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 [C 5 H 3 N(CH 2 E) 2 -2,6] (E = PPh 2 ( PNP ) or NMe 2 ( NN ‘ N )) has been found effective as catalyst precursor in N-(cyclo)alkylation reactions of aromatic amines with diols Y(CH 2 CH 2 OH) 2 (Y = CH 2, NR). With these catalysts, N -phenylpiperidine is synthesized from aniline and 1,5-pentanediol in 85% yield (at 180 °C for 24 h in 1,4-dioxane). With neutral RuCl 2 ( NN ‘ N )(PPh 3 ) as a catalyst precursor, aniline can be selectively N-monoalkylated with diols of the type HO(CH 2 ) 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(CH 2 CH 2 OH) 2 in yields up to 34%. N -[ m -(Trifluoromethyl)phenyl]- N ‘-methylpiperazine, TFMPMP, is successfully produced from m -(trifluoromethyl)aniline and MeN(CH 2 CH 2 OH) 2 in 44% yield using monocationic [RuOTf( NN ‘ N )(PPh 3 )]OTf as the catalyst precursor. A mechanism for the N-(cyclo)alkylation reaction is proposed.