Natural Compounds and Their Structural Analogs in Regio- and Stereoselective Synthesis of New Families of Water-Soluble 2H,3H-[1,3]thia- and -Selenazolo[3,2-a]pyridin-4-ium Heterocycles by Annulation Reactions

It has been found that both eugenol and isoeugenol derivatives reacted with 2-pyridinesulfenyl and 2-pyridineselenenyl halides in a regioselective mode affording products with opposite regiochemistry. Synthesis of new families of 2H,3H-[1,3]thia- and -selenazolo[3,2-a]pyridin-4-ium heterocycles has been developed by annulation reactions of 2-pyridinechalcogenyl halides with natural compounds (eugenol, isoeugenol, methyl eugenol, methyl isoeugenol, acetyl eugenol, trans-anethole) and their structural analogs. The influence of the substrate structure and the nature of halogen on the product yields are studied. The 2-pyridinesulfenyl and 2-pyridineselenenyl chlorides are more efficient reagents compared to corresponding bromides. The obtained condensed heterocycles are novel water-soluble functionalized compounds with promising biological activity.

Chemistry of natural products is very important for providing knowledge about medicines to derive active components as lead compounds for drug discovery. It is known that the majority of new drugs have been developed from natural products and synthesis of novel compounds based on natural products is prospective for searching biologically active substances.
The goal of the present research is the development of regio-and stereoselective synthesis of novel condensed heterocycles with promising biological activity based on the annulation reactions of 2-pyridinesulfenyl and 2-pyridineselenenyl halides with natural compounds (eugenol, isoeugenol, anethole) and their derivatives and structural analogs as well as studies on the influence of the substrate structure and the nature of halogen and chalcogen on the product yields.
Chemistry of natural products is very important for providing knowledge about medicines to derive active components as lead compounds for drug discovery. It is known that the majority of new drugs have been developed from natural products and synthesis of novel compounds based on natural products is prospective for searching biologically active substances.
The goal of the present research is the development of regio-and stereoselective synthesis of novel condensed heterocycles with promising biological activity based on the annulation reactions of 2-pyridinesulfenyl and 2-pyridineselenenyl halides with natural compounds (eugenol, isoeugenol, anethole) and their derivatives and structural analogs as well as studies on the influence of the substrate structure and the nature of halogen and chalcogen on the product yields.
Compounds 1 and 2 can be regarded as the products with the opposite regiochemistry with respect to the location of aryl-containing substituents: compound 1 has aryl on the position 3 of the dihydrothiazole ring whereas aryl-containing substituent is situated on the position 2 in compound 2. Thus, the reactions of 2-pyridinesulfenyl chloride with both eugenol and isoeugenol proceeded under similar conditions in a regioselective mode giving products 1 and 2 with the opposite regiochemistry (Scheme 1).
Like the synthesis of compounds 1 and 2, the reactions of 2-pyridineselenenyl chloride with eugenol and isoeugenol led to two structural isomers of the opposite regiochemistry, compounds 3 and 4, selenium analogs of heterocycles 1 and 2.
The reactions of 2-pyridinesulfenyl chloride with methyl eugenol and methyl isoeugenol were found to be more efficient compared to those with eugenol and isoeugenol. The reaction of 2-pyridinesulfenyl chloride with methyl eugenol (an equimolar ratio of the reagents) proceeded smoothly at room temperature in methylene chloride  The reaction of 2-pyridinesulfenyl chloride with eugenol (an equimolar ratio of the reagents) after overnight stirring (20 h) at room temperature in methylene chloride led to 2-[(4-hydroxy-3-methoxyphenyl)methyl]-2H,3H- [1,3]thiazolo[3,2-a]pyridin-4-ium chloride (2) (34% yield), which was precipitated from the reaction mixture as a powder. Similar result was obtained using chloroform as a solvent instead of methylene chloride. The yield was increased to 75% by refluxing the mixture of 2-pyridinesulfenyl chloride with eugenol in chloroform (Scheme 1).
