Diastereoselective Synthesis of Functionalized Diketopiperazines

Oct 19, 2017 - A diversity-oriented access to diastereoselective arylidene 2,5-diketopiperazines is elaborated via a sequential Ugi post-transformatio...
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Diastereoselective Synthesis of Functionalized Diketopiperazines through Post-transformational Reactions Saeed Balalaie,*,†,‡ Reihaneh Ramezani Kejani,† Elmira Ghabraie,† Fatemeh Darvish,† Frank Rominger,§ Fatima Hamdan,† and Hamid Reza Bijanzadeh∥ †

Peptide Chemistry Research Center, K. N. Toosi University of Technology, P.O. Box 15875-4416, Tehran, Iran Medical Biology Research Center, Kermanshah University of Medical Sciences, Kermanshah, Iran § Organisch-Chemisches Institut der Universitaet Heidelberg, Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany ∥ Department of Biophysics, Tarbiat Modares University, Tehran, Iran ‡

S Supporting Information *

ABSTRACT: A diversity-oriented access to diastereoselective arylidene 2,5-diketopiperazines is elaborated via a sequential Ugi post-transformation involving catalytic cyclization and oxidative Heck reaction sequence. This sequence offers an interesting multicomponent entry to a library of 2,5-diketopiperazines and arylidene 2,5-diketopiperazines under mild reaction conditions in good to excellent yields.

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INTRODUCTION Building complex biologically active molecules focusing on organic, organometallic, and bio-oriented processes has an interesting impact in organic synthesis.1 In this regard, the design of reactions to convert the readily available starting material to complex molecules is one of the major challenges for chemists.2,3 Designing of domino reactions and posttransformation multicomponent reactions has been used for the synthesis of different bioactive molecules.4 In our group and the Van der Eycken group, there was a long-standing interest to develop Ugi post-transformation reactions to access functionalized heterocyclic backbones such as oxindoles, pyrrolones, oxazepine, and benzazepines.5 The origin of these reactions is related to using a propiolic acid moiety as starting material in the Ugi-4CR. 2,5-Diketopiperazines are a class of naturally occurring privileged structures with extended biological activities and suitable scaffold for drug discovery, due to their rigid backbone and their metabolic properties6 (Figure 1). There are different approaches for the synthesis of 2,5-diketopiperazines.7 A known approach for the synthesis of 2,5-diketopiperzine is cyclization of dipeptides using an acid. 8 In the meantime, Ugi pseudopeptides were also used as starting material for the synthesis of 2,5-diketopiperzine with high diversity.9 © 2017 American Chemical Society

Figure 1. Structures of some diketopiperazine frameworks with biological activity.

Despite the various synthetic protocols available for the synthesis of diketopiperazines, the need for atom-economic efficient methodologies starting from simple and available starting materials and short reaction processes for their synthesis attracts synthetic chemists. Received: August 2, 2017 Published: October 19, 2017 12141

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

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The Journal of Organic Chemistry Scheme 1. Retrosynthetic Analysis of the Synthesis of Arylidene 2,5-Diketopiperazines

Scheme 2. Designed Post-transformation Approach for the Synthesis of Arylidene 2,5-Diketopiperazines

Scheme 3. Synthesis of Arylidene 2,5-Diketopiperazine 5c

cyclization products in comparison to other solvents such as methanol, toluene, and acetonitrile (Table 1, entries 1−5, Scheme 3). After specifying ethanol as the best reaction solvent, we determined the influence of different amounts of triphenylphosphine on the yield of the reaction by using 10, 20, 30, and 40 mol % of triphenylphosphine. The results showed that using 30 mol % of triphenylphosphine in ethanol led to the best yield of the reaction (Table 1).

To the best of our knowledge, there is no report for the synthesis of diketopiperazines using N-substituted 2-alkynamides. The existence of an alkyne moiety in the structure of Ugi pseudopeptide can affect their activity for further reactions. Trost showed that the nucleophilic addition of nucleophiles to an alkyne moiety can be done at the α-position in the presence of triphenylphosphine.10 We record our studies based on this pattern of reactivity. Due to the extended biological activities of arylidene 2,5diketopiperazines, designing a retrosynthetic rule based on the available starting material with reduction of reaction procedures is interesting and practical to access the desired molecules (Scheme 1). In continuation of our efforts to adapt post-transformation reactions to a high-throughput format,11 we report herein an efficient approach for the diastereoselective synthesis of diketopiperazines through the post-transformation Ugi/cyclization/oxidative Heck reaction sequences (Scheme 2).

Table 1. Optimization of Reaction Conditions for the Synthesis of 6c as Model Reactiona

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RESULTS AND DISCUSSION In the first step, Ugi-4CR of 4-chlorobenzaldehyde 1c, aniline 2a, cyclohexylisocyanide 3a, and propiolic acid 4a was chosen as the model reaction. The N-substituted 2-alkynamide 5c was precipitated and separated. The product did not need more purification and could be used for further reaction. After separation of 5c, reaction conditions were investigated for cyclization reactions. It is followed by treatment with a catalytic amount of triphenylphosphine in ethanol for the cyclization reaction. During the optimization of the reaction conditions, it was revealed that ethanol was the suitable solvent to provide

a

entry

solvent

PPh3 (%)

yield (%)

1 2 3 4 5 6 7 8

EtOH MeOH MeCN toluene DMF EtOH EtOH EtOH

10 10 10 10 10 20 30 40

66 50 42 30 NR 75 90 90

In all reaction conditions the time of the reaction was 12h at 80 °C.

In order to explore the synthesis reaction, a library Nsubstituted 2-alkynamides, different aldehydes, anilines, isocyanides, and propiolic acids were used as starting materials. In all cases, the Ugi-4CR products (5a−q) were produced in good to high yields. The results are summarized in Table 2. 12142

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The Journal of Organic Chemistry Table 2. Synthesis of N-Substitued 2-Alkynamides 5a−qa

a

Reaction conditions: aromatic aldehyde 1 (1 mmol), primary amine 2 (1 mmol), isocyanide 3 (1 mmol), and carboxylic acid 4 (1 mmol) in 5 mL of methanol was stirred at room temperature for 24 h. The precipitate was filtered. In all reaction conditions, the time of the reaction was 12−24 h at room temperature.

Scheme 4. Effect of Solvent for the Synthesis of Diketopiperazine 6o and Ethyl Ether 7o

contained tert-butyl amide led to undesired ethyl ether 7o (67%) that was formed through the nucleophilic addition of ethanol to an alkyne moiety. To solve this problem, the reactions of the compounds containing t-butyl amide were carried out in acetonitrile instead of ethanol, and in this case, the desired arylidene 2,5-diketopiperazine 6o (55%) and 6p (60%) were formed (Scheme 4).

After formation of the desired 6c, we worked to gain further insights and to extend the chemical library with our library of N-substituted 2-alkynamides 5a−q. The results are summarized in Table 2. The products were separated, and their structures were confirmed based on spectroscopic data. Then the reaction of N-substituted 2-alkynamides 5a−q was investigated in the optimized reaction conditions. However, compounds 5o,p that 12143

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

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The Journal of Organic Chemistry Table 3. Synthesis of Arylidene 2,5-Diketopiperazines 6a−qa,b

a Reaction conditions: 5a−p (1 mmol), triphenylphosphine (30 mol %), solvent (EtOH or acetonitrile) (4 mL) at 80 °C for 12 h. bIsolated yields after column chromatography.

Scheme 5. Proposed Mechanism for the Synthesis of 2,5-Diketopiperazines 6a−q through Triphenylphosphine-Catalyzed Nucleophilic Addition to Alkynes

Products 6a−q were separated, and their structures were confirmed based on the spectroscopic data. The yield of products was isolated yields and was formed after column chromatography (Table 3).

On the other hand, when we used 5r and 5q, the reaction did not proceed; it seems that it is due to the steric hindrance of the phenyl and methyl groups. 12144

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

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The Journal of Organic Chemistry Scheme 6. Difference between Mizoroki−Heck and Oxidative Heck Reactions

Table 4. Structure of the Synthesized Arylidene 2,5-Diketopiperazines 8a−ma,b

a

Reaction conditions: 6 (1 mmol), Pd(Ac)2 (20 mol %), phenanthroline (22 mol %), ArB(OH)2 (2 mmol), NMP (2 mmol) in DMF (5 mL) at 80 °C and air oxidant were mixed for 12 h. bIsolated yields after column chromatography.

