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1.
Invited for this month''s cover picture is the group of Dr. Satoko Hayashi at Faculty of Systems Engineering and Chemistry at Wakayama University. The cover picture shows the linear Se16 σ(16c–30e) interactions, illustrated by the molecular graph type on the optimized structure of the dicationic octamer of 1,5‐(diselena)cane. HOMO‐1 of ψ462 is drawn on the structure, which is located predominantly on the Se atoms. The optimized structure is stable, due to the nice engagement between the (CH2)3 moieties. The contour maps of ρ(r) are also drawn on the molecular C s planes of the dicationic dimer and trimer to demonstrate clearly the existence of the interactions between Se atoms. Read the full text of their Full Paper at 10.1002/open.202100017.

“… To improve the causality of experimental results, we have proposed a new concept, called “Keisan‐sendo…” Find out more about the story behind the front cover research at 10.1002/open.202100017.  相似文献   

2.
Invited for this month''s cover picture is the group of Young Kee Kang at Chungbuk National University (Republic of Korea). The cover picture shows the preferred conformation of the hexamer of ϵ‐amino acid Amc5a with a cyclopentane substituent in the backbone investigated using DFT methods in chloroform and water. The Amc5a hexamer adopted a stable left‐handed conformation with a rise of 4.8 Å per turn both in chloroform and water. However, the hexamer of Ampa (an analogue of Amc5a with replacing cyclopentane by pyrrolidine) adopted different conformations in chloroform and in water. Read the full text of their Research Article at 10.1002/open.202100253.

“…Finding the appropriate protocol is a crucial step for conformational prediction of peptides and peptide foldamers in solution…” Find out more about the story behind the front cover research at 10.1002/open.202100253.  相似文献   

3.
Invited for this month''s cover picture are the groups of Masahiro Ikeshita and Takashi Tsuno at Nihon University and Yoshitane Imai at Kindai University (Japan). The cover picture shows the comparison of circularly polarized luminescence (CPL) properties of square planar platinum(II) complexes with different coordination geometry. Computational studies have been carried out to investigate these structure‐dependencies, and revealed that the distortion of the coordination geometry results into an enhancement the chiroptical responses of these compounds. Read the full text of their Research Article at 10.1002/open.202100277.

“… How does the stereochemistry of transition metal complexes affect their photophysical properties…” Find out more about the story behind the front cover research at 10.1002/open.202100277.  相似文献   

4.
The Front Cover shows the preferred conformation of oligomers of the aminoacid Amc5a. The backbone sequences were investigated using DFT methods in solution. More information can be found in the Research Article by Hae Sook Park et al.  相似文献   

5.
The Front Cover shows the comparison of circularly polarized luminescence (CPL) properties of square planar platinum(II) complexes with different coordination geometries. Computational studies have revealed that the distortion of the coordination geometry is key to enhancement of the chiroptical responses of these compounds. More information can be found in the Research Article by Masahiro Ikeshita et al.  相似文献   

6.
Dr. Axel Straube 《ChemistryOpen》2022,11(1):e202100271
Happy Birthday, ChemistryOpen! The front cover sets the stage for a year of celebration as ChemistryOpen, the first society‐owned Gold Open Acces title in chemistry, has been launched 10 years ago. A small selection of cover images, past and present, and a “Thank You!” note highlight that this was only possible due to the steady and wonderful support of our authors. Step into the 1st anniversary issue – we are Open for Publishing! More information on 10 years of ChemistryOpen can be found in the Editorial by Editor in Chief Francesca Novara.

  相似文献   

7.
Electrical conduction among metallocycles has been unexplored because of the difficulty in creating electronic transport pathways. In this work, we present an electrocrystallization strategy for synthesizing an intrinsically electron-conductive metallocycle, [Ni6(NDI-Hpz)6(dma)12(NO3)6]·5DMA·nH2O (PMC-hexagon) (NDI-Hpz = N,N′-di(1H-pyrazol-4-yl)-1,4,5,8-naphthalenetetracarboxdiimide). The hexagonal metallocycle units are assembled into a densely packed ABCABC… sequence (like the fcc geometry) to construct one-dimensional (1D) helical π-stacked columns and 1D pore channels, which were maintained under the liberation of H2O molecules. The NDI cores were partially reduced to form radicals as charge carriers, resulting in a room-temperature conductivity of (1.2–2.1) × 10−4 S cm−1 (pressed pellet), which is superior to that of most NDI-based conductors including metal–organic frameworks and organic crystals. These findings open up the use of metallocycles as building blocks for fabricating conductive porous molecular materials.

Intrinsically electron-conductive metallocycle was synthesized. π-Radicals play a key role in constructing π-stacked columns among molecular hexagons and achieving high electrical conductivity over 10−4 S cm−1 in polycrystalline pellet.  相似文献   

8.
Correction for ‘Cu-catalyzed C–C bond formation of vinylidene cyclopropanes with carbon nucleophiles’ by Jichao Chen et al., Chem. Sci., 2019, 10, 10601–10606.

We regret that in the original article the structure of compound 1 in Tables 1–3 was incorrect. The correct structure is given below.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.  相似文献   

9.
Herein reported is a strategy for constructing vicinal 4°/3° carbons via reductive Cope rearrangement. Substrates have been designed which exhibit Cope rearrangement kinetic barriers of ∼23 kcal mol−1 with isoenergetic favorability (ΔG ∼ 0). These fluxional/shape-shifting molecules can be driven forward by chemoselective reduction to useful polyfunctionalized building blocks.

