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Article

Highly Efficient and Diastereoselective Synthesis of New Pyrazolylpyrrolizine and Pyrazolylpyrrolidine Derivates by a Three-Component Domino Process

by
Jairo Quiroga
1,*,
Jaime Gálvez
1,
Rodrigo Abonia
1,
Braulio Insuasty
1,
Alejandro Ortíz
1,
Justo Cobo
2 and
Manuel Nogueras
2
1
Heterocyclic Compounds Research Group, Department of Chemistry, Universidad del Valle, Cali 760032, Colombia
2
Department of Inorganic and Organic Chemistry, Universidad de Jaén, Jaén 23071, Spain
*
Author to whom correspondence should be addressed.
Molecules 2014, 19(4), 4284-4300; https://doi.org/10.3390/molecules19044284
Submission received: 6 February 2014 / Revised: 27 March 2014 / Accepted: 28 March 2014 / Published: 4 April 2014
(This article belongs to the Section Organic Chemistry)
Browse Figures
Versions Notes

Abstract

:
Diastereoselective reactions between 4-formylpyrazoles, N-substituted maleimides and glycine derivates led to new series of pyrazolyldipyrrolo [3,4-a:3',4'-f]pyrrolizines and pyrazolylpyrrolo[3,4-c]pyrroles in good yields. The reactions proceeded by a domino process through azomethine ylides formed in situ via a 1,3-dipolar cycloaddition reaction.

Graphical Abstract

1. Introduction

Multicomponent reactions (MCRs) are one of the most powerful tools in organic synthesis allowing the formation of several bonds in one step to obtain products with high structural diversity and/or molecular complexity [1,2,3]. Furthermore, the development of fast, selective and environmentally friendly MCRs involving domino processes with step and atom economy are of great importance for medicinal and synthetic chemistry [4,5,6].
The dipolar cycloaddition reaction is a known and widely studied method in organic synthesis to obtain pyrrolidine derivatives from the reaction of azomethine ylides, generated in situ, and electron-deficient olefins [7,8,9]. These five-membered ring systems belong to an important class of aza-compounds with multiple applications, for example, in the development of bioactive molecules, organocatalysts, new materials and as scaffolds in total organic synthesis [10,11,12,13].
Some interesting fused pyrrolidine systems as cyclopiazonic acid, granulatimide and isogranulatimide (Figure 1) are natural alkaloids that displayed important activities as Chk1 inhibitors and antiplasmodial agents [14,15]. Pyrrolizines are alkaloids generally isolated from plants, insects, bacteria or fungi [16,17] that have exhibited important antiproliferative activities [18,19]. In the same way, the pyrrolo[3,4-c]pyrroles have been widely applied in a variety of fields such as materials sciences, pharmaceuticals and agrochemistry [20,21,22].
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Figure 1. Pyrrolidine systems present in natural alkaloids.
Figure 1. Pyrrolidine systems present in natural alkaloids.
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Pyrazole is another five-membered ring with many applications in chemistry, especially as pharmaceuticals, pesticides and lubricants [23,24,25,26,27]. In connection with our current studies on the development of new, selective, and environmentally friendly methodologies for the synthesis of fused heterocycles [28,29,30,31], herein we report a procedure for the preparation of the scarcely studied pyrazolylpyrrolizine derivates 4 and pyrazolylpyrrolidine derivatives 5 and 6 where three moieties of known importance (i.e., pyrazole, pyrrolidine, pyrrolizine) are incorporated into a single structure. The new compounds were obtained in good yields and high diastereoselectivity by a catalyst-free three-component domino reaction between formylpyrazoles 1, N-arylmaleimides 2 and glycine-derived esters 3 (Scheme 1).
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Scheme 1. Proposed synthesis of new pyrazolylpyrrolopyrrolizine derivates 4 and pyrazolylpyrrolopyrrolidine derivates 5 and 6.
Scheme 1. Proposed synthesis of new pyrazolylpyrrolopyrrolizine derivates 4 and pyrazolylpyrrolopyrrolidine derivates 5 and 6.
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2. Results and Discussion

2.1. Synthesis of Pyrazolyldipyrrolo[3,4-a:3',4'-f]Pyrrolizines from Glycine Methyl Ester

To the best of our knowledge, not many pyrrolo[3,4-a:3',4'-f]pyrrolizine derivatives have been synthesized and few of them via 1,3-dipolar reactions [32,33,34]. Recently Zhang and coworkers reported the synthesis of pyrrolopyrrolizines from 2-furanyl and 2-thiophenylpyrrolizines by a multicomponent reaction under microwave irradiation using hetarylcarbaldehydes [33]. Similarly, our synthesis (Scheme 2) was carried out by a three-component combinatorial methodology between formylpyrazoles 1, N-substituted-maleimides 2 and glycine methyl ester 3 in refluxing toluene affording the products 4 via a double cycloaddition reaction (Table 1).
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Scheme 2. Three-component synthesis of pyrazolyldipyrrolo[3,4-a:3',4'-f]pyrrolizines 4a-j.
Scheme 2. Three-component synthesis of pyrazolyldipyrrolo[3,4-a:3',4'-f]pyrrolizines 4a-j.
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Table
Table 1. Synthesis of diverse pyrazolyldipyrrolo[3,4-a:3',4'-f]pyrrolizines 4a–j.
Table 1. Synthesis of diverse pyrazolyldipyrrolo[3,4-a:3',4'-f]pyrrolizines 4a–j.
EntryR1R2Yield (%)
4a-CH3C6H596
4b-CH3p-ClC6H473
4c-CH3p-CH3C6H484
4d-CH3p-CH3OC6H490
4e-CH3(3,4-OCH2O)C6H3CH278
4fC6H5C6H581
4gC6H5p-ClC6H475
4hC6H5p-CH3C6H493
4iC6H5p-CH3OC6H494
4jC6H5(3,4-OCH2O)C6H3CH275
The reaction consists of a domino process as shown in Scheme 3. We propose that initially the condensation of the glycine derivative 3a with the formylpyrazole 1a produced the imine 7a; subsequently, a 1,2-proton shift in imine 7a should afford the azomethine ylide 7b, which in turn should be trapped by the maleimide 2a to generate the intermediate pyrrolopyrrolidine derivative 8 (Scheme 3) [28].
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Scheme 3. Proposed mechanism for the synthesis of pyrazolyldipyrrolo[3,4-a:3',4'-f] pyrrolizine 4a.
Scheme 3. Proposed mechanism for the synthesis of pyrazolyldipyrrolo[3,4-a:3',4'-f] pyrrolizine 4a.
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A second condensation should take place between the pyrrolidine intermediate 8 and the formylpyrazole 1a affording the iminium ion 9a, which should generate the 1,3-dipolar azomethine ylide 9b by deprotonation of its acidic proton adjacent to the carbomethoxy group. Finally, the tetracyclic product 4a would be formed by the diastereoselective 1,3-cycloaddition of a second molecule of maleimide 2a to the ylide 9b. During the process, the formation of the azomethine ylides 7b and 9b should be favored by the acidity of the α-protons in the moieties 7a and 9a and the in situ stability of these species due to an intramolecular H-bond and π-conjugation [8,35,36,37].
The structural elucidation of the new compounds 4a–j was made by analysis of the corresponding NMR, infrared and mass spectrometry data. The 1H-NMR spectra of compounds 4a–j show six aliphatic signals corresponding to the protons on the stereogenic centers of the dipyrrolopyrrolizine framework. Two of them appear as triplets corresponding to the H-6a and H-9a protons, and the remaining four appear as doublets assigned to the H-3a, H-3c, H-7 and H-9 protons. Crystals of compound 4g suitable for single-crystal X-ray diffraction were obtained by slow evaporation from a DMF:EtOH (1:1), thus solution confirming the structure and stereochemistry of the racemic compounds 4a–j (Figure 2) [38].
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Figure 2. ORTEP drawing of the compound 4g with 50% probability elipsoids. In the ORTEP view of the tetracyclic scaffold, the aryl pendant groups have been removed for the sake of clarity.
Figure 2. ORTEP drawing of the compound 4g with 50% probability elipsoids. In the ORTEP view of the tetracyclic scaffold, the aryl pendant groups have been removed for the sake of clarity.
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2.2. Synthesis of Pyrazolylpyrrolo[3,4-c]Pyrroles from N-benzylglicine Ethyl Ester

