Introduction

The 2,5-Diketopiperazines (2,5-DKPs), cyclodipeptides can be prepared by the reaction of two α-amino acids. They are found in nature, and are usually created from the degradation of polypeptides found in beverages and processed food. They are present in various bacteria, fungi, mammals and the plant kingdom. For example, 2,5-DKPs abound in the structure of numerous natural products such as okaramine N [1], dysamide B [2], FR106969 [3] and citreoindole [4] (Fig. 1). Due to the ability of 2,5-diketopiperazines to bind to a number of receptors, they can be considered as attractive scaffolds in drug discovery. In these small heterocyclic molecules, it is possible to have a number of stereocenters to create diverse structures.

Fig. 1
figure 1

Naturally occurring molecules containing the 2,5-DKP scaffold

Full size image

Several reviews on the synthesis of natural products containing 2,5-diketopiperazines had been published as early as 1975 and 1990 [5, 6]. The improvements in the synthesis of 2,5-diketopiperazines [7–9], properties and biological activities of them have been reviewed [10–12].

In recent years, diversity-oriented synthesis gained much attention in the pharmaceutical industry. In this area, multicomponent reactions (MCRs), especially the Ugi four-component condensation reaction (Ugi 4CC) is a convenient method to form a large diversity of molecules [13–15]. The Ugi reaction was first reported by Ivar Ugi [16] in which a ketone or aldehyde, an amine, an isocyanide and a carboxylic acid were reacted to provide a bis-amide [17].

Post-condensation modifications, including other multicomponent reactions (MCRs), can be performed to yield a variety of heterocyclic compounds. These compounds can serve as scaffolds for the synthesis of natural products, therapeutic agents, and combinatorial libraries.

Numerous procedures have been reported for post-condensational modification (PCM). This makes the Ugi condensation a popular alternative to traditional approaches for the synthesis of complex molecules. Many advantages such as high atom efficiency, convergence of reaction and the construction of high molecular complexity in a single step make the Ugi condensation a distinguished reaction.

In order to synthesize diverse molecules, starting materials with multifunctional groups such as fumaric acid derivatives have been applied as an appropriate acid source in the Ugi reaction [12]. Santra and Andreana [18] developed a sequential Ugi/Michael/aza-Michael cascade reaction for the synthesis of natural product-like fused azaspiro tricycles and azaspirotetracycles by using microwave irradiation in water without any additives. They used o-nitrobenzaldehydes or o-nitrobenyzlamines in the formation of Ugi-adducts and reported a one-pot, two-step reaction for the synthesis of regiochemically differentiated 1,2,4,5-tetrahydro-1,4-benzodiazepin-3-ones under microwave irradiation [19]. Synthesis of precursors containing thiophene via the Ugi reaction and the transformation of them into 3-oxoisoindolines in the presence of m-CPBA have also been developed [20]. The employing of the intramolecular Diels-alder reaction in post-Ugi modification led to the synthesis of highly diverse polycyclic compounds [21–30]. Also, recently, an efficient method was developed for the preparation of functionalized β-lactams and pyrrolidine-2,5-diones via sequential Ugi-4CR/cyclization reaction. Diversity-oriented synthesis, good to high yields, short reaction times and easy work-up are some advantages of this procedure [31].

Noticeably, the Ugi condensation provides a significant procedure for the synthesis of 2,5-diketopiperazines. Due to the importance of Ugi condensation for the preparation of diverse products, we wished to try the application of aroylacrylic acids as a significant acid in the Ugi reaction. Various β-aroylacrylic acids and their derivatives show biological activities [32, 33]. Significantly, aroylacrylic acids were applied in the formation of various heterocyclic products. A number of highly substituted 2,5-diketopiperazines were synthesized through a one-pot Ugi/Aza Michael reaction by using β-acyl substituted acrylic acids and p-toluene sulfonyl methyl isocyanide as a less hindered isocyanide to generate the corresponding Ugi-adducts, which cyclized to the 2,5-diketopiperazines in a single reaction-step without any additives [34]. The synthesis of different small molecules containing 2,5-diketopiperazines through the Ugi/Aza Michael reaction under microwave conditions was also reported [35].

In continuation of our experimental researches on the synthesis of heterocyclic compounds [36–41] via Ugi reactions [42–46], and in order to investigate computational approaches as argumentative and sound tools for explication and prediction of experimental data [47–51], in this work, we wish to report the synthesis of a series of new 2,5-diketopiperazines through the cyclization of Ugi-adducts obtained from the reaction of aroylacrylic acids, aldehydes, amines, and isocyanides under mild conditions in combination with theoretical interpretations. Density functional theory (DFT) [52] and the quantum theory of atoms in molecules (QTAIM) computations [53, 54] were used to present underlying theoretical reasons for the selective behavior of the intramolecular cyclization step. A reliable agreement between experimental and computational electronic interpretations was found. Moreover, polarized continuum model (PCM) [55] computations have been carried out to analyze the solvent effect on the efficiently and selectivity of the intramolecular cyclization reaction. A reliable agreement between experimental and computational interpretations was found.

Results and discussion

Initially, aroylacrylic acids 1 were prepared by the reaction of maleic anhydride and appropriate arenes (Scheme 1) [56]. This was followed by the synthesis of Ugi-adducts 2a-l in good yields (84–96 %) in a one-pot reaction of 1 mmol each of aroylacrylic acids, aldehydes, amines and cyclohexylisocyanide (Scheme 2, Table 1). The reaction was conducted in methanol at room temperature in the absence of any catalyst or additives and took place within 24 h.

Scheme 1
scheme 1

Synthesis of aroylacrylic acids 1

Full size image
Scheme 2
scheme 2

Synthesis of Ugi-adducts 2

Full size image
Table 1 Ugi-4CC of aroylacrylic acids, amines, aldehydes and isocyanides
Full size table

Variations in the molecules were achieved by using para substituted methyl and methoxy substituted aroylacrylic acids 1a, b, formaldehyde, p-chloro (electron withdrawing), p-methyl (electron donating) and p-dimethylaminobenzaldehdye (electron donating) and various amines such as benzylamine, n-butylamine and anilines, such as aniline, p-anisidine and p-toluidine.

In the final step of the reaction, the Ugi-adduct 2 was cyclized, leading to the formation of 3. In search of the best catalyst for this reaction (E)-N-benzyl-N-(2-(cyclohexylamino)-2-oxoethyl)-4-oxo-4-(p-tolyl) was considered, but-2-enamide 2a was chosen as the test substrate (Scheme 3). The effect of various catalysts (acids and bases) and solvents under different conditions was explored. The base catalysts such as Et3N and DABCO afforded 2,5-diketopiperazine 3a in 25 % yields. The acid catalysts, H2SO4 (a protic acid) and AlCl3 (a Lewis acid) resulted in the formation of 3a with slightly better yields of 50 and 40 %, respectively. Some other bases such as pyridine, sodium carbonate, sodium hydroxide, potassium hydroxide and KOtBu were also examined; however, they formed a mixture of products. The best results were obtained using K2CO3 in dimethylformamide (DMF) at room temperature, which produced the desired product in 92 % yield from the diamide 2a (Table 2).