The proposed mechanism for the reaction contains the nucleophilic addition of triphenylphosphine to the active alkyne group (A) and then the proton transfer from the NH group of the amide forming (B). The nucleophilic addition of nitrogen led to C, and after the elimination of the triphenylphosiphine, the desired 2,5-diketopiperazines 6a−q were generated (Scheme 5). The synthesized methylidene 2,5-diketopiperazines 6a−q have a methylene group that has a very good potential for C−C bond formation. The existence of a methylene group in the

structure of 6a−q can show its activity for coupling reaction and the C−C bond formation. Transition-metal-catalyzed cross-couplings such as Heck and Suzuki reactions have been used for the formation of the C−C bond. Meanwhile, the regioselectivity of the Heck reaction is the main point which must be considered in planning synthetic routes.12 Oxidative boron Heck (oxidative Heck) reactions are catalyzed by Pd(II) instead of Pd(0) and differ from the traditional Pd(0)-catalyzed Mizoroki−Heck reactions during the first step in the catalytic cycle. The corresponding 12145

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

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The Journal of Organic Chemistry organoboronic acid [R1B(OH)2]can be used in the oxidative Heck reaction.13 To investigate the suitable reaction conditions, initially, the reaction of 6e with iodobenzene in the presence of phenanthroline was examined, but no conversion was observed at 80 °C (Scheme 7). Then, the oxidative Heck reaction condition was selected as an approach. To access this goal, the reaction of compound 6e with phenylboronic acid in the presence of palladium acetate (20%) and phenanthroline (20%) and air as oxidant was studied in DMF solvent at 80 °C, and after workup, the desired 8e was formed in 75% yield. The amount of palladium catalyst and mole ratio of phenanthroline was changed, and based on the optimized results, the best reaction conditions were selected as Pd(OAc)2 20%, phenanthroline (20%), and DMF as solvent at 80 °C (Scheme 6). With the optimized reaction condition in hand, we next examined the scope of the substrates. As shown in Table 4, different methylidene 2,5-diketopiperazines 6a−m with electron-donating and electron-deficient groups were examined in the reaction, and the desired arylidene 2,5-diketopiperazines 8a−m were afforded. An important point in the structure of 8a−m is related to the configuration of the aryl group. Investigation of the crystal structure of compound 8e confirmed the structure of the products and also the configuration of the aryl moiety (Figure 2).

oxygen was used as an oxidant to reoxidize Pd(0) to Pd(II) at the end of the catalytic cycle. The reaction procedure can be categorized as follows: (1) transmetalation, the addition of arylboronic acid to Pd(II); (2) insertion reaction to alkyne moiety and formation of intermediate A; (3) syn-elimination; and (4) finally, reductive elimination to form Pd(0). The existence of oxidant is essential for the conversion of Pd(0) to Pd (II) (Scheme 7). Based on the previous mentioned results, we proposed that the reaction can proceed through sequential Ugi/cyclization/ oxidative Heck reaction sequence with high diastereoselectivity. It seems that the steric hindrance has an essential role in the diastereoselectivity of the products. In conclusion, we have successfully established an efficient route toward the diastereoselective synthesis of a diverse array of arylidene 2,5diketopiperazines through an expedient post-transformation reaction. This procedure provides several advantageous features including synthesis of complex molecules using simple starting materials, high bond-forming efficiency, atom-economy, mild reaction conditions, the simplicity of operation, easy workup procedure, and good to high yields.

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EXPERIMENTAL SECTION

General Information. Reagents and solvents were purchased from various commercial sources and were used directly without any further purification, unless otherwise stated. Column chromatography was performed using 63−200 mesh silica gel. 1H and 13C NMR spectra were recorded at 300 and 75 MHz, respectively. Chemical shifts were reported in parts per million (δ) using TMS, and coupling constants were expressed in hertz. Melting points were recorded using an electrothermal capillary melting point apparatus and were uncorrected. HRMS spectra were recorded using high-resolution mass spectra and were recorded on Mass-ESI-POS(FT-ICR) spectrometer. General Procedure for the Synthesis of Compounds 5a−q. To a solution of aromatic aldehyde 1a−g (1 mmol) in methanol (5 mL) were added the primary amines 2a−g (1 mmol), and the mixture was stirred at room temperature for 1 h. Then, carboxylic acid 4 (1 mmol) was added, and stirring was continued for 15 min, followed by addition of isocyanides 3a−c (1 mmol). The mixture was stirred for 24 h at room temperature. Progress of the reaction was monitored by TLC (n-hexane/AcOEt 3:1). The formed precipitate was filtered and dried. Yields: 59−90%. General Procedure for the Synthesis of Compounds 6a−q. A 25 mL round-bottom flask was charged with 4 mL of EtOH, followed by 1 mmol 5a−q and triphenylphosphine (30%, 8 mg). The reaction mixture was stirred at 80 °C until the reaction reached completion as evidenced by TLC (n-hexane/EtOAc 5:1). After the completion of the reaction, the product was separated through column chromatography using a mixture of n-hexane/EtOAc (5:1). Yields: 55−90%. General Procedure for the Synthesis of Compounds 8a−m. A 25 mL round-bottom flask was charged with 5 mL of DMF, followed by the compound 6 derivatives (1 mmol), Pd(Ac)2 (20 mol %, 45 mg), arylboronic acid (2 mmol), NMP (2 mmol, 198 mg), and phenanthroline (22 mol %, 40 mg). The reaction mixture was stirred at 80 °C in the air oxidation reaction condition until the reaction reached completion as evidenced by TLC (n-hexane/EtOAc 7:1). After the completion of the reaction, water was added to the reaction mixture and was extracted by dichloromethane. After evaporation of the solvent under vacuum, the resulting residue was further purified by column chromatography using (7:1 n-hexane/EtOAc) on silica gel. Yields: 50−90%. N-(2-(Cyclohexylamino)-2-oxo-1-phenylpropiolamide (5a): Colorless solid; (90%), mp 188−189 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.01−1.97 (m, 10H, H-cyc), 2.81(s, 1H, acetylenic H), 3.77−3.89 (m, 1H, H-cyc), 5.55 (d, 1H, J = 7.6 Hz, NH), 6.02 (s, 1H, −CH), 7.13−7.34 (m, 10H, H−Ar); 13C NMR (CDCl3, 75 MHz)

Figure 2. ORTEP structures of 6c and 8e; the ellipsoid probability level of each ORTEP diagram is 50%.

All the synthesized products 8a−m were fully characterized by 1H NMR, 13C NMR, and HRMS. Meanwhile, compounds 6c and 8e were identified by X-ray crystallographic analysis. Diversion of functionalized diketopiperazines, generated through sequential Ugi/cyclization reaction, was used as the starting material for oxidative Heck reaction with various aryl boronic acid and palladium acetate as catalyst. Results of the reaction showed that arylation of diketopiperazines was completely diastereoselective. Generated aryl diketopiperazines from this approach are shown in Table 4. According to the known oxidative Heck reaction, the first step in the catalytic cycle is the transmetalation between the organoboronic acid and Pd(II) catalyst (Scheme 6). Then, migratory insertion of methylidene 2,5-diketopiperazine led to intermediate A that can be converted to the desired arylidene 2,5-diketopiperazines 8a−m. In the oxidative Heck reaction, 12146

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

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The Journal of Organic Chemistry Scheme 7. Proposed Reaction Mechanism for the Synthesis of 8a−m through Oxidative Heck Reaction

δ (ppm) = 24.7, 24.8, 25.4, 32.7, 32.8, 48.8, 64.9, 76.0, 80.5, 128.4,128.7, 129.5, 130.3, 130.7, 133.7, 139.0, 153.7, 167.6. N-(1-(4-Bromophenyl)-2-(cyclohexylamino)-2-oxoethyl)-Nphenylpropiolamide (5b): Colorless solid, 343 mg (78%), mp 228− 233 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.06−1.17 (m, 3H, H-cyc), 1.30−1.38 (m, 2H, H-cyc), 1.56−1.66 (m, 3H, H-cyc), 1.82− 1.97 (m, 2H, H-cyc), 2.82 (s, 1H, acetylenic H), 3.76−3.86 (m, 1H, Hcyc), 5.67 (d, 1H, J = 7.8 Hz, NH) 5.97 (s, 1H, −C(sp3)−H), 7.03 (d, 2H, J = 8.4 Hz, H−Ar), 7.14−7.28 (m, 5H, H−Ar), 7.33 (d, 2H, J = 8.4 Hz, H−Ar); 13C NMR (DMSO, 75 MHz) δ (ppm) = 24.4, 24.5, 25.1, 32.1, 48.0, 62.8, 76.7, 83.2, 121.2, 128.2, 130.8, 131.0, 132.3, 133.9, 138.6, 152.7, 167.4. N-(1-(4-Chlorophenyl)-2-(cyclohexylamino)-2-oxoethyl)-Nphenylpropiolamide (5c): Colorless solid, 276 mg (70%), mp 241− 244 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 0.95−1.27 (m, 5H, H-cyc), 1.49−1.75 (m, 5H, H-cyc), 3.52−3.58 (m, 1H, H-cyc), 4.15 (s, 1H, acetylenic H), 5.98 (s, 1H, −C(sp3)−H), 7.07 (d, 2H, J = 8.4 Hz, H−Ar), 7.19 (d, 2H, J = 8.4 Hz, H−Ar), 7.17−7.25 (m, 5H, H−Ar), 8.08 (d, 1H, J = 7.8 Hz, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 24.4, 24.5, 25.1, 32.1, 48.0, 62.8, 76.7, 83.1, 127.9, 128.2, 131.0, 131.9, 132.6, 133.5, 138.6, 152.7, 167.4. N-(1-(4-Cyanophenyl)-2-(cyclohexylamino)-2-oxoethyl)-Nphenylpropiolamide (5d): Cream solid, 258 mg (67%), mp 205− 208 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 0.96−1.27 (m, 5H, H-cyc), 1.49−1.74 (m, 5H, H-cyc), 3.56−3.58 (m, 1H, H-cyc), 4.18 (s, 1H, acetylenic H), 6.06 (s, 1H, −C(sp3)−H), 7.12−7.21 (m, 3H, H− Ar), 7.27−7.30 (m, 2H, H−Ar), 7.28 (d, 2H, J = 8.4 Hz, H−Ar), 7.61 (d, 2H, J = 8.4 Hz, H−Ar), 8.18 (d, 1H, J = 7.6 Hz, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 24.4, 24.5, 25.1, 32.0, 48.1, 63.2, 76.6, 83.4, 110.6, 118.4, 128.3, 130.9, 131.0, 131.8, 138.4, 140.1, 152.7, 166.8. N-(2-(Cyclohexylamino)-1-(4-methoxyphenyl)-2-oxoethyl)N-phenylpropiolamide (5e): Colorless solid, 312 mg (80%), mp 201−204 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 0.94−1.28 (m, 5H, H-cyc), 1.50−1.76 (m, 5H, H-cyc), 3.56−3.61 (m, 1H, H-cyc), 3.61 (s, 3H, −Me), 4.11 (s, 1H, acetylenic H), 5.94 (s, 1H, −C(sp3)− H), 6.66 (d, 2H, J = 8.7 Hz, H−Ar), 6.96 (d, 2H, J = 8.7 Hz, H−Ar), 7.08−7.23 (m, 5H, H−Ar), 7.97 (d, 1H, J = 7.6 Hz, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 24.4, 24.6, 25.2, 32.2, 48.0, 54.9, 63.0, 76.8, 82.8, 113.2, 126.2, 128.0, 131.1, 131.4, 138.8, 152.6, 158.6, 168.1. N-(2-Bromophenyl)-N-(2-(cyclohexylamino)-2-oxo-1phenylethyl)propiolamide (5g): Cream solid, 290 mg (66%), mp 188−194 °C; 1H NMR (DMSO, 300 MHz) δ(ppm) = 0.91−1.28 (m, 5H, H-cyc), 1.49−1.78 (m, 5H, H-cyc), 3.52−3.61 (m, 1H, H-cyc), 4.12 (s, 1H, acetylenic H), 5.90 (s, 1H, −C(sp3)−H), 7.05−7.23 (m, 6H, H−Ar), 7.28−7.38 (m, 1H, H−Ar) 7.30 (d, 1H, J = 7.9 Hz, H− Ar), 7.88 (d, 1H, J = 7.9 Hz, H−Ar), 8.06 (d, 1H, J = 7.8 Hz, NH);

