The regioselective synthesis of spirooxindolo pyrrolidines and pyrrolizidines via three-component reactions of acrylamides and aroylacrylic acids with isatins and α-amino acids

Summary The regioselective three-component condensation of azomethine ylides derived from isatins and α-amino acids with acrylamides or aroylacrylic acids as dipolarophiles has been realized through a one-pot 1,3-dipolar cycloaddition protocol. Decarboxylation of 2'-aroyl-2-oxo-1,1',2,2',5',6',7',7a'-octahydrospiro[indole-3,3'-pyrrolizine]-1'-carboxylic acids is accompanied by cyclative rearrangement with formation of dihydropyrrolizinyl indolones.

In the present work we report the synthesis of spirooxindolo pyrrolidines and pyrrolizidines by utilizing a 1,3-dipolar cycloaddition of hitherto uninvestigated acrylamides and aroylacrylic acids with azomethine ylides, generated in situ via decarboxylative condensation of isatins and N-substituted α-amino acids (sarcosine, proline and thiazolidine-4-carboxilic acid) in a three-component fashion.

Results and Discussion
The three-component condensation of equimolar amounts of isatins 1, α-amino acids 2 and acrylamides 3 in boiling aqueous methanol (1:3) afforded the spirooxindoles 4a-4g in moderate to excellent yields ( Table 1). The reaction times largely depend on the reactivity of the employed α-amino acid. The longest reaction time (7 h) was found for sarcosine, while the fastest reaction (40 min) was found for proline as a substrate (Table 1, entries 1 and 3).
The 1,3-dipolar cycloaddition of unsymmetrical dipolarophiles such as acrylamides can occur via the two pathways A and B leading to the formation of the regioisomers 4 and 4'. In our case, spirooxindol 4 is exclusively formed. All new cycloadducts obtained by the above method were characterized by mass spectrometry, 1 H and 13 C NMR, and elemental analyses. The regiochemical outcome of the cycloaddition was unambiguously confirmed by NOE experiments in 1 H NMR as well as later by a single crystal X-ray structure analysis of the cycloadduct 4a.
The NH-proton of the oxindole moiety appeared as a singlet between 10.38-10.86 ppm. The 13 C NMR spectra of compounds 4a-4g showed characteristic peaks at 71-73 ppm due to the spiro carbon nucleus.
The structure of compound 4a was determined by an X-ray diffraction study of a single crystal and supports the structure deduced from NMR spectroscopy ( Figure 2).
Dipolarophiles, such as aroylacrylic acids 5, can also be successfully used in this three-component reaction. The cyclo- addition of dipolarophiles 5 with non-stabilized azomethine ylides generated from isatins 1 and sarcosine/proline has led to spiropyrrolidines 6a,6b and spiropyrrolizidines 6c-6h in moderate to good yields. In this reaction also two regioisomers can be expected, but in all experiments solely the regioisomer 6 is isolated without detectable trace amounts of other isomers.
The higher reactivity of aroylacrylic acids induces remarkable rate acceleration and decreases the reaction time to only 10-15 min in a boiling mixture of methanol and water. The low to moderate yields of the target compounds 6c-6h can be explained by considerable resinification of the reaction mixture and by formation of byproducts. To suppress these negative adverse processes we carried out the reaction under stirring at room temperature. The results are shown in Table 2.
All compound structures are fully supported by spectroscopic data and elemental analysis as illustrated for compound 6c. The week NOE correlation was found between 1'-CH and 2'-CH, the trans-configuration of the mentioned protons is predetermined by the trans-configuration of the initial aroyl acrylic acid. Also, a NOE correlation is found between signals of 2'-CH and doublet at 7.30 ppm (J =1.8 Hz) for 2-CH of the aroyl acrylic acid moiety. In addition, the absence of NOE cross peaks between 4-CH of the isatin core and 2'-CH of the pyrrolizidine fragment supports the assignment. The NH-proton of the oxindole moiety and the 1'-COOH proton of the pyrrolidine/pyrrolizidine ring give singlets at 10.25 and 12.67 ppm, respectively. Therefore, the correct stereochemistry can be drawn as shown in Figure 3. The 13 C NMR spectrum of compound 6c shows a characteristic peak at 73 ppm due to the spiro carbon nucleus.

