Copper-mediated reactions mechanisms

Figure 8-6. Examples of copper-mediated reactions of haloaromatics. In each case, the halogen is replaced by a nucleophile. The mechanisms probably involve intermediates related to 8.3.

These copper-mediated reactions very often involve dinuclear intermediates, but detailed mechanistic studies on stoichiometric systems are relatively few. The key features are the formation of p-peroxo or p-superoxo complexes by electron transfer from cop-per(i) to dioxygen. The co-ordinated oxygen may then act as an electrophile to the aromatic ring. A possible mechanism for the ortho-hydroxylation of phenol by dioxygen in the presence of copper catalysts is shown in Fig. 9-29. 

A different mechanism was suggested by McKillop and Taylor, who considered that the copper mediated reactions involve single electron transfer from the copper Cu(I) species to the thallium substrate. The arylthallium(II) species loses a thallium(I) salt and the aryl radical. This aryl radical secondarily reacts with the copper(II) species formed in the first step by electron transfer. 5,106... 

In terms of solvent choice, DMF, DMA and toluene proved to be inferior to tet-rahydrofuran (THE) or THF/hexane solvent mixtures. It is speculated that the mechanism of this copper-mediated reaction proceeds via the oxidative addition of copper(I) to the hydroxamic acid, thereby generating a copper(III) amido species which slowly undergoes transmetallation. 

The possibilities for the formation of carbon-carbon bonds involving arenes have been dramatically increased in recent years by the use of transition metal catalysis. Copper-mediated reactions to couple aryl halides in Ulknann-type reactions [12, 13] have been known for many years, and copper still remains an important catalyst [14, 15]. However, the use of metals such as palladium [16,17] to effect substitution has led to such an explosion of research that in 2011 transition metal-catalyzed processes comprised more than half of the reactions classified as aromatic substitutions in Organic Reaction Mechanisms [18]. The reactions often involve a sequence outlined in Scheme 6.6 where Ln represents ligand(s) for the palladium. Oxidative addition of the aryl halide to the paiiadium catalyst is followed by transmetalation with an aryl or alkyl derivative and by reductive elimination to give the coupled product and legeuCTate the catalyst. Part 6 of this book elaborates these and related processes. 

A unique method to generate the pyridine ring employed a transition metal-mediated 6-endo-dig cyclization of A-propargylamine derivative 120. The reaction proceeds in 5-12 h with yields of 22-74%. Gold (HI) salts are required to catalyze the reaction, but copper salts are sufficient with reactive ketones. A proposed reaction mechanism involves activation of the alkyne by transition metal complexation. This lowers the activation energy for the enamine addition to the alkyne that generates 121. The transition metal also behaves as a Lewis acid and facilitates formation of 120 from 118 and 119. Subsequent aromatization of 121 affords pyridine 122. 

Mechanisms of Copper-mediated Addition and Substitution Reactions... 

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