Highly efficient and chemoselective synthetic route to de thiazolidinones via a microwave assisted, three component reaction

We present here the study of selective synthesis of 1,3-thiazolidin-4-ones via microwave-assisted multi-component reaction under solvent-free conditions. Although, theoretically two different products are possible (benzothiazepinones 4 and thiazolidinones 5), the reaction gave only two diasteroisomers of 1,3-thiazolidin-4-ones (48-97%) in the threecomponent reaction between 2,3 : 4,5-di-O-isopropiliden-β-D-arabino-hexos-2-ulo-2,6piranosa 1, different heteroaromatics anilines 3 and mercaptoacetic acid 2 as can be seen in the scheme of Figure 1. The synthesized compounds were characterized by IR, H-, C, DEPT and HSQC RMN. The stereochemistry of both the diasteroisomers was elucidated with the help of NOE experiments.


Introduction
Microwave irradiation is an alternative heating method based on the ability of some compounds to transform electromagnetic energy into heat.This method, which increases chemical reaction rates and forms cleaner products, can be successfully applied in pharmaceutical chemistry. 1Microwave irradiation reactions has been extended to almost all areas of chemistry with the exception of the carbohydrate chemistry which has suffered a certain delay, as it is testified by the small number of applications.
However, a limited number of these reactions regard so far the carbohydrate chemistry and since carbohydrates play an important role in a vast array of biological processes, and particularly there are many advantages, for example, in carbohydrate-based drugs such as low toxicity and immunogenicity, the interest in their preparation and reactivity by microwave heating is very high.
The 4-thiazolidinones and correlated derivatives have high biological relevance since they are present in both natural products and pharmaceutical compounds.The presence of N-C-S linkage in the compounds has been shown to have hypnotic, 2 anti-cancer, 3 cardiovascular, 4 antioxidant, 5 anti-inflamatory, 6 antitubercular, 7 antihistaminic, 8 antimicrobial, 9 anticonvulsant, 10 antiviral and anti-HIV 11 acivities.Besides, carbazole, pyrazole and tiazole skeletons constitute the structural core element of many natural and synthesized products.
Taking into account these facts and based on the versatile bioactivities of the above mentioned structures, it is promising that the integration of heteroaromatic amines, with carbohydrate scaffold and 4-thiazolidinone segment might result in the discovery of new drug candidates with unknown or enhanced bioactivities.

Results and Discussions
In order to find suitable conditions for efficient microwave-assisted formation of the 4thiazolidinones we study the reaction of benzaldehyde, aniline and mercaptoacetic acid (1:1:1).Table 1 We started the studies using two different modes of microwave irradiation: Standard Control and SPS Control.These options permit the user to control how the system applies the microwave energy to the reaction.The Standar Control option provides more flexibility in how the user program a reaction method and makes greater use of the feedback control data from the temperature and pressure systems.It applies a specified amount of power, defined by the use, to reach the control point.It modulates this set power automatically, based on the sensor feedback data, to ensure the control point is reached rapidly, but with limited error.
The SPS Control option will irradiate at the defined power to bring the reaction mixture to the control temperature and then generates cycles of power on and off for the remainder of the run time as the temperature varies between the control temperature and a user defined deviation -usually 5°C below the control temperature.
Under these last conditions and varying the power and temperature, in either case the compound of interest was obtained with acceptable yields, generating an inorganic residue

minutes reaction
Data obtained with each method using 120 ° C temperature and powers ranging between 200 and 300W for the stated reaction were tabulated in Table 1.As shown in Table 1, the best conditions of temperature and power to these solvent free multicomponent reactions is the Standard Control, using irradiation at T °: 120 ° C, power: 300 W (entry 9).

Figure 3
As will be observed later in Table 2, the Standard Condition method of irradiation using 300W power and 120 ° C temperature afforded the product 5a with good yield (87%) calculated by GC-MS on an average of three reactions performed under the same conditions (Figure 4a).From the NMR spectra analysis is deduced that the reaction product is a mixture of the two possible diastereoisomers.In this case the GC-MS shows only a broad peak due to the presence of the mixture of diastereoisomers associated to the structures of Figure 4b.The mixture of diastereomers was isolated by chromatography on neutral alumina column, using as eluent: petroleum ether 60-80 / ethyl acetate (50:50).We could not separate any of them from the mix, even using flash chromatography or preparative TLC.In the 1 H-, 13 Cand DEPT-NMR spectra are observed "duplicated signals", characteristics of the existence of the two isomers (Figure 5).
In the 1 H-NMR spectrum it is not observed the signal corresponding to the H bonded to N in the 7-membered ring benzothiazepine (which generally corresponds to a δ: 9-13 ppm). 16is fact, together with the absence of NH stretching band in the IR spectrum confirms the selective formation of the 4-thiazolidinones as single reaction product.
The area of the H bonded to the asymmetric carbon produced in the reaction (painted in blue and red in the 1 H-NMR spectrum of Figure 5), allowed to reveal that the mixture of the two diastereomers is in 40:60 ratio.The products were characterized by IR, 1 H-, 13 C-and DEPT-NMR spectroscopy, confirming the data obtained by GC-MS.

b)
Is worth highlighting that for the inputs 3, 4 and 5 in Table the heteroaromatic amines used condition the reaction to five-member products formation.In all other cases, the formation of products of 5 to 7 members is feasible, although, as can be seen, only the 4thiazolidinones are selectively obtained.
In most cases (5b, 5c, 5d, 5e, 5f) two peaks are observed in the GC with identical fragmentation, corresponding to the two formed diastereoisomers.In all other cases, if only a broad peak is observed in the GC, the NMR spectra confirm the presence of the corresponding diastereoisomeric mixture.The proportion of each in the mixture is calculated using the respective 1 H-NMR spectra.

