Nucleophilic aromatic substitution copper-catalyzed

Copper-mordenite catalyzed nucleophilic aromatic substitution reactions. 

One group of nucleophilic aromatic substitution processes does not fit mechanistically into the previous categories. This group is a series of copper-catalyzed displacements of aromatic halogen compounds. 

In addition to electrophilic aromatic substitution reaction and copper salts-mediated or -catalyzed C-H bond functionalization, nucleophilic aromatic substitution reaction has also been explored to introduce the functional groups [60, 61]. One of successful examples is the amination reaction of dichloro-substituted azacalix[2]arene[2]triazine with various amines based on the reactivity of chlorotriazine moiety (Scheme 14.18) [60]. 

In the copper catalyzed aromatic nucleophilic substitution of aryl halides bromoindole derivatives were converted to the appropriate cyanoindoles. Both 5-bromoindole and its 7V-tosyl derivative gave excellent yields, when a substoichiometric amount potassium iodide was added to the reaction mixture (6.80.), Pyrazole and benzothiophene showed a similar reactivity. The role of the added iodide is to activate the aromatic system through a bromine-iodine exchange.111... 

Mechanistic interpretations of the copper-catalyzed aromatic nucleophilic substitution reactions remain unsettled even after half-a-century of debate [19, 20]. Possible pathways involve an S Ar reaction mediated by copper complexation to the pi-system (Scheme 4a), an electron transfer reaction followed by halide dissociation (Scheme 4b), four-centered c-bond metathesis reaction (Scheme 4c) and Cu(l) oxidative addition to the Ar-X bond, followed by the nucleophile exchange and reductive elimination in the resulting Cu(lll) system (Scheme 4d). There is presently a considerable body of experimental and theoretical data for and against each of the proposed mechanisms [21]. While the mechanistic studies were mostly related to the formation of C-C, C-O and C-N bonds, it is likely that the copper-catalyzed halogen exchange reactions follow a similar trend. 

As noted in Section 11.2.2, nucleophilic substitution of aromatic halides lacking activating substituents is generally difficult. It has been known for a long time that the nucleophilic substitution of aromatic halides can be catalyzed by the presence of copper metal or copper salts.137 Synthetic procedures based on this observation are used to prepare aryl nitriles by reaction of aryl bromides with Cu(I)CN. The reactions are usually carried out at elevated temperature in DMF or a similar solvent. 

As is true for other classes of aromatic nucleophilic substitution, the halogen displacement can frequently be catalyzed by copper or copper(I) salts. Using sodium hydride as the base and copper(I) iodide as catalyst, a series of o-bromophenylethylamine derivatives, including both amides and carbamates, have been cyclized. Oxidation to the indole can be effected with manganese dioxide (81JCS(P1)290). 

Litvak, V. V., Shein, S. M. Nucleophilic substitution in an aromatic series. LI. Kinetics of the reaction of bromobenzene with phenols, catalyzed by copper salts, in the presence of alkali metal carbonates. Zh. Org. Khim. 1975,11,92-96. 

The Ohe group have investigated novel Cu-catalyzed cyclizations of cyano enones en route to highly substituted 3-pyrrohn-2-ones (2007JOMC579,2008JOC9174). Treatment of cyano enone 103 with copper triflate in the presence of furan gives 5,5-diaryl 3-pyrrohn-2-one 105 (Scheme 15). The reaction presumably proceeds via a dehydrative cycliza-tion to carbocationic intermediate 104, which is trapped by an aromatic nucleophile to give the observed product. 

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