Malic acid as an effective and valuable bioorganocatalyst for one-pot, three-component synthesis of pyrrolidinone derivatives

Malic acid was used as an effective and valuable bioorganocatalyst for the one-pot, three-component synthesis of important and noteworthy pyrrolidinone derivatives in green solvent at 50 o C. Ecofriendly, simplicity in operation, cleaner reaction profile, simple workup procedure, use of non-toxic solvent

Although a number of catalysts have been reported for the synthesis of pyrrolidinone derivatives, the use of bioorganocatalysts and green catalysts are very momentous.14,36 Malic acid is known as a fruit acid that plays a role in creating the sour taste of the fruits.Apples contain a lot of malic acid, called apple extract.This dicarboxylic acid is one of the food additives that serves as a source of extreme tartness in confectionery.It is available in two stereoisomeric [(+) and (-)] forms, although only the (-)-isomer exists naturally. 37(-)-Malic acid was used as the chiral precursor for the synthesis of (-) wikstromol which exhibits several biological activities. 38[41]

Results and Discussion
Using malic acid as a bioorganocatalyst, various reaction conditions were investigated in the reaction of aniline, diethyl acetylenedicarboxylate, and aldehyde derivatives in ethanol solvent to achieve appropriate conditions for the synthesis of pyrrolidinone derivatives (Scheme 1).We tried to make the reaction conditions in such a way that some of the problems of the methods reported in previous articles could be minimized as much as possible.We then optimized the reaction conditions, such as the effect of a suitable solvent, catalyst amount, and the value of temperature.
At the beginning of the optimization of reaction conditions, different solvents such as H2O, C2H5OH, and C2H5OH-H2O (50-50) were compared in the synthesis of 4a as a template compound.The best result was obtained by the reaction of aniline, diethyl acetylenedicarboxylate, 4-nitrobenzaldehyde in ethanol over 90 min with 92% yield (Table 1, entry 3).Water and water-ethanol afforded moderate yields of the desired products, however, they had longer reaction times (Table 1; entries 1 and 2).Thus, ethanol was selected as the most suitable solvent.Scheme 1. One-pot, three-component syntheses of pyrrolidinone derivatives in the presence of malic acid.
Thereupon, we performed the template reaction at different temperatures, including room temperature (RT), 30, 40, 50, and 60 o C for model reaction as shown in Table 2.At room temperature, a mixture of starting materials was seen during the reaction.By increasing the temperature to 30 o C, after 180 min the reaction was complete with 91% yield (Table 2, entry 2).Raising the temperature to 40 o C reduced the reaction time to 120 min.Raising the temperature to 50 °C did not have any great impact on the yield of the reaction, however, the reaction time was reduced.Increasing the temperature to 60 o C had no significant effect on the yield of product or the reaction time.Therefore, the temperature of 50 o C was chosen as the appropriate temperature for the reactions.Determination of the optimized amount of catalyst for the synthesis of compound 4a was carried out by varying the quantity of catalyst, as shown in Table 3.Since there was only a modest yield improvement (2%) with an increase of 0.5 mmol of catalyst, we chose 1 mmol of catalyst as our ideal amount in order to use less catalyst.After finding the most suitable reaction solvent (C2H5OH), temperature (50 °C), and amount of the catalyst, this method was examined by the reactions of aniline, diethyl acetylenedicarboxylate, and several substituted aldehydes 3a-q in the presence of malic acid.To check the behavior of different types of aldehydes in the synthesis of pyrrolidinones, we tested numerous, diverse aldehydes, including aromatic aldehydes with different groups in the ortho-, meta-, and para-positions under the reaction conditions.As shown in Table 4, we discovered that aromatic aldehydes with electron-withdrawing groups reacted faster.The structures of all of the synthesized products 4a-q were defined by their FT-IR, 1 H-NMR, and 13 C-NMR spectra.
Scheme 2. Mechanism of the acid-catalyzed one-pot, three-component reaction.
The possible mechanism for the one-pot, three-component synthesis of pyrrolidinone derivatives (4a-q) in the in the presence of malic acid is shown in Scheme 2. First, Aniline is added to diethyl acetylenedicarboxylate (I).An imine is then formed from the aldehyde and aniline via the acid-catalysed reaction (II).The resulting 1,3-dipolar intermediate adds to the imine, eventually yielding the target products following cyclization and elimination of aniline and ethanol.Reaction conditions: aniline 1 (1mmol), diethyl acetylenedicarboxylate 2 (1 mmol), aldehyde 3a-q (1mmol), and malic acid (1 mmol) in ethanol solvent (2 mL) at 50 °C.a Isolated yield.
Single-crystal X-ray diffraction studies were used to confirm the structure of the compound 4q.It crystallizes in the centrosymmetric monoclinic space group; therefore, the compound is racemic.The central pyrrolidinone ring is planar with substituents twisted with respect to it.The N-bound phenyl ring is twisted by 46.82(4)°, whereas the methylthiophenyl ring is twisted by 84.75(1)°.The main building block of the crystal packing is the centrosymmetric dimer (Figure 2).Table 5. Hydrogen-bond geometry (Å, º) for 4q It should be noted that we tested several other aromatic aldehydes.Their respective related product 4 could not be generated when we used trans-cinnamaldehyde, salicylaldehyde, 2-hydroxy-1-naphthaldehyde, and 4-(dimethylamino)benzaldehyde under the reaction conditions.In all cases, a mixture of several products and starting materials were observed, based on TLC.The yields of the products of these substrates were poor.Due to electronic effects, forming the imine from aniline and electron-rich aldehydes is very difficult.
We also decided to investigate the behavior of ketones in these reactions.To do this, tested a reaction with the simplest ketone, acetone.As we suspected, acetone did not respond to the reaction conditions for steric and electronic reasons.Prolonging the reaction time did not affect the reaction results.

Table 3 .
The effect of the catalyst amount on the synthesis of pyrrolidinone derivatives a a Isolated yield.