Compounds 1 and 2 can be regarded as the products with the opposite regiochemistry with respect to the location of aryl-containing substituents: compound 1 has aryl on the position 3 of the dihydrothiazole ring whereas aryl-containing substituent is situated on the position 2 in compound 2. Thus, the reactions of 2-pyridinesulfenyl chloride with both eugenol and isoeugenol proceeded under similar conditions in a regioselective mode giving products 1 and 2 with the opposite regiochemistry (Scheme 1).
Like the synthesis of compounds 1 and 2, the reactions of 2-pyridineselenenyl chloride with eugenol and isoeugenol led to two structural isomers of the opposite regiochemistry, compounds 3 and 4, selenium analogs of heterocycles 1 and 2.
The reactions of 2-pyridinesulfenyl chloride with methyl eugenol and methyl isoeugenol were found to be more efficient compared to those with eugenol and isoeugenol. The reaction of 2-pyridinesulfenyl chloride with methyl eugenol (an equimolar ratio of the reagents) proceeded smoothly at room temperature in methylene chloride  The reaction of 2-pyridinesulfenyl chloride with methyl isoeugenol occurred at reflux temperature in chloroform affording trans-3-(3,4-dimethoxyphenyl)-2-methyl-2Н,3Н- [1,3]thiazolo[3,2-а]pyridin-4-ium chloride (6) in quantitative yield (Scheme 2). Unlike the reactions with eugenol and isoeugenol (Scheme 1), the precipitation of the products 5 and 6 from the reaction mixture was not observed. The compounds 5 and 6 are two structural isomers with the opposite regiochemistry.
Similar results were obtained using 2-pyridineselenenyl chloride. This reagent reacted with methyl eugenol and methyl isoeugenol very smoothly under the same conditions as the synthesis of heterocycles 5 and 6 leading to the selenium analogs of these compounds in quantitative yields (Scheme 2). The obtained condensed selenium heterocycles 7 and 8 are also two structural isomers with the opposite regiochemistry.
2-Pyridinesulfenyl bromide and 2-pyridineselenenyl bromide were rarely used in organic synthesis and in the preparation of condensed heterocycles [37][38][39]. Usually organylsulfenyl and organylselenenyl bromides are less electrophilic than corresponding organylsulfenyl and organylselenenyl chlorides. On the other hand, the bromine atom is more reactive in the nucleophilic substitution reactions compared to the chlorine atom and can be easily substituted with nitrogen atom of the pyridine ring forming condensed heterocycles.
We studied the reactions of 2-pyridinesulfenyl and 2-pyridineselenenyl bromides with a series of substrates and found that, in general, these reagents are less efficient in the annulation reactions compared to corresponding chlorides and the yields of target products are higher in the case of 2-pyridinesulfenyl or 2-pyridineselenenyl chlorides.
The reactions of 2-pyridinesulfenyl bromide with anethole and 4-methylstyrene afforded compounds 13 and 14 in 80 and 84% yields, whereas quantitative yields of chloro analogs 11 and 15 were achieved with these substrates using 2-pyridinesulfenyl chloride (Scheme 3). The reaction of 2-pyridinesulfenyl chloride with methyl isoeugenol occurred at reflux temperature in chloroform affording trans-3- (6) in quantitative yield (Scheme 2). Unlike the reactions with eugenol and isoeugenol (Scheme 1), the precipitation of the products 5 and 6 from the reaction mixture was not observed. The compounds 5 and 6 are two structural isomers with the opposite regiochemistry.
Similar results were obtained using 2-pyridineselenenyl chloride. This reagent reacted with methyl eugenol and methyl isoeugenol very smoothly under the same conditions as the synthesis of heterocycles 5 and 6 leading to the selenium analogs of these compounds in quantitative yields (Scheme 2). The obtained condensed selenium heterocycles 7 and 8 are also two structural isomers with the opposite regiochemistry.
