Palladium Chemistry Turns Iodoalkenes Into Enynes and Alkynyl Ketones

Palladium-catalyzed cross-coupling reactions have reshaped modern synthetic chemistry, giving chemists reliable ways to forge carbon-carbon bonds that were once notoriously difficult to construct. Among these transformations, the Sonogashira reaction occupies a special place, joining terminal alkynes to organic halides to build conjugated systems found in pharmaceuticals, materials, and natural products. A new study published in the open-access journal Results in Chemistry by Laura Barbara Jenei, Alexandra Zugó, Gábor Mikle, and László Kollár now extends this classic toolkit in a direction that has been surprisingly underexplored: the use of iodoalkenes, rather than the aryl halides that dominate the literature, as the electrophilic partner in both direct and carbonylative Sonogashira couplings.

The motivation behind the work stems from a striking imbalance in the field. Carbonylative Sonogashira couplings, first demonstrated by Tanaka and coworkers in 1981, have been applied to an impressive range of substrates over the past four decades, including aryl and vinyl triflates, aryl iodides, aryl bromides, alkyl halides, benzyl chlorides, aryl triazenes, and even diazonium salts, with formic acid serving as a carbon monoxide surrogate in the latter case. More recently, aryl thianthrenium salts have opened the door to direct, selective functionalization of aromatic carbon-hydrogen bonds. Yet despite this breadth, arene derivatives have been used almost exclusively as substrates. Given the synthetic utility of alkenyl-alkynyl ketones, the Hungarian research team set out to ask whether iodoalkenes could serve as competent partners, and to map the structure-reactivity and structure-selectivity relationships that govern these transformations.

The investigation began with the direct Sonogashira coupling, using 2-iodobornene as a sterically demanding model iodoalkene and phenylacetylene as the coupling partner. The catalytically active palladium(0) species was generated in situ from palladium(II) acetate and a phosphine ligand, with copper(I) iodide as co-catalyst. As is common in Sonogashira chemistry, an unwanted side reaction loomed: the Glaser homocoupling of the terminal alkyne, which in this case produced 1,4-diphenyl-1,3-butadiyne. Optimizing the reaction therefore meant balancing conversion against selectivity toward the desired enyne product, a delicate dance of solvent, base, ligand, and stoichiometry.

The optimization data reveal how sensitive these couplings are to reaction conditions. In tetrahydrofuran with triphenylphosphine as ligand, conversions hovered around 35 to 37 percent regardless of whether 1.1 or 1.5 equivalents of alkyne were used. Switching the base from triethylamine to potassium carbonate pushed the selectivity toward the enyne to a perfect 100 percent, while omitting the phosphine ligand altogether collapsed the conversion to a mere 12 percent, underscoring its necessity. The decisive breakthrough came with the bidentate ligand Xantphos, which lifted conversion to 72 percent while maintaining complete selectivity. Dimethylformamide, a solvent widely used in such couplings, kept conversion high but came at a steep cost: selectivity plummeted, and with inorganic base the reaction produced essentially none of the desired enyne, the diyne by-product dominating instead.

With the optimized conditions in hand, the team explored the substrate scope across six structurally diverse iodoalkenes, including 2-iodobornene, 1-iodocyclohexene, 1-iodo-4-tert-butylcyclohexene, 1-iodocyclopentene, trans-1-iodo-1-octene, and 17-iodo-androst-16-ene, a steroid-derived substrate. These were paired with five terminal alkynes: phenylacetylene, 1-hexyne, 3-hydroxy-1-butyne, trimethylsilylacetylene, and ethynylferrocene. The resulting conjugated enynes were isolated in moderate to good yields. Aryl alkynes generally outperformed their aliphatic counterparts, while trimethylsilylacetylene consistently delivered the lowest yields across the iodoalkene series. Steric effects were clearly at play, as the more hindered iodoalkenes gave lower yields with bulky alkyne partners. Intriguingly, the hydroxy-functionalized alkyne proved highly effective, particularly with the parent iodoalkene, hinting that substrate-specific effects can override simple reactivity expectations.

