Conversion of 3 , 4-Dihydroxypyrrolidine-2 , 5-Dione to Maleimide through Tosylation and Mechanism Study by DFT

Pyrrolidine-2,5-dione and maleimide are important scaffolds of many organic substances, and their derivatives are now attracting more and more interests from researchers in organic synthesis, medicinal chemistry, and drug development. Tosyloxy (-OTs) group is an important functional group widely used in organic synthesis, because it can be readily prepared from alcohols and is an excellent leaving group. However, surprisingly, substances bearing tosyloxy groups on pyrrolidine-2,5-dione or maleimide scaffolds are very rare. In this study, we discovered that, when treated with TsCl/Et3N, trans-3,4-dihydroxypyrrolidine-2,5-dione will eliminate a TsOH molecule to form monotosyloxymaleimide. Thermodynamic and kinetic factors affecting this reaction were investigated by theoretical computation using density functional theory (DFT), and the possible reaction mechanism was proposed based on the computation results. Our results showed that tosylates of trans-3,4-dihydroxypyrrolidine-2,5-dione, either monotosylate or ditosylate, are thermodynamically instable and may spontaneously convert to maleimides. This knowledge could be useful in understanding the properties of pyrrolidine-2,5-diones and maleimides, as well as the related organic synthesis.


Introduction
Pyrrolidine-2,5-dione and maleimide exist in numerous organic substances and are common scaffolds of many important chemicals, drugs, nutrients, dyes, materials, etc.They are readily prepared through condensation reactions of succinic acid or maleic acid or their chiral derivatives (like tartaric acid, malic acid, etc.) with primary amines without racemization, and therefore are important building blocks in organic synthesis, especially in asymmetric synthesis [1] [2] [3] [4] [5].
We were surprised to discover that (3 R, 4 R)-3,4-dihydroxypyrrolidine-2,5-dione (L-tartarimide) tosylates may spontaneously lose a TsOH molecule to form monotosylated maleimide.Theoretical computation was then performed using density functional theory (DFT) to study the possible mechanism of this reaction; the results showed that the L-tartarimide monotosylate was thermodynamically instable and may eliminate a TsOH molecule to form the maleimide scaffold.
The kinetic factors were also examined and it was concluded that this elimination is primarily driven by thermodynamic factors.