C NMR (DMSO, 75 MHz) δ (ppm) = 24.3, 24.5, 25.1, 32.0, 32.1, 48.0, 64.1, 76.6, 81.5, 125.8, 127.5, 127.9, 128.3, 130.4, 130.5, 132.3, 132.6, 133.4, 137.6, 152.7, 167.9. N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(2iodophenyl)propiolamide (5h): Colorless solid, 316 mg (65%), mp 194−201 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 0.90−1.21 (m, 5H, H-cyc), 1.53−1.78 (m, 5H, H-cyc), 3.54−3.56 (m, 1H, H-cyc), 4.11 (s, 1H, acetylenic H), 5.86 (s, 1H, −C(sp3)−H), 6.90 (t, 1H, J = 7.3 Hz, H−Ar), 7.07−7.19 (m, 5H, H−Ar), 7.33 (t, 1H, J = 7.3 Hz, H−Ar), 7.58 (d, 1H, J = 7.7 Hz, H−Ar), 7.93 (d, 1H, J = 7.6 Hz, H− Ar), 8.03 (d, 1H, J = 7.3 Hz, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 23.7, 24.3, 24.5, 25.1, 30.4, 32.0, 32.1, 48.0, 64.2, 77.0, 81.7, 104.8, 127.4, 128.3, 128.4, 130.1, 130.9, 132.4, 132.8, 138.6, 141.0, 152.7, 168.0, 168.6. N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(4nitrophenyl)propiolamide (5i): Colorless solid, 284 mg (70%), mp 212−217 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 1.00−1.29 (m, 5H, H-cyc), 1.50−1.78 (m, 5H, H-cyc), 3.62 (m, 1H, H-cyc), 4.29 (s, 1H, acetylenic H), 6.13 (s, 1H, −C(sp3)−H), 7.13 (m, 5H, H−Ar), 7.61−7.63 (m, 2H, H−Ar), 8.03 (d, 2H, J = 8.5 Hz, H−Ar), 8.23 (d, J = 6.3 Hz, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 24.4, 24.5, 25.1, 32.1, 48.1, 63.6, 76.3, 83.9, 123.2, 128.2, 130.0, 132.4, 133.9, 145.0, 146.5, 152.0, 167.5. N-(2-(Cyclohexylamino)-2-oxo-1-phenylethyl)-N-(3,4dimethylphenyl)propiolamide (5j): Cream solid, 315 mg (81%), mp 200−204 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 1.00−1.32 (m, 5H, H-cyc), 1.50−1.76 (m, 5H, H-cyc), 2.03 (s, 3H, −Me), 2.07 (s, 3H, −Me), 3.53−3.59 (m, 1H, H-cyc), 4.11 (s, 1H, acetylenic H), 5.97 (s, 1H, −C(sp3)−H), 6.75−6.88 (m, 2H, H−Ar), 7.04−7.09 (m, 3H, H−Ar), 7.11−7.22 (m, 3H, H−Ar), 8.01 (d, J = 7.7 Hz, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 19.0, 19.2, 24.4, 24.6, 25.2, 32.1, 48.0, 63.5, 76.9, 82.9, 127.8, 128.2, 128.9, 130.1, 131.7, 134.6, 135.6, 135.8, 136.3, 152.8, 167.7. N-Benzyl-N-(2-(cyclohexylamino)-2-oxo-1-phenylethyl)propiolamide (5k): Colorless solid, 318 mg (85%), mp 169−174 °C; 1 H NMR (DMSO, 300 MHz) (mixture of two rotamers) δ (ppm) = 0.95−1.26 (m, 5H, H-cyc (mixture of two rotamers)), 1.52−1.75 (m, 5H, H-cyc(mixture of two rotamers)), 3.47−3.59 (m, 1H, Hcyc(mixture of two rotamers)), 4.31 (d, J = 15.7 Hz, NCH (minor)), 4.45 (s, 1H, acetylenic H(major)), 4.65 (d, J = 17.3 Hz, NCH (major)), 4.68 (s, 1H, acetylenic H(minor)), 4.79 (d, J = 15.7 Hz, NCH (minor)), 5.02 (d, J = 17.2 Hz, NCH (major)), 5.95 (s, 1H, −C(sp3)−H (major)), 6.13 (s, 1H, −C(sp3)−H (minor)), 6.76−6.78 (m, 1H, H−Ar), 6.88−6.90 (m, 1H, H−Ar), 7.03−7.26 (m, 8H, H− Ar), 8.09 (d, 1H, J = 7.6 Hz, NH (major)), 8.28 (d, 1H, J = 7.6 Hz, NH (minor)); 13C NMR (DMSO, 75 MHz) (mixture of two rotamers) δ (ppm) = 24.5, 25.1, 31.9, 32.1, 47.3, 47.8, 50.0, 60.6, 64.5, 13