On the other hand, it is known that a similar three-component reaction using α-amino acids can be stopped at the pyrazolyl-pyrrolo[3,4-c]pyrroles 8 if the second cycloaddition is blocked by replacing the proton on the α-carbon atom by an alkyl group [28,29]. Thus, in order to preclude the formation of compounds type 4, we performed the reaction with N-benzylglycine ethyl ester 3b instead of 3a, along with the formylpyrazoles 1a–b and maleimides 2a–e (Scheme 4). As anticipated, the second amino condensation on the pyrrolidine nitrogen was blocked and the new compounds 5a–f and 6a–f were obtained in a diastereoselective manner with good yields (Table 2).
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Scheme 4. Three-component synthesis of pyrazolylpyrrolo[3,4-c]pyrroles 5 and 6.
Scheme 4. Three-component synthesis of pyrazolylpyrrolo[3,4-c]pyrroles 5 and 6.
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Table
Table 2. Synthesis of diverse pyrazolylpyrrolo[3,4-c]pyrroles 5 and 6.
Table 2. Synthesis of diverse pyrazolylpyrrolo[3,4-c]pyrroles 5 and 6.
EntryR1R2d:r a (5:6)Yield (%) 5 + 6
1-CH3C6H51:795
2-CH3p-ClC6H41:782
3-CH3p-CH3OC6H41:796
4C6H5C6H51:775
5C6H5p-ClC6H41:772
6C6H5p-CH3OC6H41:790
a Determinated by NMR.
In this approach, the first step is a condensation between the formylpyrazole 1a and the N-benzyl glycine ethyl ester 3b affording the iminium ion 10a, which is subsequently deprotonated giving azomethine ylide 10b (Scheme 5). Then, the 1,3-dipolar cycloaddition of 10b with the N-phenyl maleimide 2a afforded the diastereomers 5a and 6a. In all cases, the reaction showed good diastereoselectivity toward isomers 6, in which repulsive interactions between the ester group on the C-1 and C-6 carbonyl group are avoided due to the trans configuration between them as shown in 6a (Scheme 5) [17].
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Scheme 5. Proposed mechanism for the synthesis of pyrazolylpyrrolo[3,4-c]pyrroles 5a and 6a.
Scheme 5. Proposed mechanism for the synthesis of pyrazolylpyrrolo[3,4-c]pyrroles 5a and 6a.
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According to the 1H-NMR analysis of compounds 6 the H-1 proton on the stereogenic center appears as a singlet due to the dihedral angle (aprox. 90°) with the H-6a proton indicating a trans configuration. On the other hand, both the H-3 and H-6a protons appear as doublets with coupling constants about 9.0 Hz corresponding to a cis configuration with the H-3a proton, which in turn appears as a double doublet. Meantime, in compounds 5 the H-1 proton is observed as a doublet with a coupling constant J ≈ 9.0 Hz because of its cis configuration with respect to the H-6a proton, while the H-3 proton appears as a doublet with a smaller coupling constant (J ≈ 5.5 Hz) due to a trans configuration with respect to the H-3a proton [39].

2.3. Theoretical Calculations

To confirm our findings about the stereochemistry of the reactions as well as the obtained compounds 4–6, theoretical calculations were carried out with the DFT approach using the B.01 revision of the Gaussian 09 program package [40]. DFT calculations were performed using Becke’s three-parameter B3LYP exchange-correlation functional and the 6-311G++ basis set. The geometry of compound 6d was theoretically optimized and the most stable configuration is depicted in Figure 3. Although the found energy values for the cis and trans configurations of the stereoisomers 5d and 6d are very close, the trans configuration for 6d is slightly favored by 7.82696 × 10−17 Kcal over the cis form for 5d. This finding is in agreement with the Karplus theory [41] and with our experimental 1H-NMR measurements, since the dihedral angle 1H-C-C-6aH for the stereoisomer 6d is −94.41° and therefore in its 1H-NMR spectrum the coupling constant between the H-1 and H-6a protons has a value J3~0.0 Hz.
In order to verify the accuracy of the theoretical method, the geometry of compound 4g was theoretically optimized and the most stable configuration is depicted in Figure 4. Geometrical parameters such as bond length and molecular angles were calculated. We observed that the calculated parameters were very close to the experimental values, measured by X-ray diffraction. Some of these geometrical stocks are listed in Table 3.
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Figure 3. Minimum-energy configuration calculated for the compound 6d at the B3LYP/6-311G++ level. Dihedral Angle (1H-C-C-6aH) = −94.41°.
Figure 3. Minimum-energy configuration calculated for the compound 6d at the B3LYP/6-311G++ level. Dihedral Angle (1H-C-C-6aH) = −94.41°.
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Figure 4. Minimum-energy configuration calculated for compound 4g at the B3LYP/6-311G++ level.
Figure 4. Minimum-energy configuration calculated for compound 4g at the B3LYP/6-311G++ level.
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Table
Table 3. Geometrical parameters of compound 4g; X-ray data is compared with theoretical calculated parameters.
Table 3. Geometrical parameters of compound 4g; X-ray data is compared with theoretical calculated parameters.
BondX-Ray Length (Å)Calculated Length (Å)Angle AtomsX-Ray Angle (°)Calculated Angle (°)
C1-O11.210(2)1.213O1-C1-N2124.61(17)125.02
C1-N21.393(2)1.398O1-C1-C8a128.00(16)127.64
C1-C8a1.508(3)1.512N2-C1-C8a107.36(14)110.73
N2-C31.399(2)1.409C1-N2-C3112.48(15)114.34
C3-O31.209(2)1.211C1-N2-C21122.84(14)120.21
C3-C3a1.529(3)1.534C3-N2-C21124.47(15)124.88
C3c-C41.507(3)1.511O3-C3-N2124.53(17)123.00

3. Experimental

3.1. General Information

The pyrazole-4-carbaldehydes 1a–b and the glycine ester derivates 3a–b (analytical reagent grade) were purchased from Aldrich (St. Louis, Missouri, United State), Fluka (St. Louis, MO, USA) and Merck (Darmstadt, Alemania) and were used without further purification. The maleimides 2a–e were obtained according to the already reported procedure [42]. Solvents and other chemicals commercially available were used as shipped. Silica gel aluminium plates (Merck 60 F254) were used for analytical TLC. Melting points were taken on Stuart SMP10 Melting point apparatus and are uncorrected. IR spectra were recorded on a Shimadzu FTIR 8400 spectrophotometer using KBr disks or CH2Cl2 as solvent. 1H- and 13C-NMR were recorded on a Bruker Avance 400 spectrometer operating at 400 and 100 MHz respectively, using CDCl3 as solvent. Mass spectra were obtained on a Shimadzu GCMS-QP 2010 spectrometer (equipped with a direct inlet probe) operating at 70 eV and with a Bruker Esquire 6000 spectrometer equipped with an electrospray ionization source and an ion-trap detector. Microanalyses were performed on a LECO CHNS-900 elemental analyzer and the values are within ± 0.4% of theoretical values.