The reactions of 2-pyridineselenenyl bromide with trans-anethole and styrene led to heterocycles 16 and 18 in 95% and 78% yields, respectively; however, analogous reactions of 2-pyridineselenenyl chloride with these substrates afforded target products 12 and 19 in 2-Pyridinesulfenyl bromide and 2-pyridineselenenyl bromide were rarely used in organic synthesis and in the preparation of condensed heterocycles [37][38][39]. Usually organylsulfenyl and organylselenenyl bromides are less electrophilic than corresponding organylsulfenyl and organylselenenyl chlorides. On the other hand, the bromine atom is more reactive in the nucleophilic substitution reactions compared to the chlorine atom and can be easily substituted with nitrogen atom of the pyridine ring forming condensed heterocycles.
We studied the reactions of 2-pyridinesulfenyl and 2-pyridineselenenyl bromides with a series of substrates and found that, in general, these reagents are less efficient in the annulation reactions compared to corresponding chlorides and the yields of target products are higher in the case of 2-pyridinesulfenyl or 2-pyridineselenenyl chlorides.
The reactions of 2-pyridineselenenyl bromide with trans-anethole and styrene led to heterocycles 16 and 18 in 95% and 78% yields, respectively; however, analogous reactions of 2-pyridineselenenyl chloride with these substrates afforded target products 12 and 19 in quantitative yields (Schemes 3 and 4). In the case of 2-pyridinesulfenyl bromide, the reaction with styrene gave product 21 in 90% yield, whereas the formation of heterocycle 20 quantitative yield was observed in the reaction of 2-pyridinesulfenyl chloride with styrene (Scheme 4).  The reactions of 2-pyridineselenenyl bromide with trans-anethole and styrene led to heterocycles 16 and 18 in 95% and 78% yields, respectively; however, analogous reactions of 2-pyridineselenenyl chloride with these substrates afforded target products 12 and 19 in quantitative yields (Schemes 3 and 4). In the case of 2-pyridinesulfenyl bromide, the reaction with styrene gave product 21 in 90% yield, whereas the formation of heterocycle 20 quantitative yield was observed in the reaction of 2-pyridinesulfenyl chloride with styrene (Scheme 4). (18)  These results indicate that, in general, 2-pyridinesulfenyl and 2-pyridineselenenyl chlorides are more efficient compared to corresponding bromides and the annulation reactions of 2-pyridinechalcogenyl chlorides afforded the desired products in higher (mostly quantitative) yields.

Hal = Br
The introduction of methyl substituent at β-position of the double bond of styrene as well as to the position 4 of the benzene ring has little influence on the yields of products in annulation reactions. However, the introduction of methyl substituent at α-position of the double bond of styrene seems to have negative effect on the annulation process. The reaction of 2-pyridinesulfenyl chloride with α-methylstyrene led to heterocycle 22 only in 81% yield (Scheme 4). A mixture of products was obtained in the reaction of 2-pyridineselenenyl chloride with α-methylstyrene, whereas product 19 was formed in quantitative yield in the reaction of 2-pyridineselenenyl chloride with styrene (Scheme 4). Some decrease in efficiency of the annulation reaction in the case of α-methylstyrene can be attributed to steric factor: the introduction of the methyl group diminishes the rate of nucleophilic substitution by the nitrogen atom of the pyridine ring in the last stage.
Allylbenzene reacted with 2-pyridinesulfenyl chloride at room temperature in a regioselective mode affording heterocycle 23 (quantitative yield) derived from anti-Markovnikov addition to the double bond (Scheme 5). Thus, allylbenzene derivatives (eugenol, methyl eugenol, acetyleugenol) and styrene derivatives (isoeugenol, methyl isoeugenol, trans-anethole) reacted with These results indicate that, in general, 2-pyridinesulfenyl and 2-pyridineselenenyl chlorides are more efficient compared to corresponding bromides and the annulation reactions of 2-pyridinechalcogenyl chlorides afforded the desired products in higher (mostly quantitative) yields.
