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Visible-light-mediated interrupted Cloke-Wilson rearrangement of cyclopropyl ketones to construct oxy-bridged macrocyclic framework

  • Zhen Liu
    Affiliations
    Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Meilong Road No.130, Shanghai, 200237, China
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  • Author Footnotes
    1 Lead contact.
    Yin Wei
    Correspondence
    Corresponding author.
    Footnotes
    1 Lead contact.
    Affiliations
    State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China
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  • Min Shi
    Correspondence
    Corresponding author. Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Meilong Road No.130, Shanghai, 200237, China.
    Affiliations
    Key Laboratory for Advanced Materials and Institute of Fine Chemicals, Key Laboratory for Advanced Materials and Feringa Nobel Prize Scientist Joint Research Center, School of Chemistry & Molecular Engineering, East China University of Science and Technology, Meilong Road No.130, Shanghai, 200237, China

    State Key Laboratory of Organometallic Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai, 200032, China
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  • Author Footnotes
    1 Lead contact.
Open AccessPublished:December 07, 2021DOI:https://doi.org/10.1016/j.tchem.2021.100001

      Abstract

      Cloke-Wilson rearrangement has been well studied, in which cyclopropyl ketones or cyclopropyl imines could be transformed to dihydrofuran or dihydropyrrole derivatives through a tandem ring-opening/recyclization process. Herein, we report a new version of Cloke-Wilson rearrangement, in which the ring-opening/recyclization of cyclopropyl ketones upon visible-light-induced photoredox catalysis can provide oxy-bridged macrocyclic frameworks under mild reaction conditions, and the reagent XRf plays dual roles in the catalytic cycle. The reaction proceeds through a ring-opening and an interrupted recyclization by intramolecular nucleophilic attack with the in situ generated radical cation. The reaction mechanism was proposed on the basis of control, deuterium labeling, Stern–Volmer quenching and CV measuring experiments. This protocol can afford a series of oxy-bridged macrocyclic frameworks with broad substrate scope and good functional-group tolerance. In addition, a variety of 2,2-disubstituted oxy-bridged macrocyclic indolinones can be obtained efficiently by simple manipulation from the products.

      Graphical abstract

      Keywords

      1. Introduction

      Cyclopropanes [
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      ]. They can easily undergo a variety of ring-opening reactions due to their high π character, inherent angle strain and intrinsic torsional strain. All the fundamental types of reactions utilizing the donor-acceptor (D-A) cyclopropanes involving donor and accepter substituents have been extensively investigated in recent years [
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      ]. The push–pull effect induces polarization in the vicinal C–C bond, and various pathways for ring-opening are feasible to generate 1,3-dipoles, which further react towards electrophiles, nucleophiles, and dipolarophiles to provide all kinds of products (Scheme 1a). The classical Cloke-Wilson rearrangement reaction involves activation of the D-A cyclopropanes by the Lewis acid or metal catalyst to promote the ring-opening process, thus generating a carbocationic intermediate that subsequently undergoes cyclization (Scheme 1b). Since Cloke first reported that cyclopropyl ketones could be transformed into dihydrofuran derivatives in 1929, the Cloke−Wilson rearrangement reactions have been well studied [
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      The formation of pyrrolines from gamma-chloropropyl and cyclopropyl ketimines1.
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      Acid-catalyzed cyclization reactions. VI. Rearrangement of protonated cyclopropyl ketones to 1-oxacyclopent-1-enyl cations.
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      ]. Notably, Yadav's group disclosed TiCl4-mediated silicon-assisted rearrangement of (tert-butyldiphenylsilyl) methylcyclopropyl ketones at a low temperature in 2001 [
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      Silicon-assisted ring opening of Donor−Acceptor substituted cyclopropanes. An expedient entry to substituted dihydrofurans.
      ]. In 2006, the Johnson's group realized mild Ni-catalyzed rearrangement of vinyl cyclopropyl ketones resting upon a Ni−π-allyl intermediate [
      • Bowman R.K.
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      ]. Recently, Xia's group presented a visible-light-induced photoredox protocol for the synthesis of furans via oxidative coupling of olefin generated in situ from cyclopropyl ketones with ketonic oxygen atom [
      • Feng L.
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      ]. Although there were a few strategies to achieve Cloke−Wilson rearrangement under mild reaction conditions, it is rare to see that carbocations or anions generated during rearrangement process were captured by nucleophilic or electrophilic reagents to construct new structural fragments containing tetrahydrofuran skeleton.
      Scheme 1
      Scheme 1Previous work and this work.
      In recent years, photo-induced catalysis has emerged as a powerful strategy for the facile generation of carbon-centered radicals [
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      Visible light photoredox catalysis with transition metal complexes: applications in organic synthesis.
      ,
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      ]. Single electron transfer (SET) process built a new bridge between photosensitizer and substrate, which made scientists to discover and master many efficient and practical photo-redox reaction modes [
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      ,
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      • Zhang M.
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      A general deoxygenation approach for synthesis of ketones from aromatic carboxylic acids and alkenes.
      ]. In recent decades, the reagent XRf (X ​= ​Br, I) has been utilized to afford fluorinated compounds via visible-light inducing process from various substrates [
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      • Sun B.
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      • Shi R.
      • Zhu R.
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      Photoinduced EDA complexes enabled radical tandem cyclization/arylation of unactivated alkene with 2-Amino-1,4-naphthoquinones.
      ]. In these reactions, XRf not only acted as a fluorine source, but also as an oxidant, which makes the photocatalyst to reach a higher oxidation state. Being attracted by the characteristic of this reagent, we expect to use XRf as an additional redox sacrificial agent to explore a new reaction mode. Herein, we wish to report a novel protocol for interrupted Cloke-Wilson rearrangement, where the reagent XRf plays dual roles in the catalytic cycle (Scheme 1c).