3.2. Synthesis and Characterization Data for Pyrazolyldipyrrolo[3,4-a:3',4'-f]Pyrrolizines 4a–j

General Synthetic Procedure

To a 25.0 mL round bottom flask equipped with a magnetic stirring bar and a reflux condenser were added pyrazole-4-carboxaldehyde 1a–b (0.2 mmol), N-substituted-maleimide 2a–e (0.2 mmol), glycine methyl ester 3a (0.2 mmol) and toluene (8 mL). The mixture was heated under reflux for 8–10 h. The reaction mixture was cooled to ambient temperature and the resulting precipitate was collected by filtration and washed with hexane-toluene (1:1) to obtain the pure compounds. In some cases, the solid was recrystallized from a mixture ethanol-DMF (1:1) to obtain the pure compound 4.
Methyl 7,9-bis(3-methyl-1-phenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxo-2,5-diphenyldodecahydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4a). Beige solid. Yield: 96%; m.p.: 182–184 °C. IR (KBr): ν 3473, 2954, 1753, 1715 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 2.01 (s, 3H), 2.26 (s, 3H), 3.51 (dd, J = 8.0 Hz; J = 8.3 Hz, 1H), 3.74 (t, J = 8.0 Hz, 1H), 3.99 (s, 3H), 4.29 (d, J = 8.3 Hz, 1H), 4.46 (d, J = 10.5 Hz, 1H), 4.64 (d, J = 8.3 Hz, 1H), 4.91 (d, J = 7.8 Hz, 1H), 6.81 (d, J = 8.8 Hz, 2H), 7.18 (d, J = 8.5 Hz, 2H), 7.20–7.26 (m, 2H), 7.28–7.39 (m, 12H), 7.53 (s, 1H), 7.57 (d, J = 8.8 Hz, 2H), 7.98 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 11.5 (CH3), 11.9 (CH3), 48.2 (CH), 48.9 (CH), 49.5 (CH), 53.2 (CH), 53.5 (OCH3), 58.1 (CH), 60.6 (CH), 79.34 (C), 112.2 (C), 118.4 (CH), 118.8 (CH), 119.4 (CH), 120.1 (C), 125.9 (CH), 126.3 (CH), 126.4 (CH), 126.8 (CH), 126.9 (CH), 127.3 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH), 129.40 (CH), 130.0 (CH), 134.3 (C), 135.4 (C), 139.6 (C), 139.7 (C), 146.6 (C), 150.7 (C), 170.2 (C), 171.7 (C), 173.2 (C), 174.7 (C), 175.7 (C). MS (EI, 70 eV) m/z (%): 771 (M+, 2), 712 (13), 598 (100), 539 (70), 268 (27), 211 (32), 171 (75). Elemental Analyses calcd. for C45H37N7O6.2H2O: C: 66.90, H: 5.12, N: 12.14. Found: C: 66.75, H: 5.47, N: 12.07.
Methyl 2,5-bis(4-chlorophenyl)-7,9-bis(3-methyl-1-phenyl-1H-pyrazol-4-yl)-1,3,4,6 tetraoxododeca-hydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4b). Pale yellow solid. Yield: 73%; m.p.: 170–172 °C. IR (KBr): ν 3479, 2953, 1716 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 2.03 (s, 3H), 2.29 (s, 3H), 3.53 (dd, J = 10.7, 8.2, 1H), 3.76 (t, J = 8.0 Hz, 1H), 4.02 (s, 3H), 4.31 (d, J = 8.3 Hz, 1H), 4.48 (d, J = 10.5 Hz, 1H), 4.66 (d, J = 8.3 Hz, 1H), 4.94 (d, J = 7.8 Hz, 1H), 6.83 (d, J = 8.8 Hz, 2H), 7.21 (d, J = 8.5 Hz, 2H), 7.26 (m, 2H), 7.37 (m, 10H), 7.55 (s, 1H), 7.60 (d, J = 8.8 Hz, 2H), 8.00 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 11.5 (CH3), 11.9 (CH3), 48.2 (CH), 48.9 (CH), 49.5 (CH), 53.2 (CH); 53.5 (OCH3), 58.1 (CH), 60.6 (CH), 79.3 (C), 112.2 (C) 118.8 (CH), 119.4 (CH), 120.1 (C), 125.9 (CH), 126.3 (CH), 126.4 (CH), 126.8 (CH), 126.9 (CH), 127.3 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH), 129.4 (C), 129.7 (C), 130.0 (CH), 134.3 (C), 135.4 (C), 139.6 (C), 139.7 (C), 146.6 (C), 150.7 (C), 170.2 (C), 171.7 (C), 173.2 (C), 174.7 (C), 175.7 (C). MS (EI, 70 eV) m/z (%): 839 (M+, 2), 780 (18), 632 (42), 268 (22), 211 (39), 171 (100). Elemental Analyses calcd. for C45H35Cl2N7O6.H2O: C: 62.94, H: 4.34, N: 11.42. Found: C: 63.32, H: 4.36, N: 11.34.
Methyl 7,9-bis(3-methyl-1-phenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxo-2,5-di-p-tolyldodecahydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4c). Beige solid. Yield: 84%; m.p.: 179–181 °C. IR (KBr): ν 3647, 2952, 1784, 1756, 1696 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 2.02 (s, 3H), 2.25 (s, 3H), 2.27 (s, 3H), 2.46 (s, 3H), 3.56 (dd, J = 10.7, 8.2 Hz, 1H), 3.71–3.77 (m, 1H), 4.00 (s, 3H), 4.28 (d, J = 8.3 Hz, 1H), 4.51 (d, J = 10.8 Hz, 1H), 4.66 (d, J = 8.3 Hz, 1H), 4.93 (d, J = 8.0 Hz, 1H), 6.75 (d, J = 8.3 Hz, 2H), 7.03 (d, J = 7.5 Hz, 2H), 7.21–7.25 (m, 4H), 7.33–7.39 (m, 5H), 7.39–7.44 (m, 5H), 7.58 (s, 1H), 8.04 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 11.5 (CH3), 11.9 (CH3), 21.0 (CH3), 21.3 (CH3), 48.2 (CH), 48.8 (CH), 49.6 (CH), 53.3 (CH), 53.4 (OCH3), 58.1 (CH), 60.5 (CH), 79.3 (C), 112.5 (C), 118.4 (CH), 118.9 (CH), 119.4 (CH), 120.3 (C), 125.4 (CH), 125.5 (CH), 125.7 (CH), 126.1 (CH), 126.3 (CH), 127.5 (CH), 128.4 (C), 128.6 (C), 129.2 (CH), 129.6 (CH), 130.4 (CH), 138.7 (C), 139.6 (C), 139.7 (C), 139.8 (C), 146.7 (C), 150.7 (C), 170.4 (C), 172.2 (C), 173.7 (C), 175.1 (C), 176.2 (C). MS (EI, 70 eV) m/z (%): 799 (M+, 2), 740 (8), 612 (100), 553 (18), 257 (60), 197 (75). Elemental Analyses calcd. for C47H41N7O6: C: 70.57, H: 5.17, N: 12.26. Found: C: 70.87, H: 5.41, N: 11.90.
