Introduction

Nitrogen-containing heterocycle pyridine occupies an important place in the field of medicinal chemistry. This privileged scaffold in the design of pharmaceutical drugs is one of the basic components of more than 7000 existing drug molecules with clinical applications.1 Thiazole derivatives are no less interesting nitrogencontaining privileged heterocycles. Currently, there are 33 approved thiazole-containing drugs and more than 90 are at various stages of clinical trials.2 The combination of pyridine and thiazole into one scaffold creates interesting condensed heterocyclic systems, known as thiazolopyridines, which are the subject of detailed research by many scientists around the world due to the wide range of their pharmacological activities.3 Thiazolo[3,2-a]pyridines are one of the least accessible and poorly studied members of this class of organic compounds. The significant amount of data on the chemical and biological activity of this class of compounds allows us to consider them promising biologically active compounds. In recent years, antimicrobial,4 apoptotic,5 and antitumor6 activities have been studied for this class of compounds with some success. It has been established that some representatives of this class of compounds are inhibitors of DNA gyrase7 and SARS-Cov-2 glycoprotein.8 These compounds also have many other useful properties – in particular, they are valuable functional organic materials.9 The current paper summarizes literature data about the main synthetic approaches toward molecules containing thiazolo- [3,2-a]pyridine.

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Taras I. Chaban, PhD in pharmacy (2013), associate professor, Department of General, Bioinorganic, Physical and Colloidal Chemistry, Danylo Halytsky Lviv National Medical University (2016). Field of scientific interests: organic synthesis, medicinal chemistry, high throughput screening, computational chemistry.

Maryan I. Lelyukh, PhD in pharmacy (2017), senior lecturer, Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University (2019). Field of scientific interests: organic synthesis, medicinal chemistry, computational chemistry, virtual screening.

Methods for the synthesis of thiazolo[3,2-a]pyridines

Recent advances in the chemistry of thiazolo[3,2-a]pyridines have become widespread, and many publications have been devoted to the methods of their synthesis. However, it should be noted that along with new approaches to the synthesis of compounds of this class, previously known approaches are also being successfully developed.10 The search for new synthetic routes for this class of compounds led Mohamed et al. to a method based on the use of 4-oxothiazolidines 1a–d as starting materials. In particular, the interaction of 2-(4-oxothiazolidin-2-ylidene)acetonitriles 1a,b with 2-arylidenemalononitriles 2 in EtOH in the presence of a catalytic amount of piperidine allowed the authors to obtain 5-amino-7-aryl-3-oxo-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6,8-dicarbonitriles 3.7

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Ihor H. Chaban, PhD in pharmacy (1991), associate professor, Department of Pharmaceutical, Organic and Bioorganic Chemistry, Danylo Halytsky Lviv National Medical University (2001). Field of scientific interests: organic synthesis, medicinal chemistry, computational chemistry, virtual screening.

Olga Y. Kasyanchuk, student at the Pharmaceutical faculty, Danylo Halytsky Lviv National Medical University. Field of scientific interests: medicinal chemistry, organic synthesis, molecular modeling, computational chemistry.

Methods for the synthesis of thiazolo[3,2-a]pyridines (continued)

Similarly, the reaction of ethyl 2-(4-oxothiazolidin-2-ylidene)-acetate derivatives 1c,d with ethyl 3-aryl-2-cyanoacrylate derivatives 4 under the same reaction conditions led to the corresponding diethyl 5-amino-7-aryl-3-oxo-3,7-dihydro-2H-thiazolo-[3,2-a]pyridine-6,8-dicarboxylates 5.7

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In the search for methods for the synthesis of thiazolo[3,2-a]pyridines, Razavi et al. developed a five-component cascade reaction based on the use of cyanoacetohydrazide (6), acetophenone derivatives 7, aromatic aldehydes 8, 1,1-bis(methylsulfanyl)-2-nitroethylene (9), and cysteamine hydrochloride (10). The above-mentioned transformation was achieved in EtOH in the presence of NEt3 and allowed the authors to obtain 5-amino-7-aryl-N'-(1-arylethylidene)-8-nitro-3,7-dihydro-2H-thiazolo[3,2-a]pyridine-6-carbohydrazides 11.11