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

Constructing sterically congested vicinal quaternary–tertiary carbons (4°/3° carbons) via Cope rearrangement is currently quite limited with only a handful of papers on the subject published over the past 40 years. This stands in stark contrast to the plethora of other methods for establishing sterically congested vicinal carbons.1–5 Central to the challenge are kinetic and thermodynamic issues associated with the transformation. In the simplest sense, Cope rearrangements proceed in the direction that results in highest alkene substitution (Fig. 1).6,7 To forge 4°/3° motifs by Cope rearrangement, additional driving forces must be introduced to reverse the [3,3] directionality and compensate for the energetic penalty associated with the steric and torsional strain of the targeted vicinal 4°/3° motif. With limited reports in all cases, oxy-Cope substrates (Scheme 1, eqn (1)),8–14 divinylcyclopropanes (Scheme 1, eqn (2)),15–20 and vinylidenecyclopropane-based 1,5-dienes21 (Scheme 1, eqn (3)) have demonstrated favourability for constructing vicinal 4°/3° carbons. Malachowski et al. put forth a series of studies on the construction of quaternary centers via Cope rearrangement driven forward by a conjugation event (Scheme 1, eqn (4)).22–25 In their work, a single example related to the construction of vicinal 4°/3° centers was disclosed, though kinetic (180 °C) and thermodynamic (equilibrium mixtures) challenges are also observed.23 And of particular relevance to this work, Wigfield et al. demonstrated that 3,3-dicyano-1,5-dienes with the potential to generate vicinal 4°/3° carbons instead react via an ionic mechanism yielding the less congested products (Scheme 1, eqn (5)).26Open in a separate windowFig. 1Cope equilibrium of 1,1,6-trisubstituted 1,5-dienes.Open in a separate windowScheme 1(A) Cope rearrangements for constructing vicinal 4°/3°-centers (B) this report.Our group has been examining strategies to decrease kinetic barriers and increase the thermodynamic favourability of 3,3-dicyano-1,5-diene-based Cope substrates.27–31 Beyond the simplest, unsubstituted variants, this class of 1,5-diene is not particularly reactive in both a kinetic and thermodynamic sense (e.g.Scheme 1, eqn (5)).26,32 Reactivity issues aside, these substrates are attractive building blocks for two main reasons: (1) they have straightforward accessibility from alkylidenemalononitriles and allylic electrophiles by deconjugative allylic alkylation.33 (2) The 1,5-diene termini are substantially different (malononitrile vs. simple alkene) thus allowing for orthogonal functional group interconversion facilitating target and analogue synthesis.34 Herein we report that a combination of 1,5-diene structural engineering28,31 and reductive conditions (the reductive Cope rearrangement29,30) can result in the synthesis of building blocks containing vicinal gem-dimethyl 4°/3° carbons along with orthogonal malononitrile and styrene functional groups for interconversion (Scheme 1B). On this line, malononitrile can be directly converted to amides34 yielding functionally dense β-gem-dimethylamides, important pharmaceutical scaffolds.35This project began during the Covid-19 pandemic lockdown (ca. March–May 2020). As such, we were not permitted to use our laboratory out of an abundance of caution. We took this opportunity to first computationally investigate a Cope rearrangement that could result in vicinal 4°/3° carbons (Scheme 2). Then, when permitted to safely return to the lab, we would experimentally validate our findings (vide infra). From our previous work, it is known that by adding either a 4-aromatic group28 or a 4-methyl group31 to a 3,3-dicyano-1,5-diene, low barrier (rt – 80 °C) diastereoselective Cope rearrangements can occur. Notably, the 4-substituent was found to destabilize the starting material (weaken the C3–C4 bond, conformationally bias the substrate for [3,3]), and stabilize the product side of the equilibrium via resonance (phenyl group) or hyperconjugation (methyl group). In this study, we modelled substrates 1, 3, and 5 that have variable 4-substitution and would result in vicinal gem-dimethyl- and phenyl-containing 4°/3° carbons upon Cope rearrangement to 2, 4, or 6, respectively. We chose to target this motif due to likely synthetic accessibility from simple starting materials but also because of the important and profound impact that gem-dimethyl groups impart on pharmaceuticals.35 Substrate 1 lacking 4-substitution had an extremely unfavourable kinetic and thermodynamic profile (ΔG = 31.6; ΔG = +5.3 kcal mol−1). When a 4-methyl group was added, the kinetic barrier (ΔG) dropped appreciably to 28.2 kcal mol; however, the thermodynamics were still quite endergonic (ΔG = +4.4 kcal mol−1). Most excitingly, it was uncovered that the 4-phenyl group dramatically impacted the kinetics and thermodynamics: the [3,3] has a barrier of 22.9 kcal mol−1G) and is ∼isoenergetic (ΔG = +0.17 kcal mol−1). Thus, the reaction appears to be fluxional/shape-shifting at room temperature.36–40 For this substrate, we also modelled the dissociative pathway (Scheme 2D). It was found that bond breakage to two allylic radical intermediates is a higher energy process than the concerted transition state (Scheme 2Cvs.Scheme 2D). Specifically, the dissociative pathway was found to be kinetically less favourable (ΔG ∼ 27.6 kcal mol; ΔG = 26.2 kcal mol−1) than the concerted process (ΔG = 22.9 kcal mol−1). While the dissociative pathway is less favourable than the concerted transformation, we surmised that the two-step process becomes accessible at elevated temperature (vide infra). Finally, the ionic pathway was calculated to be significantly higher for this substrate (see the ESI).Open in a separate windowScheme 2Computational analysis of 3,3-dicyano-1,5-diene that in theory could result in vicinal 4°/3° carbons. (A) 4-Unsubstituted 3,3-dicyano-1,5-diene. (B) 4-Methyl 3,3-dicyano-1,5-diene. (C) 4-Phenyl 3,3-dicyano-1,5-diene. (D) The dissociative mechanism for substrate 5 is higher than the closed transition state. (E) visualization of the kinetic- and thermodynamic differences of transformations (A–D).The class of substrate uncovered from our computational investigation could be accessed from γ,γ-dimethyl-alkylidenemalononitrile (7a) and 1,3-diarylallyl electrophiles (such as 8a) by Pd-catalyzed deconjugative allylic alkylation (Scheme 3A).33 As such, model 1,5-diene 5a was prepared to verify the computational results. It was found that upon synthesis of 5a, an inseparable 21 : 79 mixture of 1,5-diene 5a and the 1,5-diene 6a was observed. The predicted ratio of 5a to 6a was 57 : 43 (Scheme 2C). These two results are within the error of the calculations (predicted; slightly endergonic, observed; slightly exergonic). To determine whether the transformation was progressing through the predicted concerted pathway (Scheme 2C) over the dissociative