Scheme 3
scheme 3

Synthesis of 2,5-diketopiperazines 3

Full size image
Table 2 Examination of different conditions in the cyclization of 2a to 3a a
Full size table

Under these optimum conditions, the obtained diamides 2a–f were efficiently converted to the desired piperazine-2,5-diones 3a–f with high yields (Fig. 2). More complex 2,5-diketopiperazines 3g–l were synthesized through the cyclization reaction of their corresponding diamides 2g–l in the presence of K2CO3 at room temperature over 10–12 h (Fig. 2). Although the 2,5-diketopiperazines 3g–l have two stereocentres, under these conditions, just one diastereomer selectively formed. All substrates led to the development of products 3 in good yields (73–97 %), and their structures were confirmed and characterised by IR, 1H-NMR, 13C-NMR spectroscopy and X-ray diffraction (XRD).

Fig. 2
figure 2

The structures of 2,5-diketopiperazines 3

Full size image

The single-crystals of compound 3f were obtained by slow evaporation of the solvent. The molecular structure was elucidated unambiguously based on single-crystal X-ray analysis (Fig. 3). The crystallographic and refinement data are summarized in Table 3. Selected bond lengths and angles are shown in Table 4. Diffraction measurements for the crystals in oil were recorded on a Bruker Apex CCD diffractometer fitted with Mo-Kα radiation. The structure was solved with direct procedures and refined with full-matrix least-squares methods (SHELXTL-97) with anisotropic thermal parameters for all non-hydrogen atoms. Intensity data were collected at a temperature of 173 K on a Bruker APEX-CCD (D8 three-circle goniometer) (Bruker AXS) diffractometer with graphite monochromated Mo-Kαradiation (λ = 0.71073 Å).

Fig. 3
figure 3

ORTEP structure of 3f

Full size image
Table 3 Crystallographical data and structure refinement of compound 3f
Full size table
Table 4 The electronic energy of cyclization reaction of diamide Ugi-adducts to their corresponding 3f-6 membered and 3f-7 membered compounds, calculated at M08-HX/6-311+G** level of theory in the solution phase
Full size table

Another significant aspect of the intramolecular cyclization step is that the cyclization of diamide Ugi-adducts resulted in selective 6-membered piperazine-2,5-diones with high yields, while mechanistically the corresponding 7-membered diazepane-2,5-diones can also be produced. In the following, this selective experimental behaviour will be discussed on the basis of quantum chemical computations.

Computational section

In the present section, we have focused on quantum chemistry assessment of the cyclization reaction of diamide Ugi-adducts to their corresponding diones based on DFT [49, 53] and QTAIM [50, 51] calculations. From the experimental viewpoint, the cyclization of diamides led to the formation of the corresponding 6-membered piperazine-2,5-diones with high affordance, while mechanistically, 7-membered diazepane-2,5-diones can also be produced. In this context, we investigated the theoretical basis to present the computational underlying interpretations for the formation of 6-membered diones over their 7-membered counterparts via a reliable cyclization reaction model. The two competing reactions are depicted in Scheme 4.

Scheme 4
scheme 4

The structures of 6-membered and 7-membered diones

Full size image

In the first step, we have examined the ability of DFT methods to predict our obtained crystallographical data of 3f compound, known as 4-cyclohexyl-3-(2-oxo-2-(p-tolyl)ethyl)-1-phenylpiperazine-2,5-dione (hereafter denoted as 3f-6 membered). In this respect, we have first determined the optimized structure of the 3f-6 membered compound using B3LYP [52, 57] and M08-HX [58] density functional methods. It should be mentioned that the popular B3LYP functional is classified as a hybrid functional and incorporates a portion of exact exchange from Hartree-Fock theory with exchange and correlation from ab initio and semi-empirical sources, and the M08-HX functional has been introduced as a modern hybrid meta-GGA (generalized gradient approximation) exchange-correlation functional combined with a Hartree-Fock exchange contribution. Moreover, harmonic frequency analysis was applied to confirm that the calculated optimized structures correspond to minima. A comparison was then made between our calculated bond lengths and angles of the 3f-6 membered compound, performed at B3LYP/6-31G* and M08-HX/6-31G* levels of theory with our obtained X-ray crystallographical data. All DFT computations were performed using the GAMESS suite of programs [59].

In Fig. 4, the calculated optimized geometry of the 3f-6 membered compound obtained at the M08-HX/6-31G* level is displayed. We have also reported some of the selected bond lengths and angles of the 3f-6 membered compound calculated at the B3LYP/6-31G* and M08-HX/6-31G* levels of theory, as well as X-ray ones in Table 4. The average absolute deviation (AAD) of X-ray experimental data of the 3f-6 membered compound with B3LYP/6-31G* and M08-HX/6-31G* calculated bond lengths are 0.007 and 0.015 %, respectively. Moreover, the AAD of the X-ray data of the 3f-6 membered compound with the calculated bond angles at B3LYP/6-31G* and M08-HX/6-31G* levels are 0.020 and 0.030 %, respectively. The reported results of Table 4 indicate that in overall, these computational levels have a reliable agreement with the X-ray structure of the 3f-6 membered compound, while there is a relative superiority in using the M08-HX functional method. Thus, the rest of the computational studies were devoted to the calculations at the M08-HX level of theory.

Fig. 4
figure 4

Atomic numbering and energy-minimized structure of the 3f-6 membered compound obtained at the M08-HX/6-31G* level of theory

Full size image

In the next step, in order to expound the preference in producing of piperazine-2,5-diones as 6-membered diones with high affordance in comparison with their corresponding diazepane-2,5-diones as 7-membered diones, we focused on topological analysis of electron density functions via the QTAIM approach [53, 54]. In this respect, the resulting M08-HX/6-311+G** wave function files for the optimized structures of 3f-6 membered compound and its corresponding 7-membered dione, known as 1-cyclohexyl-7-(4-methylbenzoyl)-4-phenyl-1,4-diazepane-2,5-dione (hereafter denoted as 3f-7 membered) were applied as input parameters in the AIM2000 program [60]. Topological analysis of electron density was then performed on bond and ring critical points (BCPs and RCPs, respectively) and their associated bond paths to interpret the preference in producing a 3f-6 membered compound with high yield in comparison with a 3f-7 membered compound.

In Table 5, we report the calculated values of electron density, ρ b , its Laplacian, ∇2 ρ b , electronic kinetic energy density, G b , electronic potential energy density, V b , total electronic energy density, H b and ratio of |V b |/G b of BCPs and RCPs that were formed via the intramolecular cyclization process in 3f-6 membered and 3f-7 membered compounds. In Fig. 5, we have presented the QTAIM molecular graphs of 3f-6 membered and 3f-7 membered compounds.

