling for 60 minutes under otherwise identical conditions led to a material whose PXRD pattern was very similar, but not identical, to that of dia-topology Li-BIF-2 and Cu-BIF-2 materials, with additional Bragg reflections indicating possible lower symmetry. The structure of this material (Fig. 6B) was determined by simulated annealing structure solution from PXRD data, revealing a monoclinic (space group P2₁) unit cell with a = 7.5198(4) Å, b = 16.3763(9) Å, c = 7.5876(4) Å and β = 90.136(6)o. In contrast to structures of Li-BIF-2 and Cu-BIF-2, which all exhibited one symmetrically independent Meim⁻ ligand in a tetragonal I

\bar{4}

space group, the structure of Ag-BIF-3 displays each tetrahedral node surrounded by four symmetrically non-equivalent imidazolate ligands. This much higher multiplicity is clearly reflected by the ssNMR spectrum of the material, validating the structure (Fig. 6). The composition of the material was similarly confirmed by TGA and by elemental analysis of the metal content (see ESI^†). For both Ag-BIF-2 and Ag-BIF-3 the measured ¹³C ssNMR chemical shifts were consistent with those calculated from the herein determined crystal structures (Fig. 6D–G). Notably, while materials based on silver(i) ions are often expected to be light sensitive, the herein reported Ag-BIF-2 and Ag-BIF-3 both appeared unchanged following six months exposure storage in a transparent vial on the bench.The crystal structures of Li-, Cu- and Ag-based BIFs provide a unique opportunity to evaluate the effect of changes in the metal node on the relative stability of BIF polymorphs with SOD- and dia-topology across three metals.^43–45 The calculations were done using CASTEP plane-wave density-functional theory (DFT)⁴⁶ code. The previously published crystal structures of Li- and Cu-BIFs with Meim⁻ linkers, as well as the structures of Ag-BIFs herein determined, were geometry-optimized using the PBE⁴⁷ functional combined with many-body dispersion (MBD*)^48–50 correction scheme. The PBE + MBD* approach has previously shown excellent agreement with experimental calorimetric measurements of ZIF polymorphs,²⁴ therefore we expected the same approach to perform reliably for the structures of BIFs. In addition to calculating the relative energies of SOD- and dia-polymorphs, we have performed Gauge Including Projector Augmented Waves (GIPAW)⁵¹ simulation of the solid-state NMR spectra of Ag-BIFs to compare the simulated spectra with their experimental counterparts, confirming the low symmetry Ag-BIF-2 structure derived from PXRD data (Fig. 6D–G).Comparison of calculated energies reveals that increasing the atomic number of the metal node results in increased stabilization of the SOD-topology open framework with respect to the close-packed dia-polymorph. The energy differences (ΔE) between SOD- and dia-topology polymorphs for each pair of Li-, Cu-, and Ag-based frameworks are shown in 52–54The simulated ssNMR spectra of Ag-BIF-2 and Ag-BIF-3 showed excellent agreement with the experiment (Fig. 6) in terms of overall chemical shift and the number of distinct NMR signals arising from the crystallographic symmetry. The spectrum of the SOD polymorph is consistent with a single symmetrically unique Meim⁻ linker, while the signal splitting found in the spectrum of the dia-polymorph corresponds to four distinct 2-methylimidazolate units. The NMR simulation fully supports the structural models derived from PXRD data, with calculated chemical shifts underlining the accuracy of the herein used theoretical approach. 相似文献

14.

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

Cai You Armido Studer 《Chemical science》2021,12(47):15765

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 window Scheme 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−202 Open 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 window Scheme 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 window Scheme 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 window Scheme 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 7.²³ Open in a separate window Scheme 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. 相似文献

15.

A therapeutic keypad lock decoded in drug resistant cancer cells

Gulsen Turkoglu Gozde Kayadibi Koygun Mediha Nur Zafer Yurt Seyda Nur Pirencioglu Sundus Erbas-Cakmak 《Chemical science》2021,12(28):9754

A molecular keypad lock that displays photodynamic activity when exposed to glutathione (GSH), esterase and light in the given order, is fabricated and its efficacy in drug resistant MCF7 cancer cells is investigated. The first two inputs are common drug resistant tumor markers. GSH reacts with the agent and shifts the absorption wavelength. Esterase separates the quencher from the structure, further activating the agent. After these sequential exposures, the molecular keypad lock is exposed to light and produces cytotoxic singlet oxygen. Among many possible combinations, only one ‘key’ can activate the agent, and initiate a photodynamic response. Paclitaxel resistant MCF7 cells are selectively killed. This work presents the first ever biological application of small molecular keypad locks.

Information processing therapeutics with an implemented keypad lock logic gate selects input order for activation in drug resistant cancer cells.

