116 T HIAZOLE CORE S AS ORGANIC FLUOROPHORE UNITS: SYNTHESIS AND FLUORESCENCE DOI: http://dx.medra.org/ 10.17374/targets.2020.23.116 Nataliya P. Belskaya * a,b , Irena Kostova c , Zhijin Fan d a Ural Federal University, Mira str. 19, 620002 Ekaterinburg, Russia b Institut e of Organic Synthesis, Ural Branch of Academy of Science , 620219 E katerinburg, Russia c Department of Chemistry, Faculty of Pharmacy, Medical University , Dunav s tr. 2, 1000 Sofia, Bulgaria d State Key Laboratory of Elemento - Organic Chemistry, College of Chemis try, Nankai University, 30 0 071 Tianjin, PR China , Collaborative Innovation Center of Chemical Science and Engineering ( Tianjin ) , Nankai University, 300071 Tianjin , P . R . China (e - mail: [email protected] ) Abstract. M ethods for the synthesis of thiazole s , which display ph otoph y sical properties, are present ed and analy z ed . T he scope and limitation s of well - known pathways used to construct th is heterocyclic core , and the introduction of funct ional groups, substituents , and linear linkers to tune the fluorescence , are described . R elationships between structure and photoph y sical properties , and applications as photoswitches and in i on recognition, are also discussed . Contents 1. Introduction 2. Synthesis of fluorescent thiazoles 2.1 . M ain approaches to thiazole core construction 2.1.1. Erlenmeyer method for thiazole ring construction 2.1.2. Different methods for thiazole ring construction 2.2 . Modification of the thiazole core 2.2.1. Aryl/heteroarylation of the thiazole ring 2.2.2. Alkylation of hydroxythiazoles 2.2.3. Introduction of substituents containing C=C, С=N, and N=N bonds 2. 3 . Complexation of thiazole derivatives 3. Photophysical properties 3.1 . 4 - Hydroxythiazoles as chromophores and fluorophores 3.2 . Photophysical properties of 2 - and 5 - aminothiazoles 3.3 . Thiazoles with flexible conjugated systems 4. Photoswitches base d o n 1,3 - thiazole derivatives 5. Cation sensors 6. pH - sensitive thiazole fluorescence 7. Conclusion s Acknowledgement s References 1. Introduction T hiazole structures exhibit interesting properties that have attract ed research attention o wing to the ir abundance and potential as building blocks in the development of lead molecules , new drug candidates and biologically active compounds . 1 - 5 In the last decade , thiazoles have been applied as fluorescent dyes. 6 The thiazole heterocyclic core is key to several natural products, such as luciferin , a compound responsible for bioluminescen ce in the firefly (Lampyridae) (Figure 1) . 7 Figure 1. Structure of f irefly l uciferin and o xyluciferin . 117 Owing to the expansion of material s science in the last decade , the design of novel thiazole derivatives for application s in this field has received increasing research interest. In this chapter, we report current progress in the development of fluorophores containing thiazole core s, their properties , and the ir main application s, covering the period 2009 - 2019. 2. S ynthesis of fluorescent thiazoles These new thiazoles with substituents necessary to afford meaningful fluorescence can be obtained using different pathways. One pathway involves preparing the heterocyclic core from starting reagents in which all additional groups are already present . Another pathway decorate s the prepared thiazole with various functionalities according to the demands of the subsequent application. We hav e limited this survey to thiazoles that have exhibited photophysical properties. Fluorophore design with unique characteristics is guided by several definite rules and recommendations and usual requires introducing specific substituents, functionalities, c hains, cyclic and heterocyclic fragments, multiple bonds, and tailored constructions that provide molecules with the necessary electronic density However, in addition to the nature and strength of the electronic properties of substituents , their location in the molecule is also important . Furthermore , the design of new fluorophores must account for molecule structure symmetry , which significantly a ffect s the substance optic properties. 2.1. M ain approaches to thiazole core construction The most general and wide ly used method for construct ing thiazole cycle s is based on the condensation reaction of thi o carbamoyl compounds with - halogenocarbo nyl derivatives ( Hantzsch synthesis ) 1 at room temperature or by heat ing in solvent (EtOH, DMF, acetone, acetic acid , toluene ) in the presence of a catalytic amount of base (TEA, NaOAc, DIEA ) or without any additive . Th is synthesis does not usually require severe conditions or expensive catalysts or reagents. Furthermore , various compounds can be obtained , with the electronic structures controlled and tuned by varying the electronic nature and spatial parameters of the substituents. Employing this synthetic method (Scheme 1) , various 2,4 - di substituted and 2,4,5 - trisubstituted thiazoles have been synthesized in good yields. 