Nickel- and Brønsted Acid-Catalyzed Redox-Neutral Coupling of 1,3-Dienes and Aldehydes for Synthesis of Dienols

Abstract

Open AccessCCS ChemistryCOMMUNICATION1 Mar 2021Nickel- and Brønsted Acid-Catalyzed Redox-Neutral Coupling of 1,3-Dienes and Aldehydes for Synthesis of Dienols Xing-Wang Han†, Tao Zhang†, Wei-Wei Yao, Hao Chen and Mengchun Ye Xing-Wang Han† State Key Laboratoryand Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071. , Tao Zhang† State Key Laboratoryand Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071. , Wei-Wei Yao State Key Laboratoryand Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071. , Hao Chen State Key Laboratoryand Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071. and Mengchun Ye *Corresponding author: E-mail Address: [email protected] State Key Laboratoryand Institute of Elemento-Organic Chemistry, College of Chemistry, Nankai University, Tianjin 300071. https://doi.org/10.31635/ccschem.020.202000235 SectionsSupplemental MaterialAboutAbstractPDF ToolsAdd to favoritesTrack Citations ShareFacebookTwitterLinked InEmail Dienols are important structural motifs in organic molecules, but most of the traditional synthetic methods required multistep prefunctionalization of substrates, leading to stoichiometric waste and low atom economy. Herein, we report a redox-neutral coupling of simple 1,3-dienes and aldehydes via nickel and Brønsted acid dual catalysis, providing a highly atom-economical and by-product-free route to various dienols with up to 94% yield and up to 50∶1 EE/EZ ratio. The use of 2-isopropoxyphenol as a Brønsted acid co-catalyst was critical to the reactivity and selectivity. Download figure Download PowerPoint Introduction Dienols are important structural motifs that not only widely exist in numerous bioactive compounds (Figure 1a),1–4 but also act as versatile synthons in Diels–Alder reactions5,6 and other reactions.7,8 Although numerous methods have been developed to synthesize them, for example Wittig reaction and cross-coupling reactions,9–15 carbonyl addition reactions that join diene precursors with carbonyl compounds would undoubtedly be more attractive pathways because of easier availability of carbonyls.16–30 The first generation of methods through this pathway used moisture-sensitive dienyl metals as addition agents.16–19 Despite their high reactivity, these organometallic reagents often required tedious manipulations for their preparation, produced stoichiometric metallic waste in reactions, and were accompanied by low functional group tolerance (Figure 1b). To replace dienyl metals, enynes were then used as diene precursors, and a mild and easy-to-handle reductive coupling reaction was achieved (Figure 1c).20–30 Although an important advance, the method required stoichiometric exogenous reductants such as Et3B, Et2Zn, Et3SiH, or H2, generating undesired by-products and reducing atom economy. Figure 1 | Dienol-containing bioactive compounds and their synthesis. Download figure Download PowerPoint Therefore, the development of a direct addition of 1,3-dienes to carbonyls would be highly desirable because such reaction would be highly atom-economical and by-product-free. In addition, compared with prefunctionalized diene precursors such as dienyl metals and enynes, 1,3-dienes are more readily available and cheap. However, owing to low nucleophilicity of 1,3-dienes, the reaction still remains an elusive challenge.31–33 Herein, we report a redox-neutral coupling of 1,3-dienes and aldehydes for the first time, providing various dienols with high yield (up to 94%) and high EE/EZ ratio (up to 50∶1) (Figure 1d). In the reaction, dual catalysis by nickel (Ni) and a Brønsted acid (2-isopropoxyphenol) proved to be critical to the reactivity and selectivity. Experimental Methods General Procedure for Synthesis of Dienols In an N2-filled glove box, an oven-dried sealed tube was charged with a stir bar, Ni(cod)2 (13.8 mg, 0.05 mmol), PCyp3 (23.8 mg, 0.1 mmol), 2-isopropoxyphenol (15.2 mg, 0.1 mmol), diene 1 (1.0 mmol), aldehyde 2 (0.5 mmol), and MeOH (3 mL). The tube was then sealed with a Teflon-lined screw cap, removed from the glove box, and