Results and Discussion
In our studies, L-tartaric acid was firstly condensed with p-methoxybenzylamine (PMB-NH 2 ) to form intermediate 1 (Scheme 1), according to the method in the literature [1]. 1 was then subject to tosylation by TsCl and Et 3 N at room temperature to furnish ditosylated intermediate 2a, which was to be used in synthesis of 3,4-disubstituted pyrrolidine-2,5-dione through nucleophilic substitution in our plan.Surprisingly, neither the ditosylated product 2a nor the monotosylated product 2b was found; instead, the tosyloxymaleimide 2, which is obviously a product after eliminating a p-toluenesulfonic acid (TsOH) molecule, was obtained in high yield (85.2%).The 1 H NMR spectra of 1 and 2 are presented in  to give 2; alternatively, the monotosylated intermediate 2b might lose a TsOH to form the enol-ketone tautomers 2c and 2d, which were then tosylated to give 2.
Substructure search with SciFinder showed that none of the structure 2e and 2f, nor any compounds bearing 2e or 2f as a substructure, have been reported so far.Therefore, we proposed that the monotosylated or ditosylated derivatives of trans-3,4-dihydroxypyrrolidine-2,5-dione might be (thermodynamically and/or kinetically) instable and easily to undergo elimination reactions spontaneously.
The free energy discrepancies between the reactant and product of this elimination were evaluated for both 2a and 2b by DFT with Gaussian 09 [15] (Table 1).The reactants and products were firstly geometrically optimized with hybrid-meta GGA functional M06-2X [16] [17] and the basis set6-31G** [18] [19], followed by frequency analysis at the same computational level, to give the thermal correction values to Gibbs free energy.Finally, the optimized structures were recalculated for single point energy (ε) using double-hybrid functional B2PLYP [20]  The mechanism of this elimination and kinetic factors were then investigated.
Obviously, 2a or 2b cannot undergo E2 elimination, which needs an anti-periplanar position of two leaving groups (OTs and α-H).An E1cB elimination is also not likely because it requires a quite acidic H (or a strong base) and a poor leaving group.Since 2a or 2b bears OTs, a good leaving group, and Et 3 N is a weak base, E1 mechanism would be preferable in the elimination of TsOH (Scheme 3).Since the formation of tosylate anion by heterolysis of C-OTs bond (marked red in Scheme 3) is the rate-determining step, strength of this bond was then evaluated by analysis of the bond order and bond force constant.The Mayer bond order, Fussy bond order, and Laplacian bond order [25] of 2a and 2b were analyzed by Multiwfn 3.5 [26] (Table 2).The relaxed force constant of the C-OTs bonds were calculated according to the Compliance Matrix method using Compliance 3.0.2[27] [28] (Table 2).The corresponding properties of C-OTs bonds in 2, methyl tosylate, and C-OH bond in 2b were also calculated for references.For the same type of bonds, stronger bond usually has higher force constant, higher bond order, and shorter bond length.Generally, the trend of all these indicators are consistent; the C-OTs bonds in 2a and 2b are significantly weaker than that in 2 or C-OH bond in 2b, but are comparable to (or even slightly stronger than)the C-OTs bond in MeOTs, a compound stable in normal conditions.Therefore, the instability of 2a and 2b is more likely due to thermodynamic reasons, rather than kinetic reasons; the high thermodynamic  Scheme 3. E1 elimination mechanism of 2a and 2b.
stability of the elimination products, primarily contributed by the formation of a large conjugation system, would promote the E1 elimination.Considering the significantly greater free energy change of 2b than 2a during the elimination, and the fact that no substances bearing substructure of 2f have been reported, we concluded that this elimination reaction was more likely to take place at monotosylated stage; i.e., the reaction process should be 1 → 2b → 2c/2d → 2.
It is also worth mentioning that, the free energy difference between (2c + Et 3 N•HOTs) and (2d + Et 3 N•HOTs) (9.3 KJ/mol) indicated that the ketone form (pyrrolidine-2,3,5-trione) is thermodynamically more preferable than the enol form (3-hydroxymaleimide), agreeing with common knowledge.According to the Boltzmann distribution, the approximate ratio of 2c: 2d was calculated to be 2.3%:97.7%, the ketone form being the predominant.However, the free energy difference of 9.3 KJ/mol is not very large, otherwise the reaction would stay at 2d, without forming 2c and 2.

Conclusion
In this study, the application of tosyloxy (-OTs) group on two important scaffolds, pyrrolidine-2,5-dione and maleimide, was explored.Few compounds or studies was then tosylated to give 2 (monotosylated maleimide).DFT calculations also showed that such an elimination reaction was due to thermodynamic reasons rather than kinetic reasons; tosylates of trans-3,4-dihydroxypyrrolidine-2,5-dione are thermodynamically instable and liable to convert to maleimides.This might help to explain why so few (only one) tosylated pyrrolidine-2,5-dione substance had been known before.We hope this study will be helpful in broadening the understanding of the chemical and reaction properties of pyrrolidine-2,5-dione and maleimide, as well as in the organic synthesis involving such scaffolds.The related synthesis studies on tosylated maleimides are ongoing and will be reported soon.2) Synthesis of 3-tosyloxy-N-(4-methoxybenzyl) maleimide (2).

Figure 1 and
Figure 1 and Figure 2.Obviously, there are two possible processes for such a conversion (Scheme 2):

Table 1 .
Possible intermediates in the conversion of 1 to 2 and Gibbs free energies calculated by DFT.
p-toluenesulfonic acid to give 2c or 2d, especially in the presence of triethylamine.Similarly, 2a is also apt to convert to 2, although the free energy discrepancy is considerably smaller (−82.0KJ/mol).M. C. Yan et al.DOI: 10.4236/cc.2018.6300451 Computational Chemistry a) Thermal correction values were calculated at M06-2X/6-31G** level with the frequency scale factor of 0.9670 [24] at 298.15 K. ε values were calculated at B2PLYP/def2-TZVP level.All energies were in Hartree.

Table 2 .
Bond lengths, bond orders and relaxed force constants of the C-OTs bond cleaved in E1 elimination of 2a and 2b.a)