pathway (Scheme 2D), substrate 5b was prepared by an analogous deconjugative allylic alkylation reaction. Similarly, two Cope equilibrium isomers 5b and 6b are observed at room temperature in a 12 : 88 ratio. Upon heating at 100 °C for 3 h, the 1,5-dienes “scramble” (e.g. iso-6b is observed; 0.2 : 1.0 : 1.5 ratio of 5b : 6b : iso-6b) indicating that the dissociative pathway is only accessible at elevated temperature. This is all in good agreement with the calculated kinetics and thermodynamics of this system (Scheme 2).Open in a separate windowScheme 3(A) Observation of fluxional [3,3] and confirmation of calculated predictions. (B) Optimization of a reductive Cope rearrangement protocol for constructing vicinal 4°/3° centers. (C) The Pd-catalyzed deconjugative allylic alkylation must be regioselective.With respect to the synthetic methodology, we aimed to increase the overall efficiency and applicability of the sequence (Scheme 3B). Specifically, we wanted to avoid [3,3] equilibrium mixtures and sensitive/unstable substates and intermediates. It was found that the direct coupling of 7a with diphenylallyl alcohol 9a could take place in the presence of DMAP, Ac2O, and Pd(PPh3)4. When the coupling was complete, methanol and NaBH4 were added to drive the Cope equilibrium forward, yielding the reduced Cope rearrangement product 10a in 76% isolated yield. In terms of practicality and efficiency, this method utilizes diphenylallyl alcohols, which are more stable and synthetically accessible than their respective acetates, and the [3,3] equilibrium mixture can be directly converted dynamically to a single reduced product.With an efficient protocol in hand for constructing malononitrile–styrene-tethered building blocks featuring central vicinal 4°/3° carbons, we next examined the scope of the transformation (Scheme 4). We chose diarylallyl alcohols with the propensity to react regioselectively via an electronic bias (Scheme 3C).41,42 The combination of p-nitrophenyl and phenyl (10b) or p-methoxyphenyl (10c) yielded regioselective outcomes with the electron-deficient arene at the allylic position. This is consistent with the expected regiochemical outcome where the nucleophile reacts preferentially at the α-position and the electrophile reacts at the allylic position bearing the donor-arene (Scheme 3C).41,42 Then, reductive Cope rearrangement occurs to position the electron-deficient arene adjacent to the gem-dimethyl quaternary center. This is an exciting outcome as many pharmaceutically relevant (hetero)arenes are electron deficient. Thus, fluorinated arenes were installed at the allylic position of products 10d–10k. While the phenyl group resulted in poor regioselectivity (1 : 1–3 : 1), the p-methoxyphenyl group enhanced the regiomeric ratios in all cases (3 : 1–15 : 1). The degree of selectivity is correlated with the number and position of fluorine atoms. N-Heterocycles could be incorporated with excellent regioselectivity, generally speaking (10l–10q). For example, 3-chloro-4-pyridyl (10l/10m) groups were installed at the allylic position with >20 : 1 rr. 4-Chloro-3-pyridyl was poorly regioselective (10n), but the combination of 4-trifluomethyl-3-pyridyl/p-methoxyphenyl (10o) gave good regioselectivity of 11 : 1. 2-Pyridyl/p-methoxyphenyl (10q) was also a regioselective combination. We also examined a few other heterocycles including quinoline (10s) and thiazole (10t and 10u) with excellent and modest regioselectivity observed, respectively. As a general trend, when the arenes on the allylic electrophile become less polarized, poor regioselectivity is observed in the Pd-catalyzed allylic alkylation. For example, the combination of p-chlorophenyl and p-methoxyphenyl (10v) or phenyl (10w) yields regioisomeric mixtures of products. This can be circumvented by utilizing symmetric electrophiles (to 10x).Open in a separate windowScheme 4Scope of the 4°/3°-center-generating reductive Cope rearrangement.The phenyl or the p-methoxyphenyl group is necessary to achieve the 4°/3° carbon-generating Cope rearrangement: it functions as an “activator” by lowering the kinetic barrier and increasing thermodynamic favourability. These activating groups can be removed through alkene C Created by potrace 1.16, written by Peter Selinger 2001-2019 C cleavage reactions (e.g. metathesis (Scheme 5) and ozonolysis (Scheme 6B)). In this regard, highly substituted cycloheptenes 11 were prepared by allylation and metathesis (Scheme 4).28,43 The yields were modest to excellent over this two-step sequence. In many cases, where 10 exists as a mixture of regioisomers, the major allylation/RCM products 11 could be chromatographically separated from their minor constituents. As shown in Scheme 6A, the malononitrile can be transformed via oxidative amidation34 to products 12 containing a dense array of pharmaceutically relevant functionalities (amides, gem-dimethyl, fluoroaromatics, and heteroaromatics). Following this transformation, ozonolysis terminated with a NaBH4 quench installs an alcohol moiety on small molecule 13a.Open in a separate windowScheme 5Removal of the “activating group” by ring-closing metathesis.Open in a separate windowScheme 6(A) oxidative amidation of malononitrile. (B) Removal of “activating group” by ozonolysis.These first computational and experimental studies utilizing 3,3-dicyano-1,5-dienes as substrates for constructing vicinal 4°/3° centers sets the stage for much further examination and application. For example, while we focused our efforts on gem-dimethyl-based quaternary carbons, it is likely that other functionality can be installed at this position. For example, while unoptimized, it appears the protocol is reasonably effective at incorporating a piperidine moiety in addition to heteroarenes from the allylic electrophile (7b + 9f → 14a; Scheme 7A). Similar functional group interconversion chemistry as described in Schemes 5 and and66 can thus yield functionally dense building blocks 15 and 16 in good yields.Open in a separate windowScheme 7(A) The construction of 4/3° centres on piperidines. (B) Promoting endergonic [3,3] rearrangements is possible, assuming the [3,3] kinetic barrier is sufficiently low.While the 4,6-diaryl-3,3-dicyano-1,5-dienes offered the most attractive energetic profile (low kinetic barrier, isoenergetic [3,3] equillibrium; Scheme 2C), the 4-methyl analogue is also intriguing to consider as a viable substrate class for reductive Cope rearrangement (Scheme 2B). The challenge here is that the kinetics and thermodynamics are quite unfavourable (not observable by NMR), but potentially not prohibitively so. It is extremely exciting to find that Cope equilibria that are significantly endergonic in the desired, forward direction (e.g.3a to 4a) can be promoted by a related reductive protocol (Scheme 7B). While unoptimized, we were able to isolate product 17 in xx% yield by heating at 90 °C in the presence of Hantzsch ester in DMF.  相似文献   

