Ruthenium-complex-catalyzed N-(cyclo)alkylation of aromatic amines with diols.: Selective synthesis of N-(ω-hydroxyalkyl)anilines of type PhNH(CH2)nOH and of some bioactive arylpiperazines

A new class of well-defined neutral mono-, and dicationic ruthenium(II) complexes containing a neutral terdentate donor system [C5H3N(CH2E)(2)-2,6] (E = PPh2 (PNP) or NMe2 (NN'N)) has been found effective as catalyst precursor in N-(cyclo)alkylation reactions of aromatic amines with diols Y(CH2CH2OH)(2) (Y = CH2, NR). With these catalysts, N-phenylpiperidine is synthesized from aniline and 1,5-pentanediol in 85% yield (at 180 degrees C for 24 h in 1,4-dioxane). With neutral RuCl2(NN'N)(PPh3) as a catalyst precursor, aniline can be selectively N-monoalkylated with diols of the type HO(CH2)(n)OH (n = 4-6, 10) to give N-(n-hydroxyalkyl)anilines in 40-75% yield. To our knowledge, this represents the first useful catalytic route to this type of compounds. The new catalysts can also be used in the synthesis of arylpiperazines. For example, N-phenyl-N'-methylpiperazine is obtained from aniline and MeN(CH2CH2OH)(2) in yields up to 34%. N-[m-(Trifluoromethyl)phenyl]-N'-methylpiperazine, TFMPMP, is successfully produced from m-(trifluoromethyl)aniline and MeN(CH2CH2OH)(2) in 44% yield using monocationic [RuOTf(NN'N)(PPh3)]OTf as the catalyst precursor. A mechanism for the N-(cyclo)alkylation reaction is proposed.