An efficient protocol for the synthesis of N-fused 2,5-diketopiperazine via base catalyzed Ugi-type MCR

Numerous diversity-oriented synthesis of N-fused cyclic heterocycles have been demonstrated but most of them are based on point diversity within the same library and usually include slow sequential multistep synthesis


Introduction
2][3][4] Since the first report by Ugi et al. in 1959 5 this reaction has been considered as one of the most versatile and robust MCRs.Ugi type reaction is not only used for biological screening in medicinal chemistry but also used for synthesis of drug molecule or drug intermediate as well. 6The post functionalization of MCR [7][8][9][10][11] adducts has received considerable attention in recent years.Because of its combination with various post-transformations, typically cyclization, provides a fast and efficient entry to libraries of diverse heterocyclic scaffolds. 12socyanide-based MCR followed by other synthetic transformations emerged as a powerful tool for creating fused multicyclic skeletons.As a part of our strategy to discover novel heterocycles by the skeletal diversity of N-rich cyclic compounds, we report our approach toward the development of efficient reaction conditions with the use of diverse N-fused cyclic heterocycles through an Ugi-type MCR. 13  We are interested to synthesized 2,5-diketopiperazines via Post Ugi-MCR.2,5-diketopiperazines represent privileged moieties in medicinal chemistry and are ubiquitous substructures in pharmaceuticals. 14For example, Tadalafil (Figure 3) is potent for pulmonary arterial hypertension. 15Retosiban & Epelsiban are oral drugs which act as an oxytocin receptor antagonist used for the treatment of preterm labour. 16,17 plaviroc is a CCR5 entry inhibitor used for the treatment of HIV infection.Plinabulin (NPI-2358/KPU-2) 348 is a potent antitumor agent that is active in multidrug-resistant (MDR) tumor cell lines.Because of its biological importance, 2,5-Diketopiperazine has attracted much attention to its syntheses.However, despite much effort to its preparation, efficient methods for the synthesis of 2, 5-diketopiperazine remain to be developed. 18We report herein a novel way to construct 2,5-diketopiperazine by using the Ugi MCR and based promoted post Ugi arylation/cyclization as key synthetic steps.

Results and Discussion
Initially, the syntheses of Ugi MCR product 1a−f were achieved by the condensation of aromatic 4-(4aminophenyl) morpholin-3-one, aldehydes, chloroacetic acid and isocyanides under catalytically free reaction condition in methanol.
A small library of N-fused 2,5-dikitopiperazine have been synthesized with the use of optimized reaction conditions.In order to develop a better reaction conditions, a set of experiments were carried out by varying base, catalyst and solvent with the use of 1b as the model substrate for intramolecular cyclization reaction (Scheme 1).CuI and Pd(OAc) 2 with ligand tested as shown in Table 1 but both catalyst led to a poor yield of 2b and tedious work up procedure (entries 1-5).However, under catalytically free condition with the use of base was found more effective (table 1, entry 6) for this reaction.Subsequently, the effect of base was further investigated; K 2 CO 3 was found as the most efficient base to push the reaction forward among the several bases used (Table 2).The effect of solvent was also investigated, and DMF was found to be the best solvent at 100 ο C (Table 3).Further, the optimized conditions equally applied for the synthesis of a wide variety of Nfused cyclic heterocycles 2a−f starting from IMCRs 1a−f (Table 4).Excellent yields were observed for IMCRs 1a−f (Table 4).

Conclusions
An efficient synthesis of novel functionalized N-fused 2,5-diketopiperazines has been reported.Considering the availability of starting material, the simple reaction procedure, simple workup and robust nature, this chemical process provides a very straightforward route to construct various highly functionalized N-fused 2,5diketopiperazines.

Experimental Section
General.All reagents and solvents were purchased from commercial sources and used without purification.NMR spectra were recorded with 400 MHz spectrometers for 1 H NMR and 100 MHz for 13 C NMR in deuterated solvents with TMS as internal reference (chemical shifts δ in ppm, coupling constant J in Hz).Multiplicities are reported as follows: singlet (s), doublet (d), triplet (t), quartet (q), multiplet (m), and broad singlet (br, s).Melting points were determined in open capillary tubes on an electrically heated block and are uncorrected.
The reaction progress was routinely monitored by thin-layer chromatography (TLC) on precoated silica gel plates.Column chromatography was performed over silica gel (230−400 flash).All compounds were characterized by TLC, 1 H NMR and 13 C NMR and MS.
General Procedure for the Synthesis of IMCR Products 1a-f.A mixture of aromatic amine (1 mmol) and aromatic aldehyde (1 mmol) stirred at room temperature in methanol (3 mL) for 5 to 10 min afforded Schiff base which further undergoes the reaction with chloroacetic acid (1 mmol) and isocyanide (1 mmol) at room temperature to gives 1a-f in affordable yields.After stirring at room temperature for 24 h, the solid was filtered out to obtain crude products then wash with 1-2 mL chilled methanol for purification which is ready to use for the next step.
A post Ugi cyclisation of 1a-f were carried out by use of efficient reaction conditions by utilizing dry K 2 CO 3 (2 mmol), as a base and DMF (2 mL) solvent respectively under room temperature with portion wise addition of 1a-f for 10 min which further heated at 100 o C for 2−4 hrs.The reacNon is monitored by TLC, aOer compleNon of reaction the resulting mixture was cooled to room temperature and poured on crushed ice.Collect solid and the residue was purified by flash column chromatography on silica gel by using hexane: EtOAc (95:5) as a eluent to afford the corresponding products 2a-f in 71-80% yields.

Figure 4 .
Figure 4. Ligand used in the model substrate.

Table 2 .
Selection of base

Table 3 .
Screening of Solvent