CG-MS
The crude reaction product was subjected to column chromatography on neutral alumina to separate the isomers without succeeding.Fortunately one of them was isolated by digestion in absolute ethanol.The structure of this diastereomer was determined by 1 H, 13 C, DEPT-HSQC-NOESY.2D and 1D selective NOESY -NMR spectroscopy.
Spectroscopic data of 1 H and 13 C-NMR are summarized in Figure 7 and Table 3.
1 H-RMN  From the HSQC spectrum analysis it was determined that the singlet at 6.As shown in Figure 8, in the (R) configuration, the proton bonded to C 5 shows NOE interaction with C 3 protons and protons associated with two of the methyl groups of the 2,3-Oisopropyliden sugar structural moieties.Furthermore, and as can be noted in the NOESY spectrum of Figure 9, there is also NOE interaction with the proton of : 4.41 ppm which is associated with the C of : 70.20 ppm from the pyranose ring.These interactions would be absent in the case of the (S)-isomer, in which the only possible interaction would be that shown in Figure 8.

Figure 9
In the reaction of entry 3, Table 2, the mixture of diastereoisomers is obtained in 65:35 ratio, calculated by 1 H-NMR and GC-MS (Figure 10).
As seen in the table, the yield of the isolated mixture of isomers is far lower than in the other cases (48%).Furthermore, when analyzing the gas chromatogram it can be noted that it has the particularity of showing two peaks with identical mass fragmentation in the elution region of the reaction intermediate.
Together with the data of the 1 H-, 13 C-, DEPT-NMR spectra and previous literature,  According to previous studies, the presence of this type of intermediate generated in the reaction mixture suggests that the imine Ic is unstable under the reaction conditions favoring the formation of the oxathiolane.This is consistent with the significant decrease in the yield of the corresponding 4-thiazolidinone 5c.

Conclusions
A stereoselective synthesis of 4-thiazolidinones from a microwave-assisted multicomponent reaction under solvent-free conditions between 2,3 : 4,5-di-O-isopropiliden-β-Darabino-hexos-2-ulo-2,6-piranosa, different heteroaromatics anilines and mercaptoacetic acid has been achieved.Although two chiral products are possible (benzothiazepinones and thiazolidinones), only two diastereomers of 4-thiazolidinones were obtained.The reaction is easy to perform using inexpensive starting materials and generates products in moderate to high yields.The one-pot microwave-assisted conditions was shown to be an operational simplicity and environmentally friendly method, in terms of atom economy, energy consumption and time required, to make this new synthetic strategy highly attractive and promising for the access of compounds of potential biological interest.The studies on the purification and characterization of each of the compounds reported here is underway.
solid black, insoluble in acetone and ethanol, soluble in DMSO, with no signals of 1 H-and 13 C-NMR) probably due to the charring of the reactants or the product.Fortunately, when the reaction was carried out using the Standard Control under 300 W power microwave irradiation at 120°C it afforded the 4-thiazolidinone (5) with excellent yields.The sample is irradiated by consecutive periods of 5 minutes with addition of further amounts of mercaptoacetic acid at 5 and 10 minutes of irradiation due to its volatility (bp: 96 °C).The GC-MS of the aliquots taken at 5 and 10 minutes show large proportion of the imine (reaction intermediate I), while the aliquot taken at 15 minutes of reaction allows to see the reaction intermediate consumption and product 5 formation.After 15 min of reaction under microwave conditions, no progress in the reaction was seen by TLC analysis (Figure2).

Figure 7
Figure 7 21 ppm is attached to the new asymmetric C generated in the reaction (C 5 δ: 64.89 ppm).Furthermore, doublets with J = 16.3Hz and chemical shifts in ppm 4.12 and 3.82 ppm correspond to the protons attached to C 3 (δ 34.30 ppm).The structure of the two diasteroisomers is observed in Figure 8.The stereochemistry of the isolated diastereoisomer was elucidated by NOE experiments.The NOE.2D interactions are discussed in Figure 9.

Figure 10 ab
Figure 10

Table 1 .
a Determined by CG-MS analysis of crude reaction through a standard curve generated from isolated pure product.b Temperature and power selected in the microwave apparatus

Table 2 .
a Isolated yield of diastereomeric mixture.b Ratio of diastereomers was determined by 1 H-RMN.