      2. Results and discussion

      2.1 Experimental investigations on the reactions

      We utilized substrate 1a as the model substrate for the initial investigation and subsequently optimized the reaction conditions. The results are shown in Table 1. Using 0.5 equiv of BrCF2CO2Et as the additional oxidant, Ir(ppy)3 (10 ​mol %) as the photocatalyst, and CH3CN as the solvent upon irradiation with an 8 ​W Blue LED for 15 ​h, the desired product 2a was obtained in 30% yield (entry 1). The X-ray diffraction pattern of 2a is shown in Table 1, whose structure had been unambiguously determined. The related CIF data of 2a are shown in the Supporting Information. Then, several photocatalysts were screened; the results indicated that Ir(ppy)3 was the best suitable photocatalyst for the reaction (entries 2–4). Reducing the photocatalyst loading to 5 ​mol%, the yield of product 2a slightly increased to 34% (entry 5). We further examined solvent effects and found that CH3CN was the best solvent; a series of acids were tested and showed that simple acid catalysis did not work for this reaction (see Table S2 in Supporting Information).
      Table 1Optimization of the reaction conditions.
      All the reactions were performed on 0.1 ​mmol scale.
      .
      Table thumbnail fx1
      a All the reactions were performed on 0.1 ​mmol scale.
      b Yields were determined by 1H NMR analysis of the crude mixture using trimethoxybenzene as an internal standard.
      c No light.
      We further explored the influence of the reaction temperature. To our delight, when the reaction was conducted at 80 ​°C, the yield of product 2a increased to 46% (entry 6). Subsequently, we further screened the additives (see Table S3 in Supporting Information). The results showed that ICF2CO2Et was the best choice of the additive (entry 7). Then, we investigated the amount of additive loading, and identified that when the loading of ICF2CO2Et was increased to 1.0 equiv and 1.5 equiv, the target product 2a was accessed in 55% yield and 63% yield, respectively (entries 8–9). In addition, we also realized that when the amount of additives increased and the catalyst loading decreased to 3 ​mol%, the target product could be obtained in higher yield along with 65% isolated yield (entry 10). Furthermore, the control experiments revealed that the photocatalyst, ICF2CO2Et and lights source were essential for this reaction (entries 21–23).
      Under the optimized reaction conditions, we explored the generality of this interrupted Cloke−Wilson rearrangement reaction, and the results are summarized in Table 2. Under the optimal conditions, most substrates successfully underwent these reactions, providing the desired products in good to excellent yields. For substrates 1b-1j containing either electron-deficient or electron-rich groups located at the para position on the benzene ring, the reactions proceeded efficiently, affording the desired products 2b-2j in moderate to good yields ranging from 37% to 68%. The results indicated that the electronic property of substituent at the aromatic ring did not have significant impact on the reaction outcomes. It should be pointed out that the reaction is also compatible when the para substituents are active groups such as cyano and ester groups (2i and 2j). In addition, when there are different types of substituents at the meta position on the benzene ring, the reaction could also proceed smoothly, and the products 2k-2m are obtained in 59%–62% yields. Unfortunately, when the substituent was at the ortho position on the benzene ring, the target product was not obtained, probably due to steric hindrance. Then, when we replaced the R3 substituted benzene ring by the alkyl groups, the target products 2p and 2q could be obtained in the yields of 78% and 72%, respectively. Next, we tried to replace the R3 substituted benzene ring by naphthalene ring (1r), pyridine ring (1s) and thiophene ring (1t). The results showed that only substrate 1t involving thiophene ring could proceed smoothly to afford 2t in 36% yield. After that, we investigated the effect of substituents on indole ring. We found that when the 6-, 5- and 4-sites of indole moiety were occupied by different substituents, the reaction could proceed successfully, and the target products 2u-2 ​ag were obtained in medium to good yields ranging from 39% to 72%. The results demonstrated that the substrates involving electron-donating substituents were more favorable to the reaction than those having the electro-withdrawing substituents. We speculate that the electron-donating substituents increase the electron cloud density of indole moiety, which probably makes it easier to achieve nucleophilic attack step. Interestingly, when the 3-position of indole moiety is substituted by a methyl group (1ah), two products 2ah and 2ah′ could be obtained under different conditions, and the yields are 48% and 52%, respectively. In addition, the tryptamine derivatives substrate 1ai could also afford product 2ai in 42% yield. Employing the substrate 1aj having 7-methyl indole moiety, the target product 2aj was obtained in 55% yield. Furthermore, the product 2ak (R2 ​= ​5′-F) was delivered in 59% yield, but the product 2 ​al was failed to obtain. This result illustrated that aryl group, in which R2 was located, was essential in this visible-light-induced transformation. In an attempt to broaden the generality of the reaction, we employed substrate 1am-1au, in which the benzene moiety was replaced by alkyl groups containing different functional groups, to conduct this reaction. Under the standard protocol, substrates 1am-1ao did not undergo these reactions to afford the desired products under the standard conditions involving strong oxidizing species, probably due to they containing easily oxidized functional groups. The reactions using substrates 1ap-1au proceeded smoothly to deliver the corresponding products in the range of 53%–83%.
      Table 2Substrate Scope of 1.a.
      Table thumbnail fx2

