Combination of Copper-Catalyzed Multicomponent Cascade with 12π Electrocyclization Constructing Perifused Cycle

Open AccessCCS ChemistryCOMMUNICATIONS16 Aug 2024Combination of Copper-Catalyzed Multicomponent Cascade with 12π Electrocyclization Constructing Perifused Cycle Jingpeng Han†, Xuan Tang†, Yanchun Hou, Yi Tian, Lei Liu and Baosheng Li Jingpeng Han† , Xuan Tang† , Yanchun Hou , Yi Tian , Lei Liu and Baosheng Li *Corresponding author: E-mail Address: email protected Cite this: CCS Chemistry. 2024;0:1–9https://doi.org/10.31635/ccschem.024.202404453 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesDownload CitationsTrack Citations ShareFacebookTwitterLinked InEmail We reported a new protocol for constructing a unique indolizine-containing perifused tricycle by combining a copper relay-catalyzed three-component cascade with a 12π electrocyclization reaction from readily available starting materials. The indolizine generated by the copper-catalyzed multicomponent cascade is a key intermediate obtained during subsequent spontaneous electrocyclization. In contrast to the traditional SEAr reaction model, this study is based on the tetraene-like character of indolizine to form an aromatic heterocycle 12π electron system that can spontaneously trigger 12π electrocyclization. This transformation can not only enhance the reactivity of indolizine but also improve the electrocyclization model. This convergent strategy can significantly enhance synthetic versatility, and the resulting perifused cycle products containing indolizine may serve as a molecular platform for the discovery and characterization of pharmaceuticals and functional molecules. Download figure Download PowerPoint Introduction Indolizines are important aromatic molecules. They contain π-excessive pyrrole and a π-deficient pyridine ring with a bridgehead nitrogen,1,2 and they are commonly found in bioactive compounds,3–5 dyestuff,6 or fluorescence probes7,8 (Figure 1a). The significance of indolizine derivatives in synthetic chemistry has made them appealing targets for chemists,9–17 and many attractive protocols have been developed based on studies of their reactivity. Previous studies have focused mainly on the SEAr reaction of indolizine, an electron-rich aromatic heterocycle, with various electrophilic reagents (Figure 1b).18–22 Structurally, indolizine might have characteristics similar to those of conjugated tetraene-like compounds. However, related studies need to be conducted. An attractive goal based on the tetraene-like properties of indolizine might be the development of new methodologies for examining its unknown reactivity. Figure 1 | Background and our proposal. Download figure Download PowerPoint Electrocyclization is a fascinating pericyclic reaction due to its stereospecificity in forming or breaking a new chemical bond via concerted cyclic transition states.23,24 Specifically, 4π and 6π electrocyclizations are popular reactions in synthetic chemistry.25–32 However, studies on electrocyclizations with π-electron numbers greater than eight are rare.33–36 12π electrocyclization, as a higher-order electrocyclization model, has been reported only sporadically in the literature (Figure 1c).37 This might be attributed to the competitive and unpredictable reactivity of conjugated hexene. This result also suggested that the selective electrocyclization of conjugated polyenes is challenging. On the other hand, the design and elaboration of synthetically important molecules from simple starting materials in the minimum number of steps38,39 is one of the most challenging goals in synthetic chemistry. Multicomponent cascade reactions40,41via metal relay catalysis42,43 are useful and versatile methods for accessing a large number of molecules. To design and investigate a new electrocyclization reaction for constructing a synthetically important heterocycle,44–48 we reported a single copper relay-catalyzed multicomponent cascade reaction for preparing a 3,5-dialkene-substituted indolizine skeleton that can trigger 12π electrocyclization to construct a formal 12-membered ring49–52 involving a fused indolizine structural unit (Figure 1d). The general reaction mechanism might be divided into three stages: (1) generation of a propargylamine intermediate through copper-catalyzed cross-coupling of three-components; (2) formation of indolizine by copper-catalyzed annulation/aromatization; and (3) construction of a perifused tricycle by spontaneous 12π electrocyclization of 3,5-dialkenyl-substituted indolizine. Results and Discussion To achieve the abovementioned single-metal-catalyzed multicomponent cascade reaction, 6-vinylpicolinaldehyde 1a, alkyne 2a, and morpholine 3a were selected as model substrates for constructing the perifused tricycle (Table 1). Initially, CuSO4 (10 mol %) was utilized as the catalyst based on the recognized efficacy of copper salts in facilitating multicomponent cross-coupling into propargylamine species,53,54 thereby initiating a subsequent catalytic cycle. The expected product 4a was formed in 32% yield when the reaction was performed in toluene at 110 °С for 2 h (entry 1). Subsequently, various