CHEMICAL SCIENCE

Shanghai Jiaotong University realized multi-site programmable functionalization of olefins


On May 18, 2023, the research team of Professor Zhang Wanbin of Shanghai Jiao Tong University published a new study entitled “Multi-site programmable functionalization of alkenes via controllable alkene isomerization” in the journal Nature Chemistry.

In this study, a palladium-catalyzed method for oxidative dehydrogenation of olefins was reported, and the programmable functionalization reaction at multiple sites of olefins was realized by regulating the reaction order of olefin isomerization and oxidation functionalization. This method realizes single, bis- and triacetoxylation reactions at positions 1-, 2-, 1,2-, and 1,2,3-positions with controlled remote alkenylation for a series of unactivated terminal olefins. This method can easily convert terminal olefins from petrochemical feedstocks into unsaturated monoalcohols, diols and polyols, in particular, terminal olefins can be constructed from simple two- to three-step reactions to build a variety of monosaccharides (including rare monosaccharides) and C-glycosides.

The corresponding author of the paper is Professor Zhang Wanbin, and the first author is Assistant Researcher Wu Zhengxing.

The selective functionalization of hydrocarbon chains, including their polyfunctionalization, is a fundamental problem in synthetic chemistry. The traditional functionalization of C=C double bonds and C(sp3)–H bonds is an effective method, but the diverse selectivity of functionalization sites on the hydrocarbon chain remains a challenging problem. In the recently rapidly developing field of remote functionalization of hydrocarbon chains, combining isomerization and (oxidation) functionalization of olefins is expected to provide more opportunities in overcoming the limitations of functionalization sites. Considering that most non-cyclic compounds can be considered as products of functionalization at certain sites on the hydrocarbon chain, diverse site functionalization (including C=C double bonds and C(sp3)–H bonds) can greatly improve their synthesis efficiency. At present, the remote functionalization field of chain olefins can be divided into three types of reaction modes, namely isomerization/functionalization, oxidative functionalization/isomerization, oxidative functionalization/isomerization/functionalization and other reaction modes (Figure 1a). Although this field has made great progress in recent years, the diversity of functionalization sites is still limited, mainly concentrated in the end of the hydrocarbon chain or the proximal site of the induction group. New site selective functionalization, including polyfunctionalization, remains challenging.

In view of the problem of limited functional sites, it is urgent to develop a new model of remote functionalization. Therefore, the authors believe that regulating the reaction sequence of olefin isomerization and oxidative functionalization (abbreviated as Iso. and Func. respectively) will be an ideal strategy for developing a new mode of remote functionalization, which can realize the new function of diversified sites of chain olefins (Figure 1b). The authors hope to explore a class of PdII/O2 oxidation systems in which the reaction sequence of olefin isomerization and oxidative functionalization is controlled by the interaction between PdIIX2 and in situ PdII–H species in the system (Figure 1c). Specifically, PdII–H species in the system are responsible for isomerization processes in the reaction through PdII–H migration insertion and subsequent β-H elimination, while PdIIX2 species are responsible for oxidative functionalization processes in the reaction through nucleophilic palladylation and subsequent β-H elimination (Figure 1c). For the isomerization process responsible for PdII–H species, the authors believe that controlling the isomerization process before and after the oxidative functionalization process (represented by pathways i and ii, respectively) is key to regulating the order of the reaction (Figure 1d). The isomerization process before oxidative functionalization (pathway i) is mainly controlled by the stability of PdII–H species in the catalytic system, while the isomerization process after oxidative functionalization (pathway ii) is mainly controlled by the coordination of PdII–H species with chain olefins and the rotation of coordination bonds formed after coordination.

Based on the feasibility analysis of the above strategy, Zhang Wanbin’s team of Shanghai Jiao Tong University reported a new method of palladium-catalyzed oxidative dehydrogenation of olefins, which realized the programmable functionalization reaction of multiple sites of olefins through the regulation strategy of olefin isomerization and oxidation functionalization reaction sequence (Figure 1e). This strategy is accomplished by promoting or inhibiting pathways I and II described above (Figure 1b–d). Specifically, a series of unactivated terminal olefins were presented with 1-acetoxylation (Func./Iso. by inhibition pathway i and facilitation II), 2-acetoxylation (Iso./Func./Iso, by promoting pathway i and pathway II), 1,2-diacetoxylation and 1,2,3-triacetoxylation (Func./Func. and Func./Func./Func.) with controlled remote alkenylation, respectively. Func., by inhibiting pathway I and pathway II).

