Intramolecular Aza-Wittig Reaction: A New Efficient Tool for the Construction of Piperazine 2,5-Dione Derivatives

Abstract

A new efficient approach for the synthesis of unsymmetricaly substituted piperazine 2,5-dione derivatives is described by using intramolecular aza-Wittig reaction as the key step. The reaction conditions are very simple, offer easy isolation, and excellent yields of the products.2,5-Diketopiperazines, known as cyclic dipeptides, are frequently formed from both enzymatic and nonenzymatic processes of peptides/protein. 1 They are also wellknown as byproducts that are formed during removal of temporal protecting group of secondary amino acids. 2 The piperazine-2,5-dione moiety occurs in a variety of drugs and natural products which show interesting biological activities 3 including antiviral, 4 antifungal, 5 antitumour, 6 antithrombic, 7 and antibacterial activities. 8 Additionally this heterocyclic system has found unique applications as an acceptor for organic anions or metal cations 9 and in material science. 10 While numerous approaches have been reported 11-14 for the synthesis of piperazine 2,5-diones there is still demand for more easier synthetic pathways. Generally, synthesis of 2,5-DKP starting from amino acids or amino esters requires protection, deprotection, and cyclization reactions which occur either in situ or at elevated temperatures.The aza-Wittig reaction has become one of the most important synthetic method for the construction of C=N, N=N, and S=N double bonds especially in the preparation of nitrogen containing heterocycles. Iminophosphoranes, nitrogen analogues of phosphorus ylides, are versatile intermediates in modern synthetic chemistry. 15 Numerous research papers and reviews have appeared in the literature describing the general use of iminophosphorane as reagent and intermediate in organic synthesis, 16 including the synthesis of heterocyclic natural products by the azaWittig method. 17In continuation of our research interest in the synthesis of nitrogen heterocycles 18 we have undertaken a study to synthesize 2,5-diketopiperazine derivatives of biological interest from N-substituted amino esters using intramolecular aza-Wittig reaction as the key step, and the results are reported here.The precursors 3a-f required for our present study were synthesized from the amino esters 1a-f. Treatment of 1a-f with chloroacetyl chloride under phase-transfer-catalysis conditions gave the amides 2a-f. The amide formation reaction under the PTC conditions proceeded at a much faster rate than any normal amide formation reaction.Compound 2a-f were then treated with excess of sodium azide in DMF solution at 90°C to afford the azide compounds 3a-f in good to excellent yields (Scheme 1).Scheme 1 Reagents and conditions: (i) chloroacetyl chloride, CH 2 Cl 2 -H 2 O, K 2 CO 3 , r.t.; (ii) NaN 3 , DMF, 90°C.Initially, the intramolecular aza-Wittig reaction was conducted with the substrate 3a. When 3a was treated with triphenylphosphine in THF at room temperature, product 6a was afforded along with triphenylphosphine oxide. The intermediate iminophosphorane 4 was not isolated (Scheme 2). Scheme 2 Reagents and co...

2,5-Diketopiperazines: Synthesis, Reactions, Medicinal Chemistry, and Bioactive Natural Products

“…The azide 89 , prepared from the amino acid 87 by acylation with chloroacetyl chloride followed by displacement with sodium azide, was used to form in situ the iminophosphorane 90 . This cyclized with the C- 2 carbonyl group of the ester to give the imino ether 91 , which in the presence of moist THF gave good yields of the 2,5-diketopiperazines 92 (R = benzyl and aryl) …”

Design, Synthesis and Evaluation of Novel 1,4-Disubstituted Piperazine-2,5-dione Derivatives as Antioxidants against H2O2-Induced Oxidative Injury via the IL-6/Nrf2 Loop Pathway

“…1-(4-Methoxyphenyl)piperazine-2,5-dione ( 7e ) [ 19 ]: White Solid, 61% Yield: ESI-MS m/z: 221.1 [M + H] + .…”

Synthesis of Disubstituted Pyrazino‐Oxazine Derivatives with Controlled Stereochemistry

“…The specific class of heterocycles accessible from AAs are piperazine‐2,5‐diones (also termed diketopiperazines, DKPs) . DKPs represent a rich source of biologically interesting compounds exhibiting a broad spectrum of pharmacological activities, for example, antiviral, antifungal, antitumour, antithrombic and antibacterial , . Such scaffolds have been shown to inhibit enzymes and control the activity of many receptors;, therefore they have widespread applications in organic, medicinal and supramolecular chemistry .…”

“…DKPs are typically synthesized from dipeptides in solution or on the solid phase, followed by subsequent derivatization and cyclization under various conditions . Piperazinediones have also been synthesized by an Ugi multi‐component reaction, or aza‐Wittig cyclization . In 2011, Svete and co‐workers reported a three‐step method based on the N ‐alkylation of an amino acid ester hydrochloride, chloroacetylation and cyclization in methanolic ammonia .…”