The synthesis of N-benzylpiperazine (4) was achieved cleanly and in high yield (95% after chromatography) by monobenzylation without using a mono-protected piperazine. As shown in Scheme 1, the anhydrous piperazine (1) was
converted into its monohydrochloride 3 in situ by reaction with 2 equiv. of piperazine dihydrochloride (2) in ethanol at 65 deg * C for 3 h. Then benzyl chloride was added to the hot reaction mixture to afford compound 4. It is interesting to note that piperazine dihydrochloride (2) could be recovered quantitatively by filtration at the completion of the reaction.
As shown in Scheme 2, Blane reaction of 5a * c ^ (n - 1) using 1.5 equiv. of paraformaldehyde (HCHO) and hydrochloric acid (37%) under catalyst-free conditions gave good yields of 6ik-e.^ (0 - 1) / 2 is interesting to note that it is also quite safe to perform the Blanc reaction under our reaction conditions. Unlike most chloromethylation reactions, which produce highly carcinogenic bis (chloromethyl) ether as a by-product, none of the carcinogenic bis(chloromethyl) ether was detected during the reaction. Treatment of 6a-e with 4 in the presence of K,CD, in DMF at 80 deg * C gave 1-aralkyl-4-benzylpiperazines, which were subsequently converted into their hydrochloride salts 7a-c in good yields by addition of concentrated hydrochloric acid in anhydrous ethanol.
converted into its monohydrochloride 3 in situ by reaction with 2 equiv. of piperazine dihydrochloride (2) in ethanol at 65 deg * C for 3 h. Then benzyl chloride was added to the hot reaction mixture to afford compound 4. It is interesting to note that piperazine dihydrochloride (2) could be recovered quantitatively by filtration at the completion of the reaction.
As shown in Scheme 2, Blane reaction of 5a * c ^ (n - 1) using 1.5 equiv. of paraformaldehyde (HCHO) and hydrochloric acid (37%) under catalyst-free conditions gave good yields of 6ik-e.^ (0 - 1) / 2 is interesting to note that it is also quite safe to perform the Blanc reaction under our reaction conditions. Unlike most chloromethylation reactions, which produce highly carcinogenic bis (chloromethyl) ether as a by-product, none of the carcinogenic bis(chloromethyl) ether was detected during the reaction. Treatment of 6a-e with 4 in the presence of K,CD, in DMF at 80 deg * C gave 1-aralkyl-4-benzylpiperazines, which were subsequently converted into their hydrochloride salts 7a-c in good yields by addition of concentrated hydrochloric acid in anhydrous ethanol.