metallic catalysts were evaluated based on the known alkynophilicity of copper55,56 and silver compounds.57,58 Several copper salts produced expected product 4a in good yield in all cases (entries 2–6); CuCl2 facilitated the production of perifused tricycle with the highest yield (86%) (entry 4). Replacement of copper with various silver salts, such as AgCl and AgOTf, resulted in the formation of only trace amounts of the product (entries 7 and 8). Zinc salts used as Lewis acid-activated alkynes to trigger multicomponent cascade cyclization reactions have been widely reported.59,60 The reaction also led to the formation of the desired product for ZnCl2 and Zn(OTf)2; however, the yield was lower (entries 9 and 10). We lowered the reaction temperature to 90 °С, which allowed the reaction to proceed under milder conditions and significantly decreased the yield to 54% (entry 11). Finally, commonly used solvents, such as tetrahydrofuran (THF), CH3CN, and dimethylformamide (DMF), were screened to study the solvent effect, but a better effect was not recorded (entries 12–14). Table 1 | Optimization of the Reaction Conditionsa,b Entry Catalyst Solvents T (°С) Yield (%) 1 CuSO4 PhMe 110 32 2 Cu(OTf)2 PhMe 110 75 3 Cu(OAc)2 PhMe 110 53 4 CuCl2 PhMe 110 86 5 CuI PhMe 110 66 6 CuCl PhMe 110 63 7 AgCl PhMe 110 Trace 8 AgOTf PhMe 110 Trace 9 ZnCl2 PhMe 110 23 10 Zn(OTf)2 PhMe 110 12 11 CuCl2 PhMe 90 54 12 CuCl2 THF 110 25 13 CuCl2 CH3CN 110 43 14 CuCl2 DMF 110 Trace aAll reactions of 1a (0.1 mmol, 1.0 equiv), 2a (0.2 mmol, 2.0 equiv), 3a (0.2 mmol, 2.0 equiv), and catalyst (0.01 mmol, 10 mol %) were performed in solvent (1.0 mL) for 2 h. bIsolated yield. With the optimized reaction conditions, the generality of the substrates was investigated. Various α-pyridine aldehydes were initially examined by replacing different substituents at the vinyl end (Table 2). Alkyl substituents, such as methyl or pentyl substituents, were introduced to synthesize corresponding products 4b and 4c in yields of 97% and 69%, respectively. Cycloalkanes, including cyclohexane and cyclopropane, were also tolerated, and the desired products 4d and 4e yielded 90% and 65%, respectively. Next, the reactivity of the aryl substituent at the vinyl end was also examined. The phenyl group without any substituent could proceed, synthesizing the highest yield of product 4f. The influence of the substitution pattern on the aromatic ring was subsequently assessed by testing substrates bearing a substituent at the meta-position or para-position of the benzene ring. The meta-positions bearing electron-donating methyl or electron-withdrawing nitro groups were also tolerated, as they led to the synthesis of products 4g and 4h in yields of 93% and 74%, respectively. Similarly, due to the electronic nature of the para-substituents, high yields and electron-donating methoxyl ( 4i) or electron-withdrawing fluorine atom ( 4j) substituted aryl groups were successful. The naphthyl-substituted α-pyridine aldehyde was also a viable substrate for this three-component reaction to synthesize the desired product 4k in 69% yield. Table 2 | Substrate Scope of Aldehyde Reaction Conditions: Aldehyde 1 (0.1 mmol), alkyne 2a (0.2 mmol), amine 3a (0.2 mmol), and CuCl2 (10 mol %) were dissolved in toluene (1.0 mL), and the reaction mixture was stirred at 110 °C for 2 h. Isolated yields were provided. Replacing the benzene ring unit with pyridine also afforded the desired product 4l in excellent yield (Table 2). The transformation could be further extended using divinyl-substituted pyridine as a substrate. This substrate could be used to obtain product 4m in 62% yield, whereas competitive 14π-electrocyclization was not observed. When the β-position of vinyl with a disubstituted methyl group ( 4n) was used as a substrate to evaluate the effect of steric hindrance on the formation of a new bond, the results indicated that the cascade reaction produced the expected 12-membered ring as the only product in high yield. This multicomponent process can be further diversified through combinations of various alkynes (Table 3). Linear and annular alkyl substituents at the terminal position of the vinyl group were tolerated, resulting in the synthesis of products 4o and 4p in high yields. When the alkyl substituent was changed to a phenyl group with various electronic properties at the para-positions, such as 4-Me-Ph ( 4q), 4-OMe-Ph ( 4r), 4-F-Ph ( 4s) and 4-Br-Ph ( 4t), the results showed that all reactions could efficiently produce large quantities of the corresponding products. The naphthyl-substituted enyne was converted to the expected product 4u in 54% yield. Replacing the naphthyl substituent with 2-furanyl was also a suitable strategy, and the substrate used led to a good yield of the product ( 4v). The dienyne substrate also participated in this reaction, in which the transformation was of excellent regioselectivity in the formation of a 12-membered ring to form the desired product 4w in 83% yield. The substrate 1-ethynylcyclohexene also underwent a three-component cascade reaction, forming the corresponding tetracycle product 4x in 51% yield. The enyne components