The complex nature of diseases such as cancer necessitates smarter drugs that can discriminate each disease state or regulate drug efficacy spatially and/or temporally. With this intention, activatable drugs, drugs with on demand release properties are developed with promising selectivity.^1–4 Information processing therapeutics which are based on molecular logic gate operations are another approach to solve this problem.^5–7 Molecular logic gates are small compounds using Boolean logic operations to process inputs (i.e. the analyte concentration), and give an output as a result (fluorescence, and therapeutic activity etc.).⁸ Selective drug activation, release, multiple-analyte sensing and theranostic applications of these devices have been explored by us and others.^5,9–19Among the operations that can be carried out using small molecules, keypad locks provide an alternative application in information security.²⁰ This logic operation can give a specific output when the inputs are given in the correct form and correct sequence. For the device, each input is considered as an AND logic operation where the history of the process is also considered. A pioneering example was reported by Margulies and Shanzer in 2007 where energy transfer is modulated by chelation of Fe³⁺ in a pH dependent manner.²¹ Later, various other devices were introduced with advanced properties such as more than 2 input responsiveness and error detection capability.^22–24 All-photonic logic gates to address chemical waste production is extensively studied by Gust, Andréasson and Pischel.^25,26 Beside small molecule keypad locks, enzymes, antibodies, and DNA hybrids are used to achieve the same goal.^27–30 Although their potential use in molecular cryptology is highlighted, so far, there is no solid biological application of small molecule keypad locks.In the research presented here, a molecular keypad lock is developed which displays a photodynamic therapeutic output when a molecule is exposed to analytes in the correct order and type (PS3, Fig. 1). Two inputs of the system are chosen to be the common markers of drug resistant tumours: glutathione (GSH) and esterase enzyme (E). Cancer cells develop resistance to traditional chemotherapy in time by changing the protein expression or metabolite content of the cell. This adaptation of cancer cells is an obstacle for their treatment and needs to be addressed. Glutathione is a tripeptide used in reductive biochemical synthesis and it is known to be present in elevated levels in rapidly dividing cells such as cancer cells.³¹ A high GSH level is reported to contribute to drug resistance, since GSH adducts of the drugs are exported out of the cell much more rapidly.^32,33 Likewise, esterase enzyme activity is known to be associated with drug detoxification as this enzyme contributes to the chemical conversion of the drug.^34,35 Glutathione and esterase enzyme are chosen to be the first two inputs of the molecular keypad lock, the first two digits of the password. In the research, light is used as the final input. Although trivial, light is essential for photodynamic activity and spatiotemporal control of irradiation, further improving selectivity of the therapy.Open in a separate window Fig. 1Chemical structures of model photosensitizers (PS1 and PS2) and a molecular keypad lock (PS3). Ester bonds (red) are prone to hydrolysis by the esterase enzyme. Distyryl sites of the photosensitizers (blue) can react with thiol nucleophile provided that it is bound to an electron deficient group (i.e. pyri-dinium).Keypad lock PS3 is a photodynamic therapy (PDT) agent. PDT is a non-invasive method used for the treatment of surface cancers and certain other diseases ranging from atherosclerosis to macular degeneration.^36–39 In this therapy, a photosensitizer is excited with light, and produces cytotoxic singlet oxygen (¹O₂) thereby triggering apoptosis or necrosis of the cell, initiating an immune response and blocking microvasculature.⁴⁰ In the research, a boradiazaindecene (BODIPY) photosensitizer is used to benefit from versatile chemistry and spectroscopic properties.^41–45Near-IR absorbing PS3 shown in Fig. 1 is the molecular keypad lock and it is synthesized in 13 steps (Scheme S1^†). PS3 and model compound PS2 have heavy atoms on the structure to favour intersystem crossing required for transition to the triplet state and hence ¹O₂ generation occurs.⁴³ Ester bonds on the structure of PS3 are prone to cleavage by esterase enzyme. Distryryl bonds on the PS3 (blue) tend to reduce or form an adduct with thiol nucleophiles when it is activated by the pyridinium electron withdrawing group.⁴⁶ This property lies at the heart of sequential operation of esterase and GSH. When GSH reacts with electron poor double bonds, the extended conjugated structure is broken and PS3-a is generated (Fig. 2). This structure has absorption below 550 nm, like brominated core BODIPY molecules (compound 8, Scheme S1^†), and therefore can be excited with a green light. A quencher (green) is attached to ensure that photodynamic activity is OFF until esterase cleaves the ester bond. This is because of the energy transfer from the photosensitizer to this module, until esterase separates the photosensitizer. Since PS3 lacks absorption around the 500–550 nm region, it is inactive until GSH reacts with the compound. However, the GSH reacted photosensitizer does show absorption in this region; so, in order to avoid full activation just by GSH, a quencher module is attached. Spectral overlap between the BODIPY core (see the structure of compound 8 in the ESI,^† similar to that of PS3-a in terms of conjugation) and quencher (Q) can be seen from UV-Vis absorption and fluorescence spectra (Fig. 3 and S1^†). By this way, the photosensitizer is chemically modulated by GSH to ensure excitation, and then esterase enzyme inhibits energy transfer by removing the quencher. Lastly a green light is used to excite the photosensitizer leading to generation of photodynamic action. Since light is necessary for the final excitation of the molecule, it should always be the last input. If the order of esterase and GSH changes, as shown in Fig. 2, activation is not expected to take place since cleavage of the ester bonds generates 4-hydroxybenzyl derivative on PS3, which spontaneously faces 1,4-elimination to generate pyridine (Fig. S2^†).