      2.2 Synthetic applications

      To demonstrate the synthetic applicability of this protocol, a gram-scale reaction was conducted by employing 3.0 ​mmol of 1ap-1au, delivering the desired products 2ap-2au in 40%–72% yields (Scheme 2a). Formylation of 2a with Ac2O furnished the product 3a in 65% yield. Moreover, hydrogenation of 2a effectively afforded the corresponding product 4a in 46% yield (Scheme 2b). In order to further demonstrate the application value of this method, we transformed the products 2ap-2au into indolone derivatives by a one-pot multi-oxidation. The transformation led us to access a variety of 2,2-disubstituted oxy-bridged macrocyclic indolinones 5ap-5au in excellent yields and the proposed mechanism is shown in Scheme S3 at page S25 in Supporting Information.
      Scheme 2
      Scheme 2Scale-up Experiment and Synthetic Transformations.
      a ​1ap-1au ​(3.0 mmol), ICF2CO2Et (4.5 mmol, 1.5 equiv), Ir(ppy)3 ​(5 mol%), in MeCN (60 mL), 8 W Blue LED, 80 ​oC for 24 h and Ar atmosphere. ​b ​2a ​(0.2 mmol) was used. ​cSubstrates ​2 ​(0.4 mmol) were used. Yields were total yields of two steps.