The introduction of methyl substituent at β-position of the double bond of styrene as well as to the position 4 of the benzene ring has little influence on the yields of products in annulation reactions. However, the introduction of methyl substituent at α-position of the double bond of styrene seems to have negative effect on the annulation process. The reaction of 2-pyridinesulfenyl chloride with α-methylstyrene led to heterocycle 22 only in 81% yield (Scheme 4). A mixture of products was obtained in the reaction of 2-pyridineselenenyl chloride with α-methylstyrene, whereas product 19 was formed in quantitative yield in the reaction of 2-pyridineselenenyl chloride with styrene (Scheme 4). Some decrease in efficiency of the annulation reaction in the case of α-methylstyrene can be attributed to steric factor: the introduction of the methyl group diminishes the rate of nucleophilic substitution by the nitrogen atom of the pyridine ring in the last stage.
Allylbenzene reacted with 2-pyridinesulfenyl chloride at room temperature in a regioselective mode affording heterocycle 23 (quantitative yield) derived from anti-Markovnikov addition to the double bond (Scheme 5). Thus, allylbenzene derivatives (eugenol, methyl eugenol, acetyleugenol) and styrene derivatives (isoeugenol, methyl isoeugenol, trans-anethole) reacted with 2-pyridinesulfenyl and 2-pyridineselenenyl halides in a regioselective mode affording products with the opposite regiochemistry with respect to the location of aryl-containing substituents. Suggested reactions pathways can be regarded on the examples of reactions of 2-pyridinechalcogenyl halides with styrene and allylbenzene (Scheme 6). The reactions of 2-pyridinesulfenyl and selenenyl halides with compounds containing a double bond conjugated with the benzene ring (isoeugenol, methyl isoeugenol, trans-anethole, styrene, 4-methylstyrene, α-methylstyrene) proceed regioselectively via electrophilic addition of the chalcogen atom at β-carbon atom of the double bond. The regioselectivity is due to the formation of intermediate carbocation A, which is stabilized by the benzene ring (the relatively stable benzyl cation) (Scheme 6, B is also possible intermediate). Noteworthy, the known addition reactions of arylsulfenyl and arylselenenyl halides to styrene and its derivatives also afforded Markovnikov adducts [42,43]. In the case of eugenol, its derivatives and structural analogs, 2-pyridinesulfenyl and selenenyl halides react with allyl group as with linear 1-alkene and electrophilic addition of the chalcogen atom occurs at α-carbon atom of the double bond (C and D are possible intermediates in the reaction of 2-pyridinesulfenyl chloride with allylbenzene) followed by intramolecular nucleophilic substitution in the formed anti-Markovnikov adduct (Scheme 6). It is known that electrophilic addition of sulfenyl halides to linear 1-alkenes afforded predominantly anti-Markovnikov products [44][45][46][47]. Thiiranium [45][46][47][48] and seleniranium [47][48][49][50][51][52][53][54] cations are often regarded as intermediates in electrophilic addition of chalcogenyl halides to the double bond, and attack of the halide anion occurs at unsubstituted carbon atom of thiiranium or seleniranium cations leading to  Suggested reactions pathways can be regarded on the examples of reactions of 2-pyridinechalcogenyl halides with styrene and allylbenzene (Scheme 6). The reactions of 2-pyridinesulfenyl and selenenyl halides with compounds containing