Methyl 2,5-bis(4-methoxyphenyl)-7,9-bis(3-methyl-1-phenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxododeca-hydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4d). White Solid. Yield: 90%; m.p.: 174–176 °C. IR (KBr): ν 3478, 2955, 1714, 1598 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 2.02 (s, 3H), 2.27 (s, 3H), 3.54 (dd, J = 10.7, 8.2 Hz, 1H), 3.68–3.75 (m, 4H), 3.88 (s, 3H), 4.00 (s, 3H), 4.26 (d, J = 8.3 Hz, 1H), 4.50 (d, J = 10.5 Hz, 1H), 4.65 (d, J = 8.0 Hz, 1H), 4.92 (d, J = 7.8 Hz, 1H), 6.72 (d, J = 9.0 Hz, 2H), 6.75 (d, J = 9.0, 2H), 7.10 (d, J = 9.0 Hz, 2H), 7.20–7.29 (m, 4H), 7.30–7.44 (m, 8H), 7.57 (s, 1H), 8.05 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 11.5 (CH3), 11.9 (CH3), 48.2 (CH), 48.8 (CH), 49.6 (CH), 53.3 (CH), 53.4 (OCH3), 55.3 (OCH3), 55.6 (OCH3), 58.1 (CH), 60.5 (CH), 79.2 (C), 112.5 (C), 114.3 (CH), 115.1 (CH), 118.9 (CH), 119.4 (CH), 120.4 (C), 123.7 (C), 123.8 (C), 126.1 (CH), 126.3 (CH), 126.8 (CH), 126.9 (CH), 127.5 (CH), 129.2 (CH), 139.7 (C), 139.8 (C),146.7 (C), 150.7 (C), 159.3 (C), 160.1 (C), 170.4 (C), 172.3 (C), 173.8 (C), 175.2 (C), 176.3 (C). MS (EI, 70 eV) m/z (%): 831 (M+, 2), 772 (8), 628 (67), 268 (43), 203 (46), 171 (100). Elemental Analyses calcd. for C47H45N7O10: C: 65.04, H: 5.23, N: 11.30. Found: C: 65.44, H: 4.90, N: 11.27.
Methyl 2,5-bis(benzo[d][1,3]dioxol-5-ylmethyl)-7,9-bis(3-methyl-1-phenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxododecahydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4e). Beige Solid. Yield: 78%; m.p.: 243–245 °C. IR (KBr): ν 3459, 2898, 1749, 1694, 1598 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.56 (s, 3H), 2.11 (s, 3H), 2.91 (dd, J = 10.5, 8.5 Hz, 1H), 3.51 (t, J = 8.4 Hz, 1H), 3.65 (d, J = 10.5 Hz, 1H), 3.95 (s, 3H), 4.22 (d, J = 8.3 Hz, 1H), 4.23–4.34 (m, 2H), 4.49 (d, J = 8.5 Hz, 1H), 4.63–4.74 (m, 3H), 5.71–5.83 (m, 2H), 5.86–5.96 (m, 2H), 6.47 (d, J = 7.0 Hz, 1H), 6.63 (d, J = 7.3 Hz, 1H), 6.70 (s, 1H), 6.80 (d, J = 7.8 Hz, 1H), 6.87–7.01 (m, 1H), 7.08–7.11 (m, 1H), 7.12 (d, J = 1.5 Hz, 1H), 7.15–7.23 (m, 5H), 7.27–7.37 (m, 5H), 7.52 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 11.2 (CH3), 11.3 (CH3), 42.2 (CH2), 42.9 (CH2), 48.6 (CH), 48.7 (CH), 48.8 (CH), 52.5 (CH), 53.4 (OCH3), 59.7 (CH), 63.6 (CH), 79.3 (C), 101.0 (CH2), 101.5 (CH2), 108.1 (CH), 108.9 (CH), 109.1 (CH), 109.6 (CH), 118.5 (CH), 119.2 (CH), 122.3 (CH), 122.4 (CH), 123.3 (CH), 125.5 (CH), 125.6 (CH), 126.2 (CH), 128.1 (C), 128.8 (C), 129.0 (CH), 129.2 (CH), 139.6 (C), 139.7 (C), 147.1 (C), 147.5 (C), 148.2 (C), 148.4 (C), 150.2 (C), 170.7 (C), 172.8 (C), 174.7 (C), 175.8 (C), 176.4 (C). MS (EI, 70 eV) m/z (%): 887 (M+, 1), 657 (20), 656 (50), 231 (16), 171 (74), 135 (100). Elemental Analyses calcd. for C49H41N7O10.2H2O: C: 63.70, H: 4.91, N: 10.61. Found: C: 64.03, H: 5.15, N: 10.82.
Methyl 7,9-bis(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxo-2,5-diphenyldodecahydro-1H-dipyrrolo- [3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4f). Yellow Solid. Yield: 81%; m.p.: 284–286 °C. IR (KBr): ν 3062, 2954, 1746, 1712, 1598 cm−1. 1H-NMR (400 MHz, CDCl3-d) δ ppm: 3.59 (t, J = 8.4 Hz, 1H), 3.78–3.85 (m, 1H), 3.97 (s, 3H), 4.36 (d, J = 8.5 Hz, 1H), 4.72 (d, J = 10.5 Hz, 1H), 4.82 (d, J = 8.3 Hz, 1H), 5.15 (d, J = 8.5 Hz, 1H), 6.97 (dd, J = 6.5, 2.8 Hz, 2H), 7.02–7.08 (m, 2H), 7.11–7.17 (m, 3H), 7.21–7.25 (m, 5H), 7.28–7.35 (m, 7H), 7.37–7.51 (m, 7H), 7.53–7.59 (m, 3H), 7.83 (s, 1H), 7.91 (d, J = 7.3 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ ppm: 48.7 (CH), 49.5 (CH), 49.6 (CH), 52.9 (CH), 53.7 (OCH3), 59.2 (CH), 60.7 (CH), 80.1 (C), 111.0 (C), 119.3 (CH), 119.8 (CH), 120.3 (C), 125.7 (CH), 126.1 (CH), 126.5 (CH), 126.7 (CH), 127.1 (CH), 127.9 (CH), 128.0 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH), 128.6 (CH), 129.0 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH), 129.4 (CH), 129.8 (CH), 131.1 (C), 131.2 (C), 132.3 (C), 132.5 (C), 139.6 (C), 139.6 (C), 150.5 (C), 152.7 (C), 170.1 (C), 172.5 (C), 173.7 (C), 175.3 (C), 176.0 (C). MS (EI, 70 eV) m/z (%): 895(M+, 1), 836 (6), 722 (71), 298 (23), 273 (27), 233 (100), 173 (42). Elemental Analyses calcd. for C55H45N7O6.3H2O: C: 69.54, H: 4.99, N: 10.32. Found: C: 69.43, H: 4.94, N: 10.42.
Methyl 2,5-bis(4-chlorophenyl)-7,9-bis(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxododecahydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4g). White Solid. Yield: 75%; m.p.: 275–277 °C. IR (KBr): ν 3447, 1718, 1598, 1496 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 3.50–365 (m, 1H); 3.72–3.80 (m, 1H); 3.96 (s, 3H); 4.38 (d, J = 8.53 Hz, 1H); 4.66 (d, J = 10.54 Hz, 1H); 4.79 (d, J = 8.28 Hz, 1H); 5.16 (d, J = 8.53 Hz, 1H); 6.92–7.03 (m, 4H) 7.12–7.32 (m, 13H), 7.33–7.44 (m, 6H), 7.45–7.55 (m, 4H), 7.75 (s, 1H); 7.89 (d, J = 7.78 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ ppm: 48.6 (CH); 49.3 (CH); 49.6 (CH); 52.8 (CH); 53.7 (CH3); 59.2 (CH); 60.7 (CH); 80.2 (C); 110.8 (C) 119.2 (CH); 119.8 (CH); 120.1 (C); 125.3 (C); 126.6 (CH); 126.8 (CH); 127.0 (CH); 127.4 (CH); 127.9 (CH); 128.0 (CH); 128.2 (CH); 128.4 (CH); 128.6 (CH); 128.7 (CH); 128.9 (C); 129.1 (CH); 129.2 (CH); 129.3 (CH); 129.4 (CH); 129.5 (CH); 129.6 (C); 130.0 (CH); 132.2 (C); 132.5 (C); 134.5 (C); 135.5 (C), 139.5 (C); 139.6 (C); 150.4 (C); 152.7 (C); 169.9 (C); 172.1 (C); 173.3 (C); 175.1 (C). MS (EI, 70 eV) m/z (%): 963(M+), 756 (31), 523 (10), 298 (18), 273 (16), 233 (100), 207 (30). Elemental Analyses calcd. for C55H39Cl2N7O6.4H2O: C: 63.71, H: 4.57, N: 9.46. Found: C: 63.74, H: 4.42, N: 9.37.
