The synthesis of N-heterocycles via copper/TEMPO catalysed aerobic oxidation of amino alcohols

Flanagan, J.C.A. and Dornan, L.M. and McLaughlin, M.G. and McCreanor, N.G. and Cook, M.J. and Muldoon, M.J. (2012) The synthesis of N-heterocycles via copper/TEMPO catalysed aerobic oxidation of amino alcohols. Green Chemistry, 14 (5). pp. 1281-1283. ISSN 1463-9262

Abstract

N-Heterocycles can be prepared using alcohol oxidation as a key synthetic step. Herein we report studies exploring the potential of Cu/TEMPO as an aerobic oxidation catalyst for the synthesis of substituted indoles and quinolines. Graphical abstract: The synthesis of N-heterocycles via copper/TEMPO catalysed aerobic oxidation of amino alcohols N-Heterocycles are important scaffolds for many drugs and natural products, and substituted quinolines and indoles are the basis of many top selling pharmaceuticals; for example, Singulair® and Maxalt®. The synthesis of such substituted N-heterocycles can be challenging with many traditional approaches requiring harsh conditions and delivering poor selectivity. An attractive route for the synthesis of N-heterocycles is to utilize alcohols as substrates as they are readily available and easy to handle. There are numerous examples where catalytic transfer hydrogenations or “hydrogen borrowing” methods have been used to prepare N-heterocycles from alcohols. A particularly desirable route for the selective synthesis of substituted N-heterocycles is the intramolecular oxidative cyclization of amino alcohols. Watanabe and co-workers previously employed this route for the synthesis of indoles, using a RuCl2(PPh3)3catalyst. More recently, heterogeneous ruthenium catalysts (Ru/CeO2 and Ru/ZrO2) were used to prepare indole using the same route. Fujita et al. reported the use of a [Cp*IrCl2]2catalyst for the synthesis of indoles, 1,2,3,4-tetrahydroquinolines and 2,3,4,5-tetrahydro-1-benzazepine. For the same starting materials, it was found that when the catalyst was switched to [Cp*RhCl2]2 it produced the corresponding five-, six-, and seven-membered ring lactams. This approach would be greatly improved if we could move away from expensive precious metals and employ more earth abundant metals. Given that oxidation of an alcohol to an aldehyde is the key step in this route, the Cu/TEMPO/O2 system is an attractive alternative.9 This biomimetic system employs a Cu(ii) or Cu(i)9e salt complexed by a ligand such as 2,2-bipyridine, the stable free radical TEMPO (2,2,6,6-tetramethylpiperidinyloxyl), a base and dioxygen as the terminal oxidant. Along with the fact that it employs copper, this system was appealing because it is known to operate under mild conditions and is selective for the oxidation of primary alcohols to aldehydes.9 This feature would increase the scope of this oxidative intramolecular oxidative cyclization and allow us to prepare N-heterocycles using substrates containing secondary alcohol functionality. Furthermore, because it is an aerobic approach we envisaged that this would allow us to obtain quinolines as opposed to tetrahydroquinolines and lactams which were obtained using the Ir and Rh catalysts mentioned earlier. While there have been numerous studies exploring Cu/TEMPO for catalytic alcohol oxidation, these studies have primarily focused on simple model substrates; the catalyst had not been exploited for the synthesis of N-heterocycles.