A facile synthesis of piperazines from primary amines

Abstract

A general procedure is described for converting primary amines to N-substituted piperazines. Reaction of an amine with an N-substituted iminodiacetic acid anhydride (V) yields an iminodiacetic acid monoamide (VI) which closes to a 2,6-piperazinedione (VII) upon treatment with acetic anhydride. The diones a r e reduced to piperazines with borane-THF. Fourteen examples of this process, using twelve aliphatic o r aromatic amines and three iminodiacetic acids, a r e presented. Yields of piperazines, based upon starting amine, ranged from 2 1 to 52%. The procedure is rapid and no purification problems were encountered. Alternate methods for preparing the 2,6-piperazinedione intermediates are discussed.During a synthetic program directed toward potential antimalarial agents, it was necessary to prepare several 1,4-disubstituted piperazines from a primary aromatic amine. The procedures of Prelog (2) and Pollard (3). utilizing bis(2-haloethy1)amines and bis(2 -hydroxyethy1)amines respectively, have been widely used to effect this conversion, but both proved inadequate in the present case and another was sought. Reduction of a 2,6 -piperazinedione ( e . g . , It), wherein Ra and its attached nitrogen are provided by the primary amine, appeared a PriOri to be an attractive alternate possibility. The additional five atoms of the piperazine ring would thus be provided by an iminodiacetic acid moiety ( e . g . , Ia), several of which (N-unsubstituted, N-methyl, and N-benzyl) are commercially available. Examination of the literature revealed three examples of lithium aluminum hydride reductions of such diones to piperazines (4-6) although, in each case, the goal of the work was not the incorporation of a primary amine into the ring.Chase and Downs (4) used this procedure to prepare isotopically labeled I-methylpiperazine (IIIa) by reduction of 4-methylpiperazine-2,6-dione (IIa) .The dione was obtained by fusion of N-methyliminodiacetic acid (Ia) with urea. More recently, Cignarella (5) prepared cis-2,6-dimethylpiperazine (W) by a similar reduction of 1-benzyl-cis-3, 5dimethyl-2,6-piperazinedione (IIb) followed by removal of the benzyl group by catalytic hydrogenolysis. In this case, the dione was obtained by thermal ring closure of the iminodiacetic acid monoethyl ester monobenzylamide (Ib). Both papers report excellent yields.Roderick, Platte, and

RuO4-mediated oxidation of N-benzylated tertiary amines. 3. Behavior of 1,4-dibenzylpiperazine and its oxygenated derivatives

“…Synthesis of 8, 23, 24, and 38 will be detailed in a future paper [9]. Derivatives 3 [6], 9 [6,32], 10 [6], 12 [33], 30 [34], 33 [35], and 39 [36] Table 2. IR spectrum (CH 2 Cl 2 , cm −1 ): 1680+1700 (large and strong, ν CO ), 3400 (medium, ν NH ).…”

Large-Scale Synthesis of Piperazine-2,6-dione and Its Use in the Synthesis of Dexrazoxane Analogues

“…To optimize the above method for additional convenience, we attempted to replace the urea-assisted cyclization with a three-step imide synthesis. 19,20 In the first step, the Cbz-protected acid 8 was dehydrated to Cbz-protected morpholine-2,6-dione 11 in acetic anhydride. 21 Simple evaporation of the reaction mixture afforded product 11, which was pure enough to be used in the next step.…”

Antifilarial agents. Diazabicyclooctanes and diazabicycloheptanes as bridged analogs of diethylcarbamazine

“…8-Benzyl-3-methyl-3,8-diazabicyclo[3.2.1]octane-2,4-dione (26). Compound 22 (32.3 g, 0.123 mol) and Ac20 (160 ml) were heated together at 100°for 45 min after all solid had dissolved.…”