Table 5 The M08-HX/6-311+G** calculated values of C1–N1 and C7–N1 bond orders in 3f-6 membered and 3f-7 membered compounds, respectively, in the presence of solvent
Full size table
Fig. 5
figure 5

Complete molecular graphs (MGs) of 3f-6 membered and 3f-7 membered compounds obtained by QTAIM analysis of M08-HX/6-311+G**electron density. Bond critical points green circles; ring critical points red circles; bond paths gray lines. (Color figure online)

Full size image

It should be stated that the magnitude of ρ(r) and its Laplacian ∇2 ρ(r) at BCPs are important indicators for the nature and strength of chemical bonds [61, 62]. In order to assign the stabilization of accumulation of charge at a given BCP, densities of local electronic energy, H(r), its components (kinetic energy G(r) and potential energy V(r); as H(r) = G(r) + V(r)) and their ratio (|V b |/G b ) at BCPs are used [63, 64].

A comparative survey of the reported results clearly indicate the following facts: (1) the large positive values of electron density together with the negative values of ∇2 ρ b and H b and also |V b |/G b  > 2 values on C1–N1 and C7–N1 BCPs in 3f-6 membered and 3f-7 membered compounds, respectively, proves the covalent character of these newly formed bonds; (2) The calculated values of electron density properties and indicators on C1–N1 BCP in the 3f-6 membered compound (as a new formed bond via the intramolecular cyclization process), is larger and electron-richer than that of the 3f-7 membered compound, C7–N1 BCP (with 0.254 and 0.214 electron density values for C1–N1 and C7–N1 BCPs in 3f-6 membered and 3f-7 membered compounds, respectively). On the other hand, at (C1–C2–N2–C3–C4–N1) RCP (that is formed through the intramolecular cyclization) in the 3f-6 membered compound, the computed value of ρ(r) is larger than that of the 3f-7 membered compound, (C7–C1–C2–N2–C3–C4–N1) RCP (with 0.021 and 0.013 electron density values for the aforementioned RCPs in 3f-6 membered and 3f-7 membered compounds, respectively).

It is worthwhile to note that all calculated QTAIM results confirmed the more electronic tendency to produce the 3f-6 membered compound through an intramolecular cyclization procedure and, thus, these quantum chemical issues can be mainly considered as a theoretical basis for the experimental preference in producing the 3f-6 membered compound with high yields via the cyclization reaction.

From another viewpoint, in the next step we focused on the comparative evaluation of the effect of various chemical environments on the energetic aspects in the cyclization reaction of diamide Ugi-adducts to their corresponding diones, via PCM computations [55]. In this respect, we have determined the electronic energy of cyclization reaction at the M08-HX/6-311+G** level of theory in the presence of dimethylformamide (DMF), methanol, acetonitrile and water as solvents.

In Table 6, we have reported comparatively the M08-HX/6-311+G** calculated electronic energy changes of the cyclization reaction. The reported results of Table 6 reveal the following two facts: (1) the energetic preference in the formation of the 3f-6 membered compound through the cyclization reaction, in all solution phases (with negative values of electronic energy changes for producing 3f-6 membered compound in comparison with positive values for producing 3f-7 membered compound, and (2) the cyclization process is more favorable energetically in DMF solution than methanol, acetonitrile and water, respectively, which confirms the experimental preference trend in using DMF, methanol, acetonitrile and water as solvent.

Table 6 The selected bond lengths and angles of the 3f-6 membered compound, calculated at B3LYP/6-31G* and M08-HX/6-31G* levels of theory together with X-ray values
Full size table

Moreover, in order to assess the solvent effect more accurately on the cyclization reaction mode, we have concentrated on evaluation of some key bond orders in 3f-6 membered and 3f-7 membered compounds in the solution phases. In this respect, we have calculated C1–N1 and C7–N1 bond orders, that were newly formed via the intramolecular cyclization process in 3f-6 membered and 3f-7 membered compounds, respectively, at the M08-HX/6-311+G** level of theory in the presence of DMF, methanol, acetonitrile and water as solvents (presented in Table 7). The reported results of Table 7 demonstrate that both C1–N1 and C7–N1 bond orders in 3f-6 membered and 3f-7 membered compounds have larger calculated values in DMF solution in comparison with those calculated in methanol, acetonitrile and water, which is in reliable agreement with the obtained experimental results in more efficiency for using DMF as solvent. Furthermore, comparative analysis of C1–N1 with C7–N1 bond orders calculated values in 3f-6 membered and 3f-7 membered compounds, respectively, indicates the more electronic tendency to form the 3f-6 membered compound via an intramolecular cyclization reaction in comparison with the production of the 3f-7 membered compound.

Table 7 Mathematical properties of selected critical points (CPs) in 3f-6 membered and 3f-7 membered compounds
Full size table

Biological activity

Antibacterial and antifungal activities

In the following, the synthesized compounds were screened for their antibacterial and antifungal activity against two Gram +ve [Staphylococcus aureus (ATCC 25923) and methicillin resistant S. aureus (MRSA) (ATCC BAA-1683)] and three Gram −ve strains [E. coli (ATCC 25922), Klebsiella pneumonia (ATCC 31488) and also Pseudomonas aeruginosa (ATCC 27853)] as well as one fungal species [Candida albicans (ATCC 10231)] using the disc diffusion assay. These compounds showing a zone of inhibition >7 mm were chosen to further determine their MBC values. The results are summarized in Table 8. Ciprofloxacin and ampicillin were used as standards for the antibacterial assay, and also tioconazole was used for the antifungal assay.

Table 8 Antibacterial and antifungal activity of the synthesized compounds
Full size table

Compounds, 2b and 2f showed MBCs of 39.06 µg mL−1 (for 2b) and 19.53 µg mL−1 (for both 2f) against S. aureus. Compound 2b had a methoxy group on the aroylacrylic-derived portion and a benzyl group on the amine-derived portion, while compound 2f had a p-methylphenyl moiety instead of the benzyl moiety on the amine-derived portion. Compound 2f contained a p-methyl group on the aroylacrylic-derived portion and an unsubstituted phenyl group on the amine-derived portion. A generalization cannot be made regarding the structure of the molecules and their antibacterial activity, and; therefore, these specific groups on 2b and 2f must be regarded as important with regard to their antibacterial activity.

Compound 3h (the cyclized Ugi product) with a p-methyl aroylacrylic moiety and an anisidine-derived amine moiety were active against MRSA in at least one order of magnitude better than ampicillin (MBCs of 19.53 µg mL−1 for 3h and 625 µg mL−1 for ampicillin).

Compound 3c was the only compound active against any of the Gram −ve bacterial species, being active against E. coli with an MBC of 78.125 µg mL−1. Compound 3c had a p-methyl aroylacrylic moiety with an n-butylamine-derived amine portion. Likewise, the cyclized Ugi compound 3b from 2b mentioned above was the only compound active against C. albicans with a MBC of 117.18 µg mL−1, three times more than the standard, tioconazole. Although, some of the synthesized compounds did show antibacterial and antifungal activity, all were at least 1–2 orders of magnitude greater than that of ciprofloxacin, which was active against all the bacterial and fungal species at MBCs of 0.61 to 2.44 µg mL−1.