Methyl 7,9-bis(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4,6-tetraoxo-2,5-di-p-tolyldodecahydro-1H-dipyrrolo- [3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4h). White Solid. Yield: 93%; m.p.: 204–206 °C. IR (KBr): ν 3574, 2954, 1747, 1711, 1599 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 2.26 (s, 3H), 2.50 (s, 3H), 3.59 (t, J = 8.4 Hz, 1H), 3.80 (dd, J = 10.5, 8.3 Hz, 1H), 3.96 (s, 3H), 4.35 (d, J = 8.3 Hz, 1H), 4.71 (d, J = 10.8 Hz, 1H), 4.80 (d, J = 8.3 Hz, 1H), 5.14 (d, J = 8.5 Hz, 1H), 6.84 (d, J = 8.3 Hz, 2H), 6.93 (d, J = 8.0 Hz, 2H), 7.03 (d, J = 8.0 Hz, 2H), 7.12–7.18 (m, 2H), 7.18–7.24 (m, 1H), 7.26–7.30 (m, 5H), 7.30–7.44 (m, 10H), 7.44–7.50 (m, 3H), 7.82 (s, 1H), 7.90 (d, J = 7.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ ppm: 21.1 (CH3), 21.4 (CH3), 48.8 (CH), 49.5 (CH), 49.6 (CH), 52.9 (CH), 53.7 (OCH3), 59.1 (CH), 60.7 (CH), 80.1 (C), 100.0 (C), 111.0 (C), 119.3 (CH), 119.8 (CH), 120.4 (C), 125.5 (CH), 126.0 (CH), 126.4 (CH), 126.7 (CH), 127.2 (CH), 127.9 (CH), 128.0 (CH), 128.2 (CH), 128.3 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 129.2 (CH), 129.3 (CH), 129.7 (CH), 130.4 (CH), 132.3 (C), 132.6 (C), 138.6 (C), 138.7 (C), 139.6 (C), 139.7 (C), 139.8 (C), 150.5 (C), 152.7 (C), 170.2 (C), 172.6 (C), 173.8 (C), 175.4 (C), 176.2 (C). MS (EI, 70 eV) m/z (%): 923(M+), 865 (5), 737 (95), 503 (16), 298 (35), 233 (100), 187 (45). Elemental Analyses calcd. for C57H45N7O6.H2O: C: 72.67, H: 5.03, N: 10.41. Found: C: 72.99, H: 5.24, N: 10.50.
Methyl 7,9-bis(1,3-diphenyl-1H-pyrazol-4-yl)-2,5-bis(4-methoxyphenyl)-1,3,4,6-tetraoxododecahydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4i). Beige Solid. Yield: 94%; m.p.: 239–241 °C. IR (KBr): ν 3474, 2955, 1714, 1599 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 3.57 (t, J = 8.4 Hz, 1H), 3.70 (s, 3H), 3.76–3.80 (m, 1H), 3.92 (s, 3H), 3.96 (s, 3H), 4.33 (d, J = 8.3 Hz, 1H), 4.68 (d, J = 10.8 Hz, 1H), 4.79 (d, J = 8.3 Hz, 1H), 5.14 (d, J = 8.3 Hz, 1H), 6.73 (d, J = 9.0 Hz, 2H), 6.88 (d, J = 8.8 Hz, 2H), 6.95 (d, J = 8.8 Hz, 2H), 7.05 (d, J = 8.8 Hz, 2H), 7.12–7.122 (m, 4H), 7.24–7.36 (m, 9H), 7.38–7.44 (m, 4H), 7.46–7.50 (m, 2H), 7.81 (s, 1H), 7.91 (d, J = 7.0 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ ppm: 48.7 (CH), 49.4 (CH), 49.5 (CH), 52.8 (CH), 53.6 (OCH3), 55.4 (OCH3), 55.6 (OCH3), 59.1 (CH), 60.6 (CH), 80.1 (C), 111.1 (C), 114.3 (CH), 115.1 (CH), 119.3 (CH), 119.8 (CH), 120.5 (C), 123.7 (C), 123.8 (C), 126.4 (CH), 126.7 (CH), 126.9 (CH), 127.1 (CH), 127.4 (CH), 127.8 (CH), 128.0 (CH), 128.2 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 129.1 (CH), 129.2 (CH), 132.3 (C), 132.6 (C), 139.6 (C), 139.7 (C), 150.5 (C), 152.7 (C), 159.3 (C), 160.1 (C), 170.2 (C), 172.7 (C), 173.9 (C), 175.6 (C), 176.3 (C). MS (EI, 70 eV) m/z (%): 955(M+), 751 (38), 521 (25), 233 (100), 203 (48). Elemental Analyses calcd. for C57H45N7O8.2H2O: C: 69.01, H: 4.98, N: 9.88. Found: C: 69.42, H: 5.18, N: 9.84.
Methyl 2,5-bis(benzo[d][1,3]dioxol-5-ylmethyl)-7,9-bis(1,3-diphenyl-1H-pyrazol-4-yl)-1,3,4,6-tetra- oxododecahydro-1H-dipyrrolo[3,4-a:3',4'-f]pyrrolizine-3b-carboxylate (4j). White Solid. Yield: 75%; m.p.: 241–243 °C. IR (KBr): ν 3647, 3062, 1744, 1700, 1599, 1503 cm−1. 1H-NMR (400 MHz, CDCl3) δ ppm: 3.34 (t, J = 8.3 Hz, 1H), 3.50 (t, J = 9.3 Hz, 1H), 3.92 (s, 3H), 4.20 (d, J = 13.8 Hz, 1H), 4.24–4.31 (m, 2H), 4.39 (dd, J = 13.8, 5.0 Hz, 2H), 4.49–4.54 (m, 1H), 4.62 (d, J = 8.3 Hz, 1H), 4.75 (d, J = 8.5 Hz, 1H), 5.75–5.85 (m, 2H), 5.95 (s, 2H), 6.34 (d, J = 7.8 Hz, 1H), 6.65–6.70 (m, 1H), 6.74 (d, J = 8.0 Hz, 1H), 6.85–6.92 (m, 3H), 6.98 (d, J = 7.3 Hz, 2H), 7.04–7.10 (m, 3H), 7.13–7.24 (m, 5H), 7.27–7.36 (m, 5H), 7.38–7.50 (m, 5H), 7.86 (d, J = 7.3 Hz, 2H). 13C-NMR (100 MHz, CDCl3) δ ppm: 42.1 (CH2), 42.9 (CH2), 48.2 (CH), 48.3 (CH), 50.0 (CH), 52.0 (CH), 53.6 (OCH3), 58.6 (CH), 60.0 (CH), 80.3 (C), 100.9 (CH2), 101.2 (CH2), 108.1 (CH), 108.4 (CH), 109.0 (CH), 109.5 (CH), 111.0 (C), 119.1 (C), 119.3 (CH), 120.0 (CH), 122.2 (CH), 122.7 (CH), 126.1 (CH), 126.6 (CH), 126.7 (CH), 127.6 (CH), 127.8 (CH), 127.9 (CH), 128.2 (C), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.9 (CH), 129.2 (CH), 129.4 (C), 132.4 (C), 132.6 (C), 139.5 (C), 139.6 (C), 147.1 (C), 147.5 (C), 147.7 (C), 147.8 (C), 150.1 (C), 152.2 (C), 170.2 (C), 173.0 (C), 174.7 (C), 176.4 (C), 176.6 (C). MS (EI, 70 eV) m/z (%): 1011(M+), 780 (11), 547 (7), 257 (15), 233 (45), 135 (100). Elemental Analyses calcd. for C59H45N7O10.2H2O: C: 67.61, H: 4.71, N: 9.36. Found: C: 67.84, H: 4.39, N: 9.21.

