[3 + 2] Cycloaddition reactions of thioisatin with thiazolidine-2-carboxylic acid: a versatile route to new heterocyclic scaffolds

A facile synthesis of azabicycloadducts is described by 1,3-dipolar cycloaddition reactions of thioisatin with thiazolidine-2-carboxylic acid in the presence of various electron rich and electron deficient dipolarophiles. Theoritical calculations have been performed to study the regioselectivity of products. The geometrical and energetic properties have been analyzed for the different reactants, transition states and cycloadducts formed.


Background
The construction of sophisticated molecules requires viable, selective and highly reliable reactions as potent synthetic tools [1][2][3]. The 1,3-dipolar cycloaddition [4][5][6][7][8][9] has also become one of the most important legation method in biology and material chemistry. Thioisatin derivatives [10] have received the attention of biochemists because of their therapeutic and biological activities. Similarly thiazolidine-2-carboxylic acid [11,12] exhibit strong antioxidant properties. Therefore any heterocyclic scaffold containing these two moieties might be expected to have considerably enhanced biological activities.
The 1,3-dipolar cycloaddition reaction of an azomethine ylide with an alkene leads to the formation of pyrrolidine [13,14] derivatives. Recently, we have reported the results on azomethine ylides derived from 9,10-phenanthrenequinone and some secondary cyclic α-amino acids with different dipolarophiles [15]. Herein we report the reactivity and regioselectivity of 1,3-dipolar cycloaddition reactions of azomethine ylides derived from benzo[b]thiophene-2,3-dione with thiazolidine-2carboxylic acid in the presence of various acetylenic and ethylenic dipolarophiles. Besides synthetic work, a systematic and comprehensive theoretical study at Gaussian 03 [16] suite of programs has been carried out to address the mechanism as well as regio-and stereochemical course of the reactions.
The structure of all the cycloadducts has been ascertained from their spectral data. Thus the IR spectrum of a typical diphenylacetylene cycloadducts 8 showed characteristic bands at 1715, 1420 and 690 for > C = O, C-N and C-S stretching vibrations respectively. Its 1 H NMR spectrum showed a triplet at δ 2.51 (J = 2.7Hz) for 3H protons, another triplet at δ 2.60 (J = 3.0Hz) was associated with 2H protons, a singlet at δ 4.15 appeared for 5H and the aromatic protons resonated between δ 6.79-δ 8.12 ppm. Its 13 C NMR spectrum showed a signal at 183.54 for C-2' carbonyl carbon, aromatic carbons appeared in the range δ 146.41-δ131.32 ppm, the olefenic carbons (C-6, C-7) resonated at δ 127.32 and 126.54, spiro carbon (C-8) was noticed at δ 86.23, C-5 at δ 46.72, C-2 at δ 45.43, and C-3 at 34.56 ppm respectively. Additional evidence was gathered from the mass spectrum of cycloadduct 8. The molecular ion and the base peaks were present at m/z 413(32%) and 235(100%) respectively; another peak at m/z 385(39%) corresponded to [M-CO] .+ whereas the peak at m/z 108(35%) was assigned to [C 6 H 4 S] .+ .

Theoretical calculations: Regioselectivity of cycloadducts 5-9
The stereochemical course of the cycloaddition was examined by AM1 calculations. To calculate the relevant activation and stabilization energies, minimized geometries of the reactants, products and transition states are required. The molecular geometry of the simplest azomethine ylide (abbreviated as amy) 4 derived from thioisatin and thiazolidine-2-carboxylic acid has been optimized on Gaussian 03 program at AM1 level.
Geometry optimization showed that amy 4 has almost planar structure ( Figure 1). Instead of having an envelope shape the thiazolidine ring is planar and lies in the same plane as that of thioisatin ring. It may exist in two isomeric forms, one in which > C = O group and C-H of the dipole are syn to each other, 4 syn , and the other in which these two groups are anti, 4 anti ( Figure 2).
Methyl acrylate may approach either of the amy with the formation of products having three chiral centers.  Therefore a total 8 + 8 = 16 isomers 5a-5p are possible ( Figure 3).
Attack of methyl acrylate on syn amy results in the inward movement of thiazolidine ring towards thioisatin nucleus which imposes steric hindrance and makes it unstable. In fact we failed to locate the transition state in any such case 5i-5p. The remaining 8 isomers may be obtained by the attack of methyl acrylate on anti amy. Out of these 8 possibilities only four 5a-5d have concerted mechanism. We have optimized the geometries of all the four isomers. Results show that all isomers have almost same ΔH f , indicating that thermodynamically all are nearly equally stable.
We have carried out transition state calculations on all the four isomers but have been successful in locating the transition state for only two isomers 5a-5b ( Figure  4).
The transition state of the concerted 1,3-dipolar cycloadditions is usually controlled by frontier molecular orbitals of dipolarophiles and dipole (azomethine ylide). The favoured path involves HOMO dipole and LUMO dipolarophile . The ΔH f , HOMO, LUMO energies and HOMO-LUMO energy gaps of azomethine ylides 4 with dipolarphiles are given in Table 1.
From the Table, it may be concluded that HOMO dipole -LUMO dipolarophile energy gap is lower than the LUMO dipole -HOMO dipolarophile gap and therefore the dominant FMO approach is HOMO dipole -LUMO dipolarophile . Both the HOMO and the LUMO of the dipole show uneven distribution of the electron density along the C-N-C dipole. In the HOMO case, the orbital coefficient is larger at C 1 (0.288) than at C 2 (-0.163). Similarly in the LUMO of methyl acrylate the atomic orbital coefficient are (0.611) and (-0.521) respectively ( Figure 3). Thus it may be concluded that there is better overlap when -COOMe group lies towards thioisatin ring, giving two possibilities 5a and 5b. Out of these 5a is formed in diastereomeric excess probably due to the endo approach of -COOMe.