⁴⁷ Pyridine on its own is not sufficiently electron withdrawing to favour nucleophilic attack of double bonds by GSH and to activate it as demonstrated below. Therefore, the photosensitizer preserves extended conjugation and essentially lacks absorption at the wavelength of excitation.Open in a separate window Fig. 2Sequential operation of GSH and esterase. GSH can only react with BODIPY distyryl units when the structure has electron withdrawing pyridinium, either reducing it or forming an adduct. Esterase enzyme cleaves ester bonds, liberating the photosensitizer from the quencher module (green). Initial esterase activity converts the pyridinium unit to pyridine, thereby decreasing the reactivity of double bonds with GSH.Open in a separate window Fig. 3Normalized UV-Vis absorption and fluorescence spectra of PS1–3 in 2% water in THF (a and b). Samples are excited at 600 nm. Spectral changes of PS3 (10 μM) alone (black) or PS3 upon exposure to 0.5 mM GSH (c) and 10U esterase (d) for 90 min and 60 min at 37 °C, in 2% water in THF, respectively. A new peak at 544 nm appears upon incubation with GSH which is attributed to reduced PS3 and/orthe GSH-adduct. Esterase treatment increases the relative intensity of the shoulder peak around 600 nm.In order to understand the response of the PS3 to GSH, a molecule is incubated with 0.5 mM of GSH at 37 °C for 90 min. A new peak at 544 nm appears in UV-Vis absorption spectra consistent with the hypothesis (Fig. 3c, S1 and S9^†). The formation of the GSH adduct (PS3-a) is demonstrated by Liquid Chromatography Mass spectrometry analysis (Fig. S3^†). When control module PS1 is exposed to the same conditions, this new peak is not detected indicating that the pyridine bearing structure is neither activated enough for the nucleophilic substitution by GSH nor did it display PDT activity (Fig. S4 and S5^†). On the other hand, GSH treated pyridinium bearing PS2 immediately displayed a colour change indicative of broken conjugation (Fig. S6^†). When PS3 is incubated with esterase for 1 h, a small hypsochromic shift in the absorption peak is detected as a shoulder to the parent peak which is attributed to the conversion of pyridinium to pyridine (PS3-c, Fig. 3d). The control PS3 sample which is incubated under the same conditions but lacks esterase does not show an enhancement of this peak (Fig. 3d, black). High Resolution Mass Spectrometry analysis of the esterase treated PS2 samples confirm the hydrolysis of the ester and subsequent formation of the pyridine compound (Fig. S7^†). Esterase treated samples display an increase in the emission intensity when excited at 620 nm (Fig. S8^†). This is attributed to the initial quenching of the quencher module by the pyridinium photosensitizer. Analysis of the absorption and emission spectra suggest that the quencher module of PS3 can induce energy transfer to the pyridinium photosensitizer (Fig. 3). Once separated by esterase, fluorescence of the quencher module increases. In the case of GSH treated sample, a small enhancement in emission upon excitation at 500 nm is observed (Fig. S9^†). Note that the GSH adduct (or PS3 with reduced double bonds) has higher absorption at this wavelength, which would be the reason for the increase in emission intensity. In the spectral analysis organic solvents with a low water content are used to monitor the formation of water-insoluble, neutral, pyridine-bearing intermediate species.In the project, the molecular keypad lock is aimed to unlock in the presence of drug resistant tumour markers and get activated. Activation cannot take place when the input order differs. To demonstrate this, photodynamic action in the presence of all three inputs in a different order is investigated. ¹O₂ production can be followed by using trap molecule, 1,3-diphenylisobenzofuran (DPBF).⁴⁸ This molecule reacts with ¹O₂ and loses its absorption at 418 nm. The effect of different input combinations on the PDT action are given in Fig. 4. In the first 15 min, all samples are kept in the dark. Under such conditions no ¹O₂ generation is detected, which indicates lack of dark activity. DPBF is exposed to light from a LED source (peak 505 nm) under the same experimental conditions and no decrease in the absorption is detected. This control experiment eliminates the photodegradation of DPBF in the absence of a photosensitizer. Upon irradiation before the activation of the photosensitizer by GSH and esterase, no ¹O₂ generation is observed as expected. The results show that ¹O₂ generation, and the subsequent decrease in DPBF absorption, are significantly more in the input order of glutathione, esterase enzyme and light, consistent with the proposed mode of activation.Open in a separate window Fig. 4 ¹O₂ generation ability of PS3 (0.1 μM) when three inputs are given in a different order. All samples contain 50 μM of ¹O₂ trap molecule DPBF. In the first 15 minutes samples are kept in the dark. GSH is added in 0.5 mM concentration and incubated for 90 min at 37 °C. Samples are incubated with 10U esterase for 1 h at 37 °C. An LED light is irradiated from a 30 cm distance for 45 min.To analyse the effect of PDT action in the cell, a drug resistant cell line is generated. MCF7 cells are exposed to an increased dose of traditional cancer therapeutic agent paclitaxel as described in the literature.⁴⁹ When the spindle-shaped morphology is obtained following maximum drug dose application, cells are reported to have drug resistance. At this stage, PS3 is applied to both normal and drug resistant cells. When cell viabilities at various concentrations are analysed, it has been found that the light toxicity of PS3 is significantly enhanced in drug resistant cells (Fig. 5). The IC50 values of irradiated samples are calculated to be 124.8 μM for MCF7 cells. This value is reduced to 52.5 μM in paclitaxel resistant MCF7 (Pac-MCF7) indicating improved cytotoxicity in these cells. Efficient induction of apoptosis is also proved by Annexin V and PI staining (Fig. 6). Under dark conditions, cells do not have significant loss of viability. Upon irradiation, resistant cells are more prone to apoptosis by the photosensitizer. Relative singlet oxygen generation abilities and results of cell culture experiments altogether confirm selective activation in drug resistant cells.Open in a separate window Fig. 5Change in the cell viability of normal and paclitaxel resistant MCF7 cells (Pac-MCF7) in the presence of PS3 at various concentrations. For each group, cell viability is analysed both after incubation in the dark or after irradiation with a 505 nm LED light source from a distance of 10 cm. Average values of three independent experiments are used.Open in a separate window Fig. 6Apoptosis induction by PS3 (25 μM) in normal and paclitaxel resistant MCF7 cancer cells under dark conditions and upon irradiation with a 505 nm LED light from 10 cm distance. Scale bars: 50 μm. 相似文献

