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

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.


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].

OPEN ACCESS
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 electrondeficient 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]. 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).

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 ( 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]. 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 1 H-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].

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).  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].
According to the 1 H-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].

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 1 H-NMR measurements, since the dihedral angle 1H-C-C-6aH for the stereoisomer 6d is −94.41° and therefore in its 1 H-NMR spectrum the coupling constant between the H-1 and H-6a protons has a value J 3~0 .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.

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 F 254 ) were used for analytical TLC. Melting points were taken on Stuart SMP10 Melting point apparatus and are uncorrected. IR H1 H6a spectra were recorded on a Shimadzu FTIR 8400 spectrophotometer using KBr disks or CH 2 Cl 2 as solvent. 1 H-and 13 C-NMR were recorded on a Bruker Avance 400 spectrometer operating at 400 and 100 MHz respectively, using CDCl 3 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. [3,4- 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.   [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 1 H-NMR spectroscopy after purification.

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.