New Mechanistic Insights into the Copper-Free Heck–Cassar–Sonogashira Cross-Coupling Reaction

The copper-free Heck–Cassar–Sonogashira (HCS) reaction, known since 1975, nowadays represents one of the most powerful methods for C–C bond formation in organic synthesis with several industrial applications. Despite its great success, the mechanism is still under discussion, with several reported p...

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Published inACS catalysis Vol. 13; no. 18; pp. 12048 - 12061
Main Authors Palladino, Chiara, Fantoni, Tommaso, Ferrazzano, Lucia, Muzzi, Beatrice, Ricci, Antonio, Tolomelli, Alessandra, Cabri, Walter
Format Journal Article
LanguageEnglish
Published American Chemical Society 15.09.2023
Subjects
Heck−Cassar−Sonogashira reaction
palladium
cross-coupling reaction
mechanism
copper-free
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Abstract The copper-free Heck–Cassar–Sonogashira (HCS) reaction, known since 1975, nowadays represents one of the most powerful methods for C–C bond formation in organic synthesis with several industrial applications. Despite its great success, the mechanism is still under discussion, with several reported possible pathways. To clarify the copper-free HCS reaction mechanism, stoichiometric and catalytic reactions were carried out and monitored by 31P/1H NMR spectroscopy, HPLC, and GC chromatography. In particular, the investigation of the role of the base, mimicking the real catalytic conditions, highlighted the fact that secondary amines rapidly induce precatalyst reduction and decrease the energy barrier for the alkyne carbopalladation step. The results supported the mechanism via direct coordination of the terminal alkyne on the oxidative addition complex. Depending on the palladium counterion, and independent of the solvent, aromatic substitutions, temperature, and terminal alkyne substitution, these studies support two different pathways: with halides, a neutral route, and with the triflate, a cationic one.
AbstractList The copper-free Heck–Cassar–Sonogashira (HCS) reaction, known since 1975, nowadays represents one of the most powerful methods for C–C bond formation in organic synthesis with several industrial applications. Despite its great success, the mechanism is still under discussion, with several reported possible pathways. To clarify the copper-free HCS reaction mechanism, stoichiometric and catalytic reactions were carried out and monitored by 31P/1H NMR spectroscopy, HPLC, and GC chromatography. In particular, the investigation of the role of the base, mimicking the real catalytic conditions, highlighted the fact that secondary amines rapidly induce precatalyst reduction and decrease the energy barrier for the alkyne carbopalladation step. The results supported the mechanism via direct coordination of the terminal alkyne on the oxidative addition complex. Depending on the palladium counterion, and independent of the solvent, aromatic substitutions, temperature, and terminal alkyne substitution, these studies support two different pathways: with halides, a neutral route, and with the triflate, a cationic one.
Author Ricci, Antonio
Muzzi, Beatrice
Fantoni, Tommaso
Cabri, Walter
Ferrazzano, Lucia
Palladino, Chiara
Tolomelli, Alessandra
AuthorAffiliation P4Gi Lab − Projects for Green Innovation, Center of Chemical Catalysis, Department of Chemistry “Giacomo Ciamician”
Fresenius Kabi iPSUM Srl
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  email: walter.cabri@unibo.it
  organization: P4Gi Lab − Projects for Green Innovation, Center of Chemical Catalysis, Department of Chemistry “Giacomo Ciamician”
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CitedBy_id crossref_primary_10_1021_acssuschemeng_3c04926
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crossref_primary_10_1016_j_apcatb_2024_124310
crossref_primary_10_1039_D3CC03855F
crossref_primary_10_1039_D3QO01919E
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Keywords Heck−Cassar−Sonogashira reaction
palladium
cross-coupling reaction
mechanism
copper-free
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Snippet The copper-free Heck–Cassar–Sonogashira (HCS) reaction, known since 1975, nowadays represents one of the most powerful methods for C–C bond formation in...
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Title New Mechanistic Insights into the Copper-Free Heck–Cassar–Sonogashira Cross-Coupling Reaction
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