stirred at 75°C for 16 h. After being cooled to room temperature, the mixture was concentrated and purified by column chromatography on silica gel (PE/EA = 5∶1–10∶1). Results and Discussion Reaction proposal Recently, dual catalysis by Ni and a Brønsted acid has been proven to be a powerful strategy for redox-neutral coupling of alkenes and carbonyl compounds by the Zhou group34 and our group (Figure 2a).35–37 However, these two catalytic systems were not compatible with 1,3-dienes because of their more vulnerable structures,38–45 producing complicated mixtures through side reactions such as difunctionalization of dienes with PhB(OH)2,46 hydroamination of dienes with TsNH2,47–49,a or oligomerization of dienes.50–52 A similar mechanism to that of alkene couplings was proposed in Figure 2b.34,35 Oxidative cyclization of Ni, diene, and aldehyde forms a cyclic nickelacycle, which was then protonated by Brønsted acid, followed by β-H elimination, generating the dienol and the Ni–H species. According to this mechanism, we envisioned that the use of proper Brønsted acids instead of PhB(OH)2, and amides to inhibit transmetallations in the intermediate ( A) and ligand exchange in the intermediate ( B), would be critical. In addition, the Brønsted acid may act as a ligand of Ni, providing an extra means to tune EE/EZ selectivity of products. Figure 2 | Reaction proposal. Download figure Download PowerPoint Reaction optimization Following this hypothesis, we investigated a broad range of Brønsted acids in the model reaction of 1,3-diene ( 1a) and 3-phenylpropanal ( 2a) (entries 1–5). Ultimately, phenol was found to be the optimal one, affording the desired dienols in 52% yield and in 3.5∶1 EE/EZ ratio (entry 5).53,54,b,c The alcoholic solvent also had a strong influence on the reaction (entries 5–8). MeOH provided the highest yield, but either longer chain or bulkier alcohols led to a reduced yield. Nonalcoholic solvents such as DMF and toluene were ineffective (entry 9). The examination of ligands revealed that PCyp3 (Cyp = cyclopentyl) was a slightly superior ligand, promoting the yield to 68% (entry 12), whereas other phosphine ligands were not good (entries 10 and 11). With PCyp3 as the optimal ligand, we next examined electronic and steric effects of phenol co-catalysts (Figure 3). Electron-rich arylphenols ( B1 and B3) displayed better reactivity than electron-deficient or electron-neutral ones ( B2, B4, and B5). However, the presence of coordinating atoms significantly inhibited the reaction ( B6 to B8). Surprisingly, an o-methoxy group provided better yield and EE/EZ ratio than a p-methoxy group ( B9 vs B1). We reasoned that the o-methoxy group may have an additional coordination to Ni, thus benefiting the subsequent protonation of the nickelacycle. So we further tested various o-alkyoxyl groups ( B10 to B15) and found that 2-isopropoxyphenol ( B14) was the optimal one, providing the desired 3a in 85% yield and with 10.0∶1 EE/EZ ratio. Notably, some 2,6-di-substituted phenols were also investigated, but in general provided lower yields, albeit with higher isomer ratios. Figure 3 | Reaction optimization. Reaction conditions: 1a (0.5 mmol), 2a (0.25 mmol) under N2 for 16 h; total yield of EE and EZ isomers and EE/EZ ratio in the parentheses was determined by 1H NMR using CH2Br2 as the internal standard. [a] PPh3. [b] PhPCy2. [c] PCyp3. Download figure Download PowerPoint Scope of aldehydes After establishing the optimal conditions, we first explored the scope of aldehydes in the reaction (Figure 4). Both aromatic ( 3a to 3c) and aliphatic groups ( 3d to 3m) on the aliphatic chain were well compatible with the current reaction, providing the corresponding products in 61–93% yield and with EE/EZ ratios ranging from 6.0∶1 to 16.7∶1. In sharp contrast, aromatic aldehydes nearly shut down this reaction ( 3n). Various functional groups such as amino ( 3o), alkoxyl ( 3p), and alkenyl ( 3q and 3r) were well tolerated, providing the corresponding product in 64–94% yield and with high EE/EZ ratio. Notably, the presence of a chiral center in the aliphatic chain did not lead to any stereoselective differentiation of