Palladium-catalyzed cascade cyclization of trifluoroacetylsilane and 1,3-enyne to synthesize trifluoromethyl-substituted 2H-pyran compounds

Professor Xiao Shen's research group at Wuhan University developed a new type of palladium-catalyzed tandem cyclization reaction between trifluoroacetylsilane and 1,3-enyne. This strategy effectively suppressed competitive cyclopropanation and cyclopropenylation pathways, selectively promoting the formation of trifluoromethyl-substituted oxatrienes. Subsequently, oxa-6π-electrocyclization efficiently converted them into a series of 6-CF3-2H-pyran derivatives. The authors elucidated the tandem reaction mechanism through DFT calculations: the carbon-carbon triple bond in the 1,3-enyne substrate preferentially inserts into the Pd-Si bond of the acyl divalent palladium intermediate, followed by reductive elimination to generate trifluoromethyl-substituted oxatriene compounds, and finally undergoes oxa-6π-electrocyclization to release the 6-CF3-2H-pyran product. The article was published as an open access research article in CCS Chemistry, the flagship journal of the Chinese Chemical Society.

Background information:

Trifluoromethyl groups are important fluorine-containing groups that can effectively enhance lipophilicity, improve metabolic capacity, and increase the bioactivity of parent compounds. Therefore, developing practical methods for introducing trifluoromethyl groups into organic molecules is a cutting-edge research area in organic chemistry and medicinal chemistry. The 2H-pyran skeleton is also a core structure of many bioactive molecules, primarily prepared as oxatriene precursors through reactions such as the Knoevenagel reaction, Stille coupling reaction, and propargyl Claisen rearrangement, followed by oxa-6π-electrocyclization. However, due to the significant challenges in synthesizing trifluoromethyl-substituted oxatriene precursors, only a very few reports have to date successfully constructed trifluoromethyl 2H-pyran.

Highlights of this article:

The research group of Professor Xiao Shen at Wuhan University has long been dedicated to studying the role of fluoroalkyl acylsilanes as novel donor-acceptor carbene precursors in reactions (see Acc. Chem. Res. 2025, 58, 1519). In this work, the authors combined fluoroalkylsilanes with transition metal catalysis to achieve, for the first time, palladium-catalyzed tandem cyclization reactions of trifluoroacetylsilanes with 1,3-enynes, synthesizing a series of 6-CF3-2H-pyran derivatives with high efficiency, high chemoselectivity, and regioselectivity. The reaction proceeded via an acyl palladium intermediate, rather than a carbene palladium intermediate.

The reaction exhibits good substrate versatility (Figure 2). Trifluoroacetylsilanes containing different silane groups yielded 2H-pyran products in moderate to excellent yields. The size of the silane group affected the reactivity, with sterically less hindrance trifluoroacetylsilanes providing the highest yield (3a, 81% ). For 1,3-enyne substrates, both straight-chain alkyl-substituted and cycloalkyl -substituted 1,3-enynes of different chain lengths showed good yields. Furthermore, ether-containing substrates, pyridine-derived substrates, and silyl ethers, hemiketals, carboxylic esters, amides, and carbazole functional groups were all tolerated in this reaction system. The method is also compatible with C(sp³)-Cl bonds (3t, 79% ), providing possibilities for subsequent functionalization. Several complex bioactive molecules, such as the phenothiazine derivative 3u and the estrone derivative 3v, were obtained in yields of 59% and 72%, respectively. Under standard conditions, aryl-substituted 1,3- enynes exhibit relatively low reactivity. However, increasing the temperature to 60 °C improves the reaction efficiency, allowing electron-rich, electron-poor , and neutral aryl-substituted 1,3-enynes to yield 6-CF3-2H-pyran compounds in 36%–65% yields.

To elucidate the reaction mechanism and its regio and chemoselectivity, the authors employed density functional theory (DFT ) calculations. The reaction begins with the palladium(0) active species 6 coordinated to 1a, 2a, and an N- heterocyclic carbene (NHC) ligand. Subsequently, 1,3-enyne 2a dissociates to generate a less stable palladium(0) intermediate 7, absorbing 2.8 kcal/mol of heat. Intermediate 7 then undergoes oxidative addition via a transition state 8-ts (activation barrier 4.2 kcal/mol) to generate an acylpalladium(II) intermediate 9, which has almost the same energy as palladium(0) intermediate 7 (2.0 vs 2.8 kcal/mol). Subsequently, the C-C triple bond of 1,3-enyne 2a preferentially inserts into the Pd-Si bond of the acylpalladium(II) intermediate 9 to generate a vinylpalladium(II) intermediate 11 (10-ts, 17.5 kcal/mol). The authors also considered the regioselectivity of the alkyne insertion step, as the transition state 10-ts exhibits a higher activation barrier (25.1 kcal/mol), thus ruling out this pathway. Next, the vinyl palladium(II) intermediate 11 readily undergoes reductive elimination to yield palladium(0) intermediate 13 (12-ts,  activation barrier 0.5 kcal/mol), a step that releases a significant amount of heat. Intermediate 13 rapidly isomerizes to form E- configuration diene-coordinated palladium(0) intermediate 14 , absorbing 0.7 kcal/mol of heat. Finally, intermediate 14 undergoes palladium-assisted oxa-6π-electrocyclization via transition state 15-ts (activation barrier 14.1 kcal/mol) to release the final product 3a, as well as the regenerated active catalytic species 6. Furthermore, the authors also considered the direct oxidative addition of palladium(0) complex 6 via transition state 16-ts to form an alkyne-coordinated acyl palladium(II) intermediate 17. Since the activation energy of transition state 16-ts is 7.2 kcal/mol higher than that of transition state 8-ts, this pathway is kinetically unfavorable. Notably, no cyclopropanation or cyclopropenylation products were observed in the template reaction. DFT calculations indicate that the activation barrier for the acylpalladium(II) intermediate 9 to form palladium(II)-carbene intermediate 19 via 1,3-silyl migration is 18.9 kcal/mol (18-ts ), which is 1.4 kcal/mol higher than that of the alkyne insertion step (10-ts , 17.5 kcal/mol). Therefore, the formation and further conversion of product 4a or 4a-1 via the carbene intermediate is unfavorable.

Summary and Outlook:

In summary, Professor Xiao Shen's research group at Wuhan University has developed an efficient method for synthesizing various 6-CF3-2H-pyran derivatives via a palladium-catalyzed tandem cyclization reaction of trifluoroacetylsilane and 1,3-enyne. This reaction has a broad substrate scope, accommodating various functionalized 1,3-enynes, including alkyl, aryl, alkenyl, alkynyl, and heteroaryl-substituted derivatives, providing the corresponding 6-CF3-2H-pyran compounds in high yields. Furthermore, gram-scale reactions and subsequent transformations further demonstrate the practicality and synthetic potential of this method. Finally, DFT calculations elucidated the reaction mechanism and the sources of regio and chemoselectivity, and revealed the unfavorable formation of metal carbene intermediates.

This research was recently published as Just Accepted Research Article in CCS Chemistry. Professor Xiao Shen of Wuhan University is the corresponding author, and Peishen Jin, a doctoral student at Wuhan University, and Xiaoqian He, a postdoctoral researcher at Wuhan University, are co-first authors.

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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/.