Piperazine, Michael addition

Position 3 of the piperazine-2,5-dione nucleus has been alkylated by Michael addition of the enol to a suitable acceptor. This route has been successfully utilized for the total synthesis of bicyclomycin (83TL5627). The addition proceeded stereospecifically to give only one product (Scheme 30). 

Michael addition of amines to bis(acrylamides) has provided a versatile method for the preparation of poly(amidoamines) (70MH1102). A wide variety of piperazine-containing polyamides may be prepared by this route when a piperazine, 1,4-diacryloylpiperazine... 

Leong et al. evaluated a hyperbranched poly(amino ester) synthesized in a novel A3+2BB B approach by Michael addition polymerization of trimethylol-propane triacrylate (TMPTA) (A3-type monomer, triacrylate), with a double molar of l-(2-aminoethyl) piperazine (AEPZ) (BB B -type monomer, trifunctional amine) (Fig. 11) [127]. To check its DNA condensation behavior and cytotoxicity, the poly(TMPTAl-AEPZ2) obtained was protonated. Due to the protonation ability of... 

Sarges and Tretter found that the ester derivative of 16, upon saponification and cyclodehydration, afforded diazocine 17 (see Section II,A,2). They also found that the ester of 16 underwent base-catalyzed Michael addition to give piperazine derivative 58. Saponification of 58, followed by treatment with DCC, yielded the ring-expanded diazocine 17 (74JOC1710). 

The use of silicon carbide inserts has proved valuable in the uncatalyzed aza-Michael addition between piperazine and methyl acrylate. The reaction was low yielding using pure toluene as the solvent since the maximum temperature that could be attained was 170 °C. Adding the passive heating elements to the reaction mixture allowed for temperatures of 200 °C to be reached and, with this, a dramatic increase in the yield for the reaction was observed (Scheme 2.10). The product isolation procedure was trivial and consisted of physical removal of the heating element using a pair of tweezers followed by removal of the solvent. 

A related strategy described by Frechet (Figure 13.5b) utilizes a bis-diene amide monomer 21 that possesses an internal acetal/ketal moiety [86]. Monomer 21 is a bis-acrylamide capable of conjugate or Michael addition at unsubstituted double bonds. A diamine such as piperazine 22 can be used to prepare acetal/ketal polyamidoamines 23. One characteristic of polyacetal polyamidoamines 23 is they will be cationic and have been used in stndies to complex oligonucleotide analogues (e.g., siRNA and DNA). 

The first example of a hyperbranched gelator was reported by Yan, Huang, and coworkers in 2007. The polymer was synthesized by the Michael addition of methyl bis-acrylamide (54) to l-(2-aminoethyl)piperazine (55), which generated the hyperbranched polymer 56 (Scheme 13). 

Polymerizations of multifunctional monomers of suitable unequal reactivity have been proved to be feasible for preparing hyperbranched polymers. Wu et al. [163] have reported in situ C NMR monitoring of the synthesis of hyperbranched poly(aminoester)s prepared via the Michael addition polymerization of a triacrylate, trimethylolpropane triacrylate (TMPTA) (A3-type monomer) with a double molar l-(2-aminoethyl)piperazine (AEPZ) (BB B"-type monomer) in chloroform at room temperature. 

IR data from the model compounds indicate that the amino end groups of the ATBN can react with the double bond in the polyester. In fact, the 1645 cm-1 absorption due to the double bond almost disappeared after 40 min at 100 °C, and the absorption due to the amino groups (N-H) also diminished considerably (Figure 1). A Michael-type addition reaction between the secondary amino hydrogen of piperazine derivatives and the activated double bonds of diethylfumarate in the polyester is known (5, 6). 

A mechanism for the piperazine-catalyzed formation of 4//-chromenes is complex cascade of reactions, starting with piperazine acting as a base which activates malononitrile, promoting Knoevenagel condensation, and also formation of an enamine, followed by Michael condensation, proton transfer, intermolecular cycliza-tion via a nucleophilic addition of the enolate oxygen to the nitrile group (hetero-Thorpe-Ziegler), and finally hydrolysis and tautomerization. 

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