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Article

The Journal of Organic Chemistry

Further purification of 6c was done by recrystallization of the sample in methanol: Colorless crystal (polyhedron), dimensions 0.200 × 0.150 × 0.150 mm3, crystal system monoclinic, space group P21/c, Z = 4, a = 8.8038(14) Å, b = 17.766(3) Å, c = 13.229(2) Å, α = 90°, β = 105.812(5)°, γ = 90°, V = 1990.8(6) Å3, ρ = 1.317 g/cm3, T = 120(2) K, θmax = 21.892°, radiation Mo Kα, λ = 0.71073 Å, 0.5° ω-scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 5.42 and a completeness of 99.3% to a resolution of 0.95 Å, 13 334 reflections measured, 2397 unique (R(int) = 0.0658), 1838 observed (I > 2σ(I)); intensities were corrected for Lorentz and polarization effects; an empirical absorption correction was applied using SADABS14 based on the Laue symmetry of the reciprocal space, μ = 0.21 mm−1, Tmin = 0.88, Tmax = 0.98, structure refined against F2 with a full-matrix least-squares algorithm using the SHELXL-2014/7 software,14 253 parameters refined; hydrogen atoms were treated using appropriate riding models, goodness of fit 1.06 for observed reflections, final residual values R1(F) = 0.052, wR(F2) = 0.097 for observed reflections, residual electron density = 0.25 to 0.22 eÅ−3. CCDC 1562018 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac. uk/data_request/cif. 4-(4-Cyclohexyl-5-methylene-3,6-dioxo-1-phenylpiperazine-2-yl)benzonitrille (6d): Colorless solid, 289 mg (75%), mp 209−215 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.09−1.39 (m, 3H, H-cyc), 1.55−1.68 (m, 2H, H-cyc), 1.75−1.81 (m, 3H, H-cyc), 2.02−2.24 (m, 2H, H-cyc), 3.91−4.00 (m, 1H, H-cyc), 5.26 (s, 1H,  CH), 5.43 (s, 1H, CH), 6.01 (s, 1H, −C(sp3)−H), 7.15 (d, 2H, J = 7.5 Hz, H−Ar), 7.24 (t, 1H, J = 7.2 Hz, H−Ar), 7.26 (t, 1H, J = 7.2 Hz, H−Ar), 7.33 (t, 1H, J = 7.2 Hz, H−Ar), 7.50 (d, 2H, J = 8.3 Hz, H−Ar), 7.65 (d, 2H, J = 8.3 Hz, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.2, 25.9, 26.3, 27.7, 30.0, 59.4, 67.5, 107.5, 112.9, 118.1, 125.0, 127.0, 127.5, 129.3, 132.9, 137.4, 139.1, 141.1, 160.6, 163.2; HRMS (ESI) calcd for C24H23N3NaO2 [M + Na]+ 408.16935, found 408.16913; IR ν (cm−1) 2930, 2230, 1678, 1603. 1-Cyclohexyl-3-(4-methoxyphenyl)-6-methylene-4-phenylpiperazine-2,5-dione (6e): Colorless solid, 293 mg (75%), mp 157−162 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.11−1.41 (m, 3H, H-cyc), 1.58−1.70 (m, 2H, H-cyc), 1.80−1.84 (m, 3H, H-cyc), 2.04−2.27 (m, 2H, H-cyc), 3.78 (s, 3H, −OMe), 3.96−4.04 (m, 1H, H-cyc), 5.24 (s, 1H, CH), 5.28 (s, 1H, CH), 5.99 (s, 1H, −C(sp3)−H), 6.86 (d, 2H, J = 7.8 Hz, H−Ar), 7.18 (d, 2H, J = 7.8 Hz, H−Ar), 7.20−7.34 (m, 5H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.3, 25.9, 26.4, 27.6, 30.0, 55.2, 58.9, 67.5, 106.2, 114.4, 125.4, 127.2, 127.5, 128.2, 129.1, 138.0, 139.6, 159.8, 160.8, 164.6; HRMS (ESI) calcd for C24H27N2O3 [M + H]+ 391.20144, found 391.20148; calcd for C24H26N2NaO3 [M + Na]+ 413.18330, found 413.18335; IR ν (cm−1) 2934, 1680, 1612. 1-Cyclohexyl-6-methylene-4-phenyl-3-(p-tolyl) piperazine2,5-dione (6f): Colorless solid, 300 mg (80%), mp 148−151 °C; 1 H NMR (CDCl3, 300 MHz) δ (ppm) = 1.14−1.35 (m, 3H, H-cyc), 1.57−1.67 (m, 2H, H-cyc), 1.80−1.83 (m, 3H, H-cyc), 2.06−2.25 (m, 2H, H-cyc), 2.32 (s, 3H, −CH3), 3.95−4.03 (m, 1H, H-cyc), 5.22 (s, 1H, CH), 5.30 (s, 1H, CH), 5.99 (s, 1H, −C(sp3)−H), 7.13− 7.31 (m, 9H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 21.1, 25.3, 25.9, 26.4, 27.6, 30.0, 58.9, 67.7, 106.3, 125.3, 126.1, 127.2, 129.1, 129.7, 133.1, 138.0, 138.6, 139.6, 160.9, 164.5; HRMS (ESI) calcd for C24H27N2O2 [M + H]+ 375.20655, found 375.20658; calcd for C24H26N2NaO2 [M + Na]+ 397.18840, found 397.18845; IR ν (cm−1) 2915, 1678, 1615. 1-(2-Bromophenyl)-4-cyclohexyl-3-methylene-6-phenylpiperazine-2,5-dione (6g): Colorless solid, 391 mg (89%), mp 167− 170 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.12−1.44 (m, 3H, H-cyc), 1.66−1.69 (m, 2H, H-cyc), 1.77−1.87 (m, 3H, H-cyc), 2.13− 2.36 (m, 2H, H-cyc), 4.00−4.09 (m, 1H, H-cyc), 5.12 (s, 1H, CH), 5.33 (s, 1H, CH), 6.04 (s, 1H, −C(sp3)−H), 6.85−6.88 (m, 1H, H−Ar), 7.14−7.26 (m, 2H, H−Ar), 7.30−7.34 (brs, 5H, H−Ar), 7.68−7.71 (m, 1H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.3, 26.0, 26.4, 27.9, 30.0, 59.5, 67.5, 106.5, 122.3, 127.0, 128.2, 128.9, 129.1, 130.1, 130.4, 133.7, 136.2, 137.7, 137.8, 160.3, 164.1; HRMS (ESI)

75.8, 76.5, 83.5, 126.0, 126.3, 126.7, 127.5, 127.7, 128.0, 128.1, 128.4, 129.0, 129.3, 134.8, 135.4, 137.8, 137.9, 154.1, 154.4, 167.4. Ethyl (2-(N-Phenylpropiolamido)-2-(p-tolyl)acetyl)glycinate (5m): Cream solid, 246 mg (65%), mp 106−111 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 1.16 (t, 3H, J = 7.1 Hz, −CH3), 2.15 (s, 3H, −Me), 3.76 (dd, 1H, J = 17.3 Hz, J = 5.5 Hz, N−CH), 3.96 (dd, 1H, J = 17.3 Hz, J = 5.5 Hz, N−CH), 4.07 (q, 2H, J = 7.1 Hz, O− CH2), 4.14 (s, 1H, acetylenic H), 6.10 (s, 1H, −C(sp3)−H), 6.93 (d, 2H, J = 8.1 Hz, H−Ar), 7.49 (d, 2H, J = 8.1 Hz, H−Ar), 7.16−7.20 (m, 5H, H−Ar), 8.55 (t, 1H, J = 5.5 Hz, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 14.0, 20.6, 41.0, 60.4, 63.0, 76.7, 83.2, 128.1, 128.4, 130.4, 130.7, 131.0, 137.2, 138.6, 152.7, 169.4, 169.5. N-(2-(tert-Butylamino)-1-(4-chlorophenyl)-2-oxoethyl)-Nphenylpropiolamide (5o): Cream solid, 232 mg (63%), mp 214− 219 °C; 1H NMR (DMSO, 300 MHz) δ (ppm) = 1.23 (s, 9H, H-tBu), 4.14 (s, 1H, acetylenic H), 5.98 (s, 1H, −C(sp3)−H), 7.08 (d, 2H, J = 8.5 Hz), 7.16−7.26 (m, 5H, H−Ar), 7.18 (d, 2H, J = 8.5 Hz), 7.86 (s, 1H, NH); 13C NMR (DMSO, 75 MHz) δ (ppm) = 28.3, 50.5, 63.1, 76.7, 83.0, 127.9, 128.1, 131.0, 131.9, 132.5, 133.7, 138.6, 152.6, 167.8. N-(2-(Cyclohexylamino)-2-oxo-1-(thiophen-2-yl)ethyl)-Nphenylpropiolamide (5q): Yellow solid, 911 mg (83%), mp 159− 161 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.08−1.95 (m, 10H, H-cyc), 2.83(s, 1H, acetylenic H), 3.75−3.88 (m, 1H, H-cyc), 6.02 (d, 1H, J = 7.4 Hz, NH), 6.21 (s, 1H, −CH), 6.88 (dd, 1H, J = 4.8, 3.6 Hz, H-thienyl), 6.97 (d, 1H, J = 3.6 Hz, H-thienyl), 7.17−7.33 (m, 6H, H− Ar, H-thienyl); 13C NMR (CDCl3, 75 MHz) δ (ppm) = 24.5, 24.6, 25.4, 32.5, 32.6, 48.8, 59.9, 75.8, 80.8, 126.3, 128.0, 128.6, 128.8, 129.9, 130.0, 135.0, 138.8, 153.4, 166.7; IR ν (cm−1) 3262, 3088, 2112, 1645. 1-Cyclohexyl-6-methylene-3,4-diphenylpiperazine-2,5dione (6a): Colorless solid, 324 mg (90%), mp 163−168 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.11−1.41 (m, 3H, H-cyc), 1.58−1.68 (m, 2H, H-cyc), 1.81−1.84 (m, 3H, H-cyc), 2.06−2.26 (m, 2H, H-cyc), 3.96−4.04 (m, 1H, H-cyc), 5.24 (s, 1H, CH), 5.35 (s, 1H, CH), 6.01 (s, 1H, −C(sp3)−H), 7.18−7.26 (m, 3H, H−Ar), 7.30−7.35 (m,7H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.3, 25.9, 26.4, 27.6, 30.1, 59.0, 67.9, 106.5, 125.3, 126.2, 127.2, 128.7, 129.1, 129.2, 136.1, 137.9, 139.6, 160.8, 164.4; HRMS (ESI) calcd for C23H24N2NaO2 [M + Na]+ 383.17359, found 383.17347; calcd for C46H48N4NaO4 [2M + Na]+ 743.35780, found 743.35768; calcd for C69H72N6NaO6 [3M + Na]+ 1103.54272, found 1103.54254; IR ν (cm−1) 2930, 1645. 3-(4-Bromophenyl)-1-cyclohexyl-6methylene-4-phenylpiperazine-2,5-dione (6b): Colorless solid, 373 mg (85%), mp 175− 177 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.10−1.42 (m, 3H, H-cyc), 1.57−1.74 (m, 2H, H-cyc), 1.81−1.84 (m, 3H, H-cyc), 2.05− 2.25 (m, 2H, H-cyc), 3.93−4.03 (m, 1H, H-cyc), 5.25 (s, 1H, CH), 5.31 (s, 1H, CH), 6.00 (s, 1H, −C(sp3)−H), 7.17−7.20 (m, 2H, H−Ar), 7.22−7.26 (m, 3H, H−Ar), 7.31−7.36 (m, 2H, H−Ar), 7.49 (d, J = 7.4 Hz, 2H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.2, 25.9, 26.4, 27.7, 30.0, 59.2, 67.4, 106.9, 122.9, 125.2, 127.3, 127.8, 129.2, 132.2, 135.2, 137.7, 139.4, 160.7, 163.8; HRMS (ESI) calcd for C23H24BrN2O2 [M + H]+ 439.10197, found 439.10190; calcd for C46H47Br2N4O4 [2M + H]+ 877.19635, found 877.19630; IR ν (cm−1) 2935, 1679, 1615. 3-(4-Chlorophenyl)-1-cyclohexyl-6-methylene-4-phenylpiperazine-2,5-dione (6c): Colorless solid, 348 mg (88%), mp 175− 178 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.10−1.41 (m, 3H, H-cyc), 1.57−1.70 (m, 2H, H-cyc), 1.81−1.83 (m, 3H, H-cyc), 2.04− 2.25 (m, 2H, H-cyc), 3.93−4.02 (m, 1H, H-cyc), 5.24 (s, 1H, CH), 5.32 (s, 1H, CH), 6.00 (s, 1H, −C(sp3)−H), 7.16−7.19 (m, 2H, H−Ar), 7.22−7.26 (m, 1H, H−Ar), 7.31−7.35 (m, 6H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.2, 25.9, 26.4, 27.6, 30.0, 59.1, 67.3, 106.9, 125.2, 127.3, 127.6, 129.2, 129.3, 134.6, 134.8, 137.7, 139.4, 160.7, 163.9; HRMS (ESI) calcd for C23H24ClN2O2 [M + H]+ 395.15326, found 395.15302; calcd for C23H23ClN2NaO2 [M + Na]+ 417.13517, found 417.13495; calcd for C23H23ClKN2O2 [M + K]+ 433.10937, found 433.10911; calcd for C46H46Cl2N4NaO4 [2M + Na]+ 811.28062, found 811.28042; calcd for C46H46Cl2KN4O4 [2M + K]+ 827.25584, found 827.25551; IR ν (cm−1) 2882, 1679, 1614. 12148