Experimental section

Experimental procedures

Chemicals were purchased from Fluka, Merck, and Aldrich chemical companies. Melting points are uncorrected. IR spectra were recorded on a Shimadzu infrared spectrophotometer IR-435. Nuclear magnetic resonance NMR spectra were recorded on a Bruker Avance 400 MHz Spectrometer in CDCl3 and referenced against tetramethylsilane (TMS). A Leco CHNS, model 932, was used for elemental analysis.

Synthesis of Ugi-adducts 2: general procedure

Aroylacrylic acid (0.5 mmol) and isocyanide (0.5 mmol) were added to a stirred solution of aldehyde (0.5 mmol) and amine (0.5 mmol) in MeOH (3 mL) at room temperature. This reaction was monitored by TLC after 24 h. The obtained solid was filtered and washed with Et2O.

Cyclization of Ugi-adducts 3: general procedure

K2CO3 (1 mmol) was added into a DMF solution (2 mL) of Ugi-adduct (0.5 mmol) at room temperature. The reaction was monitored by TLC using n-hexanes and ethyl acetate as eluent. Upon completion of the reaction, water was added to the reaction mixture. The precipitated solid was filtered off and the collected solid recrystallized from EtOH.

Biological tests

The compounds were evaluated for their in vitro antibactericidal activity using the disc diffusion method. Two strains of Staphylococcus aureus (Gram +ve bacteria), S. aureus ATCC 25923 and S. aureus Rosenbach ATCC BAA-1683 (methicillin resistant S. aureus) (MRSA) and three Gram −ve bacteria, Escherichia coli ATCC 25922, K. pneumonia ATCC 31488 and P. aeruginosa ATCC 27853 were used for this study. The compounds were also evaluated for antifungal activity against C. albicans ATCC 10231.

The bacterial cultures were grown overnight at 37 °C in Mueller-Hinton nutrient broth and thereafter adjusted to a 0.5 McFarland standard using distilled water and lawn inoculated onto Mueller-Hinton agar (MHA) plates. A volume of 10 μL of each sample (19–24 mM, 1 mL DMSO) was inoculated onto antibiotic assay discs (6 mm diameter) and placed on the MHA plates, which were incubated overnight at 37 °C and, thereafter, the zones of inhibition were measured. Only some compounds showing a zone of inhibition >7 mm were selected for the broth dilution method to determine their MBCs.

For the broth dilution method, the microbial cultures were prepared as described previously for the disc diffusion method. The compounds, which were dissolved in dimethyl sulfoxide, were serially diluted with Mueller-Hinton Broth (MHB) (UKZN Biolab, South Africa), inoculated with bacterial cultures, and then incubated at 37 °C for 18 h. A volume of 10 µL of each dilution was spotted on MHA plates and incubated at 37 °C for 18 h to determine the MBC (µg mL−1). All experiments were performed in duplicate.

Conclusion

In conclusion, a two-step synthetic method for the preparation of new 2,5-diketopiperazine derivatives was demonstrated through a convenient Ugi four-component reaction of aroylacrylic acids, diverse aromatic and aliphatic aldehydes, amines and cyclohexyl isocyanide, followed by a Michael addition under K2CO3 in DMF at room temperature. All products were produced in good yields, which make it a practical protocol for the library-based synthesis of 2,5-diketopiperazines. Moreover, in order to present the theoretical interpretations for the selective behaviour of the intramolecular cyclization reaction and also the solvent effect, we have assessed these experimental features via DFT, QTAIM, and PCM computational methods in the gas and solution phases, which reliably confirmed the experimental observations. Newly products were evaluated for their antibacterial and antifungal activities.

Experimental data

  1. 1.

    (E)-N-Benzyl-N-(2-(cyclohexylamino)-2-oxoethyl)-4-oxo-4-(p-tolyl) but-2-enamide (2a); M.p.: 159–163 °C; [requires: C, 74.61; H, 7.22; N, 6.69.; O, 11.47; C26H30N2O3 (MW = 418.53), Found, C, 74.55; H, 7.25; N, 6.81 %]; FT-IR (KBr): νmax = 3292, 3086, 2933, 2854, 1658, 1637, 1553, 1495 cm−1; 1H NMR (400 MHz, CDCl3) δ = 0.92–1.89 (m, 10H), 2.43 (s, 3H), 3.65–3.79 (m, 1H), 4.03 (s, 2H), 4.79 (s, 2H), 6.84 (d, J = 7.5 Hz, 1H), 7.21 (d, J = 7.0 Hz, 1H), 7.28–7.38 (m, 5H), 7.49 (d, J = 14.9 Hz, 1H), 7.89–7.94 (m, 3H), 8.03 (d, J = 14.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.8, 24.7, 25.3, 25.5, 32.9, 48.5, 51.1, 52.7, 127.0, 128.2, 129.0, 129.6, 129.8, 134.3, 135.4, 135.8, 144.9, 164.6, 166.5, 195.6 ppm.

  2. 2.

    2.(E)-N-Benzyl-N-(2-(cyclohexylamino)-2-oxoethyl)-4-(4-methoxy-phenyl)-4-oxobut-2-enamide (2b); M.p.: 125–130 °C; [requires: C, 71.87; H, 6.96; N, 6.45; C26H30N2O4 (MW = 434.53), found: C, 72.11; H, 7.19; N, 6.56 %]; FT-IR (KBr): νmax = 3295, 3076, 2933, 2852, 1645, 1596, 1553, 1512, 1436 cm−1; 1H-NMR (400 MHz, CDCl3): δ = 0.92–1.99 (m, 10H), 3.67–3.77 (m, 1H), 3.88 (s, 3H), 4.03 (s, 2H), 4.79 (s, 2H), 6.40 (d, J = 7.5, 1H), 6.95 (d, J = 8.0 Hz, 2H), 7.20 (d, J = 8.0 Hz, 2H), 7.29–7.37 (m, 2H), 7.49 (d, J = 14.9 Hz, 1H), 7.96–8.04 (m, 3H), 8.04 (d, J = 14.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 24.8, 25.4, 25.6, 25.9, 32.9, 48.4, 51.0, 51.3, 55.7, 114.2, 127.2, 128.3, 128.8, 129.2, 129.9, 130.9, 131.4, 131.5, 135.9, 166.3, 164.4, 167.4, 187.6 ppm.

  3. 3.

    (E)-N-Butyl-N-(2-(cyclohexylamino)-2-oxoethyl)-4-oxo-4-(p-tolyl) but-2-enamide (2c); M.p.: 101–104 °C; [requires: C, 71.84; H, 8.39; N, 7.29; C23H32N2O3 (MW = 384.51), found: C, 72.15; H, 8.62; N, 7.41  %]; FT-IR (KBr): νmax = 3290, 3083, 3024, 2963, 2854, 1650, 1554, 1432 cm−1: 1H NMR (400 MHz, CDCl3): δ = 0.86–1.88 (m, 17H), 2.43 (s, 3H), 3.50–3.54 (m, 2H), 3.73–3.79 (m, 1H), 4.05 (s, 2H), 6.40 (d, J = 7.3 Hz, 1H), 7.31 (d, J = 8.1 Hz, 2H), 7.45 (d, J = 14.9 Hz, 1H), 7.95 (d, J = 8.1 Hz, 2H), 8.01 (d, J = 14.9 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 13.7, 19.9, 21.8, 24.66, 24.74, 25.5, 31.3, 32.8, 48.2, 49.9, 52.2, 129.0, 129.6, 131.1, 135.3, 144.9, 165.9, 167.9, 188.8 ppm.