16.

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

Theresa Hostmann Tom&#x; Neveselý Ryan Gilmour 《Chemical science》2021,12(31):10643

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 window Fig. 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 window Fig. 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


Entry	λ [nm]	Time [min]	Yield^b	Z : E ratio^b
1	400	15	76%	50 : 50
2	400	30	72%	68 : 32
3	400	45	74% (74%)	74 : 26 (73 : 27)
4	400	60	54%	73 : 27
5	400	90	49%	73 : 27
6	369	45	66%	27 : 73
7	374	45	61%	44 : 56
8	383	45	64%	53 : 47
9	414	45	67%	60 : 40
10	435	45	72%	26 : 74
11	520	45	67%	<5 : 95

Open in a separate window^a(i) Cp₂ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH₂Cl₂ (1.5 mL), alkyne A-1 (36 mg, 0.2 mmol, 1.0 eq.) in CH₂Cl₂ (0.5 mL); (ii) irradiation; (iii) NBS (39 mg, 0.22 mmol, 1.1 eq.).^baverage yield and Z : E ratio of two reactions determined by ¹H-NMR with DMF as internal standard; isolated yield of the Z : E-mixture and Z : E-ratio in parentheses.Having identified standard conditions to enable a hydrozircononation/isomerization/bromination sequence, the scope and limitations of the method was explored using a range of electronically and structurally diverse phenylacetylenes (Fig. 3). This constitutes a net anti-Markovnikov hydrobromination of alkynes.¹¹ Open in a separate window Fig. 3Aromatic scope for the formal anti-hydrozirconation of terminal alkynes; reaction conditions: (i) Cp₂ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH₂Cl₂ (1.5 mL), alkyne A-1-17 (0.2 mmol, 1.0 eq.) in CH₂Cl₂ (0.5 mL), 15 min; (ii) irradiation (λ = 400 nm), 45 min; (iii) NBS (39 mg, 0.22 mmol, 1.1 eq.), 15 min; ^aisolated yield of Z : E-mixture as average of two reactions; ^b(i) Cp₂ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH₂Cl₂ (1.5 mL), alkyne A-15 (26 mg, 0.2 mmol, 1.0 eq.) in CH₂Cl₂ (0.5 mL); (ii) irradiation (λ = 400 nm), 45 min; (iii) PdPPh₃ (7 mg, 0.006 mmol, 0.03 eq.) in THF (0.4 mL), BnBr (24 μL, 0.2 mmol, 1.0 eq.), rt, 18 h.¹²The introduction of halogen substituents in the 4-position proved to be compatible with the reaction conditions, enabling the formation of (Z)-1-4 in up to 81% yield (up to Z : E = 74 : 26). Interestingly, the introduction of the o-F (Z)-5 substituent led to a drop in the yield and selectivity: this is in stark contrast to cinnamoyl derivatives that have previously been examined in this laboratory.¹² The m-Br proved to be less challenging enabling (Z)-6 to be generated smoothly (74%, Z : E = 67 : 33). The parent phenylacetylene (A-7) could be converted with a similar Z : E-ratio to (Z)-7 albeit less efficiently (36%, Z : E = 72 : 28). Electron donating groups in the para position such as (Z)-8-10 led to a general improvement in selectivity (up to 80%, Z : E = 81 : 19). Whereas methylation at the ortho-position compromised efficiency [(Z)-11, 37%, Z : E = 68 : 32], translocation to the meta-position led to a recovery in terms of yield and Z : E-ratio [(Z)-12, 71%, Z : E = 75 : 25]. Extending the π-system from phenyl to naphthyl enabled the generation of (Z)-13 90% and with a Z : E-ratio of 77 : 23. To enable a direct comparison of strongly and weakly donating groups on the reaction outcome the p-CF₃ and p-OMe derivatives were examined. In the trifluoromethyl derivative (Z)-14 a decrease in yield (31%) and selectivity (Z : E = 48 : 52) was noted. In contrast, the para methoxy group in (Z)-15 led to an enhanced Z : E ratio of 86 : 14 (68% yield). This behavior was also observed with the trimethoxy derivative (Z)-16 (Z : E-ratio of 81 : 19). The piperonyl derivative performing similarly to the para methoxy derivative thereby enabling the formation of (Z)-17 with a Z : E-ratio of 85 : 15 (67% yield). Finally, to demonstrate the utility of the method, a direct transmetallation protocol was performed to intercept the Z-vinyl zirconium species with benzyl bromide.