Copper-free Sonogashira reaction

Hierso et al reported a copper-free, Sonogashira reaction for a number of activated and deactivated aryl halides with alkyl-/aryl acetylenes and using a variety of metallic precursors, bases and tertiary phosphanes in [bmim][BF4]. They found that a combination of [Pd(/7 -C3H5)Cl]2/PPh3 with 1 % pyrrolidine in the absence of copper showed the highest activity. 

Scheme 8. Copper-free Sonogashira reactions in [C4mim][PF6].

Choudhary BM, Madhi S, Chowdari NS, Kantam ML, Sreedhar B (2002) Copper-free Sonogashira reaction with transition-metal nanoparticles. J Am Chem Soc 124 14127... 

Li and coworkers reported the use of Pd(OAc)2/DABCO/air/CH3CN for a copper-free Sonogashira reaction using only 0.01 mol% [100]. 

Interesting is the development of concept of copper-free Sonogashira reaction in which Cul catalyst was not used (Scheme 2.15). In these reactions, coupUng products 47 in various yields were still obtained (Table 2.14), probably due to the presence of trace amounts of copper in palladium reagent. When copper catalyst-free reaction was carried out with copper milling balls as a source of copper, yields increased to 31-88% (Table 2.15). Finally, copper vials in combination with copper balls as a source of copper afforded respectable yields in the range of42-90% (Table 2.16). 

Table 2.14 Copper-Free" Sonogashira Reactions of p-Substituted Benzenes ...

Both binuclear and trinuclear oxalamidinate palladium complexes were employed by Rau, Walther and coworkers [79] in copper-free Sonogashira reactions. The peculiarity of the system was seen to reside in the presence of chemical bridges that allowed electronic communication between metal centers (Scheme... 

In 2007, Lee and coworkers reported the synthesis of a core-shell type polymer-supported (NHC)-Pd catalyst 28 (Figure 4.8), which was used to catalyze copper-free Sonogashira reactions under ambient atmosphere [39]. The... 

Two alternative mechanisms are proposed for the copper-free Sonogashira reactions, performed from Phi and HO—CH GHj—C=CH (Scheme 19.34) path A when the alkyne is a better ligand than the amine for the Pd center in PhPdlL [43a, c] or path B when the amine is a better ligand than the alkyne [43a]. This explains why the catalytic reactions are very sensitive to the base (path B more efficient than path A) [43a]. Consequently, the amine does not react as a simple base in copper-free Sonogashira reactions but may also be involved as ligand for aryl-Pd complexes [43a, b]. 

Over the last years, two reaction mechanisms proposed for the copper-free Sonogashira reaction have been somewhat discussed in the literature. Recently, the experimental group of Martensson demonstrated that one of them can be discarded, and further proposed two alternatives for the other mechanism on the basis of the electronic nature of the alkyne s substituents. Hence, in order to shed light on the reaction mechanism for this process, we decided to carry out a theoretical study in close contact with the experimental group of Prof. Carmen Nijera with the following main objectives ... 

Evaluating all the mechanistic pathways proposed in the literature for the copper-free Sonogashira reaction. 

Scheme 5.2 Copper-free Sonogashira reaction between several 4-substituted phenylacetylenes and iodobenzene...

The first step in all the proposed mechanisms for the copper-free Sonogashira reaction corresponds to the oxidative addition of the organic halide R-X to the starting [Pd(0)] complex. This step has been extensively studied (see Chap. 1) and is well known that in the case of organic iodides does not use to be rate-limiting. Even so, we decided to examine it for completeness. Hence, the oxidative addition of Phi to the complex [Pd(PH3)2] was computed. The optimized structures for this process are shown in Fig. 5.4. 

The theoretical investigation of the copper-free Sonogashira reaction with pheny-lacetylene as a model substrate (R = H) through a carbopalladation mechanism afforded the reaction profile shown in Fig. 5.5. 

With the carbopalladation mechanism ruled out as operative mechanism, the copper-free Sonogashira reaction through a deprotonation mechanism was next investigated. As commented in the introduction, for this mechanism two different alternatives have been proposed, namely the cationic and the anionic mechanisms (Fig. 5.3) [43]. This two mechanistic alternatives only differ in the order in which the steps in the deprotonation mechanism occur. 

As above stated, the reaction steps in the anionic mechanism take place in reverse order than in the cationic mechanism (Fig. 5.8). Thus, in the anionic mechanism the deprotonation of the alkyne by the external base in complex 2 occurs first, followed by the iodide-for-phosphine substitution. The Gibbs energy profile obtained for the copper-free Sonogashira reaction with phenylacetylene (R = H) through the anionic mechanism is shown in Fig. 5.10. 

In the study presented in this chapter, the reaction mechanism for the model copper-free Sonogashira reaction between iodobenzene and several 4-substituted phenylacetylenes (R = H, CF3, OMe, NMe2) was investigated by means of DFT calculations. Importantly, to the best of our knowledge, this study was the first theoretical study that investigated all the reported mechanistic proposals for the copper-free Sonogashira reaction. 

For the copper-free Sonogashira reaction, the mechanistic study reported in this thesis revealed that, just like in other cross-coupling reactions (i.e. Stille, Negishi), there are several competing reaction pathways and a change on the reaction conditions (e.g. solvent, ligands, substrates, base) might favor one over the other ones. Moreover, a new mechanism in which the acetylide (formed by deprotonation of the alkyne) directly reacts with the catalyst was also proposed. 

M. Garcia-Melchor, M. C. Pacheco, C. Nljera, G. Ujaque, A. Lledos. Mechanistic Exploration of the Pd-Catalyzed Copper-Free Sonogashira Reaction . ACS Catal. 2012, 2, 135-144. 

A. Cwik, Z. HeU, F. Figueras, A copper-free Sonogashira reaction using a Pd/MgLa mixed oxide. Tetrahedron Lett. 47 (2006) 3023-3026. 

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