Meilin Zheng

Improved Preparation of 2,4-Thiazolidinedione

The widely utilized industrial product 2,4-thiazolidinedione (3) has been chosen as the starting material for our ongoing research on rosiglitazone,1 which is a selective PPAR-γ receptor inhibitor for the treatment of type-II diabetes.2 Based on the literature3 and our own experience, we developed an efficient one-step method to obtain 3 using conc. hydrochloric acid.4 This improved synthesis seemed to be much better than the previous methods,3 all of which shared the disadvantage that the strongly acidic waste from the reaction and solvents from the recrystallization process have to be disposed of without harm to the environment. In order to alleviate these problems, we decreased the amount of hydrochloric acid and our results show that the yield of 3 is still acceptable while the concentration of HCl has been decreased by more than one half (Table 1). This result encouraged us to do further research,5 which resulted in a green and inexpensive method to prepare 3. Herein, we report this economic and environmentally friendly synthesis of 3, starting from chloroacetic acid (1) and thiourea (2) using water as the solvent for the preparation as well as the recrystallization process.

An Eco-friendly Preparation of 2-Iminothiazolidin-4-ones Derivatives

Functionalized 2-thiazolidin-4-ones are important heterocyclic compounds owing to their biological activities,1,2 such as anti-tuberculosis,3 anti-convulsant,4 fungistatic,5 bacteriostatic,6 antimicrobial,7 antiviral,8 anti-cancer,9 and immunomodulation properties.10 2-Iminothiazolidin-4-one (3a) and 3-ethyl-2-(ethylimino)thiazolidin-4-one (3b) are two important basic structures in this category. The active methylene group (CH2) at the 5-position of 3 might provide opportunities for structure modifications, viz. via Knoevenagel condensation with various aldehydes to give 5-substituted derivatives. Compounds 3 have thus been used as important intermediates for synthesis of many biologically active compounds, such as rosiglatazone,11 picoglatazone,12 etc. Conventional synthesis of 2-iminothiazolidin-4-ones (3) involved cyclization from thioureas with chloroacetic acid derivatives via using various catalysts,13,14 which include mineral acid15 and organic or inorganic bases such as sodium acetate,6,16–18 sodium hydride,10 triethylamine,9 and pyridine.10 Chloroacetic acid may be replaced by its esters,19 acid chloride,9,10 acylamides10,20 or 2-mecaptoacetic acid.21 All these methods share shortcomings and are not suitable for large-scale green manufacture.22 In order to solve this problem, we have developed an environmentally friendly method to synthesize 3 based on our experiences.15 Chloroacetic acid ionizes in water into protons which catalyze the reaction, thus making it a self-catalyzed reaction. The improved simple procedure involves heating the thioureas and chloroacetic acid in water and recrystallizing the products from water. The process offers an eco-friendly preparing of 3 for industrial purposes (Scheme 1).

An Improved Two-step Preparation of 2,4-Dimethylpyrrole

2,4-Dimethylpyrrole (1) is a very important intermediate in the synthesis of fluorescent molecules (such as BODIPY),1,2 the new tyrosine kinase inhibitor (such as sunitinib),3–5 anti-inflammatory/analgesic agent6 and so forth. The traditional synthetic methods of 1 usually involved several steps including the construction of the pyrroles skeleton by the Knorr reaction using 1,3-diketones,7 and by oximation of either acetoacetic esters or malonates via a dissolving-zinc reduction and subsequent hydrolysis, acidification and decarboxylation (Scheme 1).8,9