Regioselectivity of the addition of symmetrical and unsymmetrical acetylenes
Parallel to methyl acrylate, diphenylacetylene can also attack either of the azomethine ylide (4 syn or 4 anti ) with the formation of products having two chiral centers. Therefore a total of 4 + 4 = 8 isomers (4 pairs of enantiomers) could be possible 8a-8h ( Figure 5). Attack of diphenylacetylene on syn-azomethine ylide 4 syn results in the inward movement of the thiazolidine ring towards the thioisatin nucleus and the transition state could not be located even in a single case ( Figure  2) ruling out the possibility of the formation of products 8e-8h. Thus it leaves the possibility of attack on the anti azomethine ylide 4 anti and hence only four isomers 8a-8d are left for consideration. We have optimized the geometry of all the four isomers. Results show that all isomers have almost same ΔH f , indicating that thermodynamically all are nearly equally stable.
Of remaining four possibilities 8c and 8d where N and H atoms on the adjacent carbon atoms do not lie on the same side, the transition state could not be located because concerted mechanism is not possible in such a situation. This leaves only two isomers 8a-8b for consideration. Out of these two isomers we could optimize the transition state in case of 8a only ( Figure 6). This can be explained using the FMO approach along with the endo approach of the phenyl ring (Figure 7) as discussed above.
Similarly attack of unsymmetrical dipolarophile, such as ethyl phenyl propiolate, on syn or anti azomethine ylide may produce a cycloadduct having two chiral centres and therefore a total of 4 + 4 = 8 stereoisomers 9a-9h could be possible ( Figure 8) and it was concluded that isomer 9a is formed preferentially (Figure 9). The energy profile diagrams for azabicycloadducts 5-9 are presented in (Figure 10).
ΔH f-R , ΔH f-Ts , ΔH f-P , Ea(activation energy) and stabilization energy of amy with different dipolarophiles have been tabulated in Table 2.

Conclusions
From the above discussions, it may be concluded that: a.The azomethine ylide exits in two conformations; 4 syn and 4 anti . b. The dominant FMO approach is HOMO dipole -LUMO dipolarophile as this energy gap is lower than the LUMO dipole -HOMO dipolarophile gap. c. Azomethine ylide is stabilized by the delocalization of dipolar charge into thioisatin nucleus, thus increasing the activation energy for the reaction path.

Experimental
The uncorrected melting points were taken in open glass capillaries. The IR spectra were recorded on a Nicolet Magna IR Spectrometer Model 550 in KBr pellets and band positions are reported in wave numbers (cm -1 ). The 1 H NMR spectra and 13 C NMR spectra have been recorded on a Bruker DRX-300 MHz and 75.47 MHz model respectively in CDCl 3 and DMSO using tetramethylsilane as an internal standard. The chemical shifts are given in δ ppm values. The mass spectra were recorded on a JEOL-SX 102 (FAB). Most of the spectra were recorded at CDRI, Lucknow, India. Elemental analyses were performed on a Perkin Elmer Series C, H, N, S Analyzer 2400. The solvents were purified by standard procedures [18,19]. Acetonitrile was dried by refluxing with anhydrous calcium chloride for 5-6 h and then distilling it. Column chromatography was performed on silica gel 60 (Merck).