Multivariate Screening-Guided Development of a Sustainable Copper- and Amine-Free Heck–Cassar–Sonogashira Cross-Coupling Reaction in Ethanol
Abstract
Transition-metal-catalyzed cross-coupling reactions have significantly advanced carbon-carbon bond formation. The Heck-Cassar-Sonogashira reaction, traditionally using Pd catalysts, copper cocatalysts, and amines in polar solvents, has drawbacks, including oxidative homocoupling and harmful solvents. Recent innovations address these issues with copperfree conditions, greener solvents, and alternative metals, but none offer a perfect solution. Starting from a recently characterized cationic palladium precatalyst, [Pd(π-allyl)(t-BuXPhos)]Cl, formed in situ in alcoholic solvents, we used a multivariate screening strategy to identify conditions allowing a copper-and amine-free Heck-Cassar-Sonogashira reaction using 0.25 mol % [Pd] loading with K₃PO₄ in ethanol at 40 °C. The protocol features broad substrate scope (34 examples), good functional group compatibility, high yields, and gram-scale applicability.
Related
- PPM-Level Palladium-Catalyzed Sonogashira Coupling Promoted by Fe3(CO)12 and α,β-Ynone Ligands
- Physically aligned forest fire risk prediction: A deep learning framework coupling fuel and climate multivariate factors
- Magnetically recyclable CoFe₂O₄@HKUST-1 nanocatalyst for sustainable carbon–nitrogen coupling, and structure-affinity relationship study of the synthesized products via molecular docking
- Highly active and stable functionalized MOF-based heterogeneous catalyst (Zn-MOF-Gly-Cef@Pd) for the Suzuki and Sonogashira reactions
- Electronic screening as a design lever in La-doped BaTiO3: coupling between polarization, dielectric response, and optical anisotropy
BibTeX
@article{hammoud2026multivariate,
title = {{Multivariate Screening-Guided Development of a Sustainable Copper- and Amine-Free Heck–Cassar–Sonogashira Cross-Coupling Reaction in Ethanol}},
author = {Sokaina Hammoud and Lydia Ouadfel and Laurence Grimaud and Alice Balfourier and Maxime R Vitale and Martine Schmitt and Frédéric Bihel},
journal = {Journal of Organic Chemistry},
year = {2026},
month = jul,
doi = {10.1021/acs.joc.6c00901},
url = {https://hal.science/hal-05779113v1},
note = {CC BY-NC 4.0},
}
RIS
TY - JOUR
TI - Multivariate Screening-Guided Development of a Sustainable Copper- and Amine-Free Heck–Cassar–Sonogashira Cross-Coupling Reaction in Ethanol
AU - Sokaina Hammoud
AU - Lydia Ouadfel
AU - Laurence Grimaud
AU - Alice Balfourier
AU - Maxime R Vitale
AU - Martine Schmitt
AU - Frédéric Bihel
PY - 2026
DA - 2026/07/09
JO - Journal of Organic Chemistry
DO - 10.1021/acs.joc.6c00901
UR - https://hal.science/hal-05779113v1
AB - Transition-metal-catalyzed cross-coupling reactions have significantly advanced carbon-carbon bond formation. The Heck-Cassar-Sonogashira reaction, traditionally using Pd catalysts, copper cocatalysts, and amines in polar solvents, has drawbacks, including oxidative homocoupling and harmful solvents. Recent innovations address these issues with copperfree conditions, greener solvents, and alternative metals, but none offer a perfect solution. Starting from a recently characterized cationic palladium precatalyst, [Pd(π-allyl)(t-BuXPhos)]Cl, formed in situ in alcoholic solvents, we used a multivariate screening strategy to identify conditions allowing a copper-and amine-free Heck-Cassar-Sonogashira reaction using 0.25 mol % [Pd] loading with K₃PO₄ in ethanol at 40 °C. The protocol features broad substrate scope (34 examples), good functional group compatibility, high yields, and gram-scale applicability.
SN - 0022-3263
SN - 1520-6904
ER -