  4. 4.

    (E)-N-(2-(Cyclohexylamino)-2-oxoethyl)-N-(4-methoxyphenyl)-4-oxo-4-(p-tolyl)but-2-enamide (2d); M.p.: 183–186 °C; [requires: C, 71.87; H, 6.96; N, 6.45; C26H30N2O4 (MW = 434.53), found: C, 72.12; H, 7.17; N, 6.59 %]; FT-IR (KBr): νmax = 3298, 3075, 3024, 2926, 2853, 1648, 1556, 1511, 1414 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.13–1.92 (m, 10H), 2.40 (s, 3H), 3.72–3.81 (m, 1H), 3.80 (m, 3H), 4.34 (s, 2H), 6.21 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 15.1 Hz, 1H), 6.93(d, J = 8.0 Hz, 2H), 7.17 (d, J = 8.0 Hz, 2H), 7.26 (d, J = 8.0 Hz, 2H), 7.87 (d, J = 8.0 Hz, 2H), 7.96 (d, J = 15.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.9, 24.9, 25.6, 33.1, 48.5, 55.0, 55.7, 115.3, 128.6, 129.6, 132.2, 134.5, 134.8, 144.9, 159.8, 165.8, 167.4, 189.1 ppm.

  5. 5.

    (E)-N-(2-(Cyclohexylamino)-2-oxoethyl)-4-oxo-N,4-di-p-tolylbut-2-enamide (2e); M.p.: 226–229 °C; [requires: C, 74.61; H, 7.22; N, 6.69; C26H30N2O3 (MW = 418.53), found: C, 74.52; H, 7.43; N, 7.05 %]; FT-IR (KBr): νmax = 3300, 3078, 3034, 2926, 2851, 1652, 1605, 1553, 1510, 1443 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.13–1.93 (m, 10H), 2.37 (s, 3H), 2.41 (s, 3H), 3.74–3.80 (m, 1H), 4.36 (s, 2H), 6.21 (d, J = 7.5 Hz, 1H), 6.92 (d, J = 15.0 Hz, 1H), 7.12 (d, J = 8.2 Hz, 2H), 7.20 (d, J = 8.2 Hz, 2H), 7.27 (d, J = 7.5 Hz, 2H), 7.87 (d, J = 7.5 Hz, 2H), 7.97 (d, J = 15.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.2, 21.9, 24.9, 25.4, 33.1, 48.5, 54.9, 127.4, 129.6, 130.9, 132.2, 134.5, 134.8, 138.9, 139.0, 144.9, 165.7, 167.4, 189.1 ppm.

  6. 6.

    (E)-N-(2-(Cyclohexylamino)-2-oxoethyl)-4-oxo-N-phenyl-4-(p-tolyl) but-2-enamide (2f); M.p.: 185–187 °C; [requires : C, 74.23; H, 6.98; N, 6.93; C25H28N2O3 (MW = 404.50), found: C, 74.49; H, 7.19; N, 7.25 %]; FT-IR (KBr): νmax = 3292, 3085, 2930, 2854, 1647, 1600, 1552, 1494, 1494, 1450 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.14–2.1 (m, 10H), 2.42 (s, 3H), 3.77–3.81 (m, 1H), 4.38 (s, 2H), 6.18 (d, J = 7.4 Hz, 1H), 6.91 (d, J = 15.0 Hz, 1H), 7.26–7.45 (m, 7H), 7.87 (d, J = 8.3 Hz, 2H), 7.99 (d, J = 15.0 Hz, 1H) ppm; 13CNMR (100 MHz, CDCl3): δ = 21.9, 25.1, 25.6, 33.1, 48.5, 55.7, 127.7, 128.9, 129.1, 130.2, 132.1, 135.1, 141.6, 144.8, 165.6, 167.3, 189.1 ppm.

  7. 7.

    (E)-N-(1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-4-oxo-N,4-di-p-tolylbut-2-enamide (2g); M.p.: 209–212 °C; [requires: C, 72.65; H, 6.29; N, 5.29; C32H33ClN2O3 (MW = 529.07), found: C, 72.19; H, 6.41; N, 5.48 %]; FT-IR (KBr): νmax = 3266, 3078, 3032, 2931, 2854, 1648, 1493, 1447 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.05–1.98 (m, 10H), 2.30 (s, 3H), 2.40 (s, 3H), 3.79–3.88 (m, 1H), 5.73 (d, J = 8.1 Hz, 1H), 6.02 (s, 1H), 6.76 (d, J = 15.0 Hz, 1H), 7.02 (d, J = 8.2 Hz, 2H), 7.13 (d, J = 8.3 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.22 (d, J = 8.4, 2H), 7.34 (d, J = 8.3 Hz, 2H), 7.84 (d, J = 8.2 Hz, 2H), 7.94 (d, J = 15.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.3, 21.9, 24.9, 25.6, 33.0, 48.9, 65.4, 73.6, 128.8, 129.1, 129.6, 130.1, 132.9, 133.0, 134.7, 136.1, 138.9, 144.8, 165.9, 168.1, 189.2 ppm.

  8. 8.

    (E)-N-(2-(Cyclohexylamino)-1-(4-(dimethylamino) phenyl)-2-oxoethyl)-4-oxo-N,4-di-p-tolylbut-2-enamide (2 h); M.p.: 131–135 °C; [requires: C, 75.95; H, 7.31; N, 7.81; C34H39N3O3 (MW = 537.69), found: C, 76.15; H, 7.45; N, 8.02 %]; FT-IR (KBr): νmax = 3284, 3082, 3033, 2927, 2850, 1649, 1447 cm−1; 1HNMR (400 MHz, CDCl3): δ = 1.01–1.95 (m, 10H), 2.29 (s, 3H), 2.39 (s, 3H), 2.92 (s, 6H), 3.81–3.84 (m, 1H), 5.59 (d, J = 7. 0 Hz, 1H), 5.98 (s, 1H), 6.57 (d, J = 8.0 Hz, 2H), 6.76 (d, J = 15.0 Hz, 1H), 6.99–7.02 (m, 6H), 7.23 (d, J = 8.0, 2H), 7.84 (d, J = 8 Hz, 2H), 7.92 (d, J = 15.0 Hz, 1H) ppm; 13CNMR (100 MHz, CDCl3): δ = 21.3, 21.9, 24.9, 25.7, 33.1, 48.9, 65.8, 129.8, 130.2, 131.5, 133.6, 134.1, 134.6, 136.7, 138.3, 144.6, 165.4, 168.8, 189.5 ppm.