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

Article

The Journal of Organic Chemistry

NMR (CDCl3, 300 MHz) δ (ppm) = 1.15 (t, 3H, J = 7.1 Hz, −CH3), 4.15 (q, 2H, J = 7.1 Hz, −OCH2), 4.21 (d, 1H, J = 17.2 Hz, N−CH2), 4.84 (d, 1H, J = 17.2 Hz, N−CH2), 4.94 (d, 1H, J = 1.8 Hz, CH), 5.45 (s, 1H, −C(sp3)−H), 6.03 (d, 1H, J = 1.8 Hz, CH), 7.10−7.13 (m, 2H, H−Ar), 7.25−7.32 (m, 3H, H−Ar), 7.36 (m, 5H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 14.0, 45.3, 53.5, 61.8, 67.8, 104.7, 126.4, 127.0, 127.8, 129.1, 129.3, 136.2, 137.1, 139.3, 158.4, 164.0, 167.0; HRMS (ESI) calcd for C21H21N2O4 [M + H]+ 365.14958, found 365.14930; calcd for C21H20N2NaO4 [M + Na]+ 387.13153, found 387.13103; IR ν (cm−1) 2981, 1689, 1615. Ethyl 2-(2-Methylene-3,6-dioxo-4-pheny-5-(p-tolyl) piperazine-1-yl)acetate (6m): Yellow solid, 322 mg (85%), mp 117−124 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.17 (t, 3H, J = 7.1 Hz, −CH3), 2.33 (s, 3H, −Me), 4.15 (q, 2H, J = 7.1 Hz, −OCH2), 4.23 (d, 1H, J = 17.3 Hz, N−CH2), 4.84 (d, 1H, J = 17.3 Hz, N−CH2), 4.93 (d, 1H, J = 1.9 Hz, CH), 5.41 (s, 1H, −C(sp3)−H), 6.03 (d, 1H, J = 1.9 Hz, CH), 7.11−7.17 (m, 4H, H−Ar), 7.24−7.35 (m, 5H, H− Ar); 13C NMR (75 MHz, CDCl3) δ 14.0, 21.1, 45.2, 61.8, 67.6, 104.5,126.4, 126.8, 127.7, 129.2, 129.8, 133.3, 137.2, 139.0, 139.4, 158.5, 164.1, 167.1; HRMS (ESI) calcd for C22H23N2O4 [M + H]+ 379.16515, found 379.16523; calcd for C22H22N2NaO4 [M + Na]+ 401.14706, found 401.14718; IR ν (cm−1) 2988, 1686, 1612. Ethyl 2-(3-(4-Methoxyphenyl)-6-methylene-2,5-dioxo-4phenypiperazine-1-yl)acetate (6n): Yellow solid, 316 mg (80%), mp 87−92 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.19 (t, 3H, J = 7.2 Hz, −CH3), 3.78 (s, 3H, −OMe), 4.17 (q, 2H, J = 7.2 Hz, −OCH2), 4.20 (d, 1H, J = 17.2 Hz, N−CH2), 4.85 (d, 1H, J = 17.2 Hz, N−CH2), 4.93 (d, 1H, J = 1.9 Hz, CH), 5.37 (s, 1H, −C(sp3)− H), 6.02 (d, 1H, J = 1.9 Hz, CH), 6.84 (d, 2H, J = 7.8 Hz, H−Ar), 7.09−7.12 (m, 2H, H−Ar), 7.22−7.36 (m, 5H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 14.0, 45.2, 55.3, 61.8, 67.4, 104.5, 114.5, 126. 5, 127.8, 128.3, 129.3, 137.1, 139.3, 158.3, 160.1, 164.2, 167.1; HRMS (ESI) calcd for C22H23N2O5 [M + H]+ 395.15991, found 395.15996; calcd for C22H22N2NaO5 [M + Na]+ 417.14161, found 417.14170; IR ν (cm−1) 2946, 1688, 1615. 1-(tert-Butyl)-3-(4-chlorophenyl)-6-methylene-4-phenylpiperazine-2,5-dione (6o): Colorless solid, 203 mg (55%), mp 195− 199 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.36 (s, 9H, t-Bu), 5.48 (d, 1H, J = 2.3 Hz, CH2), 5.94 (s, 1H, −C(sp3)−H), 5.95 (d, 1H, J = 2.3 Hz, CH2), 7.21−7.26 (m, 2H, H−Ar), 7.34−7.37 (m, 3H, H−Ar), 7.42−7.50 (m, 4H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 28.5, 52.3, 75.1, 112.4, 119.3, 127.4, 128.8, 128.9, 129.2, 129.9, 134.9, 135.0, 151.1, 160.9, 166.4; HRMS (ESI) calcd for C21H22ClN2O2 [M + H]+ 369.13676, found 369.13670; calcd for C42H43Cl2N4O4 [2M + H]+ 737.26696, found 737.26680; IR ν (cm−1) 2971, 1672. 1-(tert-Butyl)-3-(4-chlorophenyl)-6-methylene-4-phenylpiperazine-2,5-dione (6p): Colorless solid, 211 mg (60%), mp 195− 199 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.36 (s, 9H, t-Bu), 5.48 (d, 1H, J = 2.2 Hz, CH2), 5.94 (s, 1H, −C(sp3)−H), 5.94 (d, 2H, J = 2.2 Hz, CH2, C(SP3)-H), 6.93−7.00 (m, 2H, H−Ar), 7.26− 7.37 (m, 3H, H−Ar), 7.44−7.51 (m, 4H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 28.5, 29.7, 52.2, 75.1, 112.2, 115.9, 116.2, 119.8, 119.9, 127.5, 128.8, 128.9, 132.5, 132.6, 135.0, 151.2, 157.8, 160.9, 161.1, 166.5; HRMS (ESI) calcd for C21H22FN2O2 [M + H]+ 353.16589, found 353.16590; IR ν (cm−1) 2971, 1677. 1-Cyclohexyl-6-methylene-4-phenyl-3-(thiophen-2-yl) piperazine-2,5-dione (6q): Colorless solid, 205 mg (56%), mp 132−135 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.14−1.45 (m, 3H, H-cyc), 1.66−1.86 (m, 5H, H-cyc), 2.12−2.33 (m, 2H, Hcyc), 3.97−4.08 (m, 1H, H-cyc), 5.30 (s, 1H, CH), 5.55 (s, 1H,  CH), 6.01 (s, 1H, −C(sp3)−H), 6.95 (dd, 1H, J = 4.8, 3.6 Hz, Hthienyl), 7.01−7.02 (m, 1H, H−Ar), 7.25−7.40 (m, 6H, H−Ar, Hthienyl); 13C NMR (75 MHz, CDCl3) δ 25.2, 25.9, 26.4, 27.6, 30.0, 59.2, 64.4, 106.9, 125.7, 126.3, 126.4, 127.1, 127.5, 129.2, 137.8, 139.0, 139.2, 160.4, 163.6; MS-ESI found for C21H23N2O2S [M + H]+ 367.73; IR ν (cm−1) 3054, 1687, 1614. (Z)-3-Benzylidene-4-cyclohexyl-1,6-diphenylpiperazine-2,5dione (8a): Colorless solid, 393 mg (90%), mp 172−177 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.36−0.49 (m, 1H, H-cyc), 0.88−1.10 (m, 2H, H-cyc), 1.38−1.42 (m, 1H, H-cyc), 1.48−1.52 (m,