¹³ This enabled the synthesis of (Z)-18 in 67% yield.To demonstrate the compatibility of this platform with other common electrophiles, the deuterated, chlorinated and iodinated systems (Z)-19, -20 and -21 were prepared (Fig. 4). Yields and selectivities that are fully comparable with Fig. 3 were observed (up to 80% yield and Z : E = 80 : 20). Finally, to augment the photostationary composition further, a process of structural editing was conducted. It was envisaged that integrating a stabilizing non-covalent interaction in the Z-vinyl zirconium species may bias isomerization selectivity. Recent studies from this laboratory have established that a stabilizing interaction between the boron p-orbital and an adjacent non-bonding electron pair can be leveraged to induce a highly selective geometric isomerization of β-borylacrylates (Fig. 5, top).¹⁴ Open in a separate window Fig. 4Scope of electrophiles for the formal anti-hydrozirconation; reaction conditions: (i) Cp₂ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH₂Cl₂ (1.5 mL), A-9 (36 mg, 0.2 mmol, 1.0 eq.) in CH₂Cl₂ (0.5 mL); (ii) irradiation (λ = 400 nm), 45 min; (iii) E⁺ (DCl, NCS or NIS) (0.22 mmol, 1.1 eq.), 15 min; isolated yields of the Z : E-mixture are reported.Open in a separate window Fig. 5Enhancing the selectivity of anti-hydrozirconation by leveraging a postulated n_S → Zr interaction. Reaction conditions: (i) Cp₂ZrHCl (62 mg, 0.24 mmol, 1.2 eq.), CH₂Cl₂ (1.5 mL), alkyne A-22-24 (0.2 mmol, 1.0 eq.) in CH₂Cl₂ (0.5 mL), rt, 15 min; (ii) irradiation (λ = 400 nm), 45 min; (iii) NBS (39 mg, 0.22 mmol, 1.1 eq.), rt, 15 min.Gratifyingly, the 5-bromo thiophenyl derivative (Z)-22 was generated with a Z : E ratio of 87 : 13 in 73% yield, and the unsubstituted derivative (Z)-23 was obtained in 41% yield higher selectivity (Z : E = 90 : 10). As a control experiment, the regioisomeric product (Z)-24 was prepared in which the sulfur atom is distal from the zirconium center. This minor alteration resulted in a conspicuous drop of selectivity (Z : E = 78 : 22), which is in line with the phenyl derivatives. Given the prominence of Frustrated-Lewis-Pairs (FLPs) in small molecule activation,¹⁵ materials such as (Z)-22 and (Z)-23 may provide a convenient starting point for the development of future candidates.To provide structural support for the formation of a Z-vinyl zirconium species upon irradiation at λ = 400 nm, the standard experiment was repeated in deuterated dichloromethane and investigated by ¹H NMR spectroscopy. The spectra shown in Fig. 6 confirm the formation of transient E- and Z-vinyl zirconium species (E)-Zr1 and (Z)-Zr1 and are in good agreement with literature values.⁸ Diagnostic resonances of (E)-Zr1 include H¹ at 7.76 ppm, whereas the analogous signal in (Z)-Zr1 is high field shifted to 6.33 ppm (Δδ(H¹_Z−E) = −1.43 ppm). In contrast, the H² signal for (Z)-Zr1 appears at 7.56 ppm, which is at lower field compared to the H² signal for (E)-Zr1 at 6.64 ppm (Δδ(H²_Z−E) = 0.92 ppm). In the ¹³C-NMR spectra (see the ESI^‡) the carbon signal of C1 and C2 are both low field shifted for (Z)-Zr1 compared to (E)-Zr1 (Δδ(C1_Z−E) = 10.5 ppm and Δδ(C1_Z-E) = 5.6 ppm).Open in a separate window Fig. 6¹H-NMR of the transient vinylzirconium species (E)-Zr1 (top) and (Z)-Zr1 (bottom).A computational analysis of the vinyl zirconium isomers (E)-Zr1 and (Z)-Zr1 revealed two low energy conformers for each geometry (Fig. 7. For full details see the ESI^‡). These optimized structures served as a basis for more detailed excited state calculations using a time-dependent density functional theory (TDDFT) approach. These data indicate that isomerization of the styrenyl zirconium species by direct irradiation is highly improbable using λ = 400 nm LEDs. However, upon measuring the absorption spectrum of the reaction mixture (Fig. 8, bottom), the shoulder of a band reaching to the visible part of the spectrum is evident (for more details see the ESI^‡). Furthermore, the fluorescence spectrum (Fig. 8, top) clearly shows light emission from the reaction mixture. Collectively, these data reinforce the working hypothesis that a minor reaction product functions as a productive sensitizer, thereby enabling the isomerization to occur via selective energy transfer.Open in a separate window Fig. 7A comparative analysis of (E)-Zr1 and (Z)-Zr1.Open in a separate window Fig. 8(Top) Fluorescence spectra of the reaction mixture before and after irradiation, and the diene 25 (c = 0.1 mm, irradiation at λ = 350 nm). (Bottom) Absorption spectra of the reaction mixture before and after irradiation (c = 0.1 mm), the alkyne A-1 and the diene 25 (c = 0.05 mm).As previously highlighted, phenylacetylenes are known to dimerize in the presence of Cp₂Zr* based complexes.