Indoles coupling with pyridine //-oxides

Recently, Li and co-workers reported the C3-selective oxidative aryla-tion of indoles with pyridine N-oxides (Scheme 56,110L1766). Using Pd (OAc)2 and Ag2C03 as the oxidant, the cross-coupling of N-methyl, N-benzyl, and N-phenylindole derivatives with different pyridine N-oxides... 

Scheme 56 Zhang and Li s oxidative coupling of N-protected indoles with pyridine N-oxides.

A similar methodology has been reported concurrently by Yamagushi and Itami (11CL555). Optimized conditions allowed the coupling of a variety of N-MOM and N-Ts indoles with pyridine and pyrazine N-oxides - also the latter required the use of AcOH instead of 2,6-lutidine (Scheme 57). Notably the authors applied their methodology to the synthesis of eudistomin U, a marine alakaloid with DNA-binding activity. 

Scheme 7 Coupling of pyridine iV-oxides with iV-substituted indoles...

Oxidative coupling between pyridine A-oxides (and analogues) and A-substituted indoles via twofold C-H bond activation was achieved in up to 88% yield with high selectivity using Ag2C03 as the oxidant and Pd(OAc)2 as the catalyst in the presence of DMF and pyridine as base and tetrbutylammonium bromide as additive. ... 

It was also reported that the use of quinoxaline A-oxide gives rise to coupling in even a higher yield than the parent indole-pyridine coupling reaction (Scheme 8) [26], The coupling reactions with isoquinoline, phthalazine, and pyrimidine A-oxides proved to proceed smoothly, and their regioselective outcomes were found to be consistent with the parent coupling reaction. 

The C-2 selective oxidative C-H coupling of unactivated pyridines with heterocycles was achieved in the presence of Pd(OAc)2, phenanthroline as the ligand, a silver oxidant, and pivalic acid (eq 145). Moderate to good yields were obtained when heteroarenes, such as thiophenes, indoles, furans, indazoles, or xanthines, were coupled to p3uidine (or p3razine, quinoline, pyrimidine). Virtually no homo-coupling or other regioselective (C-3 or C-4) products were observed in the reaction. 

Several oxidative arylation processes have been described. A common theme of these processes is the need for a stoichiometric oxidant, t3q)ically a silver salt, to regenerate the active pal-ladium(II) catalyst. Pyridine JV-oxide coupling partners typically involve indole or p3rrole species, with the points of reaction being the 2-position of the JV-oxide and the 3-position of the joining heterocycle (eq 27). Interestingly, triazole IV-oxides are also viable coupling partners (eq 28). 

Copper(I) complexed with 1,10-phenanthroline has been used in the arylation of imidazo[l,2-a]pyridines by aryl bromides, iodides, and triflates to give products, (139), substituted at the 3-position. The mechanism is likely to involve initial deprotonation at the 3-position followed by cupration and oxidative addition of the aryl halide. The copper-mediated cross-coupling of indoles with 1,3-azoles is assisted by chelation of a, readily removed, 2-pyrimidyl group and leads to products such as (140). In this reaction, two carbon-hydrogen substitutions are required and it is likely that initial cupration of the 1,3-azole is followed by chelation-assisted formation of a bis(heteroaryl) copper species before oxygen-promoted reductive elimination... 

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