8 - 2 7 Scheme 1 . Classical Hantzsch thiazole synthesis . This r eaction has a large scope , with a romatic - halo carbon y l compounds and many different heterocyclic derivatives often used as electrophilic reagent s . 1 0,13,14,16,17,19,25 - 27 For example, a library of 4 - het ero arylthiazoles 6 has been synthesized with good yields , as shown in Scheme 2 . Scheme 2 . Synthes is of 4 - het ero aryl thiazole s 6 . Furthermore , various heterocyclic thioamides 7 can be used in this reaction (Scheme 3) . 12,15 - 20,22 ,26,27 New thiazole derivatives 12 and 13 ( Scheme 4 ) with conjugated system including flexible groups containing enamine (NH – CH=C – ) or aza - enamine (NH – N=C – ) chains on the C2 ring atom were synthesized by heating in DMF. 21 - 24 118 Scheme 3 . Synthesis of 2 - het ero arylthiazoles 9 . Scheme 4 . Synthesis of enamine and aza - enamine thiazoles 1 2 and 1 3 . 3 - A ryl - 2 - (thiazol - 2 - yl)acrylonitriles 1 6 were also synthesiz ed using the Hantzsch thiazole synthesis, in which thioacetamides 1 4 were condensed with the corresponding - halocarbon yl compounds 1 5 in DMF or ethanol (Scheme 5 ) . 25 Scheme 5 . Synthesis of thiazoles 1 6 . 4,4 ' - Bis - thia z ole 19 and its isomeric form 2,2 ' - bisthiazole 2 3 were synthesized in good yield s by the Hantzsch reaction of 2 - hydroxythiobenzamide 1 7 with 1,4 - dibromo - 2,3 - butan e dione 18 and dithiooxamide 21 with 2 - bromo - 2 - methoxyacethophenone 2 0 , respectively, in refluxing ethanol (Scheme 6 ) . 28 Scheme 6 . Synthesis of bisthiazole s 19 and 2 3 . Thiourea has also been explored as a nucleophilic partner with haloketones to give 2 - amino thiazole. 2 9 - 3 6 2 - A mino - 4 - aryl thiazole derivatives 25 have been synthesized in a solution of - bromoarylethanones 2 and thiourea 2 4 using different conditions (Scheme 7 ). 30 - 3 3 Several studies have reported multicomponent one - pot implementations of the Hantzsch reaction. Styrenes 26 reacted with N - bromosuccinimide (NBS) and carbothioamide to afford the corresponding 2,4 - disubstituted and 2,4,5 - trisubstituted thiazoles 29 (Scheme 8). 37 The reaction mechanism involved the formation of bromohydrin 27 followed by NBS - mediated oxidation and in - situ formation of phenacyl 119 bromide 28 , which then underwent condensation with a carbothioamide to form thiazoles 29 with good and high yields (Scheme 8 ) . 37 Scheme 7 . Synthesis of 2 - aminothiazoles 25 . Scheme 8 . NBS - assisted o ne - p ot synthesis of substituted thiazoles from styrenes in water . In a one - pot procedure using available arylalkyl ketones 3 0 , NBS , and thiourea , citric acid was employed as catalyst for t he synthesis of 2 - amino - 4 - aryl thiazoles 3 2 via - bromination with subsequent C – S and C – N bond formations (Scheme 9) . 38 Scheme 9 . One - pot s ynthesis of 2 - amino - 4 - aryl substituted thiazoles. A m ultistep synthesis was developed to obtain n ovel push - pull dye 35 , which contains a benzimidazole fluorophore and thiazole unit. D ye 3 5 was polar and showed poor solubility (Scheme 10). 39 - 4 3 Scheme 1 0 . Synthesis of ( benzoimidazol - 2 - yl)thiazole 3 5 . Coumarin and pyran - 2 - оne derivatives form an important class of oxygen - containing heterocyclic compounds with interesting photophysical, photochemical, and fluorescent properties. Therefore, many heterocyclic systems incorporating these oxygen - containing and thiazole cycles, have been synthesized . 44 - 46 A multi component reaction strategy was used to synthesize the desired series of coumarinyl thiazoles 39 . 46 First, 3 - (2 - bromoacetyl) - 2 H - chromen - 2 - one 3 7 was readily synthesized by the base - catalyzed condensation of salicylaldehyde with ethyl acetoacetate, followed by bromination ( Scheme 11) . 46 I ntermediate 37 was then treated with differently substituted acetophenones 38 and thiosemicarbazide in one - pot i n the presence of glacial acetic acid as catalyst to obtain compounds 39 in 63 - 78% yields. 120 Scheme 1 1 . Synthetic route toward coumarinyl thiazole analogues 3 9 via a one - pot reaction . Systems containing both thiazole and pyrazole cycles were synthesized by using thiosemicarbazide as the thiocarbamoyl nucleophilic center. 44 - 49 A novel series of pyran - and coumarin - substituted thiazolyl - pyrazole - chromen - 2 - one derivatives 41 were efficiently synthesized through a co nvenient one - pot multicomponent transformation using the Hantzsch thiazole and Knorr pyrazole syntheses (Scheme 12). 44 Scheme 1 2 . Synthesis of multiheterocycle thiazolyl