^9,16 Therefore, to provide support for the involvement of such species, diene 25 was independently prepared and its absorption and emission spectra were compared with those of the reaction mixture (Fig. 8). The emission spectra of the reaction mixture and of diene 25 are closely similar. It is also pertinent to note that diene 25 was also detected in the crude reaction mixture by HRMS (see the ESI^‡).Whilst the spectral measurements in Fig. 8 are in line with diene 25 functioning as an in situ photocatalyst, more direct support was desirable. Frustratingly, efforts to subject (E)-Zr-1 and (Z)-Zr-1 to standard Stern–Volmer quenching studies were complicated by difficulties in removing diene 25 from the samples. It was therefore envisaged that doping reactions with increasing quantities of diene 25 might be insightful. To that end, the hydrozirconation/isomerization sequence was performed with 0.5, 1.0 and 2.5 mol% of diene 25 and the reactions were shielded from light after 5 minutes. Analysis of the mixture by ¹H NMR spectroscopy revealed a positive impact of 25 on the Z : E selectivity, (Z : E = 23 : 77, 24 : 76 and 30 : 70, respectively. Fig. 9, top). To further demonstrate the ability of diene 25 to act as an energy transfer catalyst for geometric isomerization, two model alkenes containing the styrenyl chromophore were exposed to the standard reaction conditions and the photostationary composition was measured after 45 min. Exposing trans-stilbene (E)-26 to the isomerization conditions furnished a Z : E photostationary composition of 44 : 56. Similarly, trans-β-methyl styrene (E)-27 could be isomerized to the cis-β-methyl styrene (Z)-27 with a Z : E ratio of 47 : 53. No isomerization was observed at λ = 400 nm in the absence of the catalyst. Whilst direct comparison with the isomerization of vinyl zirconium species must be made with caution, these experiments demonstrate that dienes such as 25 have the capacity to act as photosensitizers with styrenyl chromophores.Open in a separate window Fig. 9(Top) Exploring the impact of adding diene 25 as an external photocatalyst. (Bottom) Validating photosensitization of the styrenyl chromophore using diene 25.Collectively, these data support the hypothesis that isomerization does not result from direct irradiation alone,¹⁷ but that conjugated dienes, which are produced in small amounts, function as in situ energy transfer catalysts (Fig. 10). This antenna undergoes rapid inter-system crossing (ISC)¹⁸ to generate the triplet state and, upon energy transfer to the alkene fragment, returns to the ground state.¹⁹ This mechanistic study has guided the development of an operationally simple anti-hydrozirconation of alkynes that relies on inexpensive LED irradiation. Merging this protocol with a sequential metal–halogen exchange enables the formal anti-Markovnikov hydrobromination of alkynes¹¹ and provides a sterodivergent platform to access defined alkene vectors from simple alkynes. This complements existing strategies to isomerize vinyl bromides,²⁰ and circumvents the risks of vinyl cation formation and subsequent degradation.²¹ Finally, the selectivity of this geometric isomerization can be further augmented through the judicious introduction of stabilizing non-covalent interactions (up to Z : E = 90 : 10). It is envisaged that this selective, controlled geometric isomerization of an organometallic species will find application in contemporary synthesis. Furthermore, it contributes to a growing body of literature that describes the in situ formation of photoactive species upon irradiation.²² Open in a separate window Fig. 10Postulated energy transfer catalysis cycle predicated on in situ formation of a conjugated diene photocatalyst. 相似文献

