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

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.

Copper-Free Heck–Cassar–Sonogashira and Suzuki–Miyaura Reactions of Aryl Chlorides: A Sustainable Approach

“…The reaction was carried out with 2 mol % of Pd (0) catalyst, generated in situ starting from Pd(CH 3 CN) 2 Cl 2 and sSPhos, in HEP/water 70/30 and N,N,N′,N′-tetramethyl guanidine (TMG) as a base. These standard conditions were used to evaluate the effect of the leaving group and, for PhCl 1a Cl , to define concentration, temperature, and stoichiometry (Table 1 The enyne side product, (E)-4-[phenylbut-1-en-3-ynyl]benzene, 4a 36,37,43 became instead the main product moving from PhI 1a I to PhBr 1a Br and PhCl 1a Cl at 60 °C (compare entries 1−3). These results are determined by the competition between the oxidative addition OA of ArX (Figure 1, cycle I) and PhC�CH 2a (Figure 1, cycle II).…”

“…The enyne side product, ( E )-4-[phenylbut-1-en-3-ynyl]­benzene, 4a ,, became instead the main product moving from PhI 1a I to PhBr 1a Br and PhCl 1a Cl at 60 °C (compare entries 1–3). These results are determined by the competition between the oxidative addition OA of ArX (Figure , cycle I) and PhCCH 2a (Figure , cycle II) .…”

“…Taking advantage of our experience in the Heck–Cassar–Sonogashira reaction using aryl iodides, bromides, and triflates based on the use of green protocols, − we explored the application of commercially available Buchwald’s palladium ligand, sodium 2′-dicyclohexylphosphino-2,6-dimethoxy-1,1′-biphenyl-3-sulfonate (sSPhos), in the N-hydroxyethylpyrrolidone (HEP)/water mixture for the HCS and SM cross-coupling using aryl chlorides. HEP is a safe and potentially biogenic solvent, , which in a mixture with water proved to be a valid alternative to the use of toxic DMF or NMP .…”

Palladium-catalyzed radical arylation of N-hydroxyphthalimides with triphenyl phosphites as an unusual arylating agent via C(sp2)–O bond cleavage

“…24,26 The resulting complex 5a could readily be reduced to the active catalytic species 6a in the presence of an excess amount of TPP and water. 24,26,27 Next, the radical PINO derived from NHPI could react with complex 6a 28 to form intermediate II . Then, intermediate II could be converted into intermediate III via intramolecular electron transfer.…”