The carbonylative variant, the true centerpiece of the study, introduces carbon monoxide as a one-carbon synthon into the catalytic cycle. Under atmospheric pressure of CO, the alkenyl-palladium species formed after oxidative addition undergoes CO insertion to generate an acyl-palladium intermediate, which is then trapped by the alkynyl nucleophile to yield an alkynyl ketone bearing both alkenyl and alkynyl fragments. These alkenyl-alkynyl ketones are valuable building blocks, and accessing them from iodoalkenes under mild conditions represents a meaningful addition to the synthetic repertoire. The optimization, however, revealed an even greater sensitivity to the solvent-base combination than the direct coupling.

In dimethylformamide with potassium carbonate, conversions climbed rapidly, reaching 100 percent within three hours, but the direct Sonogashira product and the carbonylative product formed in nearly equal amounts, an unacceptable outcome for chemoselectivity. Replacing the inorganic base with triethylamine slowed the reaction at short times but dramatically improved selectivity toward the alkynyl ketone; at complete conversion after six hours, the ratio of carbonylative product to direct coupling product to diyne stood at an impressive 89 to 9 to 2. Tetrahydrofuran with triethylamine fared far worse, delivering only partial conversion even after 24 hours while the proportion of non-carbonylative and homocoupled by-products steadily grew. Dimethylformamide with triethylamine was therefore selected as the standard for preparative work.

Applying these conditions across the full substrate matrix yielded alkenyl-alkynyl ketones in yields ranging from 19 to 92 percent. Sterically hindered iodoalkenes again lagged behind with the bulky ethynylferrocene partner, while 1-hexyne proved an especially willing participant, its acylation by the acyl-palladium intermediate being more favorable than that of the other alkynes. Not every alkyne cooperated, however. Trimethylsilylacetylene, a reliable partner in many coupling chemistries, took an unexpected detour under the carbonylative conditions: instead of the desired silylated alkynyl ketone, desilylation occurred, followed by addition of diethylamine generated from the triethylamine-containing medium, producing a beta-diethylamino enone or enaminone-type by-product. Switching to potassium carbonate only partially suppressed this pathway and triggered additional side reactions, including a doubly coupled product and a dimethylamino compound derived from dimethylformamide itself, as confirmed by gas chromatography-mass spectrometry. The authors concluded that trimethylsilylacetylene is not a generally reliable partner for the carbonylative protocol under these conditions.

The analytical rigor underpinning the study deserves note. Reaction progress was monitored by gas chromatography with dodecane as an internal standard, using a carefully calibrated single-point relative response factor for the model iodoalkene. Structural assignments rested on nuclear magnetic resonance spectroscopy recorded on a 500-megahertz instrument, complemented by mass spectrometry and infrared spectroscopy with attenuated total reflectance sampling. All isolated compounds were fully characterized, and where products had been reported previously, the analytical data matched the literature values, lending confidence to the reported yields and selectivities.

Taken together, the findings establish iodoalkenes as genuinely useful substrates for accessing two complementary product classes under mild palladium catalysis: conjugated enynes from the direct reaction, performed with a palladium acetate, Xantphos, and copper iodide system in tetrahydrofuran with potassium carbonate, and carbonylated enynone-type products from the carbonylative variant in dimethylformamide with triethylamine under atmospheric carbon monoxide. The study demonstrates that reaction outcome is governed by an interplay of solvent and base, the steric demand of the iodoalkene, and the nature of the terminal alkyne. The successful use of ethynylferrocene as a redox-active alkyne partner adds an intriguing dimension for future materials-oriented applications, while the trimethylsilylacetylene limitation offers a candid map of the protocol’s boundaries. For a transformation whose aryl halide chemistry has been exhaustively catalogued, this systematic exploration of the alkenyl frontier shows that even forty-year-old catalytic reactions still hold surprises worth pursuing.

Subject of Research: Palladium-catalyzed direct and carbonylative Sonogashira coupling reactions of iodoalkenes with terminal alkynes

Article Title: Direct and carbonylative Sonogashira reactions of iodoalkenes

Article References: Jenei, L. B., Zugó, A., Mikle, G., & Kollár, L. (2026). Direct and carbonylative Sonogashira reactions of iodoalkenes. Results in Chemistry, 31, Article 103924. https://doi.org/10.1016/j.rechem.2026.103924

Image Credits: AI Generated

DOI: 10.1016/j.rechem.2026.103924

Keywords: Sonogashira coupling, carbonylation, iodoalkenes, palladium catalysis, cross-coupling, alkynyl ketones, enynes, Xantphos, carbon monoxide, terminal alkynes, homogeneous catalysis, synthetic chemistry