bearing a disubstitution at the terminal position and internal position of the vinyl group formed the multicyclic product 4y in excellent yield. Table 3 | Substrate Scope of Alkyne Reaction Conditions: Aldehyde 1a (0.1 mmol), alkyne 2 (0.2 mmol), amine 3a (0.2 mmol), and CuCl2 (10 mol %) were dissolved in toluene (1.0 mL), and the reaction mixture was stirred at 110 °C for 2 h. Isolated yields were provided. When an additional aryl group as a π-component of electrocyclization participated in the formation of the 12-membered ring, the reaction was relatively difficult because it involved the simultaneous dearomatization and rearomatization of two different aromatics. When the enynes were changed into heteroarene-substituted alkynes, such as 2-ethynyl-benzofuran and thiophene, these heteroaryl-containing substrates also underwent electrocyclization to form corresponding polycycle products 4z and 4aa in yields of 84% and 81% (Table 3), respectively. The reaction component 3-ethynyl-thiophene also participated in the cascade sequence to produce the corresponding tetracycle product 4ab in 84% yield, and its structure was confirmed by X-ray single crystal diffraction analysis (Please see the Supporting Information Figure S1). The functional group tolerance and scope of the amine as a reaction component were systematically investigated, and the results are shown in Table 4. Aliphatic amines, including annular-piperidine ( 4ac), linear-dibutylamine ( 4ad), -dibenzylamine ( 4ae). and -N-methyl-benzylamine ( 4af), were transformed into large quantities of the desired products. Some synthetically important functional groups, such as esters ( 4ag), nitriles ( 4ah) and alcohols ( 4ai), had high reactivity, but the addition of a hydroxyl group decreased the yield to 44%. To evaluate the viability of this method in more structurally intricate settings, we used bioactive molecules ( 4aj and 4ak) as coupling partners to test the effect on the reaction performance, and the results indicated that the complex molecules were also compatible with the three-component cascade sequence, leading to the formation of the expected products in good yields. This finding suggested that this method might be used for the late-stage modification of bioactive targets. The aromatic secondary amines, including N-phenyl- ( 4al), -benzyl- ( 4am) and -allylic-anilines ( 4an), acted as suitable substrates, yielding the desired products in excellent yields. Tetrahydroquinoline, a cyclic aromatic amine, reacted to complete the cascade sequence, forming a 12-membered ring product ( 4ao) in 80% yield. In addition, to further verify the generality of our strategy, we also examined various primary amines, including aniline, benzylamine and n-butylamine. However, the expected perifused tricycle products could not be observed under our standard reaction conditions except for the recovery of the starting materials Table 4 | Substrate Scope of Amine Reaction Conditions: aAldehyde 1a (0.1 mmol), alkyne 2a (0.2 mmol), amine 3 (0.2 mmol), and CuCl2 (10 mol %) were dissolved in toluene (1.0 mL), and the reaction mixture was stirred at 110 °C for 2 h. bCu(OTf)2 was used as catalyst. cThe reaction was performed under solvent-free condition. Isolated yields were provided. To further access the chiral 12-membered ring products, amines bearing a steric center at the α-position of the nitrogen atom were investigated, and various chiral amines were found to be viable substrates, delivering optically pure products ( 4ap–4au) in good to excellent yields (Table 4). These results also indicated that increasing the steric hindrance of the amine did not affect the product yield. In general, the protocol was related to tolerance for structural diversity and good functional group compatibility. It was also short and highly selective, and its modularity provided access to various analogs. To illustrate the applicability of this protocol, scale-up experiments and several transformations of the products were conducted. Initially, we performed a gram-scale reaction as a representative example, delivering product 4ae in 85% yield (Figure 2a). The product with an ester structural unit ( 4ag) was selected as our target to facilitate conversion and potential application. According to the property of an electron-rich aromatic heterocycle, formaldehyde on the indolizine ring could be selectively generated, accessing the π-expanded analog 5a in 93% yield. Similarly, the same position could also be modified by the Rh-catalyzed reaction of 4ag with diazo malonate, which afforded tricycle product 6a from C–H functionalization in 56% yield (Figure 2b). We also modified the external amine fragment via mild oxidation. When we used MnO2 as an oxidant, alkyl elimination occurred, producing imine product 7a in good yield and retaining an intact core skeleton. Finally, the structure of 7a could be confirmed by X-ray single crystal diffraction analysis (Figure 2b and please see the Supporting Information Figure S2). These results highlighted the practical utility of this special indolizine compound. Figure 2 | Gram-scale synthesis and synthetic transformations. Download