Figure 1: Remote functionalization of olefins.

Exploring suitable conditions to regulate the reaction sequence between olefin isomerization and oxidative functionalization is critical, where the control of the isomerization process before and after oxidative functionalization (pathways I and II) is critical. First, the authors suggest that the acidity of the reaction system can affect the stability of PdII–H in the catalytic system through the equilibrium between PdII–H and Pd0, allowing the isomerization process to be controlled prior to oxidative functionalization (Pathway I) (Figure 1d). Second, amide solvents can affect the coordination of PdII–H with chain olefins (e.g., N,N-dimethylformamide (DMF) or N,N-dimethylacetamide (DMA) can maintain PdII–H coordination with olefin chains); When chloride ions are coordinated with PdII–H, chloride ions can promote the rotation of coordination bonds between PdII–H and alkenyls. Therefore, the authors envisage that the synergistic coordination of amide solvents and chloride ions can control the isomerization process following oxidative functionalization (Pathway II) (Figure 1D). The authors apply the above factors affecting the isomerization process to the regulation of reaction order.

Table 1: Substrate range for anti-Markovian oxidation 1-hydroxylation reactions.

The authors inhibited the initial isomerization process of terminal olefins (pathway i) by inhibiting the stability of PdII–H in the catalytic system, and specifically added the additive sodium acetate (NaOAc) to the acetic acid (AcOH) solvent system to adjust the acidity of the reaction system. In addition, the authors used DMF or DMA as a solvent and added a catalyzed amount of sodium chloride (NaCl) to the reaction mixture to promote the isomerization process after oxidative functionalization (Pathway II). Through the optimization of reaction conditions, the product is obtained with good yield2a, a small amount of 2-acetoxylation by-products were also observed3a(Table 1). For easier purification, primary alcohols are obtained at good yields by 1-acetoxylation and subsequent alcoholysis4a。 The reaction conditions were suitable for olefin substrates with phenyl groups with different chain lengths as remote inducers (4a–4qIn addition, carbonyl, ester, and amide groups in this reaction can also be used as remote inducible groups (4r–4v)。

Table 2: Substrate range for oxidative 2-hydroxylation reactions.

Next, the authors explored the possibility of other order of reactions. As a new mode of remote functionalization, isomerization/oxidative functionalization/isomerization can realize diversified site functionalization. To this end, it is critical to facilitate the isomerization process (pathways I and II) before and after oxidative functionalization (Figures 1b–1d). To facilitate the initial isomerization process of terminal olefins (pathway i), the authors explored different ratios of AcOH/NaOAc in solvents to improve the stability of PdII–H in catalytic systems. To facilitate the isomerization process following oxidative functionalization (Pathway II), the authors used the solvent DMA and the catalytic amount of chloride ions. By optimizing the conditions, the 2-acetoxylation reaction accompanied by remote alkenylation proceeded smoothly to obtain the product3aand a small amount of by-products2a(Table 2). Similarly, a 2-acetoxylation reaction and subsequent alcohololysis in a pot can obtain a secondary alcohol5a。 A range of olefin substrates with aryl, carbonyl, ester and amide groups as remote inducible groups can be obtained5b–5r

Table 3: Substrate range for oxidation of 1,2-diacetoxylation.

In addition to the oxidative 1- and 2-acetoxylating reactions described above, the oxidative functionalization of successive multiple sites of olefins can theoretically be solved using the regulatory strategy of the reaction order (Figure 1e). To overcome this challenge, it is critical to inhibit the isomerization process (pathways I and II) before and after oxidative functionalization (Figures 1b–1d). To inhibit the initial isomerization process of terminal olefins (Pathway I), the authors modulated the acidity of the reaction system. In order to inhibit the isomerization process following oxidative functionalization (Pathway II), the authors investigated different solvents on the one hand to replace DMA (weaken the coordination of PdII–H with the alkene chain) and reduce the chloride concentration on the other (weaken the rotation of the coordination bond between PdII–H and the alkenyl group). Under optimized reaction conditions, the oxidation of 1,2-diacetoxylation can proceed smoothly and obtain the product6aand small amounts of 1- and 2-acetoxylation byproducts (Table 3). Ester groups, amide groups, carbonyl groups, and aryl groups can all be used as inducing groups, and the reaction yields the corresponding products with good yields (6a–6l)。

Table 4: Substrate range for oxidation of 1,2,3-triacetoxylation.

