Philip Boehm

Nature, Published online: 20 November 2024; doi:10.1038/s41586-024-08195-1

A transition-metal-free platform enables the formation of challenging C(sp3)–C(sp3) bonds in organic compounds via single-electron transfer, facilitating the coupling of functionalized fragments and expanding possibilities for efficient organic synthesis and reaction design.

Using a catalytic system comprised of Pd and Xantphos, acid chlorides can be added across strained alkenes or tethered alkynes to form two new C−C bonds via formal C−COCl cleavage. This reaction allows for a dicarbofunctionalisation in which an acid chloride group is retained in the product. DFT studies are used to rationalise a plausible pathway, while product derivatisation highlights the synthetic utility of the method.

Abstract

Here we report a palladium-catalysed difunctionalisation of unsaturated C−C bonds with acid chlorides. Formally, the C−COCl bond of an acid chloride is cleaved and added, with complete atom economy, across either strained alkenes or a tethered alkyne to generate new acid chlorides. The transformation does not require exogenous carbon monoxide, operates under mild conditions, shows a good functional group tolerance, and gives the isolated products with excellent stereoselectivity. The intermolecular reaction tolerates both aryl- and alkenyl-substituted acid chlorides and is successful when carboxylic acids are transformed to the acid chloride in situ. The reaction also shows an example of temperature-dependent stereodivergence which, together with plausible mechanistic pathways, is investigated by DFT calculations. Moreover, we show that benzofurans can be formed in an intramolecular variant of the reaction. Finally, derivatisation of the products from the intermolecular reaction provides a highly stereoselective approach for the synthesis of tetrasubstituted cyclopentanes.

An efficient and broadly applicable palladium-catalyzed iodination of inexpensive and abundant aryl and vinyl carboxylic acids via in situ activation to the acid chloride and formation of a phosphonium salt was developed. The use of 1-iodobutane as iodide source in combination with a base and a deoxychlorinating reagent gives access to a wide range of aryl and vinyl iodides under Pd/Xantphos catalysis.

Abstract

We report an efficient and broadly applicable palladium-catalyzed iodination of inexpensive and abundant aryl and vinyl carboxylic acids via in situ activation to the acid chloride and formation of a phosphonium salt. The use of 1-iodobutane as iodide source in combination with a base and a deoxychlorinating reagent gives access to a wide range of aryl and vinyl iodides under Pd/Xantphos catalysis, including complex drug-like scaffolds. Stoichiometric experiments and kinetic analysis suggest a unique mechanism involving C−P reductive elimination to form the Xantphos phosphonium chloride, which subsequently initiates an unusual halogen exchange by outer sphere nucleophilic substitution.

An efficient palladium‐catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high‐value products from readily available aryl (pseudo)halides.

Abstract

An efficient palladium‐catalyzed chlorocarbonylation of aryl (pseudo)halides that gives access to a wide range of carboxylic acid derivatives has been developed. The use of butyryl chloride as a combined CO and Cl source eludes the need for toxic, gaseous carbon monoxide, thus facilitating the synthesis of high‐value products from readily available aryl (pseudo)halides. The combination of palladium(0), Xantphos, and an amine base is essential to promote this broadly applicable catalytic reaction. Overall, this reaction provides access to a great variety of carbonyl‐containing products through in situ transformation of the generated aroyl chloride. Combined experimental and computational studies support a reaction mechanism involving in situ generation of CO.

From aryl siloxane to aryl fluorides: A method is reported to convert aryl trisiloxanes to aryl fluorides. This process is valuable because this type of silane can be produced by the silylation of C−H bonds with inexpensive heptamethyl trisiloxane.

Abstract

A method for the nucleophilic fluorination of heptamethyl aryl trisiloxanes to form fluoroarenes is reported. The reaction proceeds in the presence of Cu(OTf)₂ and KHF₂ as the fluoride source under mild conditions for a broad range of heptamethyltrisiloxyarenes with high functional group tolerance. The combination of this method with the silylation of aryl C−H bonds enables the regioselective fluorination of non‐activated arenes controlled by steric effects following a two‐step protocol.