a double bond conjugated with the benzene ring (isoeugenol, methyl isoeugenol, trans-anethole, styrene, 4-methylstyrene, α-methylstyrene) proceed regioselectively via electrophilic addition of the chalcogen atom at β-carbon atom of the double bond. The regioselectivity is due to the formation of intermediate carbocation A, which is stabilized by the benzene ring (the relatively stable benzyl cation) (Scheme 6, B is also possible intermediate). Noteworthy, the known addition reactions of arylsulfenyl and arylselenenyl halides to styrene and its derivatives also afforded Markovnikov adducts [42,43]. In the case of eugenol, its derivatives and structural analogs, 2-pyridinesulfenyl and selenenyl halides react with allyl group as with linear 1-alkene and electrophilic addition of the chalcogen atom occurs at α-carbon atom of the double bond (C and D are possible intermediates in the reaction of 2-pyridinesulfenyl chloride with allylbenzene) followed by intramolecular nucleophilic substitution in the formed anti-Markovnikov adduct (Scheme 6). It is known that electrophilic addition of sulfenyl halides to linear 1-alkenes afforded predominantly anti-Markovnikov products [44][45][46][47]. Thiiranium [45][46][47][48] and seleniranium [47][48][49][50][51][52][53][54] cations are often regarded as intermediates in electrophilic addition of chalcogenyl halides to the double bond, and attack of the halide anion occurs at unsubstituted carbon atom of thiiranium or seleniranium cations leading to In the case of eugenol, its derivatives and structural analogs, 2-pyridinesulfenyl and selenenyl halides react with allyl group as with linear 1-alkene and electrophilic addition of the chalcogen atom occurs at α-carbon atom of the double bond (C and D are possible intermediates in the reaction of 2-pyridinesulfenyl chloride with allylbenzene) followed by intramolecular nucleophilic substitution in the formed anti-Markovnikov adduct (Scheme 6). It is known that electrophilic addition of sulfenyl halides to linear 1-alkenes afforded predominantly anti-Markovnikov products [44][45][46][47].
We attempted the reaction of 2-pyridinesulfenyl chloride with one representative of linear 1-alkenes: 1-heptene and observed the formation of two regioisomers 24 and 25 in a 9:2 ratio (Scheme 5). The major product 24 was derived from anti-Markovnikov addition to the double bond. Thus, like 1-alkenes, allylbenzene reacted with 2-pyridinesulfenyl chloride affording heterocycle 23 derived from anti-Markovnikov addition to the double bond (Scheme 5).
The structural assignments of the synthesized compounds were made using 1 H and 13 C-NMR spectroscopy including two-dimensional and NOESY experiments and confirmed by elemental analysis. The products of opposite regiochemistry have characteristic signals of the carbon atoms bonded with charged nitrogen (N + ) in 13 C-NMR spectra: CH 2 N + (63-67 ppm) and (Ar)CHN + (75-84 ppm). The values of proton spin-spin coupling constant ( 3 J H-H ) in the (Me)CH-CH(Ar)N fragment of the dihydrothiazole cycle correspond to trans-configuration of these protons. Spectral characteristics of compounds 19 and 20 are described elsewhere [32,35]. Elemental analysis was performed on a Thermo Scientific FLASH 2000 Organic Elemental Analyzer (Thermo Fisher Scientific Inc., Milan, Italy). Melting points were determined on a Kofler Hot-Stage Microscope PolyTherm A apparatus (Wagner & Munz GmbH, München, Germany). Absolute solvents were used in the reactions.