Next, the authors applied reaction conditions to the 1,2,3-triacetoxylation reaction of multistage oxidation of olefins (Table 4). By simply adjusting the conditions of the 1,2-diacetoxylation reaction, the authors successfully realized the oxidative 1,2,3-triacetoxylation reaction and obtained the product7a。 In addition, a small amount of 1,3-diacetoxylation reaction byproducts were observed8a。 It is worth mentioning that the activation of five consecutive sites on the hydrocarbon chain in this reaction (one C=C double bond and three C(sp3)–H bonds) is achieved in one step. Inducers can also be extended to different ester and amide groups (7b-7k)。 The method is also compatible with important structural fragments such as furanoses, budazone, and glycine structures (7i–7k)。 Also from Weinreb amide productssyn-7eDifferent ketone products (syn-7l–7o)。

Figure 2: Regionally aggregated 2-hydroxylation reaction and transformation of catalytic products.

Based on the above pattern of olefin isomerization/oxidation functionalization/isomerization, the authors used mixed olefins to achieve a 2-functionalization reaction with controlled remote alkenylation of regions convergence (Figure 2a), which differs from the reported regional convergence at the end of the hydrocarbon chain or the proximal site of the induction group. Unsaturated 1,2,3-triol9aIt can be easily passedsyn-7eSimple alcohololysis is obtained (Figure 2B). Hydroxyl groups in unsaturated alcohols can also be easily converted to cyanogenic or amine functional groups (9band9c)。 By controlling the functionalization on the double bonds generated in the catalytic product, modifications at the sites on the chain olefins can be further extended, such as selective monofunctionalization (9dand9e) and bifunctionalization reactions (9f(Figure 2b). In addition, catalytic products can be converted into pentose of different configurations (9gand9h) and hexose (9i–9l(Figure 2C). This method can also obtain a class of C-glycosides (9mand9n(Figure 2d).

Figure 3: Reaction mechanism studies and hypothetical catalytic cycles.

The authors first verified possible intermediates in different acetoxylation reactions. Based on the experimental results, the authors speculate that in the oxidation of 1- and 2-acetoxylation reactions, Substrate 4-phenyl-1-butene1bCorresponding catalytic products2band3bRespectively through intermediates10aand1bFormation (Figures 3a and 3b). For oxidative 1,2-diacetoxylation and 1,2,3-triacetoxylation reactions (presumably having the same mechanistic pathway), the authors consider the compounds10fIt is ethyl pentyl-4-enoate as a substrate1rIntermediates in the 1,2-diacetoxylation reaction (Figure 3C). Despite from diene10gThe 1,2-diacetoxylated product can also be obtained at a yield of 67%.6a, but based on the distribution of by-products and the stereochemistry of the associated catalytic products, the authors excluded dienes10gPossibility as a major intermediate. In addition, the deuterated reaction shows that the reaction proceeds through the mechanistic path of oxopalladination, in which the main trans-oxpalladylation process is the process. The specific catalytic cycle involves three primitive reactions of oxopalladation, β-H elimination, and PdII-H migration insertion (Figures 3d–3f).

summary

Wanbin Zhang’s team at Shanghai Jiao Tong University used a palladium/oxygen catalytic system to realize programmable functionalization reactions at multiple sites with controllable remote alkenylation for a series of unactivated end olefin substrates by using the regulation strategy of isomerization and oxidation functionalization reaction sequence. This method is compatible with a range of remotely induced groups, such as phenyl, carbonyl, ester, and amide groups. This reaction sequence regulation strategy can promote the development of selective functionalization and multifunctionalization of hydrocarbon chain sites. (Source: Science Network)

Related paper information:https://doi.org/10.1038/s41557-023-01209-x



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