What are the best conditions to perform monoalkylation in piperazine with an primary alkyl iodide, avoiding elimination?

[João Paulo Fernandes]

I'm trying to do a reaction between an alkyl iodide (a little bit unstable) and piperazine, in order to obtain the monoalkylated piperazine. However, I'm having trouble obtaining a good yield and controlling the mono/dialkylation ratio. Could anyone help with suggestions?I've tried to do the reaction with 2 eq. of piperazine monohydrochloride in EtOH, and a yellow solid was formed. However, the product seems to stay in the aqueous phase during the work-up... How can I obtain it from the aqueous solution without extract the piperazine?

[Horza2002]

This reaction will be very difficult to do. The problem arises because the initally formed monoalkylated product is more nucleophilic that the start material (due to the alkly chain electron donating properties). What you are probably ending up with is the quaternary nitrogen salts resulting from another subsitution of the alkly iodide.

 

If I were you, I would stop trying to do this and try a reductive amination (using the corrossonding aldehyde and sodium cyanoborohydride) and the monoprotected piperazine. That way you will only get the product you want without any over alkyation reactions.