Palladium-catalyzed coupling of propargyl alcohol esters with various nucleophiles to construct polysubstituted functionalized conjugated dienes

The research team led by Liang'an Chen from Nanjing Normal University and Liangliang Song from Nanjing Forestry University has made a new breakthrough in the field of conjugated diene chemistry. Based on the neutral reaction mechanism of oxidative addition-reductive elimination and utilizing a ligand angle control strategy, they achieved palladium-catalyzed regio-, chemo-, and stereoselective coupling of propargyl alcohol esters with a variety of nucleophiles (including fluorides, phenols, alcohols, carboxylic acids, and amides), constructing a series of high-value-added multi-substituted conjugated dienes. The practicality of this method has been demonstrated through the application and transformation of these functionalized 1,3-dienes in cycloaddition and coupling reactions, as well as the subsequent modification of natural products and bioactive molecules. The article was published as an open access research article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background:

Conjugated dienes are key building blocks in chemistry, not only widely found in bioactive molecules, natural products, and functional materials (Figure 1b), but also playing an important role as versatile building blocks in synthetic chemistry. The number and type of substituents, as well as the stereochemistry of the double bond, play crucial roles in their synthetic utility and biological activity. Researchers have long sought to achieve the efficient synthesis of various functionalized 1,3-dienes. However, due to the limited regio-stereochemical controllability of the two double bonds in polysubstituted conjugated dienes (possibly resulting in four stereoisomers: 1E/3E, 1E/3Z, 1Z/3Z, and 1Z/3E) (Figure 1a), stereoselective synthetic strategies for polysubstituted, particularly heteroatom-substituted, non-terminal conjugated dienes are relatively scarce (Figure 1c). Overall, how to introduce diverse heteroatom substituents into the conjugated diene backbone and manipulate the double bond stereochemistry remain pressing scientific challenges in this field.

Building on the research group's previous work on the selective and controllable transformation of propargyl/alkenyl metal intermediates, this study manipulated the regioselectivity (C1, C2, C3) of the reaction between nucleophiles and propargyl/alkenyl palladium intermediates by adjusting the ligand angle. It was found that a large bite angle promoted C2-conjugated dienylation and inhibited competing C1-propargyl and C3-alkenylations, enabling the introduction of a series of heteroatoms (N, O, F, etc.) with high regio-, chemo-, and stereoselectivity. This provides a practical solution for the efficient synthesis of widely used and challenging heteroatom-substituted conjugated diene molecules.

Highlights of this article:

(1) A ligand-chelating-based conjugated dienylation reaction model for propargyl alcohol esters was developed, achieving simultaneous regulation of chemical, regioselectivity (suppressing competitive propargylation, allenylation, and alkenylation), and stereoselectivity.

(2) A catalytic synthesis system with broad compatibility was established, which achieved efficient coupling with F, O, and N nucleophilic species and constructed a series of functionalized multi-substituted conjugated dienes.

(3) It can allow drugs and bioactive molecules to directly participate in the reaction as nucleophilic species, demonstrating its application potential in the field of medicinal chemistry (Figure 2).

Summary and Outlook:

In summary, this paper reports the first palladium-catalyzed highly selective conjugated dienylation of substituted propargyl alcohol esters with a wide range of nucleophiles (fluorides, phenols, alcohols, carboxylic acids, and amides), rather than traditional propargyl and allenylation reactions. This method prepares highly functionalized 1,3-dienyls in a chemo-, regio-, and stereoselective manner, and exhibits promising synthetic applications in Diels-Alder cycloadditions and carbon-carbon coupling reactions. This work not only provides a reliable and complementary solution for the challenging stereoselective synthesis of multi-substituted 1,3-dienes, but also offers new insights for the construction of more heteroatom-substituted conjugated diene skeletons, expanding the field of selective transformation of propargyl alcohol esters.

The related results were published as a research article in CCS Chemistry . Doctoral student Mengfu Dai and master's student Jianchao Chang from the School of Chemistry and Materials Science at Nanjing Normal University are co-first authors of the paper, with Professor Liang'an Chen and Associate Professor Liangliang Song from Nanjing Forestry University serving as co-corresponding authors. This work was funded by the National Natural Science Foundation of China, the Natural Science Foundation of Jiangsu Province, and the Open Research Fund of the State Key Laboratory of Coordination Chemistry, School of Chemistry and Chemical Engineering, Nanjing University.

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About the journal: CCS Chemistry is the Chinese Chemical Society’s flagship publication, established to serve as the preeminent international chemistry journal published in China. It is an English language journal that covers all areas of chemistry and the chemical sciences, including groundbreaking concepts, mechanisms, methods, materials, reactions, and applications. All articles are diamond open access, with no fees for authors or readers. More information can be found at https://www.chinesechemsoc.org/journal/ccschem.

About the Chinese Chemical Society: The Chinese Chemical Society (CCS) is an academic organization formed by Chinese chemists of their own accord with the purpose of uniting Chinese chemists at home and abroad to promote the development of chemistry in China. The CCS was founded during a meeting of preeminent chemists in Nanjing on August 4, 1932. It currently has more than 120,000 individual members and 184 organizational members. There are 7 Divisions covering the major areas of chemistry: physical, inorganic, organic, polymer, analytical, applied and chemical education, as well as 31 Commissions, including catalysis, computational chemistry, photochemistry, electrochemistry, organic solid chemistry, environmental chemistry, and many other sub-fields of the chemical sciences. The CCS also has 10 committees, including the Woman’s Chemists Committee and Young Chemists Committee. More information can be found at https://www.chinesechemsoc.org/.