Synthesis of Compounds 1-18, 21-24
trans-3-(4-Hydroxy-3-methoxyphenyl)-2-methyl-2H,3H- [1,3]thiazolo[3,2-a]pyridin-4-ium chloride (1). A solution of sulfuryl chloride (0.135 g, 1 mmol) in chloroform (10 mL) was added dropwise to a solution of di(2-pyridine) disulfide (0.218 g, 1 mmol) in chloroform (10 mL) and the mixture was stirred for 10 min at room temperature. A solution of isoeugenol (0.328 g, 2 mmol) in chloroform (10 mL) was added dropwise and the reaction mixture stirred for 4 h at room temperature and 8 h at reflux temperature. On cooling the formed precipitate was filtered off and dried in vacuum giving the product (0.527 g, 85% yield) as a white powder, mp 235-237 • C. 1 (2) (5). A solution of sulfuryl chloride (0.068 g, 0.5 mmol) in methylene chloride (7 mL) was added dropwise to a solution of di(2-pyridine) disulfide (0.109 g, 0.5 mmol) in methylene chloride (7 mL) and the mixture was stirred for 10 min at room temperature. A solution of methyl eugenol (0.178 g, 1 mmol) in methylene chloride (7 mL) was added dropwise and the reaction mixture was stirred for 20 h at room temperature. The solvent was removed by rotary evaporator (RE-52AA, Xi'an Heb Biotechnology Co., Xi'an, China) and the residue was dried in vacuum giving the product (0.324 g, quantitative yield) as a light yellow oil.   (6). A solution of sulfuryl chloride (0.068 g, 0.5 mmol) in chloroform (7 mL) was added dropwise to a solution of di(2-pyridine) disulfide (0.109 g, 0.5 mmol) in chloroform (7 mL) and the mixture was stirred for 10 min at room temperature. A solution of methyl isoeugenol (0.178 g, 1 mmol) in chloroform (7 mL) was added dropwise and the reaction mixture stirred for 1 h at room temperature and 5 h at reflux temperature. The solvent was removed by rotary evaporator and the residue was dried in vacuum giving the product (0.324 g, quantitative yield) as a light yellow oil. 1   trans-3-(4-Methoxyphenyl)-2-methyl-2H,3H-selenazolo[3,2-a]pyridin-4-ium chloride (12). A solution of sulfuryl chloride (0.122 g, 0.9 mmol) in chloroform (10 mL) was added dropwise to a solution of di(2-pyridine) diselenide (0.28 g, 0.9 mmol) in chloroform (20 mL) and the mixture was stirred for 20 min at room temperature. A solution of trans-anethole (0.266 g, 1.8 mmol) in chloroform (10 mL) was added dropwise and the reaction mixture stirred for 1 h at room temperature and 4 h at reflux temperature. The solvent was removed by rotary evaporator and the residue was dried in vacuum giving the product (0.613 g) in quantitative yield as a yellowish powder, mp 141-143 • C. 1  trans-3-(4-Methoxyphenyl)-2-methyl-2H,3H- [1,3]selenazolo[3,2-a]pyridin-4-ium bromide (16). A solution of bromine (0.051 g, 0.32 mmol) in chloroform (10 mL) was added dropwise to a solution of di(2-pyridine) diselenide (0.1 g, 0.32 mmol) in chloroform (10 mL) and the mixture was stirred for 20 min at room temperature. A solution of trans-anethole (0.095 g, 0.64 mmol) in chloroform (10 mL) was added dropwise and the reaction mixture stirred for 1 h at room temperature and 5 h at reflux temperature. The mixture was filtered and the solvent was removed by rotary evaporator. The residue was dried in vacuum giving the product (0.234 g, 95% yield) as a light orange oil. 1
First studies on the influence of the substrate structure and the nature of halogen and chalcogen on the product yields in the reactions of 2-pyridinesulfenyl and 2-pyridineselenenyl halides with alkenes were carried out. The introduction of methyl substituent at β-position of the double bond of styrene as well as to the position 4 of the benzene ring has little influence on the yields of products in annulation reactions. However, the introduction of methyl substituent at α-position of the double bond of styrene has negative effect on the annulation process. The 2-pyridinesulfenyl and 2-pyridineselenenyl chlorides are more efficient compared to corresponding bromides and the annulation reactions of 2-pyridinechalcogenyl chlorides usually afforded the desired products in higher (mostly quantitative) yields. Regarding the influence of the chalcogen nature, 2-pyridinesulfenyl and 2-pyridineselenenyl chlorides exhibit close reactivity.