10.
β-Difluoroalkylborons, featuring functionally important CF2 moiety and synthetically valuable boron group, have great synthetic potential while remaining synthetically challenging. Herein we report a hypervalent iodine-mediated oxidative gem-difluorination strategy to realize the construction of gem-difluorinated alkylborons via an unusual 1,2-hydrogen migration event, in which the (N-methyliminodiacetyl) boronate (BMIDA) motif is responsible for the high regio- and chemoselectivity. The protocol provides facile access to a broad range of β-difluoroalkylborons under rather mild conditions. The value of these products was demonstrated by further transformations of the boryl group into other valuable functional groups, providing a wide range of difluorine-containing molecules.

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

Organofluorine compounds have been widely applied in medicinal chemistry and materials science.1ad In particular, the gem-difluoro moiety featuring unique steric and electronic properties can act as a chemically inert isostere of a variety of polar functional groups.2ac Therefore, the construction of gem-difluoro-containing compounds has received considerable attention in recent years. Efficient methods including deoxyfluorination of carbonyl compounds,3a,b photoredox difluorination,4 radical difluorination,5 and cross-coupling reactions with suitable CF2 carriers6af are well developed. Alternatively, iodoarene-mediated oxidative difluorination reactions provide valuable access to these motifs by using simple alkenes as starting materials.7ai Previously, these reactions were generally associated with a 1,2-aryl or 1,2-alkyl migration (Scheme 1a).7af Recent developments also allowed the use of heteroatoms as migrating groups, thereby furnishing gem-difluoro compounds equipped with easily transformable functional groups (Scheme 1b). In this regard, Bi and coworkers reported an elegant 1,2-azide migrative gem-difluorination of α-vinyl azides, enabling the synthesis of a broad range of novel β-difluorinated alkyl azides.7g Jacobsen developed an iodoarene-catalyzed synthesis of gem-difluorinated aliphatic bromides featuring 1,2-bromo migration with high enantioselectivity.7h Almost at the same time, research work from our group demonstrated that not only bromo, but also chloro and iodo could serve as viable migrating groups.7iOpen in a separate windowScheme 1Hypervalent iodine-mediated β-difluoroalkylboron synthesis.We have been devoted to developing new methodologies for the assembly of boron-containing building blocks by using easily accessible and stable MIDA (N-methyliminodiacetyl) boronates8ac as starting materials.9ae Recently, we realized a hypervalent iodine-mediated oxidative difluorination of aryl-substituted alkenyl MIDA boronates.9d Depending on the substitution patterns, the reaction could lead to the synthesis of either α- or β-difluoroalkylborons via 1,2-aryl migration (Scheme 1c). Recently, with alkyl-substituted branched alkenyl MIDA boronates, Szabó and Himo observed an interesting bora-Wagner–Meerwein rearrangement, furnishing β-difluorinated alkylboronates with broader product diversity (Scheme 1d).10 While extending the scope of our previous work,9d we found that the use of linear alkyl-substituted alkenyl MIDA boronates also delivers β-difluoroalkylboron products. Intriguingly, instead of an alkyl- or boryl-migration, an unusual 1,2-hydrogen shift takes place. It should be noted that internal inactivated alkenes typically deliver the 1,2-difluorinated products, with no rearrangement taking place.11ad Herein, we disclose our detailed study of our second generation of β-difluoroalkylborons synthesis (Scheme 1e). The starting linear 1,2-disubstituted alkyl-substituted alkenyl MIDA boronates, unlike the branched ones,10 could be readily prepared via a two-step sequence consisting of hydroborylation of the terminal alkyne and a subsequent ligand exchange with N-methyliminodiacetic acid. This intriguing 1,2-H shift was found to be closely related to the boron substitution, probably driven thermodynamically by the formation of the β-carbon cation stabilized by a σ(C–B) bond via hyperconjugation.12adTo start, we employed benzyl-substituted alkenyl MIDA boronate 1a as a model substrate (9d the use of F sources such as CsF, AgF and Et3N·HF in association with PhI(OAc)2 (PIDA) as the oxidant and DCM as the solvent led to no reaction (entries 1 to 3). The use of Py·HF (20 equiv) successfully provided β-difluorinated alkylboronate 2a, derived from an unusual 1,2-hydrogen migration, in 39% yield (entry 4). By simply increasing the loading of Py·HF to 40 equivalents, a higher conversion and thus an improved yield of 61% was obtained (entry 5). No further improvement was observed by using a large excess of Py·HF (100 equiv) (entry 6). Other hypervalent iodine oxidants such as PhIO or PIFA were also effective but resulted in reduced yields (entries 7 and 8). A brief survey of other solvents revealed that the original DCM was the optimal one (entries 9 and 10).Optimization of reaction conditions
EntryF (equiv)OxidantSolventYield (%)
1CsF (2.0)PIDADCM0
2AgF (2.0)PIDADCM0
3Et3N·HF (40.0)PIDADCM0
4Py·HF (20.0)PIDADCM39
5 Py·HF (40.0) PIDA DCM 61
6Py·HF (100.0)PIDADCM55
7Py·HF (40.0)PIFADCM52
8Py·HF (40.0)PhIODCM26
9Py·HF (40.0)PIDADCE49
10Py·HF (40.0)PIDAToluene46
Open in a separate windowWith the optimized reaction conditions in hand, we set out to investigate the scope and limitation of this gem-difluorination reaction. The reaction of a series of E-type 1,2-disubstituted alkenyl MIDA boronates were first examined. As shown in Scheme 2, the reaction of substrates with primary alkyl (1b, 1e–g), secondary alkyl (1c, 1d), or benzyl (1h–k) groups proceeded efficiently to give the corresponding gem-difluorinated alkylboronates in moderate to good yields. Halides (1i–k, 1m) and cyano (1l) were well tolerated in this reaction. Of note, cyclic alkene 1n is also a viable substrate, affording an interesting gem-difluorinated cyclohexane product (2n).Open in a separate windowScheme 2Scope of 1,2-H migratory gem-difluorinations. a 4 h. b PIFA was used.To define the scope further, the substrates with Z configuration were also employed under the standard reaction conditions (eqn (1) and (2)). The same type of products were isolated with comparable efficiency, suggesting that the reaction outcome is independent of the substrate configuration and substrates with Z configuration also have a profound aptitude of 1,2-hydrogen migration. Nevertheless, the reaction of t-butyl substituted alkenyl MIDA boronate (1p) delivered a normal 1,2-difluorinated alkylboron product (eqn (3)). The 1,2-hydrogen migration was completely suppressed probably due to unfavorable steric perturbation. With an additional alkyl substituent introduced, a 1,2-alkyl migrated product was formed as expected (eqn (4)).1The gem-difluorination protocol was amenable to gram-scale synthesis of 2a (Scheme 3, 8 mmol scale of 1a, 1.24 g, 50%). To assess the synthetic utility of the resulting β-difluorinated alkylborons, transformations of the C–B bond were carried out (Scheme 3). Ligand exchange of 2a furnished the corresponding pinacol boronic ester 4 without difficulty, which could be ligated with electron-rich aromatics to obtain 5 and 6 in moderate yields. On the other hand, 2a could be oxidized with high efficiency to alcohol 7 using H2O2/NaOH. The hydroxyl group of 7 could then be converted to bromide 8 or triflate 9. Both serve as useful electrophiles that can undergo intermolecular SN2 substitution with diverse nitrogen- (10, 13), oxygen- (14), phosphorus- (11) and sulfur-centered (12) nucleophiles.Open in a separate windowScheme 3Product derivatizations. PMB = p-methoxyphenyl.To gain insight into the reaction mechanism, preliminary mechanistic studies were conducted. The reaction employing deuterated alkenyl MIDA boronate [D]-1a efficiently afforded difluorinated product [D]-2a in 72% isolated yield, clearly demonstrating that 1,2-H migration occurred (Scheme 4a). However, when the MIDA boronate moiety was replaced with a methyl group (15), no difluorinated product (derived from 1,2-migration) was detected at all, suggesting an indispensable role of boron for promoting the 1,2-migration event (Scheme 4b). Also, with a Bpin congener of 1a, the reaction led to large decomposition of the starting material, with no desired product being formed (Scheme 4b).Open in a separate windowScheme 4Mechanistic studies and proposals.Based on the literature precedent and these experiments, a possible reaction mechanism is proposed in Scheme 4c. With linear alkenyl MIDA boronates, the initial coordination of the double bond to an iodium ion triggered a regioselective fluoroiodination to deliver intermediate B. The regioselectivity could arise from an electron-donating inductive effect from boron due to its low electronegativity, consistent with previous observations.13a,b Thereafter, a 1,2-hydrogen shift, rather than the typical direct fluoride substitution of the C–I bond, provides carbon cation C. The formation of a hyperconjugatively stabilized cation is believed to be the driving force for this event.12ad The trapping of this cation finally forms the product.In conclusion, we demonstrated herein our second generation of β-difluoroalkylboron synthesis via oxidative difluorination of easily accessible linear 1,2-disubstituted alkenyl MIDA boronates. An unexpected 1,2-hydrogen migration was observed, which was found to be triggered by a MIDA boron substitution. Mild reaction conditions, moderate to good yields and excellent regioselectivity were achieved. The applications of these products allowed the facile preparation of a wide range of gem-difluorinated molecules by further transformations of the boryl group.  相似文献   

11.
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 EZ isomerization of an organometallic species. Through an Umpolung metal–halogen exchange process (Cl, Br, I), synthetically useful vinyl halides can be generated (up to Z : E = 90 : 10). This enabling platform provides a strategy to access nucleophilic and electrophilic alkene fragments in both geometric forms from simple arylacetylenes.