3.3. Synthesis and Characterization Data for Pyrazolylpyrrolo[3,4-c]Pyrroles 5a–f and 6a–f.

General Synthetic Procedure

To a 25.0 mL round bottom flask equipped with a magnetic stirring bar and a reflux condenser were added pyrazole-4-carboxaldehyde 1a–b (0.2 mmol), N-substituted-maleimide 2a–e (0.2 mmol), N-benzyl glycine ethyl ester 3b (0.22 mmol) and toluene (8 mL). The mixture was heated under reflux until TLC showed the absence of the starting materials (6–10 h). After the reaction mixture was cooled down to room temperature, the solvent was removed under reduced pressure and the resulting crude product was purified by column chromatography on silica gel, using a mixture of dichloromethane/hexane (7:3) as eluent. In all cases the minor diastereomers were characterized by 1H-NMR spectroscopy after purification.
Ethyl 2-benzyl-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-4,6-dioxo-5-phenyloctahydropyrrolo[3,4-c]-pyrrole-1-carboxylate. White Solid. Yield: 95%; m.p.: 172–174 °C. IR (KBr): ν 1717, 1598, 1502 cm−1. Minor diastereomer 5a. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.26 (t, J = 7.3 Hz, 3H), 2.38 (s, 3H), 3.34 (d, J = 13.8 Hz, 1H), 3.57 (dd, J = 9.7, 5.4 Hz, 1H), 3.86 (d, J = 4.8 Hz, 1H), 3.89 (d, J = 9.3 Hz, 1H), 4.20 (q, J = 7.3 Hz, 2H), 4.24 (d, J = 9.0 Hz, 1H), 4.79 (d, J = 5.5 Hz, 1H), 7.22–7.28 (m, 4H), 7.29–7.34 (m, 4H), 7.40–7.53 (m, 5H), 7.66 (d, J = 7.5 Hz, 2H), 7.92 (s, 1H). Major diastereomer 6a1H-NMR (400 MHz, CDCl3) δ ppm: 1.32 (t, J = 7.2 Hz, 3H), 2.45 (s, 3H), 3.53 (d, J = 8.0 Hz, 1H), 3.65 (d, J = 14.0 Hz, 1H), 3.80–3.87 (m, 1H), 4.05 (d, J = 14.1 Hz, 1H), 4.17–4.34 (m, 2H), 4.39 (s, 1H), 4.94 (d, J = 9.5 Hz, 1H), 7.13 (d, J = 6.8 Hz, 2H), 7.19–7.30 (m, 4H), 7.31–7.42 (m, 7H), 7.52 (d, J = 7.8 Hz, 2H), 7.72 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 12.4 (CH3), 14.2 (CH3), 48.6 (CH), 48.7 (CH), 52.1 (CH2), 59.8 (CH), 60.9 (CH2), 62.9 (CH), 118.5 (CH), 125.5 (CH), 126.0 (CH), 127.3 (CH), 127.7 (CH), 128.2 (CH), 128.3 (CH), 128.6 (CH), 129.0 (CH), 129.2 (CH), 130.3 (C), 131.6 (C), 137.6 (C), 139.8 (C), 149.8 (C), 170.9 (C), 174.3 (C), 175.6 (C). MS (EI, 70 eV) m/z (%): 534 (M+, 15), 461 (65), 91 (100). Elemental Analyses calcd. for C32H30N4O4.2H2O: C: 67.35, H: 6.01, N: 9.82. Found: C: 67.45, H: 6.13, N: 9.66.
Ethyl 2-benzyl-5-(4-chlorophenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-4,6-dioxooctahydropyrrolo-[3,4-c]pyrrole-1-carboxylate. Yellow Solid. Yield: 82%; m.p.: 69–71 °C. IR: ν 1782, 1738, 1598 cm−1. Minor diastereomer 5b. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.24 (t, J = 7.3 Hz, 3H), 2.36 (s, 3H), 3.31 (d, J = 13.8 Hz, 1H), 3.54 (dd, J = 9.5, 5.5 Hz, 1H), 3.77–3.85 (m, 3H), 4.22–4.30 (m, 2H), 4.75 (d, J = 5.3 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 7.18–7.23 (m, 2H), 7.29–7.34 (m, 3H), 7.37 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.67 (d, J = 7.5 Hz, 2H), 7.91 (s, 1H). Major diastereomer 6b. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.30 (t, J = 7.2 Hz, 3H), 2.42 (s, 3H), 3.50 (d, J = 7.8 Hz, 1H), 3.63 (d, J = 14.3 Hz, 1H), 3.78–3.81 (m, 1H), 4.02 (d, J = 14.3 Hz, 1H), 4.15–4.22 (m, 2H), 4.35 (s, 1H), 4.91 (d, J = 9.5 Hz, 1H), 7.06 (d, J = 8.3 Hz, 2H), 7.18–7.23 (m, 3H), 7.29–7.34 (m, 3H), 7.37 (t, J = 7.8 Hz, 2H), 7.44 (d, J = 8.5 Hz, 1H), 7.49 (d, J = 8.0 Hz, 2H), 7.63–7.69 (m, 2H). 13C-NMR (100 MHz, CDCl3) δ ppm: 12.4 (CH3), 14.2 (CH3), 46.4 (CH), 48.7 (CH), 52.1 (CH2), 59.8 (CH), 60.9 (CH2), 62.9 (CH), 118.4 (CH), 119.6 (C), 126.1 (CH), 126.6 (CH), 127.3 (CH), 127.7 (CH), 128.6 (CH), 129.1 (CH), 129.2 (CH), 129.3 (CH), 130.1 (C), 133.9 (C), 137.5 (C), 139.7 (C), 170.8 (C), 170.8 (C), 174.1 (C), 175.3 (C). MS (EI, 70 eV) m/z (%): 568 (M+, 1), 497 (11), 496 (10), 495 (30), 91 (100). Elemental Analyses calcd. for C32H29ClN4O5.H2O: C: 65.47, H: 5.32, N: 9.54. Found: C: 65.28, H: 5.39, N: 9.76.
Ethyl 2-benzyl-5-(4-methoxyphenyl)-3-(3-methyl-1-phenyl-1H-pyrazol-4-yl)-4,6-dioxooctahydro-pyrrolo[3,4-c]pyrrole-1-carboxylate. White Solid. Yield: 96%; m.p.: 85–87 °C. IR: ν 1775, 1728, 1602 cm−1. Minor diastereomer 5c. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.26 (t, J = 7.2 Hz, 3H), 2.38 (s, 3H), 3.34 (d, J = 13.8 Hz, 1H), 3.55 (dd, J = 9.5, 5.3 Hz, 1H), 3.82–3.91 (m, 5H), 4.19 (q, J = 7.3 Hz, 2H), 4.23 (d, J = 8.8 Hz, 1H), 4.78 (d, J = 5.5 Hz, 1H), 7.00 (d, J = 9.0, 2H), 7.21–7.26 (m, 5H), 7.27–7.34 (m, 3H), 7.45 (t, J = 8.5, 7.3 Hz, 2H), 7.66 (dd, J = 8.7, 1.1 Hz, 2H), 7.91 (s, 1H). Major diastereomer 6c. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.32 (t, J = 7.2 Hz, 3H), 2.44 (s, 3H), 3.51 (d, J = 7.8 Hz, 1H), 3.65 (d, J = 14.3 Hz, 1H), 3.76 (s, 3H), 4.04 (d, J = 14.1 Hz, 1H), 4.16–4.32 (m, 3H), 4.38 (s, 1H), 4.92 (d, J = 9.5 Hz, 1H), 6.84 (d, J = 9.0 Hz, 2H), 7.04 (d, J = 8.8 Hz, 2H), 7.21–7.27 (m, 3H), 7.30–7.35 (m, 3H), 7.36–7.41 (m, 2H), 7.53 (d, J = 7.8 Hz, 2H), 7.70 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 12.4 (CH3), 14.2 (CH3), 46.4 (CH), 48.6 (CH), 52.0 (CH2), 55.3 (OCH3), 59.8 (CH), 60.9 (CH2), 62.9 (CH), 114.3 (CH), 118.5 (CH), 119.8 (C), 124.3 (C), 126 (CH), 126.8 (CH), 127.3 (CH), 127.7 (CH), 128.2 (CH), 128.6 (CH), 129.2 (CH), 137.7 (C), 139.8 (C), 149.8 (C), 159.1 (C), 171.0 (C), 174.5 (C), 175.8 (C). MS (EI, 70 eV) m/z (%): 564 (M+, 6), 493 (14), 492 (71), 491 (99), 473 (37), 270 (33), 91 (100). Elemental Analyses calcd. for C33H32N4O5.2H2O: C: 65.99, H: 6.04, N: 9.33. Found: C: 66.12, H: 6.24, N: 9.02.
