# Synthesis and Anticancer Activity of Novel Thiazole-5-Carboux Derivatives
## 1 Introduction  
Substituted thiazole compounds play an important role in nature and have a diverse range of biological effects such as antitumor [1; 2; 3] antibacterial [4], antimicrobial [5], anti-viability [6], anti-inflammatory [7], Syk inhibitor [8], antiviral [9], antiproliferative [10], and anticandidal activity [11]. In past decades, amide containing heterocycles are reported as a class of compounds displaying extensive biological activities, which consist of a large number of natural and synthetic products and are extremely versatile building blocks for the manufacture of bioactive compounds in pharmaceutical drug design and agrochemical industry [12; 13; 14; 15; 16; 17; 18]. We noticed that most optimizations focused on the pyridine [19], pyrazole [20], piperazine [21] and oxadiazole [22] heterocycles, but the thiazole ring, as an active moiety widely used in pesticides and medicine, has not been fully reported. For example, phthalic diamides [23] and anthranilic diamides [24] were reported by Nihon Nohyaku (Tokyto, Japan), Bayer CropScience (Monheim, Gemmany) and DuPont (Delaware, USA), respectively.  
In view of all these facts and as continuation of our research on bioactive compounds [25; 26; 27; 28; 29; 30; 31; 32; 33; 34; 35; 36; 37], the promising bioactive diversity of this class of heteroaryl compounds encourage us to synthesize and biologically evaluate a series of novel structural variants of 2-phenyl-4-trifluoromethyl thiazole-5-carboxamide derivatives and related intermediates. Their antitumor activity was tested in A-549 lung cancer cell lines, Bel7402 liver cancer cell lines and HCT-8 intestine cancer cell lines.  
Due to the incomplete dehydration to form the thiazole ring, the yield of **4** was low (**4a**: 39.5%, **4b**: 56.2%). The yield could not be significantly improved by extending the reaction time or increasing the reaction temperature (using DMF (Dimethyl Formamide) as solvent, when T > 120 \({}^{\circ}\)C, **5** would disappear in 1 h, which was accompanied by the decomposition of **4a**, reducing the yield down to 30%). Compared with the yield using trifluoroacetyl ethyl acetate and substituted bentiamine (<40%) in our experiments, a much better yield (81.5%) using acetyl ethyl acetate and bentiamine was reported by relevant literature [38], which probably results from the strong electron withdrawing properties of the CF\({}_{3}\) moiety. However, under the same condition, by-product **5** could also be hydrolyzed to get the key intermediate **5** in yield of 50%. After by-product **5** hydrolyzed under basic conditions, the acidification process with dilute hydrochloric acid might promote the dehydration reaction of **5**. Therefore, **4** and **5** could be hydrolyzed together to get **6**, avoiding the need for separation.  
Based on the above mechanism, we analyzed the transformation process: When **2** and **3** were reflexed in EtOH directly, the formation of HCl would make the reaction system acidic, dehydrating a portion of product **5** to obtain compound **4**. However, due to the strong electron withdrawing effect of the CF\({}_{3}\) moiety, coupled with the weak acidity of the reaction system, the transformation would not be complete. Therefore, we propose that, in the synthesis of compounds **4**, the HCl gas could be introduced into the system to facilitate the generation of the thiazole ring.  
The final amide derivatives **7** (Scheme 4) and **8** (Scheme 5) were produced by reaction of the acyl chloride of **6** with appropriate arylamines at room temperature in dichloromethane. The reaction to produce compounds 7 and 8 required \(N\),\(N\)-diisopropylplethylamine as a base to give acceptable yields. In addition, pyridine, triethylamine and some inorganic bases (Na\({}_{2}\)CO\({}_{3}\), K\({}_{2}\)CO\({}_{3}\), NaHCO\({}_{3}\)) were trialed and gave decreased yields. Inorganic bases were not suitable for the organic reaction system used.