  9. 9.

    (E)-N-(1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-4-(4-methoxyphenyl)-4-oxo-N-(p-tolyl)but-2-enamide (2i); M.p.: 207–210 °C; [requires: C, 70.51; H, 6.10; N, 5.14; C32H33ClN2O4 (MW = 545.07), found: C, 70.63; H, 6.23; N, 5.26  %]; FT-IR (KBr): νmax = 3271, 3073, 3033, 2929, 2852, 1650, 1493 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.01–1.98 (m, 10H), 2.29 (s, 3H), 3.7–3.8 (m, 1H), 3.86 (s, 3H), 5.78 (d, J = 8.0 Hz, 1H), 6.02 (s, 1H), 6.74 (d, J = 15.0 Hz, 1H), 6.91 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 7.13 (d, J = 8.5 Hz, 3H), 7.19 (d, J = 8.5 Hz, 3H), 7.92 (d, J = 8.0 Hz, 2H), 7.95 (d, J = 15.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.3, 24.85, 24.93, 25.6, 33.0, 48.9, 55.7, 65.3, 114.1, 128.8, 130.1, 131.4, 131.8, 132.6, 133.0, 134.7, 134.8, 136.1, 138.9, 164.2, 165.8, 167.9, 187.9 ppm.

  10. 10.

    (E)-N-(2-(Cyclohexylamino)-2-oxo-1-(p-tolyl)ethyl)-4-oxo-N,4-di-p-tolylbut-2-enamide (2j); M.p.: 188–190 °C; [requires: C, 77.92; H, 7.13; N, 5.51; C33H36N2O3 (MW = 508.65), found: C, 78.12; H, 7.19; N, 5.63 %]; FT-IR (KBr): νmax = 3273, 3063, 2926, 2852, 1646, 1555, 1511, 1450 cm−1; 1H NMR (400 MHz, CDCl3): δ = 0.99–1.96 (m, 10H), 2.29 (s, 6H), 2.40 (s, 3H), 3.83–3.86 (m, 1H), 5.61 (d, J = 7.8 Hz, 1H), 5.99 (s, 1H), 6.77 (d, J = 15.1 Hz, 1H), 6.99–7.71 (m, 8H), 7.23 (d, J = 8.0 Hz, 2H), 7.84 (d, J = 8.0 Hz, 2H), 7.93 (d, J = 15.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.2, 21.9, 24.9, 25.6, 33.0, 48.9, 66.2, 129.1, 129.4, 129.5, 129.9, 130.1, 130.5, 133.4, 136.7, 138.5, 144.7, 165.5, 168.4, 189.4 ppm.

  11. 11.

    (E)-N-(1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-4-oxo-N-phenyl-4-(p-tolyl)but-2-enamide (2k); M.p.: 168–172 °C; [requires: C, 72.29; H, 6.07; N, 5.44; C31H31ClN2O3 (MW = 515.04), found: C, 72.51; H, 6.23; N, 5.71 %]; FT-IR (KBr): νmax = 3271, 3069, 3034, 2932, 2852, 1650, 1492, 1650, 1492, 1450 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.04–2.02 (m, 10H), 2.43 (s, 3H), 3.83–3.92 (m, 1H), 5.79 (d, J = 8.0 Hz, 1H), 6.07 (s, 1H), 6.77 (d, J = 15.0 Hz, 1H), 7.15 (d, J = 8.0 Hz, 3H), 7.21 (d, J = 8.0 Hz, 3H), 7.27–7.30 (m, 5H), 7.86 (d, J = 8.1 Hz, 2H), 7.97 (d, J = 15.0 Hz, 1H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.9, 24.9, 25.6, 33.0, 49.0, 65.4, 128.3, 128.9, 129.1, 129.4, 129.6, 130.4, 132.9, 134.5, 134.8, 138.8, 144.8, 165.5, 167.9, 189.2 ppm.

  12. 12.

    (E)-N-Butyl-N-(1-(4-chlorophenyl)-2-(cyclohexylamino)-2-oxo-ethyl)-4-oxo-4-(p-tolyl)but-2-enamide (2l); M.p.: 156–159 °C; [requires: C, 70.36; H, 7.13; N, 5.66; C29H35ClN2O3 (MW = 494.05), found: C, 70.52; H, 7.21; N, 5.74  %]; FT-IR (KBr): νmax = 3279, 3086, 3035, 2930, 2851, 1648, 1489, 1449, 1416 cm−1; 1HNMR (400 MHz, CDCl3): δ = 0.76–1.93 (m, 17H), 2.43(s, 3H), 3.41–3.47 (m, 2H), 3.80–3.82 (m, 1H), 5.89 (s, 1H), 5.95 (d, J = 7.6 Hz, 1H), 7.30 (d, J = 8.0 Hz, 2H), 7.33–7.39 (m, 4H), 7.42 (d, J = 14.8 Hz, 1H), 7.94 (d, J = 8.0 Hz, 2H), 8.02 (d, J = 14.8, 1H) ppm; 13CNMR (100 MHz, CDCl3): δ = 13.6, 20.1, 21.9, 24.8, 25.6, 32.8, 32.9, 47.1, 48.8, 62.5, 128.7, 129.2, 129.7, 130.8, 132.1, 133.8, 135.5, 145.0, 166.1, 168.1, 189.1 ppm.

  13. 13.

    4-Benzyl-1-cyclohexyl-3-(2-oxo-2-(p-tolyl) ethyl)piperazine-2,5-dione (3a); M.p.: 142–145 °C; [requires: C, 74.61; H, 7.22; N, 6.69; O, 11.47, C26H30N2O3 (MW = 418.53), found: C, 74.52; H, 7.43; N, 6.82  %]; FT-IR (KBr): νmax = 3067, 3032, 2961, 2854, 1647, 1474 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.06–1.89 (m, 10H), 2.43 (s, 3H), 3.60–3.64 (m, 2H), 3.74–3.83 (m, 1H), 4.27 (d, J = 17.0 Hz, 1H), 4.46 (s, 2H), 4.49–4.52 (t, J = 4.2 Hz, 1H), 4.57 (d, J = 17.0 Hz, 1H), 7.22–7.32 (m, 7H), 7.80 (d, J = 8.2 Hz, 2H) ppm; 13CNMR (100 MHz, CDCl3): δ = 21.9, 25.5, 26.1, 26.3, 29.7, 30.8, 41.1, 49.6, 50.3, 55.1, 56.9, 128.1, 128.3, 128.6, 129.7, 129.9, 134.0, 135.4, 144.8, 164.7, 166.8, 195.6 ppm.

  14. 14.