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

The venerable Schwartz reagent (Cp2ZrHCl) is totemic in the field of hydrometallation,1 where reactivity is dominated by syn-selective M–H addition across the π-bond.2,3 This mechanistic foundation can be leveraged to generate well-defined organometallic coupling partners that are amenable to stereospecific functionalization. Utilizing terminal alkynes as readily available precursors,4 hydrozirconation constitutes a powerful strategy to generate E-configured vinyl nucleophiles that, through metal–halogen exchange, can be converted to vinyl electrophiles in a formal Umpolung process.5 Whilst this provides a versatile platform to access the electronic antipodes of the E-isomer, the mechanistic course of addition renders access to the corresponding Z-isomer conspicuously challenging. To reconcile the synthetic importance of this transformation with the intrinsic challenges associated with anti-hydrometallation and metallometallation,6 it was envisaged that a platform to facilitate geometric isomerization7 would be of value. Moreover, coupling this to a metal–halogen exchange would provide a simple Umpolung matrix to access both stereo-isomers from a common alkyne precursor (Fig. 1).Open in a separate windowFig. 1The stereochemical course of alkyne hydrometallation using the Schwartz reagent and an Umpolung platform to generate both stereo-isomers from a common alkyne precursor.Confidence in this conceptual blueprint stemmed from a report by Erker and co-workers, in which irradiating the vinyl zirconium species derived from phenyl acetylene (0.5 M in benzene) with a mercury lamp (Philips HPK 125 and Pyrex filter) induced geometric isomerization.8 Whilst Hg lamps present challenges in terms of safety, temperature regulation, cost and wavelength specificity, advances in LED technology mitigate all of these points. Therefore, a process of reaction development was initiated to generalize the anti-hydrozirconation of arylacetylenes. Crucial to the success of this venture was identifying the light-based activation mode that facilitates alkene isomerization. Specifically, it was necessary to determine whether this process was enabled by direct irradiation of the vinyl zirconium species, or if the EZ directionality results from a subsequent selective energy transfer process involving a facilitator. Several accounts of the incipient vinyl zirconium species reacting with a second alkyne unit to generate a conjugated diene have been disclosed.9,10 It was therefore posited that the minor by-product diene may be a crucial determinant in driving this isomerization (Fig. 2).Open in a separate windowFig. 2A working hypothesis for the light-mediated anti-hydrozirconation via selective energy transfer catalysis.To advance this working hypothesis and generalize the formal anti-hydrozirconation process, the reaction of Cp2ZrHCl with 1-bromo-4-ethynylbenzene (A-1) in CH2Cl2 was investigated ( for full details). This generates a versatile electrophile for downstream synthetic applications. Gratifyingly, after only 15 minutes, a Z : E-composition of 50 : 50 was reached (entry 1) and, following treatment with NBS, the desired vinyl bromide (Z)-1 was obtained in 76% yield (isomeric mixture) over the two steps. Further increasing the irradiation by 15 minute increments (entries 2–4) revealed that the optimum reaction time for the isomerization is 45 minutes (74%, Z : E = 73 : 27, entry 3). Extending the reaction time to 60 minutes (entry 4, 54%) did not lead to an improvement in selectivity and this was further confirmed by irradiating the reaction mixture for 90 minutes (entry 5). In both cases, a notable drop in yield was observed and therefore the remainder of the study was performed using the conditions described in entry 3. Next, the influence of the irradiation wavelength on the isomerization process was examined (entries 6–11). From a starting wavelength of λ = 369 nm, which gave a Z : E-ratio of 27 : 73 (entry 6), a steady improvement was observed by increasing the wavelength to λ = 374 nm (Z : E = 44 : 56, entry 7) and λ = 383 nm (Z : E = 53 : 47, entry 8). The selectivity reached a plateau at λ = 400 nm, with higher wavelengths proving to be detrimental (Z : E = 60 : 40 at λ = 414 nm, entry 9; Z : E = 26 : 74 at λ = 435 nm, entry 10). It is interesting to note that at λ = 520 nm, Z-1 was not detected by 1H NMR (entry 11).Reaction optimizationa
Entryλ [nm]Time [min]YieldbZ : E ratiob
14001576%50 : 50
24003072%68 : 32
34004574% (74%)74 : 26 (73 : 27)
44006054%73 : 27
54009049%73 : 27
63694566%27 : 73
73744561%44 : 56
83834564%53 : 47
94144567%60 : 40
104354572%26 : 74
115204567%<5 : 95
Open in a separate windowa(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.11Open in a separate windowFig. 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).14Open in a separate windowFig. 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 windowFig. 5Enhancing the selectivity of anti-hydrozirconation by leveraging a postulated nS → 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(H1Z−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(H2Z−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(C1Z−E) = 10.5 ppm and Δδ(C1Z-E) = 5.6 ppm).Open in a separate windowFig. 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 windowFig. 7A comparative analysis of (E)-Zr1 and (Z)-Zr1.Open in a separate windowFig. 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 windowFig. 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.22Open in a separate windowFig. 10Postulated energy transfer catalysis cycle predicated on in situ formation of a conjugated diene photocatalyst.  相似文献   

12.
The construction of C(sp2)–X (X = B, N, O, Si, P, S, Se, etc.) bonds has drawn growing attention since heteroatomic compounds play a prominent role from biological to pharmaceutical sciences. The current study demonstrates the C(sp2)–S/Se and C(sp2)–N bond formation of one carbon of isocyanides with thiophenols or disulfides or diselenides and azazoles simultaneously. The reported findings could provide access to novel multiple isothioureas, especially hitherto rarely reported selenoureas. The protocol showed good atom-economy and step-economy with only hydrogen evolution and theoretical calculations accounted for the stereoselectivity of the products. Importantly, the electrochemical reaction could exclusively occur at the isocyano part regardless of the presence of susceptible radical acceptors, such as a broad range of arenes and alkynyl moieties, even alkenyl moieties.

We have developed an efficient and sustainable electrochemical strategy for the double C(sp2)–X (S/Se, N) bond formation of isocyanides simultaneously. A series of novel isothio/selenoureas were obtained via a three-component cross-coupling.