calcd for C23H23BrN2O2 [M + H]+ 439.10279, found 439.10256; calcd for C23H23BrN2NaO2 [M + Na]+ 461.08470, found 461.08449; calcd for C23H23BrKN2O2 [M + K]+ 477.05895, found 477.05869; calcd for C46H47Br2N4O4 [2M + H]+ 877.19803, found 877.19781; calcd for C46H46Br2N4NaO4 [2M + Na]+ 899.17800, found 899.17788; calcd for C46H46Br2KN4O4 [2M + K]+ 915.15529, found 915.15494; calcd for C69H69Br3N6NaO6 [3M + Na]+ 1337.27776, found 1337.27737; IR ν (cm−1) 2929, 1685, 1614. 1-Cyclohexyl-4-(2-iodophenyl)-6-methylene-3-phenylpiperazine-2,5-dione (6h): Colorless solid, 267 mg (55%), mp 181−186 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.12−1.44 (m, 3H, Hcyc), 1.65−1.70 (m, 2H, H-cyc), 1.85−1.88 (m, 3H, H-cyc), 2.15− 2.39 (m, 2H, H-cyc), 4.00−4.14 (m, 1H, H-cyc), 5.06 (s, 1H, −C(sp3)−H), 5.35 (s, 1H, CH), 6.06 (s, 1H, CH), 6.81 (dd, 1H, J = 7.8, 1.4 Hz, H−Ar), 7.01−7.07 (dt, J = 7.8, 1.5 Hz, 1H, H−Ar), 7.18−7.23 (dt, 1H, J = 7.8, 1.4 Hz, H−Ar), 7.32−7.37 (brs, 5H, H− Ar), 7.92−7.95 (dd, 1H, J = 7.8, 1.2 Hz, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.3, 26.0, 26.4, 27.9, 30.1, 59.7, 67.9, 98.6, 106.6, 127.1, 129.0, 129.1, 129.7, 130.2, 136.1, 137.9, 140.0, 141.2, 160.2, 164.1; HRMS (ESI) calcd for C23H24IN2O2 [M + H]+ 487.08728, found 487.08735; calcd for C23H23IN2NaO2 [M + Na]+ 509.06913, found 509.06921; IR ν (cm−1) 2928, 1682, 1610. 1-Cyclohexyl-6-methylene-4-(4-nitrophenyl)-3-phenylpiperazine-2,5-dione (6i): Yellow solid, 324 mg (80%), mp 162−165 °C; 1 H NMR (CDCl3, 300 MHz) δ (ppm) = 1.10−1.41 (m, 3H, H-cyc), 1.55−1.68 (m, 2H, H-cyc), 1.80−1.83 (m, 3H, H-cyc), 2.03−2.21 (m, 2H, H-cyc), 3.92−4.02 (m, 1H, H-cyc), 5.27 (s, 1H, CH), 5.45 (s, 1H, CH), 6.01 (s, 1H, −C(sp3)−H), 7.27−7.40 (m, 5H, H−Ar), 7.44 (d, 2H, J = 9.1 Hz, H−Ar), 8.18 (d, 2H, J = 9.1 Hz, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.2, 25.9, 26.3, 27.6, 30.1, 59.2, 67.1, 107.8, 124.5, 124.6, 125.6, 129.1, 129.4, 134.9, 137.3, 145.1, 145.4, 161.3, 163.6; HRMS (ESI) calcd for C23H24IN2O2 [M + H]+ 487.08728, found 487.08735; calcd for C23H23IN2NaO2 [M + Na]+ 509.06913, found 509.06921 C23H24N3O4 [M + H]+ 406.17644, found 406.17611; calcd for C23H23N3NaO4 [M + Na]+ 428.15808, found 428.15803; calcd for C46H46N6NaO8 [2M + Na]+ 833.32705, found 833.32704; IR ν (cm−1) 2931, 1692, 1620. 1-Cyclohexyl-6-methylene-4-(4-nitrophenyl)-3-phenylpiperazine-2,5-dione (6j): Colorless solid, 311 mg (80%), mp 162−165 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.15−1.40 (m, 3H, Hcyc), 1.58−1.68 (m, 2H, H-cyc), 1.75−1.84 (m, 3H, H-cyc), 2.05− 2.25 (m, 2H, −CH2 cyc), 2.18 (s, 3H, −Me), 2.20 (s, 3H, −Me), 3.96−4.04 (m, 1H, H-cyc), 5.22 (s, 1H, CH), 5.29 (s, 1H, CH), 6.00 (s, 1H, −C(sp3)−H), 6.00 (s, 1H, H−Ar), 6.85 (dd, 1H, J = 8.1, 1.8 Hz, H−Ar), 7.00 (brs, 1H, H−Ar), 7.05 (d, 1H, J = 8.1 Hz, H− Ar), 7.30−7.37 (m, 5H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 19.4, 19.8, 25.3, 26.0, 26.4, 27.6, 30.0, 58.9, 68.2, 106.2, 122.8, 126.4, 126.8, 128.6, 129.0, 130.2, 136.0, 136.3, 137.2, 137.6, 138.0, 160.8, 164.5; HRMS (ESI) calcd for C25H29N2O2 [M + H]+ 389.22347, found 389.22324; calcd for C25H28N2NaO2 [M + Na]+ 411.20538, found 411.20517; calcd for C25H28KN2O2 [M + K]+ 427.17950, found 427.17926; calcd for C50H57N4O4 [2M + H]+ 777.44041, found 777.44007; calcd for C50H56N4NaO4 [2M + Na]+ 799.42116, found 799.42096; calcd for C50H56KN4O4 [2M + K]+ 815.39551, found 815.39527; IR ν (cm−1) 2893, 1682, 1614. 1-Benzyl-4-cyclohexyl-3-methylene-6-phenylpiperazine2,5-dione (6k): Colorless solid, 332 mg (89%), mp 123−128 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.06−1.38 (m, 3H, H-cyc), 1.54−1.65 (m, 2H, H-cyc), 1.72−1.82 (m, 3H, H-cyc), 2.03−2.26 (m, 2H, H-cyc), 3. 60 (d, J = 14.7 Hz, 1H, -N−CHPh), 3.88−4.01 (m, 1H, -N−CH-cyc), 4.87 (s, 1H, CH), 5.23 (s, 1H, CH), 5.50 (d, 1H, J = 14.7 Hz, -N−CHPh), 6.03 (s, 1H, −C(sp3)−H), 7.20−7.24 (m, 2H, H−Ar), 7.25−7.29 (m, 2H, H−Ar), 7.30−7.40 (m, 6H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.2, 26, 26.4, 27.6, 29.7, 47.5, 58.9, 63.4, 105.3, 126.7, 128.1, 128.6, 128.8, 128.9, 129.2, 135.2, 135.8, 137.0, 160.6, 164.0; HRMS (ESI) calcd for C 24H27N2O2 [M + H]+ 375.20633, found 375.20641; calcd for C24H26N2NaO2 [M + Na]+ 397.18824, found 397.18832; IR ν (cm−1) 2927, 1677, 1609. Ethyl 2-(2-Methylene-3,6-dioxo-4,5-diphenylpiperazine-1yl)acetate (6l): Yellow solid, 292 mg (80%), mp 76−82 °C; 1H 12149