    1-Benzyl-4-cyclohexyl-3-(2-(4-methoxyphenyl)-2-oxoethyl)-piperazine-2,5-dione (3b); M.p.: 143–146 °C; [requires: C, 71.87; H, 6.96; N, 6.45; C26H30N2O4 (MW = 434.53), found: C, 72.15; H, 6.71; N, 6.62  %]; FT-IR (KBr): νmax = 3075, 3036, 3005, 2931, 2856, 1667, 1465, cm−1; 1H-NMR (400 MHz, CDCl3): δ = 1.06–1.84 (m, 10H), 3.54–3.57 (m, 2H), 3.69–3.74 (m, 2H), 3.74 (m, 2H), 3.84 (s, 3H), 4.22 (d, J = 17.0 Hz, 1H), 4.46 (t, J = 3.9 Hz, 1H), 4.52 (d, J = 17.0 Hz, 1H), 6.9 (d, J = 8.8 Hz, 2H), 7.2 (m, 2H), 7.27 (d, J = 7.4 Hz, 2H), 7.86 (d, J = 8.8 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3) δ = 25.35, 25.98, 29.6, 30.6, 31.4, 36.5, 40.7, 49.4, 50.2, 55.0, 55.5, 56.9, 113.98, 127.9, 128.4, 128.8, 129.4, 130.4, 135.3, 162.6, 164.0, 164.5, 166.8, 194.4 ppm.

  15. 15.

    1-Butyl-4-cyclohexyl-3-(2-oxo-2-(p-tolyl) ethyl) piperazine-2,5-dione (3c); M.p.: 111–115 °C; [requires: C, 71.84; H, 8.39; N, 7.29; C23H32N2O3 (MW = 384.51), found: C, 72.11; H, 8.48; N, 7.52  %]; FT-IR (KBr): νmax = 3028, 2930, 2856, 1663, 1452 cm−1; 1H NMR (400 MHz, CDCl3): δ = 0.88–1.82 (m, 17H), 2.40 (s, 3H), 3.21–3.27 (m, 2H), 3.42–3.46 (m, 2H), 3.74–3.79 (m, 1H), 3.83 (d, J = 16.8 Hz, 1H), 4.38–4.39 (t, J = 4.8 Hz, 1H), 4.43 (d, J = 16.8 Hz, 1H), 7.25 (d, J = 7.9 Hz, 2H), 7.79 (d, J = 7.9 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 13.9, 20.1, 21.8, 25.5, 26.1, 28.5, 29.7, 30.7, 41.0, 46.1, 50.9, 55.2, 57.1, 128.2, 129.6, 134.0, 144.7, 164.8, 166.4, 195.7 ppm.

  16. 16.

    1-Cyclohexyl-4-(4-methoxyphenyl)-3-(2-oxo-2-(p-tolyl)ethyl) piperazine-2,5-dione (3d); M.p.: 159–162 °C; [requires: C, 71.87; H, 6.96; N, 6.45; C26H30N2O4 (MW = 434.53), found: C, 72.01; H, 7.15; N, 6.55 %]; FT-IR (KBr): νmax = 3062, 3012, 2934, 2853, 1603, 1449 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.13–1.91 (m, 10H), 2.39 (s, 3H), 3.69–3.72 (m, 1H), 3.75 (s, 2H), 3.80 (s, 3H), 4.08 (d, J = 16.7, 1H), 4.49 (t, J = 3.9 Hz, 1H), 4.81 (d, J = 16.7 Hz, 1H), 6.89 (d, J = 8.0 Hz, 2H), 7.15 (d, J = 8.4 Hz, 2H), 7.25 (d, J = 8.0 Hz, 2H), 7.86 (d, J = 8.4 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.9, 24.9, 25.6, 26.2, 29.8, 33.1, 41.3, 48.5, 54.3, 55.1, 55.6, 57.3, 115.3, 126.9, 128.3, 129.1, 133.2, 134.8, 144.9, 159.7, 164.7, 165.9, 167.4, 189.1, 195.9 ppm.

  17. 17.

    4-Cyclohexyl-3-(2-oxo-2-(p-tolyl)ethyl)-1-(p-tolyl) piperazine-2,5-dione (3e); M.p.: 181–185 °C; [requires: C, 74.61; H, 7.22; N, 6.69; C26H30N2O3 (MW = 418.53), found: C, 74.82; H, 7.41; N, 6.85 %]; FT-IR (KBr): νmax = 3030, 2930, 285, 1665, 1448 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.089–1.92 (m, 10H), 2.34 (s, 3H), 2.42 (s, 3H), 3.69–3.72 (m, 2H), 3.83–3.84 (m, 1H), 4.11 (d, J = 16.6 Hz, 1H), 4.53 (t, J = 4.0 Hz, 1H), 4.85(d, J = 16.6 Hz, 1H), 7.15 (d, J = 8.4 Hz, 2H), 7.19 (d, J = 8.4 Hz, 2H), 7.27 (d, J = 8.4 Hz, 2H), 7.83 (d, J = 8.4 Hz, 2H) ppm; 13CNMR (100 MHz, CDCl3): δ = 21.2, 21.8, 25.5, 26.2, 29.8, 30.9, 41.3, 53.9, 55.63, 57.2, 125.4, 128.3, 130.0, 133.9, 137.7, 144.8, 164.7, 166.9, 195.9 ppm.

  18. 18.

    4-Cyclohexyl-3-(2-oxo-2-(p-tolyl)ethyl)-1-phenyl piperazine-2,5-dione (3f); M.p.: 167–170 °C; [requires: C, 74.23; H, 6.98; N, 6.93; C25H28N2O3 (MW = 404.50), found: C, 74.65; H, 7.23; N, 7.18 %]; FT-IR (KBr): νmax = 3032, 2933, 2856, 1665, 1493 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.12–1.92 (m, 10H), 2.41 (s, 3H), 3.65–3.77 (m, 2H), 3.83–3.86 (m, 1H), 4.14 (d, J = 16.6 Hz, 1H), 4.54 (t, J = 3.8 Hz, 1H), 4.89 (d, J = 16.6 Hz, 1H), 7.26 (s, 1H), 7.29 (d, J = 7.8, 4H), 7.40 (t, J = 7.8, 2H), 7.83 (d, J = 8.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.8, 25.6, 26.2, 29.4, 30.8, 41.3, 53.9, 55.3, 57.3, 125.6, 127.6, 128.3, 129.5, 129.7, 133.9, 140.3, 144.6, 164.6, 166.9, 195.9 ppm.

  19. 19.

    3-(4-Chlorophenyl)-1-cyclohexyl-6-(2-oxo-2-(p-tolyl)ethyl)-4-(p-tolyl)piperazine-2,5-dione (3g); M.p.: 232–235 °C; [requires: C, 72.65; H, 6.29; N, 5.29; C32H33ClN2O3 (MW = 529.07), found: C, 72.75; H, 6.48; N, 5.45  %]; FT-IR (KBr): νmax = 3033, 2927, 2860, 1677, 1605, 1513, 1485, 1430 cm−1; 1HNMR (400 MHz, CDCl3): δ = 1.07–1.80 (m, 10H), 2.24 (s, 3H), 2.43 (s, 3H), 3.47–3.53 (m, 1H), 3.78–3.90 (m, 2H), 4.60 (t, J = 3.7 Hz, 1H), 5.72 (s, 1H), 6.95 (d, J = 8.2 Hz, 2H), 7.03 (d, J = 8.2 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.23 (d, J = 8.5 Hz, 2H), 7.28 (d, J = 8.0 Hz, 2H), 7.85 (d, J = 8.0, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.2, 21.9, 25.5, 26.3, 30.2, 40.9, 56.2, 59.1, 67.3, 127.2, 128.2, 128.9, 129.65, 129.90, 129.92, 134.0, 136.9, 137.6, 144.8, 166.1, 167.5, 196.4 ppm.