17.

A dual-caged resorufin probe for rapid screening of infections resistant to lactam antibiotics

Jinghang Xie Ran Mu Mingxi Fang Yunfeng Cheng Fiona Senchyna Angel Moreno Niaz Banaei Jianghong Rao 《Chemical science》2021,12(26):9153

相似文献

18.

Synthesis and enantioseparation of chiral Au13 nanoclusters protected by bis-N-heterocyclic carbene ligands

Hong Yi Kimberly M. Osten Tetyana I. Levchenko Alex J. Veinot Yoshitaka Aramaki Takashi Ooi Masakazu Nambo Cathleen M. Crudden 《Chemical science》2021,12(31):10436

相似文献

19.

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

Qi Zhang Mong-Feng Chiou Changqing Ye Xiaobin Yuan Yajun Li Hongli Bao 《Chemical science》2022,13(23):6836

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).⁵ Open in a separate window Fig. 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)15TFETrace Open 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 window Fig. 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 window Fig. 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 window Fig. 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 window Fig. 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 window Fig. 6Gibbs free energy profile for the synthesis of 4a in the TFE solvent model. 相似文献

20.

Stereoselective tandem iridium-catalyzed alkene isomerization-cope rearrangement of ω-diene epoxides: efficient access to acyclic 1,6-dicarbonyl compounds

Rahul Suresh Itai Massad Ilan Marek 《Chemical science》2021,12(27):9328

The Cope rearrangement of 2,3-divinyloxiranes, a rare example of epoxide C–C bond cleavage, results in 4,5-dihydrooxepines which are amenable to hydrolysis, furnishing 1,6-dicarbonyl compounds containing two contiguous stereocenters at the 3- and 4-positions. We employ an Ir-based alkene isomerization catalyst to form the reactive 2,3-divinyloxirane in situ with complete regio- and stereocontrol, which translates into excellent control over the stereochemistry of the resulting oxepines and ultimately to an attractive strategy towards 1,6-dicarbonyl compounds.

Iridium catalyzed alkene isomerization-cope rearrangement of ω-diene epoxide furnishes 3,4-dihydrooxepines. These oxepines are hydrolyzed to diastereomerically pure 1,6-dicarbonyl compound containing two contiguous stereocenters within acyclic system.

