Aromatic substitution copper-catalyzed

Scheme 11.10. Copper- and Palladium-Catalyzed Aromatic Substitution...

Direct aromatic substitution of unactivated aryl halides is slow and generally requires a catalyst to become a useful synthetic method. Copper reagents have been used in some cases in classical procedures for the formation of products from aromatic substitution. In many cases these copper-mediated reactions occur at high temperatures and are substrate dependent. Since the 1970s, transition metal catalysts have been developed for aromatic substitution. Most of the early effort toward developing metal-catalyzed aromatic substitution focused on the formation of... 

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... 

The copper catalyzed carbon-heteroatom bond forming reactions are also efficient in the introduction of oxygen and phosphorous based substitutents onto the aromatic ring. 3-Iodopyridine was reacted with -butanol in the presence of 10 mol% copper(I) iodide and 20 mol% 1,10-phenantroline... 

Other processes, limited to heteroaromatic systems, include the Sn(ANRORC) reaction (Scheme 4),17,18 and ring transformation reactions.18,19 Reactions which proceed via a-adduct intermediates, but do not lead to substitution on the aromatic nuclei, such as the Sn(AEAE) reaction,20 or give nonaromatic products, are not included. Also not covered are processes involving aryl-metal intermediates, such as most copper-catalyzed aromatic substitutions. 

Copper-mordenite catalyzed nucleophilic aromatic substitution reactions. 

A synthesis of 4-alkyl-3-pyridinols (55) from 3-benzyloxypyridine (52) utilizes a copper-catalyzed Grignard reaction. The dihydropyridine intermediates 53 are aromatized to 4-alkyl-3-benzyloxypyridines (54), which on hydrogenolysis provide the pyridinols 55 (85JHC1419). Substitution at the 4-position of 3-pyridinecarboxaldehydes can be achieved via 1-acylpyri-dinium salt 56. The intermediate acetal 57 is hydrolyzed to give pyridine-carboxaldehyde 58 (84H339). 

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. 

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. 

Indazoles were prepared by many different methods. Indazoles 41 were synthesized from nitroaromatics 39 and N-tosylhydrazones 40 with bases (14CC5061). A rhodium(III)-catalyzed oxidative olefination of 1,2-di-substi-tuted arylhydrazines with alkenes via sp C-H bond aaivation followed by an intramolecular aza-Michael reaction yielded indazoles (140L2494). Copper-catalyzed C-H amidation with aromatic imines 42 with tosyl azide provided a route to 3-substituted indazoles 43 (14OL4702). 4,5,6,7-Tetrahydro-lH-inda-zol-3-(2fJ)-one derivatives were prepared in two-step one-pot process (14SC1076). A regioselective synthesis of 2H-indazoles 45 was achieved using... 

---