The construction of C(sp2)–X (X = B, N, O, Si, P, S, Se, etc.) bonds has drawn increased attention from researchers since heteroatomic compounds play a prominent role in various fields.1 Traditionally, the transition-metal-catalyzed cross-coupling of a nucleophile and an electrophile is an important method for the formation of C(sp2)–X bonds.2 Obviously, the direct cross-coupling of C(sp2)–H/X–H is a time-, effort-, and resource-economical process to construct C(sp2)–X bonds as it avoids the pre-functionalization of substrates.3 Alternatively, radical chemistry provides greener and more mild strategies for the formation of C(sp2)–X bonds, and a variety of high added-value compounds can be afforded successfully.4 Despite the numerous advances, these reported reactions are limited as they involve only single C(sp2)–X bond formation. Access to double C(sp2)–X bonds formation of one carbon remains still a room for improvement stimultaneously.As an ideal connector, isocyanides could be inserted into metal–carbon and metal–heteroatom bonds to construct double C(sp2)–X bonds.5 On the other hand, isocyanides could transform into heteroatomic molecules with electrophiles, nucleophiles and radicals.6 Although many elegant studies have been reported, the above methods are largely limited by the pre-functionalization of the substrate, the toxicity of metals or tedious synthesis steps. From the point of synthetic efficiency and economy, exploiting a novel, efficient, and diverse radical strategy to access double C(sp2)–X bonds under mild conditions and with broad functional group tolerance is of paramount importance and in urgent demand.Radical transformation processes are ubiquitous throughout synthesis chemistry and provide new ideas for forging new bonds and novel molecules, especially valuable product motifs.7 As a complementary strategy to conventional radical-based reactions, electrochemistry, effectively transferring electrons from the electrode surface to the substance, has been developed into a powerful synthetic technique toward radical chemistry.8 This electrochemical strategy further stimulated a resurgence of interest in radical chemistry with good atom-economy and step-economy.9 Myriad electrochemical-induced radical reactions have been reported via single-electron oxidation/reduction with a plethora of radicals and radical acceptors. As reported, alkenes, alkynes, and cyano and aromatic compounds could be considered to be favorable radical acceptors in diverse transformations, such as cross-coupling, cyclization and difunctionalization reactions.10 However, the application of isocyanides as radical acceptors is limited in utility due to electrochemical tandem cyclization.11 Therefore, on the basis of our research on electrochemical oxidative functionalization of isocyanides,12 we continued to explore the properties of isocyanides as radical acceptors under electrochemical conditions.Initially, we commenced our investigations by using abundant and inexpensive phenyl disulfide (1), ethyl 2-isocyanoacetate (2) and 1H-benzo[d][1,2,3]triazole (3) as model substrates in a single operation via a three-component cross-coupling. After systematic optimization, the isothiourea 21 could been obtained in 90% isolated yield. To gain insights into the reaction process, we continued to carry out a series of control experiments as shown in Scheme 1. The control experiment demonstrated that electricity is indispensable. Under standard conditions, addition of 2.0 equivalents of 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) showed no traces of product. Similarly, the reaction was suppressed in the presence of butylated hydroxytoluene (BHT). The P(OEt)3-trapping product could be detected by gas chromatography mass spectrometry (GCMS). Simultaneously, a S-centred radical signal (g = 2.0070, AN = 13.40 G, AH = 14.88 G) was quickly trapped by 5,5-dimethyl-1-pyrroline N-oxide (DMPO) via electron paramagnetic resonance (EPR) experiments. The reported results revealed that this reaction might proceed via S-radical pathways.Open in a separate windowScheme 1Control experiments.For deeper research of the priority of interaction for isocyanides vs. other radical acceptors with radicals, we sought to conduct robustness screening of a wide range of radical acceptors as shown in Scheme 2.13 The addition of an aryl olefin led to the complete shutdown of product formation (21) and the products of difunctionalization of alkenes were also not detected. To our delight, the alkenyl moiety did not affect the reaction efficiency under the electrochemical conditions. Unlike the aryl olefin, the addition of phenylacetylene did not inhibit product formation (21), delivering a yield of 93%. Similarly, ethyl 2-isocyanoacetate could be transformed into product (21) smoothly with 1-heptyne. The addition of mesitylene preserved the yield, while the yield decreased slightly with anisole. With the addition of furan and thiophene, an excellent yield of product (21) could still be obtained. Beside electron-donating arenes, we continued to add electron-withdrawing arenes to the reaction system. As expected, a satisfactory yield was obtained with 4-cyanopyridine. The results revealed that the electrochemical reaction exclusively occurred at the isocyano part regardless of the presence of electron-withdrawing arenes, electron-donating arenes and the alkynyl moiety, even the alkenyl moiety, which are also susceptible to radical conditions.Open in a separate windowScheme 2Competitive experiments of isocyanides vs. other radical acceptors with radicals. Conditions: 1 (0.15 mmol), 2 (0.6 mmol), 3 (0.5 mmol), R. A. = radical acceptors (0.6 mmol), nBu4NBF4 (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N2, 2.25 h. 1HNMR yield, dibromomethane as an internal standard.In order to further investigate the compatibility, we firstly examined the substrate scope of alkyl disulfides for the synthesis of isothioureas with ethyl 2-isocyanoacetate (2) and 1H-benzo[d][1,2,3]triazole (3) as shown in Scheme 3. To our delight, the yields did not decrease significantly with the increase of the carbon chain from methyl to decyl in this transformation (4–7). Isopropyl, isobutyl, cyclopentyl and cyclohexyl were well tolerated with good to excellent yields (8–11). Substances, containing sensitive benzylic C–H bonds, were tolerated to access novel isothioureas in this electrochemical induced-radical process (12–14, 34). Afterwards, we continued to explore the applicability from alkyl disulfides to thiophenol and a series of molecule isothioureas were obtained successfully with satisfactory yield. Thiophenol, containing electron-neutral (F, Cl, Br, H), electron-withdrawing (OCF3, CF3, and CO2Me) and electron-donating (Me, Et, tBu, OMe, and SMe) groups, could smoothly transform to realize this process with high stereoselectivity under mild conditions (15–26). The structure of Z-conformer (16) was confirmed by X-ray crystallographic analysis. In addition, this protocol was successfully applied to thiophenols bearing diverse groups at different positions with good yields, indicating that steric hindrance has no obvious effect (20, 27–31). With curiosity, we tried to evaluate the tolerance of diselenides to construct novel Se–C–N bonds simultaneously. Unexpectedly, regardless of alkyl diselenides (32–33), benzyl diselenide (34) or aryl diselenide (35), all were well tolerated under electrochemical conditions, providing a series of unprecedented isoselenoureas, which were inaccessible by conventional methods. The compatibility of sensitive functional groups provides an opportunity for further molecular modification. The sensitive functional architectures including but not limited to ester (36), benzyloxy (37), allyl and allyloxy as well as endene (38, 41–44), labile alkyl chloride (39) and alkyl bromide (40), propargyl (44), and thiophene (45), all remained intact, enriching the diversity of heteroatom compounds. The merit of this methodology was further demonstrated by elaboration of a wide gamut of functional molecules and drug molecules to diverse isothioureas. Natural products including l-menthol and geraniol (46–47), food additives including isopulegol and furfuryl alcohol (48–49), and pharmaceuticals including ibuprofen (50) were apt to give rise to the corresponding isothioureas in 50–78% yields.Open in a separate windowScheme 3Scope of thiophenols/disulfides/diselenides. Conditions: a disulfides/diselenides (0.15 mmol) or b thiophenols (0.3 mmol), isocyanides (0.6 mmol), 1H-benzotriazole (0.5 mmol), nBu4NBF4 (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N2, 2.25 h. Isolated yield.After defining the scope of thiophenols and disulfides, we turned our attention to explore the substrate scope with respect to nucleophiles in Scheme 4. Benzotriazole, with mono-substitution or multi-substitution, could be efficiently converted to the corresponding skeletons in 55–75% yields (51–54). Under standard conditions, pyrazole also showed great reactivity with phenyl disulfide or ethyl disulfide (55–56). The introduction of a halogen group in pyrazolylcycle, especially a subtle C–I bond, was compatible with satisfactory results (57–59, 64–65). 4-Methyl-1H-pyrazole as a coupling partner also realized the aminosulfenylation of isocyanide, albeit less efficiently (62). Of note is that the yield was increased to 70% from 40% by replacing methyl with phenyl (63). In addition to benzotriazole and pyrazole derivatives, other triazoles and tetrazole were proved to be viable coupling partners as well, enabling access to the target products in synthetically useful yields (66–70). Subsequently, with this established-optimized condition, we set out to investigate substrates for isocyanide coupling partners. With methyl isocyanoacetate (71), a similar effect was observed in an electrochemical difunctionalization reaction. As expected, both tosylmethyl isocyanide and benzyl isocyanide were demonstrated to be competent substrates (72–73). Cyclohexyl isocyanide, as a representative of secondary isocyanides, converted into the corresponding product (74). Gratifyingly, isocyanides, regardless of the steric effect, could engage with thiophenols to give the corresponding adducts in good yields (75–76). Aryl isocyanides however afforded the desired products in low yields under standard reaction conditions (77–78).Open in a separate windowScheme 4Scope of azazoles. Conditions: a disulfides/diselenides (0.15 mmol) or b thiophenols (0.3 mmol), isocyanides (0.6 mmol), azazoles (0.5 mmol), nBu4NBF4 (0.5 mmol), MeCN (6 mL), cloth anode, Pt cathode, undivided cell, constant current = 10 mA, room temperature, N2, 2.25 h. Isolated yield.To evaluate the feasibility of this electrochemical protocol, we monitored the reaction on a 4.5 mmol scale as shown in Scheme 5. Under similar conditions, by prolonging the reaction time to 34 h, a good isolated yield of 72% was obtained, which provided an opportunity for further synthetic manipulations.Open in a separate windowScheme 5Gram-scale synthesis.In order to account for the stereoselectivity of products, theoretical calculations were performed. The result demonstrated that the free energy of the Z-conformer of the product 16 is 2.3 kcal mol−1 smaller than that of the E-conformer.Based on a previously reported mechanistic study14 and these above observations, a synthetically possible mechanism for the electrochemical intermolecular difunctionalization reaction is depicted in Scheme 6. A sulfur radical was formed via single-electron-transfer (SET) reduction of the disulfide or SET oxidation of the thiophenol. Subsequently, the exclusive capture of the S-radical by the isocyano part yields the imine C-radical I. Further SET oxidation of this radical intermediate to the corresponding imine carbocation II, followed by nucleophilic trapping intermolecularly, affords the final isothioureas.Open in a separate windowScheme 6Proposed reaction mechanism.  相似文献   