Scheme 1:
The mechanism of the regioselective synthesis of compounds 4 and 6.  A single crystal X-ray study of compound 6a provided a conclusive support for the assigned structure ( Figure 4). Interesting feature of this structure is a pincers-like con-formation of the molecule. The substituent at the C9 atom has equatorial orientation (the N2-C7-C9-C14 torsion angle is 122.7(2)°) and its carbonyl group is almost coplanar to the C9-C10 endocyclic bond (the C10-C9-C14-O4 torsion angle is 10.2(4)°). Such an orientation of this substituent creates conditions for appearance of intramolecular stacking interactions between the aromatic rings of the indole fragment and the aryl substituent (angle between planes of aromatic rings is 22.9°a nd the shortest distance between carbon atoms (C6…C15) is 3.04 Å).
The mechanism of the azomethine ylide formation by a decarboxylative route has been repeatedly described by a number of authors and is depicted in Scheme 1 [35,36]. The reaction between isatin and the α-amino acid affords the azomethine ylide, which regioselectively adds to the C=C bond of acrylamide or aroylacrylic acid.
Since the stereochemistry of the cycloadducts 4a and 6a was clarified by a single-crystal X-ray analysis, the structures of the reacting systems -the azomethine ylide and dipolarophiles (acrylamide and benzoylacrylic acid) -were investigated computationally. The geometrical structures of all possible conformers of the reacting systems were optimized using M06-2X [37] theory with the cc-pVTZ basis set [38] in the GAUSSIAN09 program [39]. The character of stationary points on the potential energy surface was verified by calculations of vibrational frequencies within the harmonic approximation, using analytical second derivatives at the same level of theory. All stationary points possess zero imaginary frequencies. It was found that the acrylamide conformer I was more stable than conformer II by 1.24 kcal/mol. The most stable conformation of benzoylacrylic acid possesses the benzoyl and carboxylic groups trans to each other ( Figure 5).  The atom charges for the analysis of the Fukui function indices were calculated within the Natural Bonding Orbitals theory [40] with the NBO 5.0 program [41], that revealed the most reactive sites of the reagents. The reaction proceeds regioselectively with the addition of the most nucleophilic methylene group carbon of the azomethine ylide to the most electrophilic sites of the acrylamide and benzoylacrylic acid, which affords only one stereoisomer of cycloadducts 4 and 6 stereoselectively despite the presense of several stereocenters in the molecules ( Figure 6).
For assigning structures of byproducts we carried out the reaction of isatins 1, aroylacrylic acids 5 and proline in a boiling mixture of EtOH and water, which resulted in the formation and isolation of compounds 7a-7c (Scheme 2). The unexpected structure of rearranged product 7a was confirmed by 1 H, 13 C and 2D NMR spectroscopy ( Table 3).
The main feature of the 13 C spectra of compounds 7a-7c is the absence of the signal of the 3C-spiro nucleus. The 1 H NMR spectrum of compound 7a displays a singlet at 5.30 ppm for the 7-CH of the dihydropyrrolizinyl moiety, which shows a H,H-NOESY correlation with a singlet at 4.56 ppm (3-CH of the oxindole ring) and HMBCs with 7a-C at 138.34 ppm. The singlet at 4.56 ppm of 3-CH of the oxindole ring shows H,H-COSY and H,H-NOESY correlations with a singlet at 7.05 ppm of 4-CH (oxindole ring) and HMBCs with 2-CO at 178.09 ppm, 4-C at 127.55 ppm and 6-C at 120.38 ppm (Figure 7). The NH proton of the oxindole ring gives a singlet at 10.59 ppm.

Scheme 2:
The synthesis of compounds 7a-7c. The tentative mechanism for the formation of 7a is outlined in Scheme 3. First, the initially formed spiropyrrolizidine undergoes decarboxylation via ring opening of the spiro cycle. The subsequent enolization of the intermediate leads to the formation of the dihydropyrrolizinyl oxindole system.

Conclusion
The 1,3-dipolar cycloaddition of azomethine ylides generated in situ from isatins and sarcosine or cyclic amino acids to acrylamides or aroylacrylic acids afforded regio-and stereoselectively the spirooxindoles 4 and 6 in moderate to good yields.
The selectivity of the three-component condensation of isatins and α-amino acids with aroylacrylic acids can be controlled by the reaction temperature and the reaction medium. While spiro cycloadducts can be obtained in methanol dihydropyrrolizinyl oxindoles are formed in aqueous ethanol media at higher temperatures. Therefore, reactions involving aroylacrylic acids as substrates can afford the product in a regiocontrolled manner.  DRX-500 (500 MHz) instruments in DMSO-d 6 with TMS as an internal standard. The 13 C NMR spectra were recorded on a Bruker Avance DRX-500 (125 MHz) and Bruker AM-300 (75 MHz) instruments in DMSO-d 6 with TMS as an internal standard. The COSY, NOESY, HSQC, and HMBC spectra were recorded using the standard procedure with gradient separation of the signal. The mass spectra were recorded on a Varian 1200L GC-MS instrument, ionization by EI at 70 eV.

Experimental
Elemental analysis was carried out on an EA 3000 Eurovector elemental analyzer. Melting points were determined on a Kofler hot bench. The progress of reactions and also the purity of the obtained compounds were monitored by TLC on Silufol UV-254 plates with acetone/heptane (4:1) as an eluent. Commercially available reagents and solvents were used without further purification. The aroylacrylic acids 5 were prepared according to the previously reported procedure [42].  The structures were solved by direct methods using the SHELXTL package [43]. The absorption correction was performed using the multi-scan method (T min = 0.582, T max = 0.751 for 4a and T min = 0.563 T max = 0.671 for 6a). Position of the hydrogen atoms were located from electron density difference maps and refined by "riding" model with U iso = nU eq of the carrier atom (n = 1.5 for methyl and hydroxy groups and n = 1.2 for other hydrogen atoms). Full-matrix least-squares refinement of the structures against F 2 in anisotropic approximation for non-hydrogen atoms using 3908 (4a), 3801 (6a) reflections was converged to: wR 2 = 0.