products (dr = 1∶1, 3h, 3o and 3r). Figure 4 | Scope of aldehydes. Reaction conditions: 1a (1.0 mmol), 2 (0.5 mmol), MeOH (3.0 mL) under N2 for 16 h; combined yield of isolated two isomers; EE/EZ ratio was determined by 1H NMR. [a] dr = 1∶1, determined by 1H NMR. Download figure Download PowerPoint Scope of dienes The compatibility of dienes was also examined in the coupling reaction with 3-phenylpropanal ( 2a) (Figure 5). Although 1,3-butadiene and alkyl-substituted dienes were not compatible with the reaction, various aryldienes bearing either electron- or electron-rich groups on the phenyl ring were well tolerated, providing the corresponding product in 66–93% yield and with 7.7∶1–14.3∶1 EE/EZ ratio ( 4a– 4l). An exception was the aryldiene bearing a Me2N group ( 4h) that afforded 46% yield, which was attributed to the ease of oxidation of the product. Figure 5 | Scope of dienes. Reaction conditions: 1 (1.0 mmol), 2a (0.5 mmol), MeOH (3.0 mL) under N2 for 16 h; combined yield of isolated two isomers; EE/EZ ratio was determined by 1H NMR. Download figure Download PowerPoint In addition, other aromatic dienes such as 2-naphthyldiene ( 4m) and 2-furyldiene ( 4n) gave good yield and good EE/EZ ratio. Notably, the disubstituted diene still participated into this dienylation reaction, providing the product in moderate yield but with fairly high EE/EZ ratio (50∶1, 4o). Reaction utilization To demonstrate the applicability of the method, a gram-scale reaction and the synthesis of bioactive compounds were conducted (Figure 6). The gram-scale reaction worked very well, providing the desired dienol 4a in 90% yield (Figure 6a). Diarylheptanoids are widely found in numerous monocot and dicot plant species.55–57 Most of them exhibit important bioactivity, such as strong antioxidant and chemopreventive properties. Two of these bioactive molecules ( 10 and 11) were selected to be synthesized from the corresponding aryldiene and aldehyde (Figure 6b). Compared with traditional synthetic routes that required alkyl lithium or ylide reagents,55 the current method eliminated the use of these reactive reagents, providing a mild and atom-economical alternative. Figure 6 | Reaction utilization. Download figure Download PowerPoint Discussion Control experiments showed that both Ni and phosphine ligand are indispensable (see Page S17 of Supporting Information), suggesting that a typical Prins process may be ruled out.58–60 In the absence of 2-isoproxyphenol, the reaction still gave a moderate yield (48%), whereas without MeOH, only trace amounts of the product were observed. The result suggested that MeOH could enhance the acidity of 2-isopropoxyphenol by H-bonding interaction, which would be critical to the protonation step. A further detailed study on the mechanism is still needed in the future. Conclusion In summary, we have developed a redox-neutral coupling of 1,3-dienes and aldehydes via dual catalysis by Ni and a Brønsted acid. This atom-economical and by-product-free reaction joins readily available dienes and aldehydes into dienols, avoiding the use of metallic reagents and reductants. The use of 2-isopropoxyphenol as the Brønsted acid is critical to ensure both good reactivity and good selectivity. Searching for wider applications of this new dual-catalytic system in other redox-neutral couplings is under way in our laboratory. Supporting Information Supporting Information is available. Conflict of Interest The authors declare no competing financial interests. Acknowledgments We thank the National Natural Science Foundation of China (21672107 and 21871145), the Fundamental Research Funds for the Central Universities (Nankai University; 63191601), and the Tianjin Applied Basic Research Project and Cutting-Edge Technology Research Plan (19JCZDJC37900) for financial support. Footnotes a For a recent relevant example, see Long et al.47 b Major EE isomers were identified by comparing their 1H NMR spectra with those of their analogues in literatures.53 c Minor EZ isomers were determined by mechanistic analysis first and then by literature comparison.54 References 1. 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