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

Article

The Journal of Organic Chemistry

89.234(3)°, β = 71.160(3)°, γ = 75.601(3)°, V = 1237.5(3) Å3, ρ = 1.209 g/cm3, T = 110(2) K, θmax= 25.119°, radiation Mo Kα, λ = 0.71073 Å, 0.5° ω-scans with CCD area detector, covering the asymmetric unit in reciprocal space with a mean redundancy of 2.50 and a completeness of 99.3% to a resolution of 0.84 Å, 10 960 reflections measured, 4388 unique (R(int) = 0.0389), 3215 observed (I > 2σ(I)), intensities were corrected for Lorentz and polarization effects; an empirical absorption correction was applied using SADABS14 based on the Laue symmetry of the reciprocal space, μ = 0.08 mm−1, Tmin = 0.93, Tmax = 0.96, structure refined against F2 with a full-matrix least-squares algorithm using the SHELXL-2014/7 software,14 308 parameters refined; hydrogen atoms were treated using appropriate riding models, goodness of fit 1.11 for observed reflections, final residual values R1(F) = 0.056, wR(F2) = 0.111 for observed reflections, residual electron density −0.30 to 0.20 eÅ−3. CCDC 1562017 contains the supplementary crystallographic data for this paper. These data can be obtained free of charge from The Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/ data_request/cif. (Z)-3-Benzylidene-1-(2-bromophenyl)-4-cyclohexyl-6-phenylpiperazine-2,5-dione (8f): Colorless solid, 258 mg (50%), mp 177−182 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.34−0.46 (m, 1H, H-cyc), 0.86−1.17 (m, 2H, H-cyc), 1.37−1.59 (m, 3H, H-cyc), 1.66−1.77 (m, 2H, H-cyc), 2.04−2.16 (m, 1H, H-cyc), 2.31−2.48 (m, 1H, H-cyc), 2.96−3.05 (m, 1H, H-cyc), 5.15 (s, 1H, −C(sp3)−H), 7.08−7.11 (m, 2H, H−Ar), 7.15−7.18 (m, 1H, H−Ar), 7.20−7.30 (m, 5H, H−Ar, CH), 7.33−7.35 (m, 2H, H−Ar), 7.37−7.42 (m, 2H, H−Ar), 7.55−7.57 (m, 2H, H−Ar), 7.73 (dd, 1H, J = 7.5, 2.1 Hz H− Ar); 13C NMR (75 MHz, CDCl3) δ 25.0, 26.2, 29.6, 30.0, 65.2, 69.3, 122.6, 124.9, 126.0, 128.4, 128.6, 128.7, 128.8, 129.1, 129.4, 130.0, 133.7, 133.8, 133.9, 135.0, 138.6, 163.3, 166.3; HRMS (ESI) calcd for ̂ Br [M + H]+ 515.13396, found 515.13378; calcd for C29H28N2O279 ̂ Br [M + H]+ 517.13183, found 517.13167; IR ν (cm−1) C29H28N2O281 2926, 1684, 1621. Ethyl (Z)-2-(2-Benzylidene-5-(4-nitrophenyl)-3,6-dioxo-4phenylpiperazin-1-yl)acetate (8g): Yellow solid, 409 mg (85%), mp 114−120 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.42−0.51 (m, 1H, H-cyc), 0.92−1.06 (m, 2H, H-cyc), 1.34−1.42 (m, 1H, Hcyc), 1.49−1.53 (m, 2H, H-cyc), 1.63−1.67 (m, 2H, H-cyc), 1.83− 2.01 (m, 2H, H-cyc), 2.28−2.40 (m, 1H, H-cyc), 2.94−3.02 (m, 1H, H-cyc), 5.54 (s, 1H, −C(sp3)−H), 6.86−6.89 (m, 2H, H−Ar), 7.22− 7.26 (m, 2H, H−Ar,  CH), 7.31−7.33 (m, 1H, H−Ar), 7.35−7.49 (m, 6H, H−Ar), 7.52−7.58 (m, 2H, H−Ar), 8.17−8.27 (m, 2H, H− Ar); 13C NMR (75 MHz, CDCl3) δ 24.9, 25.3, 25.9, 26.1, 29.3, 30.0, 31.8, 59.8, 64.4, 67.8, 68.3, 123.6, 123.7, 124.6, 125.0, 125.1, 126.4, 128.1, 128.3, 128.6, 129.0, 129.1, 129.3, 129.4, 133.1, 133.5, 133.8, 133.9, 145.0, 145.5, 161.6, 163.9, 165.2, 165.7; HRMS (ESI) calcd for C29H28N3O4 [M + H]+ 482.20872, found 482.20850; IR ν (cm−1) 2929, 1688, 1525. (Z)-1-Benzyl-3-benzylidene-4-cyclohexyl-6-phenylpiperazine-2,5-dione (8h): Colorless solid, 392 mg (87%), mp 118−123 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.29−0.43 (m, 1H, Hcyc), 0.84−1.07 (m, 2H, H-cyc), 1.24−1.78 (m, 5H, H-cyc), 1.89− 2.02 (m, 1H, H-cyc), 2.20−2.38 (m, 1H, H-cyc), 2.88−3.02 (m, 1H, H-cyc), 3.91 (d, 1H, J = 14.9 Hz, −CH2Ph), 4.94 (s, 1H, −C(sp3)− H), 5.53 (d, 1H, J = 14.9 Hz, −CH2Ph), 7.02−7.06 (m, 2H, H−Ar), 7.22−7.31 (m, 6H, H−Ar, CH), 7.34−7.40 (m, 8H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.0, 26.2, 26.2, 29.4, 29.8, 48.4, 64.6, 65.0, 124.0, 125.7, 128.0, 128.4, 128.5, 128.6, 128.7, 128.9, 129.1, 133.3, 134.2, 134.6, 135.5, 164.2, 166.3; HRMS (ESI) calcd for C30H31N2O2 [M + H]+ 451.23786, found 451.23789; calcd for C30H30N2NaO2 [M + Na]+ 473.21970, found 473.21974; IR ν (cm−1) 2930, 1683, 1624. Ethyl (Z)-2-(2-Benzylidene-3,6-dioxo-4,5-diphenylpiperazin1-yl)acetate (8i): Yellow solid, 242 mg (55%), mp 165−170 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.22 (t, 3H, J = 6.3 Hz, −CH3), 3.64 (d, 1H, J = 17.3 Hz, N−CH2), 4.08−4.18 (m, 2H, −OCH2), 4.54 (d, 1H, J = 17.3 Hz, N−CH2), 5.61 (s, 1H, −C(sp3)−H), 7.05−7.08 (m, 2H, H−Ar), 7.25−7.31 (m, 5H, H−Ar, CH), 7.33−7.44 (m, 7H, H−Ar), 7.52−7.55 (m,2H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 14.1, 47.4, 61.7, 68.0, 123.9, 124.9, 125.6, 127.1, 128.9, 129.0, 129.3,

2H, H-cyc), 1.63−1.68 (m, 2H, H-cyc), 1.92−2.04 (m, 1H, H-cyc), 2.29−2.42 (m, 1H, H-cyc), 2.94−3.02 (m, 1H, H-cyc), 5.46 (s, 1H, −C(sp3)−H), 6.90−6.93 (m, 2H, H−Ar), 7.22−7.29 (m, 6H, H−Ar, CH), 7.30−7.44 (m, 7H, H−Ar), 7.50−7.53 (m, 2H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.0, 26.2, 29.4, 30.0, 64.3, 68.5, 69.0, 115.4, 124.2, 125.1, 125.4, 125.5, 126.8, 127.2, 128.1, 128.3, 128.5, 128.7,128.9, 129.1, 129.5, 133.2, 133.9, 134.0, 135.0, 140.2, 161.6, 163.8, 166.6; HRMS (ESI) calcd C29H29N2O2 [M + H]+ 437.22293, found 437.22282; calcd for C29H28N2NaO2 [M + Na]+ 459.20495, found 459.20495; IR ν (cm−1) 2933, 1680, 1615. (Z)-3-Benzylidene-6-(4-bromophenyl)-4-cyclohexyl-1-phenylpiperazine-2,5-dione (8b): Colorless solid, 454 mg (88%), mp 165−170 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.36−0.49 (m, 1H, H-cyc), 0.88−1.10 (m, 2H, H-cyc), 1.37−1.41 (m, 1H, H-cyc), 1.48−1.52 (m, 2H, H-cyc), 1.64−1.69 (m, 2H, H-cyc), 1.88−2.03 (m, 1H, H-cyc), 2.26−2.42 (m, 1H, H-cyc), 2.94−3.03 (m, 1H, H-cyc), 5.39−5.46 (s, 1H, −C(sp3)−H), 6.89−6.98 (m, 2H, H−Ar), 7.22− 7.36 (m, 9H, H−Ar, CH), 7.38 (d, 2H, J = 8.4 Hz, H−Ar), 7.54 (d, 2H, J = 8.4 Hz, H−Ar); 13C NMR (75 MHz, CDCl3) δ 24.9, 26.1, 29.4, 30.0, 64.4, 68.6, 122.7, 124.2, 125.3, 126.9, 127.1, 128.3, 128.5, 128.6, 128.9, 129.1, 129.2, 132.2, 133.5, 133.7, 134.2, 140.0, 163.5, 166.0; HRMS (ESI) calcd C29H28BrN2O2 [M + H]+ 515.13304, found 515.13301; calcd for C29H27BrN2NaO2 [M + Na]+ 537.11491, found 537.11489; IR ν (cm−1) 2926, 1684, 1627. (Z)-3-Benzylidene-6-(4-chlorophenyl)-4-cyclohexyl-1-phenylpiperazine-2,5-dione (8c): Colorless solid, 353 mg (75%), mp 165−170 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.36−0.50 (m, 1H, H-cyc), 0.88−1.10 (m, 2H, H-cyc), 1.38−1.42 (m, 1H, H-cyc), 1.49−1.56 (m, 2H, H-cyc), 1.64−1.68 (m, 2H, H-cyc), 1.91−2.04 (m, 1H, H-cyc), 2.29−2.43 (m, 1H, H-cyc), 2.95−3.03 (m, 1H, H-cyc), 5.42 (s, 1H, −C(sp3)−H), 6.96−6.99 (m, 2H, H−Ar), 7.25−7.30 (m, 6H, H−Ar), 7.31−7.37 (m, 3H, H−Ar, CH), 7.39 (d, 2H, J = 8.5 Hz, H−Ar), 7.43 (d, 2H, J = 8.5 Hz, H−Ar).; 13C NMR (75 MHz, CDCl3) δ 25.0, 26.1, 29.4, 30.0, 64.4, 68.5, 124.2, 125.3, 126.8, 126.9, 128.3, 128.6, 128.9, 129.2, 129.3, 133.6, 133.7, 133.8, 134.6, 139.9, 163.5, 166.1; HRMS (ESI) calcd C29H28N2O2̂35Cl [M + H]+ ̂ Cl [M + 471.18320, found 471.18323; calcd for C29H27N2NaO235 Na]+ 493.16510, found 493.16514; IR ν (cm−1) 2926, 1685, 1625. (Z)-3-Benzylidene-4-cyclohexyl-6-(4-methoxyphenyl)-1-phenylpiperazine-2,5-dione (8d): Colorless solid, 396 mg (85%), mp 167−171 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.34−0.49 (m, 1H, H-cyc), 0.87−1.17 (m, 2H, H-cyc), 1.37−1.41 (m, 1H, H-cyc), 1.48−1.55 (m, 2H, H-cyc), 1.64−1.70 (m, 2H, H-cyc), 1.85−2.07 (m, 1H, H-cyc), 2.29−2.43 (m, 1H, H-cyc), 2.94−3.03 (m, 1H, H-cyc), 3.79 (s, 3H, −OMe), 5.38 (s, 1H, −C(sp3)−H), 6.92 (d, 2H, J = 8.7 Hz, H−Ar), 6.98−7.01 (m, 2H, H−Ar), 7.22−7.27 (m, 5H, H−Ar,  CH), 7.32−7.38 (m, 4H, H−Ar), 7.42 (d, 2H, J = 8.7 Hz, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.0, 26.2, 29.4, 30.0, 55.3, 64.2, 68.6, 114.4, 124.3, 124.7, 126.7, 126.8, 127.1, 128.4, 128.5, 128.7, 129.1, 134.0, 140.2, 159.7, 163.6, 166.8; HRMS (ESI) calcd for C30H31N2O3 [M + H]+ 467.23285, found 467.23286; calcd for C30H30N2NaO3 [M + Na]+ 489.21476, found 489.21478; IR ν (cm−1) 2933, 1683, 1615. (Z)-3-Benzylidene-4-cyclohexyl-1-phenyl-6-(p-tolyl) piperazine-2,5-dione (8e): Colorless solid, 401 mg (89%), mp 174−178 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.36−0.49 (m, 1H, Hcyc), 0.89−1.11 (m, 2H, H-cyc), 1.28−1.42 (m, 1H, H-cyc), 1.51− 1.52 (m, 2H, H-cyc), 1.65−1.68 (m, 2H, H-cyc), 1.93−2.05 (m, 1H, H-cyc), 2.34 (s, 3H, −Me), 2.35−2.39 (m, 1H, H-cyc), 2.95−3.03 (m, 1H, H-cyc), 5.41 (s, 1H, −C(sp3)−H), 6.95−6.98 (m, 2H, H−Ar,  CH), 7.20 (bs, 1H, H−Ar), 7.22−7.23 (m,2H, H−Ar), 7.25−7.27 (m, 4H, H−Ar)7.33−7.41 (m, 6H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 21.1, 25.0, 26.2, 29.4, 30.0, 64.2, 68.9, 124.3, 124.8, 125.3, 126.7, 128.4, 128.5, 128.6, 129.1, 129.7, 132.1, 134.1, 138.3, 140.2, 163.7, 166.7; HRMS (ESI) calcd for C30H31N2O2 [M + H]+ 451.23817, found 451.23814; calcd for C30H30N2NaO2 [M + Na]+ 473.22002, found 473.22001; IR ν (cm−1) 2929, 1688, 1627. Further purification of 8e was done by recrystallization of the sample in methanol: Colorless crystal (polyhedron), dimensions 0.190 × 0.160 × 0.110 mm3, crystal system triclinic, space group P1̅, Z= 2, a = 9.0717(11) Å, b = 11.0319(12) Å, c = 13.5250(18) Å, α = 12150