      2.3 Mechanistic studies

      To gain mechanistic insights into this photocatalytic system, we performed a series of mechanistic studies. When TEMPO as a radical scavenger was added to our reaction system, the reaction was inhibited completely, and no desired product 2a was obtained (Scheme 3a). In order to determine the whereabouts of the hydrogen atom at 2-position of indole moiety, the deuterated substrate [D]-1a was employed to perform this reaction, providing the product [D]-2a derived from intramolecular deuterium atom migration in 45% yield along with 30% deuterium incorporation (Scheme 3b).
      Scheme 3
      Scheme 3The Control Experiment and Deuterium Labeling Experiment.
      To further probe the mechanistic paradigm of this transformation, a series of Stern–Volmer quenching studies were performed. The emission of photocatalyst Ir(ppy)3 could be quenched by ICF2CO2Et and not be quenched by substrate 1a, suggesting that a SET process probably took place between Ir(ppy)3 and ICF2CO2Et (Scheme 4). We also found that substrate 1a had strong fluorescence and could be quenched by ICF2CO2Et slightly. Furthermore, the redox potentials of 1a and ICF2CO2Et were also measured (see Figures S3a-S3d in the SI).
      Scheme 4
      Scheme 4Stern–Volmer Quenching Studies.
      A) Ir(ppy)3 ​emission quenching with ICF2CO2Et. B) Substrate ​1a ​emission quenching with ICF2CO2Et. C) Ir(ppy)3 ​emission quenching with substrate ​1a.
      Based on the results of mechanistic studies, a proposed catalytic cycle for this reaction is shown in Scheme 5. This catalytic cycle starts from photoexcitation of Ir(III) to generate the excited Ir(III)∗. ICF2CO2Et (Epred ​= ​−0.59 ​V vs. SCE) first acts as an oxidation agent with Ir(III)∗ to undergo a SET process to produce Ir(IV) (E1/2 Ir(III∗)/Ir(IV) ​= ​−1.73 ​V vs. SCE for Ir(ppy)3) [
      • Xiao Y.
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      ]. Meanwhile, ICF2CO2Et is reduced to •CF2CO2Et and I. Subsequently, the substrate 1a (Epred ​= ​−1.02 ​V vs SCE) undergoes a SET process with Ir(IV) (E1/2Ir(IV)/Ir(III) ​= ​0.77 ​V vs. SCE) to produce an aryl radical cation intermediate int1 with the regeneration of the ground state of photocatalyst, which can readily be transformed to an intermediate int2 by a radical cation inducing ring-opening step. According to the experimental result, the substrate 1 ​al could not undergo this reaction to get the desired product smoothly, indicating that the formation of the aryl radical cation intermediate is essential for this reaction.
      Then, an intramolecular nucleophilic attack step occurs to give an intermediate int3 [
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      ]. The intermediate int3 undergoes an intramolecular nucleophilic attack process to produce int4. Afterwards the intermediate int4 is reduced by in situ generated I to afford a zwitterionic intermediate int5 and I2 [
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      ]. By monitoring the residual amount of ICF2CO2Et in the reaction process, we found that the ICF2CO2Et consumption decreased rapidly at the beginning of the reaction, and then increased slowly to a steady state along with some other unidentified fluorinated products (Fig. 1) (see Page S20 in the SI). This result indicates that there is a possibility of ICF2CO2Et regeneration in the reaction process. By consulting the literature, we speculate that the ICF2CO2Et is regenerated by the reaction between I2 and •CF2CO2Et, and this reaction process is relatively slow [
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      ]. Subsequently, the intermediate int5 goes through aromatization and hydrogen atom-shift to generate product 2a. Moreover, the mechanism for generation of 2ah’ is proposed and shown in Scheme S2 in Supporting Information.
      Fig. 1
      Fig. 1Monitoring the change of ICF2CO2Et residue with reaction time (the remaining percentage of the ICF2CO2Et was quantitatively analyzed by 19F NMR, CF3COOH as the internal standard).

      3. Conclusions

      In conclusion, we have demonstrated a novel photocatalyzed interrupted Cloke−Wilson rearrangement via a photooxidized ring-opening of cyclopropyl ketone derivatives for the construction of oxy-bridged macrocyclic framework in moderate to good yields with excellent functional group compatibility upon visible-light irradiation under mild conditions. We identified the critical role of reagent ICF2CO2Et, which provided an oxidant and a reductant at the different reaction stages. The plausible reaction mechanism is proposed on the basis of control, deuterium labeling, Stern–Volmer quenching and CV measuring experiments. Moreover, further transformation of the products could afford a variety of 2,2-disubstituted oxy-bridged macrocyclic indolinones and this reaction could be achieved in a gram scale. The utilization of this synthetic strategy for the synthesis of natural products or pharmaceutical important molecules is currently under investigation.

      4. Experimental procedures

      Full experimental procedures are provided in the Supplemental Information.

      5. Resource availability

      5.1 Lead contact

      Further information and requests for resources and reagents should be directed to and will be fulfilled by the lead contact, Yin Wei ( [email protected] ).

      5.2 Materials availability

      All other data supporting the findings of this study are available within the article and the supplemental information or from the lead contact upon reasonable request.

      5.3 Data and code availability

      There is no dataset or code associated with this paper. Full experimental procedures are provided in the supplemental information.

      Author contributions

      Zhen Liu conducted the experiments and wrote the paper; Yin Wei reviewed and edited the paper; Min Shi designed the experiments and supervision.

      Declaration of competing interest

      The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

      Acknowledgments

      We are grateful for the financial support from the National Natural Science Foundation of China ( 21372250 , 21121062 , 21302203 , 21772037 , 21772226 , 21861132014 , 91956115 and 22171078 ), Shanghai Municipal Science and Technology Major Project (Grant No. 2018SHZDZX03 ) and the Fundamental Research Funds for the Central Universities 222201717003 .

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      1. A possible process of ICF2CO2Et regeneration:
        I2 + CF2CO2Et → ICF2CO2Et + I
        2I → I2