  20. 20.

    1-Cyclohexyl-3-(4-(dimethylamino)phenyl)-6-(2-oxo-2-(p-tolyl) ethyl)-4-(p-tolyl) piperazine-2,5-dione (3h); M.p.: 153–159 °C; [requires: C, 75.95; H, 7.31; N, 7.81; C34H39N3O3 (MW = 537.69), found: C, 76.22; H, 7.51; N, 8.02  %]; FT-IR (KBr): νmax = 3029, 2926, 2860, 2799, 1675, 1477 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.06–2.20 (m, 10H), 2.23 (s, 3H), 2.42 (s, 3H), 2.91 (s, 6H), 3.42–3.52 (m, 1H), 3.82–3.87 (m, 2H), 4.63 (t, J = 3.7 Hz, 1H), 5.54 (s, 1H), 6.96 (d, J = 8.2 Hz, 2H), 7.02 (d, J = 8.1 Hz, 2H), 7.11 (d, J = 8.2 Hz, 2H), 7.26–7.29 (m, 4H), 7.86 (d, J = 8.1 Hz, 2H) ppm; 13CNMR (100 MHz, CDCl3): δ = 21.2, 21.8, 25.6, 26.4, 30.1, 40.9, 56.2, 59.1, 67.5, 127.3, 128.2, 129.1, 129.6, 129.8, 134.2, 137.2, 144.6, 167.3, 196.3 ppm.

  21. 21.

    3-(4-Chlorophenyl)-1-cyclohexyl-6-(2-(4-methoxyphenyl)-2-oxoethyl)-4-(p-tolyl) piperazine-2,5-dione (3i); M.p.: 241–245 °C; [requires: C, 70.51; H, 6.10; N, 5.14; C32H33ClN2O4 (MW = 545.07), found: C, 70.21; H, 6.33; N, 5.24 %]; FT-IR (KBr): νmax = 3010, 2928, 2587, 1675, 1489, 1434 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.08–1.80 (m, 10H), 2.23 (s, 3H), 3.46–3.52 (m, 2H), 3.79–3.82 (m, 1H), 3.88 (s, 3H), 4.59 (t, J = 3.7 Hz, 1H), 5.71 (s, 1H), 6.94–6.97 (m, 4H), 7.02 (d, J = 8.5 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.22 (d, J = 8.5 Hz, 2H), 7.94 (d, J = 8.5 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.2, 25.5, 26.2, 26.3, 30.2, 40.6, 55.7, 56.3, 59.1, 67.3, 114.1, 127.2, 128.9, 129.5, 129.9, 130.4, 134.0, 137.0, 137.2, 137.6, 164.1, 166.1, 167.6, 195.2 ppm.

  22. 22.

    1-Cyclohexyl-3-(2-oxo-2-(p-tolyl)ethyl)-4,6-di-p-tolylpiperazine-2,5-dione (3j); M.p.: 223–226 °C; [requires: C, 77.92; H, 7.13; N, 5.51 C33H36N2O3 (MW = 508.65), found: C, 78.20; H, 7.41; N, 5.71 %]; FT-IR (KBr): νmax = 3029, 2924, 2860, 1678, 1606, 1513, 1432 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.04–2.04 (m, 10H), 2.20 (s, 3H), 2.24 (s, 3H), 2.40 (s, 3H), 3.43–3.49 (m, 1H), 3.76–3.86 (m, 2H), 4.59 (t, J = 3.1 Hz, 1H), 5.60 (s, 1H), 6.93 (d, J = 8.0 Hz, 2H), 6.98 (d, J = 8.0 Hz, 2H), 7.02 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 8.0 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 7.83 (d, J = 8.0 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.1, 21.7, 25.4, 26.2, 30.0, 40.8, 56.1, 58.9, 67.6, 127.1, 128.1, 128.2, 129.3, 129.5, 129.6, 133.9, 135.5, 137.16, 137.7, 144.5, 166.5, 167.2, 198.2 ppm.

  23. 23.

    3-(4-Chlorophenyl)-4-cyclohexyl-6-(2-oxo-2-(p-tolyl)ethyl)-1-phenylpiperazine-2,5-dione (3 k); M.p.: 222–225 °C; [requires: C, 72.29; H, 6.07; N, 5.44; C31H31ClN2O3 (MW = 515.04), found: C, 72.49; H, 6.21; N, 5.62  %]; FT-IR (KBr): νmax = 3020, 2925, 2858, 1672, 1595, 1438 cm−1; 1H NMR (400 MHz, CDCl3): δ = 1.03–2.01 (m, 10H), 2.39 (s, 3H), 3.42–3.48 (m, 1H), 3.79–3.80 (m, 2H), 4.54 (t, J = 3.3 Hz, 1H), 5.67 (s, 1H), 6.93 (d, J = 8.6 Hz, 2H), 7.13 (d, J = 8.1 Hz, 2H), 7.21 (d, J = 8.1 Hz, 3H), 7.25(d, J = 8.1 Hz, 2H), 7.32 (d, J = 8.6 Hz, 2H), 7.81 (d, J = 8.1 Hz, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 21.9, 25.5, 26.3, 29.9, 30.2, 40.9, 56.2, 59.3, 67.1, 121.7, 128.3, 129.1, 129.3, 129.7, 129.9, 132.5, 134.3, 136.7, 138.7, 145.1, 165.7, 167.6, 196.5 ppm.

  24. 24.

    1-Butyl-3-(4-chlorophenyl)-4-cyclohexyl-6-(2-oxo-2-(p-tolyl) ethyl) piperazine-2,5-dione (3 l); M.p. 156–159 °C; [requires: C, 70.36; H, 7.13; N, 5.66 C29H35ClN2O3 (MW = 495.05), found: C, 70.46; H, 7.25; N, 6.1 %]; FT-IR (KBr): νmax = 3034, 2933, 2857, 1752, 1658, 1572, 1491, 1407 cm−1; 1H NMR (400 MHz, CDCl3): δ = 0.76–1.92 (m, 17H), 2.38 (s, 3H), 2.45–2.48(m, 2H), 3.38–3.42 (m, 1H), 3.69–3.76 (m, 4H), 4.4 (t, J = 3.3 Hz, 1H), 5.3 (s, 1H), 7.23–7.42 (m, 4H), 7.79 (d, J = 8.0, 2H) ppm; 13C NMR (100 MHz, CDCl3): δ = 13.8, 20.2, 25.4, 26.1, 26.3, 27.7, 30.0, 40.6, 44.6, 55.7, 58.9, 63.95, 128.2, 129.2, 129.4, 129.6, 144.8, 166.1, 167.5, 196.4 ppm.