Ethyl 2-benzyl-3-(1,3-diphenyl-1H-pyrazol-4-yl)-4,6-dioxo-5-phenyloctahydropyrrolo[3,4-c]pyrrole-1-carboxylate. White Solid. Yield: 75%; m.p.: 181–183 °C. IR (KBr): ν 1721, 1597, 1498 cm−1. Minor diastereomer 5d. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.27 (t, J = 7.1 Hz, 3H), 3.38 (d, J = 13.6 Hz, 1H), 3.72 (dd, J = 9.7, 5.6 Hz, 1H), 3.83 (d, J = 9.0 Hz, 1H), 3.89–3.93 (m, 1H), 4.28–4.32 (m, 3H), 5.05 (d, J = 5.5 Hz, 1H), 7.14–7.18 (m, 2H), 7.32–7.35 (m, 5H), 7.40–7.43 (m, 4H), 7.50–7.53 (m, 5H), 7.82–7.85 (m, 2H), 7.97–8.02 (m, 2H), 8.15 (s, 1H). Major diastereomer 6d. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.32 (t, J = 7.2 Hz, 3H), 3.58 (d, J = 7.8 Hz, 1H), 3.67 (d, J = 14.3 Hz, 1H), 3.92–3.98 (m, 1H), 4.06 (d, J = 14.1 Hz, 1H), 4.21–4.29 (m, 2H), 4.45 (s, 1H), 5.11 (d, J = 9.8 Hz, 1H), 7.22–7.26 (m, 3H), 7.30 (dd, J = 7.4, 1.9 Hz, 2H), 7.32–7.35 (m, 1H), 7.36–7.40 (m, 4H), 7.43–7.48 (m, 2H), 7.49–7.52 (m, 2H), 7.55–7.60 (m, 2H), 7.65 (d, J = 7.5 Hz, 2H), 7.86–7.90 (m, 2H), 7.92 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 14.3 (CH3), 49.0 (CH), 49.5 (CH), 52.3 (CH2), 60.2 (CH), 61.1 (CH2), 63.1 (CH), 118.9 (CH), 119.0 (CH), 119.1 (C), 125.6 (CH), 126.1 (CH), 126.6 (CH), 126,7 (CH), 127.4 (CH), 128.4 (CH), 128.5 (CH), 128.6 (CH), 128.7 (CH), 129.2 (CH), 129.4 (CH), 131.8 (C), 133.1 (C), 137.8 (C), 139.9 (C), 153.3 (C), 171.0 (C), 174.6 (C), 175.7 (C). MS (EI, 70 eV) m/z (%): 596 (M+, 4), 523 (100), 505 (32). Elemental Analyses calcd. for C37H32N4O4.H2O: C: 72.30, H: 5.58, N: 9.11. Found: C: 72.68, H: 5.28, N: 9.05.
Ethyl 2-benzyl-5-(4-chlorophenyl)-3-(1,3-diphenyl-1H-pyrazol-4-yl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate. White Solid. Yield: 72%; m.p.: 108–110 °C. IR (KBr): ν 1719, 1599, 1496 cm−1. Minor diastereomer 5e. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.23 (t, J = 7.0 Hz, 3H), 3.33 (d, J = 13.6 Hz, 1H), 3.68 (dd, J = 9.7, 5.6 Hz, 1H), 3.75–3.83 (m, 1H), 3.86–3.89 (m, 1H), 3.92 (d, J = 8.0 Hz, 1H), 4.15–4.24 (m, 2H) 4.97 (d, J = 5.5 Hz, 1H), 7.09–7.13 (m, 2H), 7.22–7.26 (m, 3H), 7.32–7.36 (m, 2H), 7.41 (br. s., 3H), 7.50 (d, J = 3.3 Hz, 2H), 7.52–7.55 (m, 3H), 7.78 (br. s., 3H), 7.94 (d, J = 6.8 Hz, 1H), 8.10 (s, 1H). Major diastereomer 6e. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.28 (t, J = 7.2 Hz, 3H), 3.53 (d, J = 7.8 Hz, 1H), 3.62 (d, J = 14.1 Hz, 1H), 3.88–3.95 (m, 1H), 4.00 (d, J = 14.3 Hz, 1H), 4.12–4.21 (m, 2H), 4.39 (s, 1H), 5.05 (d, J = 9.8 Hz, 1H), 7.15–7.20 (m, 3H), 7.20–7.26 (m, 2H), 7.29–7.32 (m, 4H), 7.39–7.48 (m, 4H), 7.49–7.55 (m, 2H), 7.58 (d, J = 7.8 Hz, 2H), 7.76–7.85 (m, 3H). 13C-NMR (100 MHz, CDCl3) δ ppm: 14.2 (CH3), 48.9 (CH), 49.4 (CH), 52.2 (CH2), 60.1 (CH), 61.0 (CH2), 63.0 (CH), 118.8 (CH), 125.8 (C), 126.7 (CH), 127.4 (CH), 127.8 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 128.5 (CH), 128.7 (CH), 129.1 (CH), 129.3 (CH), 129.4 (CH), 130.2 (C), 132.9 (C), 134.1 (C), 137.6 (C), 139.7 (C), 153.2 (C), 170.8 (C), 174.2 (C), 175.4 (C). MS (EI, 70 eV) m/z (%): 630 (M+, 2), 557 (49), 554 (43), 553 (100), 535 (45). Elemental Analyses calcd. for C37H31ClN4O4: C: 70.41, H: 4.95, N: 8.88. Found: C: 70.72, H: 5.04, N: 8.54.
Ethyl 2-benzyl-3-(1,3-diphenyl-1H-pyrazol-4-yl)-5-(4-methoxyphenyl)-4,6-dioxooctahydropyrrolo[3,4-c]pyrrole-1-carboxylate. Yellow Solid. Yield: 90%; m.p.: 78–80 °C. IR: ν 1712, 1600, 1548 cm−1. Minor diastereomer 5f. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.26 (t, J = 7.0 Hz, 3H), 3.37 (d, J = 13.6 Hz, 1H), 3.71 (d, J = 5.5 Hz, 1H), 3.82–3.86 (m, 4H), 3.88–3.91 (m, 1H), 4.21–4.31 (m, 3H), 5.04 (d, J = 5.5 Hz, 1H), 7.01 (d, J = 9.0, 2H), 7.27–7.32 (m, 6H), 7.49–7.56 (m, 7H), 7.84 (d, J = 7.8, 2H), 8.00 (d, J = 7.0, 2H), 8.15 (s, 1H). Major diastereomer 6f. 1H-NMR (400 MHz, CDCl3) δ ppm: 1.31 (t, J = 7.2 Hz, 3H), 3.55 (d, J = 8.0 Hz, 1H), 3.66 (d, J = 14.3 Hz, 1H), 3.80 (s, 3H), 3.93 (dd, J = 9.5 Hz, 8.0 Hz 1H), 4.05 (d, J = 14.1 Hz, 1H), 4.15–4.28 (m, 2H), 4.44 (s, 1H), 5.10 (d, J = 9.5 Hz, 1H), 6.89 (d, J = 9.0 Hz, 2H), 7.16 (d, J = 8.8 Hz, 2H), 7.21–7.27 (m, 2H), 7.28–7.32 (m, 2H), 7.32–7.38 (m, 2H), 7.42–7.52 (m, 3H), 7.57 (t, J = 7.4 Hz, 2H), 7.66 (d, J = 7.5 Hz, 2H), 7.88 (d, J = 7.0 Hz, 2H), 7.91 (s, 1H). 13C-NMR (100 MHz, CDCl3) δ ppm: 14.1 (CH3), 48.7 (CH), 49.3 (CH), 52.1 (CH2), 55.3 (OCH3), 60.0 (CH), 60.9 (CH2), 63.0 (CH), 114.2 (CH), 118.7 (CH), 119.8 (C), 124.3 (C), 126.4 (CH), 126.7 (CH), 127.2 (CH), 127.7 (CH), 128.1 (CH), 128.3 (CH), 128.4 (CH), 128.5 (CH), 129.0 (CH), 129.3 (CH), 132.9 (C), 137.7 (C), 139.7 (C), 153.1 (C), 159.1 (C), 170.8 (C), 174.6 (C), 175.8 (C). MS (EI, 70 eV) m/z (%): 626 (M+, 4), 554 (39), 553 (100), 535 (42). Elemental analyses calcd. for C38H34N4O5.H2O: C: 70.79, H: 5.63, N: 8.69. Found: C: 70.56, H: 5.81, N: 8.51.