1,6-Dicarbonyl compounds are widespread as targets and intermediates in organic synthesis.¹ Due to the “dissonant” polarizing effect induced by the two carbonyl groups,² these motifs are challenging to retrosynthetically disconnect into classical synthons. Unsurprisingly, many approaches toward 1,6-dicarbonyls rely on dimerization of α,β-unsaturated carbonyl compounds (Scheme 1a)³ or oxidative cleavage of substituted cyclohexene derivatives⁴ which significantly limits the range of possible products. Alternative strategies, such as the ring-opening of donor–acceptor cyclopropanes with enolate nucleophiles, efficiently form the 1,6-dicarbonyl skeleton, albeit with limited substrate scope (Scheme 1b).⁵ The Cope rearrangement of 1,5-dienes, featuring oxygen functionality in the 3- and 4-positions,⁶ represents a promising strategy towards 1,6-dicarbonyl compounds but suffers from lack of stereocontrol over the diene substrates, resulting in diastereomeric mixtures of products (Scheme 1c).Open in a separate window Scheme 1Selected approaches towards the formation of 1,6-dicarbonyl compounds and our proposed approach.A conceptually related approach towards the preparation of 1,6-dicarbonyl compounds is through the hydrolysis of 3,4-dihydrooxepines (Scheme 1d), which are in turn generated through the Cope rearrangement of 2,3-divinyloxiranes.⁷ Such a sigmatropic rearrangement is also noteworthy as a rare example where an epoxide C–C bond is selectively cleaved over the usually more reactive C–O bond. This intriguing rearrangement has been studied but its use in synthesis is scarce, presumably due to difficulties in the stereoselective synthesis and handling of the key divinyl epoxides.In line with our interest in the strategic application of alkene isomerization to generate reactive synthetic intermediates in stereodefined form,⁸ we posited to form the reactive 2,3-divinyloxiranes in situ, through alkene isomerization^9,10 of the simpler allyl epoxides, which are accessible in enantiomerically enriched form.¹¹ Such a strategy might greatly facilitate access to these intermediates and therefore uncover a synthetically attractive route toward 1,6-dicarbonyl compounds featuring two contiguous stereocenters.With this idea in mind, we first explored the isomerization and subsequent Cope rearrangement of allyl-vinyl epoxides 1 (Scheme 2). To induce isomerization, we employed a cationic iridium-based catalytic system,¹² which is known to reliably isomerize alkenes with high degrees of regio- and stereocontrol.¹³ Open in a separate window Scheme 2Substrate scope for the tandem iridium-catalyzed alkene isomerization-Cope rearrangement of allyl-vinyl epoxides.In line with our expectations, our model substrate 1a (R² = R³ = H, R⁴ = Me, R⁵ = CO₂Et) was smoothly isomerized at 65 °C in the presence of 1.5 mol% of Ir dimer to obtain the corresponding divinyl epoxide with a complete E-selectivity. With suitable conditions for alkene isomerization in hand, we exposed substrate 1a to the Ir-based catalytic system at 120 °C and were equally pleased to observe the 4,5-dihydrooxepine product 2a, resulting from the tandem isomerization-Cope rearrangement as a single diastereoisomer in 81% yield. We proceeded to test the generality of our protocol with respect to different alkene and epoxide substitution patterns. Pleasingly, product 2b was generated with complete stereoselectivity, showcasing the compatibility of the reaction conditions with potentially labile tertiary stereocenters α to the ester group. We then wondered whether the anti-diastereomer could be accessed starting from the corresponding cis allyl-vinyl epoxide. Indeed, in line with the known stereospecific behavior of the Cope rearrangement, we obtained the complementary diastereomer 2c. Turning our attention to more highly substituted epoxides, we were pleased to observe the formation of dihydrooxepines 2d and 2e, which correspond to 1,6-keto-aldehyde and diketone products, respectively. Substrate 1f (R² = R⁴ = R⁵ = H, R³ = Ph), which features an unactivated vinyl group, also underwent the rearrangement, demonstrating that an activated alkenyl group is not required for a successful outcome. Similarly, product 2g featuring two alkyl groups is also generated, with high diastereoselectivity albeit in moderate yield. Products featuring ethyl and methyl ester 2h, 2i could also be obtained in good yields and diastereoselectivity. We next tested substrate 1j (R² = Me, R³ = Ph, R⁴ = CH₂CH₂Ph, R⁵ = H), as a geometric-mixture of the double bond (E : Z = 1.1 : 1) and in accordance with the stereospecificity of the process, the oxepine 2j was obtained as a mixture of two diastereomers with the same ratio. Disappointingly, substrate 1k did not undergo isomerization, presumably due to the Lewis basic nature of the ketone, likely poisoning the Ir-catalyst.During our study, we noticed that allyl-vinyl epoxides bearing electron donating groups on the vinyl moiety tend to decompose during purification by column chromatography on silica gel. This obstacle further motivated us to explore diallyl epoxides 3 as substrates, where the reactive divinyl epoxide would be generated by isomerization of both allyl fragments. Notably, these diallyl epoxides are much more stable compared to their vinyl counterparts and can be readily prepared in two steps from simple alkynes.¹⁴ To our delight, diallyl epoxide 3a (R = CH₂OMe) smoothly underwent the double isomerization-Cope rearrangement cascade at 140 °C, furnishing oxepine 2l with impressive yield and diastereoselectivity (Scheme 3). The use of alkene isomerization to form the reactive divinyl epoxide in situ avoids the isolation of the unstable divinyl epoxide, while controlling the stereochemistry of both double bonds, particularly not trivial to achieve using classical olefination reactions. Products 2m and 2n feature ester and silyl groups, highlighting the functional group tolerance of the catalytic system.Open in a separate window Scheme 3Substrate scope for tandem iridium-catalyzed double alkene isomerization-Cope rearrangement of diallyl epoxides.Our next objective was to hydrolyze the diastereomerically pure oxepines obtained through the rearrangement in a stereoretentive fashion, revealing the acyclic 1,6-dicarbonyl motif. Pleasingly, diversely substituted oxepines 2 underwent smooth hydrolysis either using 5 mol% of Pd(MeCN)₂Cl₂¹⁵ at 50 °C or an acidic aqueous solution to form 1,6-dicarbonyls 4 in diastereomerically pure form (Scheme 4).¹⁶ Dicarbonyl products featuring labile tertiary centers 4a and 4b are formed under these conditions with excellent diastereoselectivities and yields. Without surprise, oxepine 2f (R² = R⁴ = R⁵ = H, R³ = Ph) furnished the keto-substituted product 4c in good yield. The relative stereochemistry of 4b was unambiguously confirmed by single crystal X-ray diffraction analysis of the corresponding carboxylic acid 7 (Scheme 4b).¹⁷ The reaction is scalable to ½ gram of substrate and could be performed in a single-pot operation without isolation of the intermediate oxepine (Scheme 4b). By using this approach, 1h provides 4b in 61% yield as a single diastereomer, underlining the synthetic potential and efficiency of this method.Open in a separate window Scheme 4Hydrolysis of oxepines and one-pot sequence. 相似文献