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Another interesting method for closing the thiazolo[3,2-a]pyridine ring is the method proposed by Guseynov et al., which consists of the interaction of 1-aryl-2-bromo-3,3-diethoxypropan-1-ones 12 with pyridine-2-thiol (13) in dry i-PrOH. This transformation leads to the synthesis of 2-aroylthiazolo[3,2-a]pyridin-4-ium bromides 14.12

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The annulation of sulfenyl chloride 15 with phenyl vinyl chalcogenides 16 and allyl phenyl chalcogenides 17 is presented in the work of Potapov et al.13 These reactions proceeded regioselectively, but with different regiochemical outcomes. In particular, the addition of the sulfur atom to vinyl chalcogenides occurred at the terminal atom of the double bond, while the formation of addition products in the case of allyl chalcogenides occurred against the Markovnikov rule. The presented transformations were carried out in CH2Cl2. Based on these reactions, the authors developed efficient one-pot methods for the synthesis of 2- and 3-substituted [1, 3] thiazolo[3,2-a]pyridinium derivatives 18, 19.

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Kalashnik and Dyachenko14 proposed a method for obtaining thiazolo[3,2-a]pyridines, which consists of the interaction of triethylammonium 3-cyano-5-ethoxy-4-(furan-2-yl)-6-propylcarbonyl-1,4-dihydropyridine-2-thiolate (20) with 1,2-dibromoethane (21) in DMF to form ethyl 8-cyano-7-(furan-2-yl)-5-propyl-3,7-dihydro-2Hthiazolo[3,2-a]pyridine-6-carboxylate (22).

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Nasri et al.15 described a sequential multicomponent reaction of cysteamine hydrochloride (10), nitroketenedithioacetals 23, isatin (24), and various CH acids. This method provides access to new functionalized spirooxindoles fused with thiazolopyridine 25.

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The construction of the thiazolo[3,2-a]pyridine ring can also be accomplished by the reaction of penta-2,4-dienthioamides 26 with acetylenedicarboxylic acid or its derivatives 27 in AcOH. The proposed method allowed the authors to obtain target 2,3-dihydro-5H-thiazolo[3,2-a]pyridines 28.16

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Methods for the synthesis of thiazolo[3,2-a]pyridines (continued)

Abadleh et al.17 developed a method for the synthesis of thiazolo-[3,2-a]pyridines, which involved the reaction of N'-(4-fluorophenyl) hydrazide of thiobenzoic acid (29) with 2,4-dihalogensubstituted methyl 2-chloro-3-nitro-5-nitrophenyl-4-oxo-4,7-dihydrothieno[2,3-b]pyridine-5-carboxylates 30. The reaction was carried out in MeCN using NEt3 as a catalyst. This transformation allowed to obtain (Z)-methyl-7-halogen-substituted 4-{3-(4-fluorophenyl)-5-phenyl-1,3,4-thiadiazol-2(3H)-ylidene](nitro)methyl}-8-nitro-3-oxo-3H-benzo[4,5]thiazolo[3,2-a]pyridine-2-carboxylates 31.

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Shirani et al.18 proposed an interesting approach for the synthesis of 1-amino-3-aryl-2-(1,3-benzothiazol-2-yl)-3-hydrobenzo[4, 5]-thiazolo[3,2-a]pyridine-4-carbonitriles 33, which involved the reaction of 2-(1,3-benzothiazol-2-yl)acetonitrile (32) with aldehydes 8. This transformation takes place in EtOH in the presence of piperidine as a catalyst under ultrasonic irradiation at room temperature, which provides several advantages, including shorter reaction time, cleaner reaction, and high yields.

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In order to afford novel thiazolo[3,2-a]pyridines, Raslan and Sayed19 proposed two methods for the synthesis of this class of compounds using 2-(thiazol-2-yl)acetonitriles 34 as a starting material. The first method is a two-step process. In particular, at the first stage, compound 34 reacted with aromatic aldehydes 8, which allowed to obtain the corresponding (Z)-3-aryl-2-(thiazol-2-yl)acrylonitriles 35. Further reaction of these compounds with malononitrile led to 5-amino-7-aryl-7H-thiazolo[3,2-a]pyridine-6,8-dicarbonitriles 36. In contrast to the previous method, another method involved the reaction of compound 34 with arylidenemalononitrile derivatives 2 in the presence of a catalytic amount of piperidine. This transformation led to the same compounds 36 in one step.

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