13.

Benzoxazoles are of special interest because of having various types of biological properties such as antihistaminic, antihelmintic antifungal and antibacterial activities. 1 Hisano, T., Ichikawa, M., Tsumoto, K. and Tasaki, M. 1982. Chem. Pharm. Bull, 30: 2996 [CSA][Crossref], [Web of Science ®] [Google Scholar], 2 Prudhomme, M., Guyot, J. and Jeminet, G. 1986. J. Antibiotics, 39: 934 [CSA][Crossref], [PubMed], [Web of Science ®] [Google Scholar], 3 Ersan, S., Nacak, S., Berkem, R. and Özden, T. 1997. Arzneim. Forsch, 47: 963 [CSA][PubMed], [Web of Science ®] [Google Scholar], 4 Sener, E., Yalc?n, ?., Temeiz, Ö., Ören, ?., Ak?n, A. and Ucartürk, N. 1997. Farmaco, 52: 99 [CSA][PubMed] [Google Scholar], 5 Ören, ?., Temiz, Ö., Yalc?n, ?., Sener, E., Ak?n and Ucartürk, N. 1997. Forsch, 47: 1393 [CSA] [Google Scholar], 6 Temiz, Ö., Ören, ?., Sener, E., Yalc?n, ?. and Ucartürk, N. 1998. Farmaco, 53: 337 [CSA][CROSSREF][Crossref], [PubMed] [Google Scholar], 7 Yalc?n, ?., Ören, ?., Sener, E., Ak?n, A. and Ucartürk, N. 1992. J. Med. Chem, 27: 401 [CSA][CROSSREF][Crossref], [Web of Science ®] [Google Scholar], 8 Temiz, Ö., Ören, ?. and Altanlar, N. 2002. Farmaco, 57: 175 [CSA][CROSSREF][Crossref], [PubMed] [Google Scholar], 9 Sener, E., Temeiz, Ö., Yalc?n, ?. and Altanlar, N. 2000. Farmaco, 55: 397 [CSA][CROSSREF][Crossref], [PubMed] [Google Scholar], 10 Ören, ?., Temiz, Ö., Yalc?n, ?., Sener, E. and Altanlar, N. 1998. Eur. J. Pharm. Sci., 7: 153 [CSA][Crossref], [Web of Science ®] [Google Scholar] Benzamide derivatives, as the possible metabolites of benzoxazoles, show various types of biological activities. 11 Sener, E., Bingöl, K., Ören, ?., Arpac?, Ö., Yalc?n, K. ?. and Altanlar, N. 2000. Farmaco, 55: 469 [CSA][CROSSREF][Crossref], [PubMed] [Google Scholar], 12 Sener, E., Yalc?n, K. ?. and Altanlar, N. 2002. Farmaco, 57: 451 [CSA][CROSSREF][Crossref], [PubMed] [Google Scholar] Some N-(2-hydroxyphenyl)- benzamides, which showed significant activity compared to phenylacetamides and furamides,11 have been synthesized by treating 2-aminophenol with carboxylic acid chlorides under weak basic solution. 11 Sener, E., Bingöl, K., Ören, ?., Arpac?, Ö., Yalc?n, K. ?. and Altanlar, N. 2000. Farmaco, 55: 469 [CSA][CROSSREF][Crossref], [PubMed] [Google Scholar], 12 Sener, E., Yalc?n, K. ?. and Altanlar, N. 2002. Farmaco, 57: 451 [CSA][CROSSREF][Crossref], [PubMed] [Google Scholar] However, synthesis and especially biological activity of N-(3-hydroxy-2-pyridyl)benzamides were not studied well. Owing to the versatility of benzamides we have extended the reaction of 2-amino-3-pyridinol with different carboxylic acid chlorides in order to preparation of some new benzamide derivatives containing a hydroxypyridyl ring.  相似文献   