4. Conclusions

We described here a practical synthesis of pyrazoylpyrrolizines 4 and pyrazolylpyrrolidines derivatives 5 and 6 from pyrazolyl-carboxaldehydes, glycine derivates and maleimides by a three-component catalyst free domino process involving both the formation of a 1,3-dipolar species and 1,3-cycloaddition reaction to afford the desired products in good yields and with good atom economy. This high-throughput methodology provides an easy execution, rapid access and good diastereoselectivity. When the N-benzyl glycine ethyl ester was used two diastereomers 5 and 6 were obtained, with the diastereomers 6a-f being favored by the minor repulsive interaction between the carbonyl group on 1-C and 6-C=O carbon due to their trans configuration.

Acknowledgments

Authors thank COLCIENCIAS, Universidad del Valle, the Spanish “Consejería de Innovación, Ciencia y Empresa, Junta de Andalucía” and ‘Centro de Instrumentación Científico-Técnica de la Universidad de Jaén for financial support.

Author Contributions

JQ, JG, RA, BI, AO, JC and MN designed research. All authors read and approved the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

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  • Sample Availability: Samples of the compounds 4a–j, 5a–f and 6a–f are available from the authors.

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MDPI and ACS Style

Quiroga, J.; Gálvez, J.; Abonia, R.; Insuasty, B.; Ortíz, A.; Cobo, J.; Nogueras, M. Highly Efficient and Diastereoselective Synthesis of New Pyrazolylpyrrolizine and Pyrazolylpyrrolidine Derivates by a Three-Component Domino Process. Molecules 2014, 19, 4284-4300. https://doi.org/10.3390/molecules19044284

AMA Style

Quiroga J, Gálvez J, Abonia R, Insuasty B, Ortíz A, Cobo J, Nogueras M. Highly Efficient and Diastereoselective Synthesis of New Pyrazolylpyrrolizine and Pyrazolylpyrrolidine Derivates by a Three-Component Domino Process. Molecules. 2014; 19(4):4284-4300. https://doi.org/10.3390/molecules19044284

Chicago/Turabian Style

Quiroga, Jairo, Jaime Gálvez, Rodrigo Abonia, Braulio Insuasty, Alejandro Ortíz, Justo Cobo, and Manuel Nogueras. 2014. "Highly Efficient and Diastereoselective Synthesis of New Pyrazolylpyrrolizine and Pyrazolylpyrrolidine Derivates by a Three-Component Domino Process" Molecules 19, no. 4: 4284-4300. https://doi.org/10.3390/molecules19044284

APA Style

Quiroga, J., Gálvez, J., Abonia, R., Insuasty, B., Ortíz, A., Cobo, J., & Nogueras, M. (2014). Highly Efficient and Diastereoselective Synthesis of New Pyrazolylpyrrolizine and Pyrazolylpyrrolidine Derivates by a Three-Component Domino Process. Molecules, 19(4), 4284-4300. https://doi.org/10.3390/molecules19044284

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