SYNTHESIS AND CHARACTERIZATION OF NEW THIAZOLIDINONES AND 2-OXOPYRROLIDINES DERIVED FROM SCHIFF BASES

Thiazolidinones (Figure 1a) are classified as doubly unsaturated five-membered heterocyclic compounds contain one nitrogen, one sulfur and three carbon atoms including a carbonyl group. Thiazolidinones and their derivatives show a large variety of biological activities such as antibiotic, diuretic, tuberculostatic, organoleptic, antileukemic and antiparasitic.1,2 As far as literature is concerned, only a few information is available about thiazolidinones and their bioactivity. The chemistry of thiazolidin-4-one ring system is considerable interest because it is the core structure in various pharmaceuticals.


Introduction
Thiazolidinones (Figure 1a) are classified as doubly unsaturated five-membered heterocyclic compounds contain one nitrogen, one sulfur and three carbon atoms including a carbonyl group.Thiazolidinones and their derivatives show a large variety of biological activities such as antibiotic, diuretic, tuberculostatic, organoleptic, antileukemic and antiparasitic. 1,2As far as literature is concerned, only a few information is available about thiazolidinones and their bioactivity.The chemistry of thiazolidin-4-one ring system is considerable interest because it is the core structure in various pharmaceuticals.Five-membered ring lactams, which are known as γlactams or 2-oxopyrrolidines (Figure 1b), are essential structural motifs in biologically active natural products and used in medicines and approved drugs. 3γ -Lactams have attracted considerable attention in recent years because they are valuable building blocks in the structure of several biologically active molecules. 4Substituted γ-lactams, in particular, have potential application in drug synthesis, but the development of the stereoselective synthesis of chiral γlactams remains a challenge. 5,6Various γ-lactams are components of natural products, 7 and some biologically important lactams 8 are obtained from the reaction of imines with phenylsuccinic anhydride.

Experimental part
All solvents were distilled/dried prior to use, whenever this seemed necessary, by standard methods.All solvent extracts were dried over anhydrous sodium sulfate unless otherwise specified.
FT-IR spectra were recorded using a Shimadzu FT-IR spectrophotometer as KBr.The absorption bands of interest are reported and expressed in cm -1 .
1 H-NMR spectra were recorded using a Bruker Varian NMR spectrometer (500 MHz).The chemical shift values are expressed in δ(ppm), using tetramethylsilane (TMS) as internal standard and DMSO-d6 as a solvent. 13C-NMR spectra and 13 C-NMR DEPT spectra were recorded using a Bruker Varian spectrometer (75 MHz).The chemical shift values are expressed in δ(ppm), δ(ppm), using tetramethylsilane (TMS) as internal standard and CDCl3 as a solvent.
Mass spectra were recorded using a 70 eV HPLC-LCQ Fleet/Thermo Scientific instrument with 5973 type mass selective detector.

General procedure for preparation of imines
In general, the imines (2a-2d) were prepared by reaction the corresponding amines with an aldehyde or a ketone in 40 mL of methanol and 4-6 drops of glacial acetic acid with refluxing the reaction mixtures for 1-5 h under stirring.The progress of the reaction is followed by TLC.After completion the reaction, the solvent was evaporated then the residue was recrystallized from a suitable solvent.The physical data of the prepared imines (2a-2f) are gathered in Table 1.

General procedure for preparation of thiazolidinones (3)
A mixture of compound 2a-2d and thioglycolic acid in chloroform (15) ml was allowed to react in a Teflon beaker in a microwave oven at 100 W for 6-12 minutes.Progress of the reaction is checked by TLC using hexane-ethyl acetate as eluent.After the completion of reaction, chloroform was removed by distillation to give a solid residue.The solids were washed successively with 1 N HCl (20 mL), water (2×20 mL), 5% NaHCO3 (20 mL) and brine (20 mL).The organic layer was dried with Na2SO4 The solvent was removed by evaporation.The following thiazolidinones were prepared:

General procedure of γ-lactams (4)
In general the γ-lactam were prepared by reaction the mixture of imines 2a, 2b, 2e and 2f) with phenylsuccinic anhydride in 20 mL of chloroform, then the mixture was refluxed for 1-12 h with stirring.The progress of the reaction was followed by TLC.After completion the reaction, the solvent was evaporated and the residue was recrystallized from ethanol.The following γ-lactams were prepared:

Results and discussion
The Schiff bases are formed by the condensation of primary amines and an aldehyde or ketone.
A simple synthetic way to prepare the biologically active thiazolidinones 9,10 is based on the reaction of imines with thioglycolic acid: The IR spectra of imines 2a-2f made is characterized by four principal band groups correspond to the stretching vibrations of the aromatic C-H bonds, aliphatic C-H bonds, azomethine bonds (C=N), and aromatic C=C bonds of the and substituted aromatic ring, which occur within the ranges of 3224-3047, 3007-2777, 1638-1610, and 1586-1475 cm -1 , respectively.
The 1 H-NMR spectrum of 2-(2-bromo-6-hydroxyphenyl)-3-(pyridin-2-yl)thiazolidin-4-one (3a) (see Electronic Supporting Information) is evaluated as an example.The signal at chemical shift δ 2.50-2.51ppm belongs to the DMSO-d6 solvent.There are two doublet signals at chemical shift δ 3.81 ppm (J=3 Hz) and δ 4.19 ppm (J=3Hz) for methylene protons of thiazolidin-4-one ring (Fig. 1).The chiral carbon atom (No.2) gives a singlet signal at δ 5.68 ppm (racemic mixture (R, S) configuration) and there is a multiple signal system for three protons of the phenol ring at δ 6.02-7.51.A multiplet signal for four protons of pyridine ring at δ 7.80-8.12ppm also appears.γ-Lactams also represent important substructures for the synthesis of biologically relevant compounds in drug discovery 11 and natural products. 12,13The prevalence of these structures 14,15 resulted in the development of several efficient methods 16 and preparation of diverse libraries of small molecules for biological evaluation. 17,18Based on these earlier studies, a practical way, the cyclization of imines with phenylsuccinic anhydride in chloroform was followed: Bands characterize the IR spectra of γ-lactams 4a, 4b, 4e and 4f belong to the stretching vibrations of the carboxylic OH, aromatic C-H, aliphatic C-H, carboxylic carbonyl group, carbonyl amide group, aromatic C=C and substituted aromatic ring in the ranges of 3134-3026, 3064-2742, 1727-1695, 1651-1586, 1602-1536 and 939-809 cm -1 , respectively.

The 13 C
NMR spectrum of 2-(2-bromo-6-hydroxyphenyl)-3-(pyridin-3-yl)thiazolidin-4-one (3a) as example (see Electronic Supplementary Information) shows a signal at δ 76.34-76.96ppm for the CDCl3 solvent.There are two singlets at δ 42.96 ppm and 52.12 for the methylene group carbon and No.2 carbon of the thiazolidin-4-one ring.A multiplet signal between δ 128.13-151.34ppm for aromatic carbon atoms (pyridine + phenol) ring and a singlet signal at δ 180.52 ppm for the carbon of the amide carbonyl group are also identified.