14.
ω‐Isonitrosoacetophenone 1 Uçan, H. ? and Mirzao?lu, R. 1990. Synth. React. Inorg. Met.‐Org. Chem., 20: 437[Taylor & Francis Online], [Web of Science ®] [Google Scholar], phenylglyoxime 2 Burakevich, J. V., Lore, A. M. and Volpp, G. P. 1971. J. Org. Chem., 36: 1[Crossref], [Web of Science ®] [Google Scholar], chlorophenylglyoxime 1 Uçan, H. ? and Mirzao?lu, R. 1990. Synth. React. Inorg. Met.‐Org. Chem., 20: 437[Taylor & Francis Online], [Web of Science ®] [Google Scholar], dopaminophenylglyoxime 3 Uysal, ?., Co?kun, A., Koç, Z. E., Uçan, M. and Uçan, H. ?. 2007. R. J. Coord. Chem., 33: 351357. [Crossref] [Google Scholar] and [(salen/saloph)Fe]2O 4 Kopel, P., Sindelar, Z. and Klicka, R. 1998. Trans. Met. Chem., 23: 139[Web of Science ®] [Google Scholar] have been synthesized as described in the literature procedure. [Fe(III)(salen/saloph)dopaminophenylglyoxime)] (starting complexes) have been synthesized from dopaminophenylglyoxime and tetradentate schiff bases which contain dinuclear Fe(III) oxygen‐bridges N,N′‐bis(salicylidene)ethylenediamine (salenH2) and bis(salicylidene)‐o‐phenylenediamine (salophH2). The new heterotrinuclear complexes have been obtained from starting complexes and Co(II), Ni(II), Cu(II) salts. Then, heterotrinuclear vic‐dioxime complexes containing BF2 + capped have been synthesized. The complexes have been characterized as low‐spin distorted octahedral Fe(III) bridged by o‐hydroxyphenolic groups. The o‐hydroxyphenolic groups play a role as bridges for weak antiferromagnetic intramolecular exchange. The structure of dioxime and its complexes were identified by using elemental analysis, ICP‐AES, 1H‐NMR and IR spectral data.  相似文献   

15.
β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics. Here, we report a novel one-step approach for the synthesis of α-(trifluoromethyl)-β-lactams and related products from fluorinated olefins, anilines and CO. Utilization of an advanced palladium catalyst system with the Ruphos ligand allows for selective cycloaminocarbonylations to give diverse fluorinated β-lactams in high yields.

β-Lactam compounds play a key role in medicinal chemistry, specifically as the most important class of antibiotics.  相似文献   

16.
《Chemical science》2021,12(1):16
A welcome to 2021 from May Copsey, Executive Editor, Chemical Science.

Diamond or platinum open access; open and free, for authors and readers. However you describe it, being open and accessible is at the heart of what we are aiming to achieve in Chemical Science.  相似文献   

17.
Tertiary phosphines(iii) find widespread use in many aspects of synthetic organic chemistry. Herein, we developed a facile and novel electrochemical oxidative N–H/P–H cross-coupling method, leading to a series of expected tertiary phosphines(iii) under mild conditions with excellent yields. It is worth noting that this electrochemical protocol features very good reaction selectivity, where only a 1 : 1 ratio of amine and phosphine was required in the reaction. Moreover, this electrochemical protocol proved to be practical and scalable. Mechanistic insights suggested that the P radical was involved in this reaction.

A facile and novel electrochemical oxidative N–H/P–H cross-coupling method for obtaining tertiary phosphines(iii) was developed.  相似文献   

18.
Dibenzocycloheptanones containing a tricyclic 6–7–6-system are present in numerous biologically active natural molecules. However, the simple and efficient preparation of derivatives containing a dibenzocycloheptanone scaffold remains difficult to date. Herein, we report a versatile strategy for the construction of these challenging seven-membered rings using a 7-endo-trig cyclization which is initiated by a phosphorus-centered radical. This approach provides a step-economical regime for the facile assembly of a wide range of phosphorylated dibenzocycloheptanones. Remarkably, we also have devised a traceless addition/exchange strategy for the preparation of dephosphorylated products at room temperature with excellent yields. Therefore, this protocol allows for the concise synthesis of biorelevant allocochicine derivatives.

Dibenzocycloheptanones containing a tricyclic 6–7–6-system are present in numerous biologically active natural molecules.  相似文献   

19.
Correction for ‘Suppressing carboxylate nucleophilicity with inorganic salts enables selective electrocarboxylation without sacrificial anodes’ by Nathan Corbin et al., Chem. Sci., 2021, DOI: 10.1039/D1SC02413B.

We regret that there was a minor error in the structure of the benzyl chloride in Scheme 2, Fig. 2 and the ESI. The structure of the benzyl chloride should be 4-methyl benzyl chloride but was instead given as 3-methyl benzyl. The correct figure and scheme are shown below, and the ESI has been updated.Open in a separate windowFig. 2(A) Comparison of acid yields for non-sacrificial-anode and sacrificial-anode carboxylation of various substrates. (B) Ratio of carboxylic acid to nucleophilic side products (ester + carbonate + alcohol) for various systems and substrates. Effect of adding MgBr2 to the sacrificial-anode system on the (C) acid yield and (D) ratio of acid to SN2 side products for benzyl bromide. Acid yields are tabulated in Table S6.† ND: acid not detected (acid-to-SN2 ratio <0.1).Open in a separate windowScheme 2Substrate scope for the sacrificial-anode-free electrochemical carboxylation of organic halides. aStandard reaction conditions: 100 mM electrolyte, 100 mM substrate, 100 mM MgBr2, silver cathode, platinum anode, 20 sccm CO2, 2.2 mL DMF, −20 mA cm−2 for 3.5 h. TBA-Br was used for chlorinated substrates because bromide oxidizes more readily than chloride, and only a small amount of chloride was replaced by bromide (<1% for the alkyl chloride, ∼4% for the benzylic chloride). Yields are referenced to the initial amount of substrate and were calculated from 1H NMR spectroscopy using either 1,3,5-trimethoxybenzene or ethylene carbonate as internal standards. b−15 mA cm−2 instead of −20 mA cm−2. c150 mM MgBr2 instead of 100 mM MgBr2.The Royal Society of Chemistry apologises for these errors and any consequent inconvenience to authors and readers.  相似文献   

20.
We have developed a novel copper-catalyzed cyclization of cyclopropenes/diazo compounds and bromodifluoroacetamides, efficiently synthesizing a series of α,α-difluoro-β-lactams in moderate to excellent yields under mild reaction conditions. This reaction represents the first example of [3 + 1] cyclization for the synthesis of β-lactams utilizing a metal carbene intermediate as the C1 synthon.

A copper-catalyzed [3 + 1] cyclization of cyclopropenes and bromodifluoroacetamides/diazo compounds has been successfully developed, efficiently synthesizing a wide range of α,α-difluoro-β-lactams.  相似文献   

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