Sonogashira reaction complexes

The original Sonogashira reaction uses copper(l) iodide as a co-catalyst, which converts the alkyne in situ into a copper acetylide. In a subsequent transmeta-lation reaction, the copper is replaced by the palladium complex. The reaction mechanism, with respect to the catalytic cycle, largely corresponds to the Heck reaction.Besides the usual aryl and vinyl halides, i.e. bromides and iodides, trifluoromethanesulfonates (triflates) may be employed. The Sonogashira reaction is well-suited for the synthesis of unsymmetrical bis-2xy ethynes, e.g. 23, which can be prepared as outlined in the following scheme, in a one-pot reaction by applying the so-called sila-Sonogashira reaction ... 

The coupling of terminal alkynes with aryl or alkenyl halides catalysed by palladium and a copper co-catalyst in a basic medium is known as the Sonogashira reaction. A Cu(I)-acetylide complex is formed in situ and transmetallates to the Pd(II) complex obtained after oxidative addition of the halide. Through a reductive elimination pathway the reaction delivers substituted alkynes as products. 

The first examples of NHC-Pd complexes applied to the Sonogashira reaction were reported to show a limited scope in the coupling of aryl iodides and activated aryl bromides with acetylene [23,33,52]. However, the use of A-carbamoyl-substituted heterocyclic carbene Pd(ll) complexes expanded the use to alkyl-acetylenes and deactivated aryl iodides and bromides [124] (Scheme 6.40). 

The chemical structure of the polymers was confirmed by NMR and elemental analysis, and spectroscopically characterized in comparison with monodisperse low molecular weight model compounds. Scheme 5 outlines the approach to the model compounds. Model compounds 31-34 were synthesized by complexation of the ruthenium-free model ligands 29/30 with 3/4. The model ligands were synthesized in toluene/diisopropylamine, in a similar fashion as the polycondensation using Pd(PPh3)4 and Cul as catalyst (Sonogashira reaction) [34,47-49]. 

Suzuki-Miyaura as well as moderate activity in the Stille reaction ([M] = SnRa) were observed. In contrast to bis(NHC) complexes, inactivity in the Sonogashira reaction was due to increased activity in the homocoupling of alkynes [Eq. (47)], an undesired side reaction. 

Corma et al compared the use of different IL solvents and polyethylene glycol (PEG) using a carbopalladacycle complex as catalyst for Suzuki and Sonogashira reactions. They showed that the dialkyl-substituted imidazolium compounds had poor stability, reactivity and recyclability when compared with trialkyl substituted imidazolium compounds and PEG. They concluded that this result could be attributed to the stabilization of the Pd nanoparticles in the solvent. They showed that PEG was a better solvent since it gave better yields, had good stability, low cost and low toxicity. 

Sonogashira reaction. The first system consisted in the use of the oxime palladacycles 7a-f at elevated temperatures, without the aid of Cul or an amine base, for the coupling of aryl iodides and bromides. They also reported on the use of complex 48b in aqueous media for the coupling of aryl iodides and bromides and terminal acetylenes in excellent yields. ... 

The Sonogashira reaction of 2-chloropyrazine 1-oxide gave only recovered starting material. Pentylation and octylation of 2-chloropyrazine 1-oxide also failed [9]. Possible explanations for these results were either catalyst agglomeration or metal formation from pyrazinylpalladium complex. 

The mechanism of the Sonogashira reaction has not yet been established clearly. This statement, made in a 2004 publication by Amatore, Jutand and co-workers, certainly holds much truth [10], Nonetheless, the general outline of the mechanism is known, and involves a sequence of oxidative addition, transmetalation, and reductive elimination, which are common to palladium-catalyzed cross-coupling reactions [6b]. In-depth knowledge of the mechanism, however, is not yet available and, in particular, the precise role of the copper co-catalyst and the structure of the catalytically active species remain uncertain [11, 12], The mechanism displayed in Scheme 2 includes the catalytic cycle itself, the preactivation step and the copper mediated transfer of acetylide to the Pd complex and is based on proposals already made in the early publications of Sonogashira [6b]. 

The coupling of terminal alkynes with aryl or vinyl halides under palladium catalysis is known as the Sonogashira reaction. This catalytic process requires the use of a palladium(0) complex, is performed in the presence of base, and generally uses copper iodide as a co-catalyst. One partner, the aryl or vinyl halide, is the same as in the Stille and Suzuki couplings but the other has hydrogen instead of tin or boron as the metal to be exchanged for palladium. 

Erdelyi, M., Gogoll, A. Rapid Microwave Promoted Sonogashira Coupling Reactions on Solid Phase. J. Org. Chem. 2003, 68, 6431-6434. Najera, C., Gil-Molto, J., Karlstroem, S., Falvello, L. R. Di-2-pyridylmethylamine-Based Palladium Complexes as New Catalysts for Heck, Suzuki, and Sonogashira Reactions in Organic and Aqueous Solvents. Org. Lett. 2003, 5,1451-1454. 

These complexes are stable to the conditions of the Sonogashira reaction, silica gel chromatography (EtOAc/Hex), dilute TEA, KF in DME, POCI3, PSCI3, MCPBA, MMPP, Arbuzov conditions (neat (EtO)3P, 110°C), and Nal/acetone. Reagents that release HCl will require an acid scavenger to prevent premature deprotection. The 9-BBN chelate of amino alcohols has been used to selectively monoalkylate primary amines, a process that is often problematic because of bisalkylation. ... 

A new type of soluble polystyrene-supported palladium complex was synthesised (Figure 6.1) as an excellent and recyclable palladacycle catalyst for carbon-carbon bond formation in Heck, Suzuki and Sonogashira reactions to give high yields of the desired products. 

Schreiber s early efforts in this area were focused on libraries of compounds having structural features reminiscent of rigid, complex, stereochemically rich natural products. In a key early example, solid-phase split-pool synthesis was used to generate a combinatorial library of over two million complex, polycyclic compounds derived from shikimic acid [17]. A stereoselective tandem acylation-nitrone cycloaddition was used to generate 18 tetracyclic scaffolds, to which 30 alkynes were coupled using a Sonogashira reaction, 62 amines were coupled via y -lactone aminolysis, and 62 carboxylic acids were coupled by alcohol esterification (Fig. 9.1-3(c)). In addition, a portion of the solid supports were left unreacted at each of the last three steps to generate a skip codon that further increased the diversity of the library. 

It was also found that the Sonogashira reaction [69] takes place under aqueous alkaline conditions in the presence of the PS-PEG-supported palladium complex 59 [95]. The combination of the resin catalyst 59, cesium hydroxide [96], and water is essential to promote high yielding coupling of 69. Using copper-free conditions, a one-step preparation of the benzofurans 70 was achieved in water via coupling of 2-iodophenol 68 (X=OH) and the terminal alkynes (Scheme 23). 

---