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

The Journal of Organic Chemistry

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131.5, 132.7, 135.1, 140.4, 162.8, 166.9, 167.4; HRMS (ESI) calcd for C27H25N2O4 [M + H]+ 441.18132, found 441.18124; calcd for C27H24N2NaO4 [M + Na]+ 463.16302, found 463.16299; IR ν (cm−1) 2984, 1695, 1632. Ethyl (Z)-2-(2-Benzylidene-3,6-dioxo-4-phenyl-5-(p-tolyl) piperazin-1-yl)acetate (8j): Yellow solid, 341 mg (75%), mp 160−164 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.21 (t, 3H, J = 7.1 Hz, −CH3), 2.34 (s, 3H, C−CH3), 3.64 (d, 1H, J = 17.3 Hz, N−CH2), 4.08−4.18 (m, 2H, −OCH2), 4.53 (d, 1H, J = 17.3 Hz, N−CH2), 5.56 (s, 1H, −C(sp3)−H), 7.08−7.11 (m, 2H, H−Ar), 7.19−7.22 (m, 2H, H−Ar), 7.26−7.42 (m, 11H, H−Ar, CH); 13C NMR (75 MHz, CDCl3) δ 14.0, 21.1, 47.4, 61.7, 67.9, 123.6, 124.9, 125.5, 127.0, 128.8, 129.0, 129.2, 129.9, 131.6, 132.1, 132.8, 138.7, 140.4, 162.8, 167.0, 167.4; HRMS (ESI) calcd for C28H27N2O4 [M + H]+ 455.19696, found 455.19688; calcd for C28H26N2NaO4 [M + Na]+ 477.17889, found 477.17882; IR ν (cm−1) 2921, 1692, 1632. Ethyl (Z)-2-(2-Benzylidene-5-(4-methoxyphenyl)-3,6-dioxo4-phenylpiperazin-1-yl)acetate (8k): Yellow solid, 282 mg (60%), mp 87−92 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 1.21 (t, 3H, J = 7.1 Hz, −CH3), 3.66 (d, 1H, J = 17.3 Hz, N−CH2), 3.79 (s, 3H, −OCH3), 4.09−4.17 (m, 2H, −OCH2), 4.54 (d, 1H, J = 17.3 Hz, N−CH2), 5.53 (s, 1H, −C(sp3)−H), 6.89−6.94 (m, 2H, H− Ar), 7.09−7.13 (m, 2H, H−Ar), 7.24−7.34 (m, 6H, H−Ar, CH), 7.34−7.36 (m, 2H, H−Ar), 7.37−7.41 (m, 1H, H−Ar), 7.42−7.46 (m, 2H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 14.1, 47.4, 55.3, 61.7, 67.6, 114.6, 123.7, 125.0, 126.9, 127.0, 127.1, 128.9, 129.0, 129.2, 131.5, 132.8, 140.4, 159.9, 162.7, 167.1, 167.5; HRMS (ESI) calcd for C28H26N2O5 [M + H]+ 471.19213, found 471.19200; calcd for C56H53N4O10 [2M + H]+ 941.37648, found 941.37640; IR ν (cm−1) 1693, 1627. (Z)-3-(4-(tert-Butyl)benzylidene)-4-cyclohexyl-1-phenyl-6-(ptolyl) piperazine-2,5-dione (8l): Colorless solid, 456 mg (90%), mp 180−183 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.31−0.44 (m, 1H, H-cyc), 0.88−1.11 (m, 2H, H-cyc), 1.28 (s, 9H, t-Bu), 1.34−1.54 (m, 3H, H-cyc), 1.64−1.68 (m, 2H, H-cyc), 1.82−2.05 (m, 1H, Hcyc), 2.35 (m, 4H, −Me, H-cyc), 2.90−2.98 (m, 1H, H-cyc), 5.40 (s, 1H, −C(sp3)−H), 6.88 (d, 2H, H−Ar), 7.20−7.23 (m, 3H, H−Ar), 7.25−7.30 (m, 3H, H−Ar, CH), 7.33−7.44 (m, 6H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 21.1, 25.0, 26.1, 26.2, 29.5, 29.9, 31.2, 34.7, 64.1, 68.9, 124.3, 124.9, 125.4, 126.7, 128.1, 128.2, 129.1, 129.7, 131.0, 131.1, 132.2, 133.8, 135.1, 138.3, 140.3, 152.1, 163.8, 166.5, 166.7; HRMS (ESI) calcd for C34H39N2O2 [M + H]+ 507.30090, found 507.30085; calcd for C34H38N2NaO2 [M + Na]+ 529.28255, found 529.28283; IR ν (cm−1) 2958, 1686, 1628. (Z)-1-Benzyl-3-(4-(tert-butyl)benzylidene)-4-cyclohexyl-6phenylpiperazine-2,5-dione (8m): Colorless solid, 456 mg (90%), mp 158−163 °C; 1H NMR (CDCl3, 300 MHz) δ (ppm) = 0.26−0.37 (m, 1H, H-cyc), 0.90−1.06 (m, 2H, H-cyc), 1.28 (s, 9H, t-Bu), 1.35− 1.51 (m, 3H, H-cyc), 1.57−1.70 (m, 2H, H-cyc), 1.90−2.02 (m, 1H, H-cyc), 2.24−2.36 (m, 1H, H-cyc), 2.89−2.99 (m, 1H, H-cyc), 3.89 (d, 1H, J = 14.7 Hz, −CH2Ph), 4.92 (s, 1H, −C(sp3)−H), 5.53 (d, 1H, J = 14.7 Hz, −CH2Ph), 6.98 (d, 2H, J = 8.1 Hz, H−Ar), 7.22−7.25 (m, 2H, H−Ar), 7.26−7.34 (m, 5H, H−Ar, CH), 7.35−7.38 (m, 6H, H−Ar); 13C NMR (75 MHz, CDCl3) δ 25.0, 26.1, 26.2, 29.6, 29.8, 31.1, 34.7, 48.3, 64.4, 65.0, 124.1, 125.4, 125.7, 127.9, 128.0, 128.1, 128.5, 128.9, 129.0, 131.2, 133.0, 134.6, 135.6, 152.0, 164.3, 166.2; HRMS (ESI) calcd for C34H39N2O2 [M + H]+ 507.30108, found 507.30100; calcd for C68H77N4O4 [2M + H]+ 1013.59401, found 1013.59400; IR ν (cm−1) 2957, 1683, 1622.

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AUTHOR INFORMATION

Corresponding Author

*E-mail: [email protected]. Tel: +98-21-23064226. Fax: +9821-22889403. ORCID

Saeed Balalaie: 0000-0002-5764-0442 Notes

The authors declare no competing financial interest.

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ACKNOWLEDGMENTS We thank the National Institute for Medical Research Development (NIMAD) for financial support.

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DEDICATION Dedicated to Prof. Dr. Rolf Gleiter on the occasion of his 80th birthday.

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REFERENCES

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ASSOCIATED CONTENT

S Supporting Information *

The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.joc.7b01855. Figures, tables, and CIF files giving 1H NMR, 13C NMR, IR, and HRMS spectra for compounds 6a−q and 8a−m (PDF) X-ray crystal data for 6c (CIF) X-ray crystal data for 8e (CIF) 12151

DOI: 10.1021/acs.joc.7b01855 J. Org. Chem. 2017, 82, 12141−12152

Article

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