figure Download PowerPoint Several control experiments were conducted to validate the reaction mechanism. First, deuterium-labeling experiments were carried out to ascertain the source of hydrogen atoms at the C2- and C7-positions (Figure 3a). The three-component cascade annulation was performed using a mixture of toluene and D2O (toluene/D2O = 1/0.2), resulting in product 4a′ with a deuteration ratio of 70% and 80% at the C2- and C7-positions, respectively. These results suggested that the hydrogen source atom came from the reaction system rather than via intramolecular hydrogen migration. Next, when the deuterium-labeled substrate 1a′ was used under our standard conditions (Figure 3b), the NMR signal of the deuterium atom disappeared from the spectrum of product 4a, which indicated that the reaction underwent deprotonation during the formation of indolizine (The NMR data of all new compounds, please see the Supporting Information Figures S3–S136). Figure 3 | Control experiments and possible mechanism. Download figure Download PowerPoint To verify our assumption regarding the 12π electrocyclization of indolizine as an 8π-component, we designed a route for preparing the precursor 3,5-dialkenyl-substituted indolizine. First, the copper-catalyzed three-component cascade reaction of 6-(hydroxymethyl)picolinaldehyde, (E)-but-1-en-3-yn-1-ylbenzene and morpholine was conducted under our conditions to produce the corresponding alcohol 4av in 52% yield. Alcohol 4av was oxidized to aldehyde 4aw by tetra-n-propylammonium perruthenate. When the Wittig reaction of aldehyde 4aw was conducted to prepare 3,5-dialkenyl-substituted indolizine 4ax, the 12π electrocyclization product 4a (84% yield from 4av to 4a; for experimental details, please see the Supporting Information, Pages 3 and 8) was directly isolated by column chromatography, and we did not observe indolizine intermediate 4ax in the reaction process (Figure 3c). This result suggested that 12π electrocyclization of indolizine occurred spontaneously, and the 8π electrocyclization of the metal, proposed in previous work, might be excluded.48 Based on the results of our control experiment and previous studies, we proposed a possible reaction mechanism (Figure 3d). First, intermediate III was formed by the reaction of Cu-acetylide species I with iminium II. Then, intermediate III underwent 5-endo-cyclization under the catalysis of copper to form intermediate IV, which further triggered deprotonation to generate copper species V. The protonation of intermediate V produced 3,5-dialkenyl-substituted indolizine VI, which spontaneously underwent 12π electrocyclization to form 12-membered ring intermediate VIIvia dearomatization. Finally, protonation at the C7-position triggered the isomerization of the polyene, resulting in the formation of the final product. Conclusion In conclusion, we reported a combination of a copper relay-catalyzed three-component cascade with a 12π electrocyclization reaction as an efficient strategy for constructing a perifused cycle. This single metal relay-catalyzed multicomponent approach highlights the efficiency of the process, and these attractive skeletons might be used as pharmacological or functional materials in the future. The conjugated tetraene-like character of indolizine was realized, expanding the reactivity of traditional aromatic heterocycles. We speculated that the uncommon 12π electrocyclization might open a new path for regioselectivity and stereoselectivity in the production of synthetically important molecules. Supporting Information Supporting Information is available and includes experimental procedures, compound characterization data and NMR spectra for new compounds. Conflict of Interest The authors declare no competing financial interest. Funding Information This research was made possible as a result of a generous grant from the National Natural Science Foundation of China (NSFC; grant nos. 21772019 and 22371024), The Venture and Innovation Support Program for Chongqing Overseas Returnees (grant nos. cx2019007 and cx20200047) and The Basic and Frontier Research Project of Chongqing (grant no. CSTB2022NSCQMSX0320). Acknowledgments The authors thank NSFC (grant nos. 21772019 and 22371024), acknowledge the support from the Venture Holland D. O.The Chemistry of the Pyrrocolines and the Octahydropyrrocolines.Chem. 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Google Scholar Previous articleNext article FiguresReferencesRelatedDetails Issue AssignmentNot Yet AssignedSupporting Information Copyright & Permissions© 2024 Chinese Chemical SocietyKeywordsmulticomponent cascade12π electrocyclizationperifused cycleindolizineconvergent synthesisAcknowledgmentsThe authors thank NSFC (grant nos. 21772019 and 22371024), acknowledge the support from the Venture & Innovation Support Program for Chongqing Overseas Returnees (grant nos. cx2019007 and cx2020047), and the Basic and Frontier Research Project of Chongqing (grant no. CSTB2022NSCQ-MSX0320) and the Analytical and Testing Centers of Chongqing University are gratefully acknowledged for instrumental facilities. Downloaded 63 times PDF downloadLoading ...