Efficient Regioselective Synthesis of Novel Condensed Sulfur–Nitrogen Heterocyclic Compounds Based on Annulation Reactions of 2-Quinolinesulfenyl Halides with Alkenes and Cycloalkenes

The preparation of novel reagents 2-quinolinesulfenyl chloride and bromide based on available 2-mercaptoquinoline has been described. This approach opens up opportunities for the introduction of 2-quinolinesulfenyl chloride and bromide into organic synthesis. Regioselective synthesis of novel 1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium derivatives in high yields has been developed by annulation reactions of 2-quinolinesulfenyl chloride and bromide with alkenes. Condensed tetracyclic products have been obtained by the reactions of 2-quinolinesulfenyl chloride and bromide with cycloalkenes. The opposite regiochemistry in the reactions with styrene, isoeugenol and 1-alkenes was discussed.


Introduction
The vast majority of drugs contain heterocyclic fragments in their structures [1]. The sulfur heterocycles are structural parts of many drugs that are used in modern pharmacotherapy [2]. Drugs containing condensed nitrogen and sulfur heterocycles are some of the most commonly used medications [2]. Penicillin and cephalosporin scaffolds contain condensed nitrogen and sulfur heterocycles and represent examples of antibiotics that played an outstanding role in the history and development of pharmaceutical chemistry.

Results and Discussion
The reactions of 2-quinolinesulfenyl halides are unknown, and the preparation of 2-quinolinesulfenyl chloride and bromide has not yet been described in the literature (the SciFinder database). Previously we generated 8-quinolinesulfenyl halides from di(8-quinolinyl) disulfide by the action of sulfuryl chloride or bromine and involved in further reactions without isolation (Scheme 1). However, di(2-quinolinyl) disulfide is a hard-to-get reagent, whereas 2-mercaptoquinoline is an available compound. It would seem that di(2-quinolinyl) disulfide can be easily prepared by oxidation of 2-mercaptoquinoline. Unfortunately, the oxidation reactions of 2-mercaptoquinoline are complicated by side processes that make it difficult to obtain pure di(2-quinolinyl) disulfide.
We developed a simple and efficient method for the generation of 2-quinolinesulfenyl chloride (2) and bromide (3) by the action of sulfuryl chloride or bromine on 2-mercaptoquinoline (1) in methylene chloride or chloroform. The generated 2-quinolinesulfenyl halides 2 and 3 were involved in further reactions without isolation (Scheme 3).

Results and Discussion
The reactions of 2-quinolinesulfenyl halides are unknown, and the preparation of 2-quinolinesulfenyl chloride and bromide has not yet been described in the literature (the SciFinder database). Previously we generated 8-quinolinesulfenyl halides from di(8quinolinyl) disulfide by the action of sulfuryl chloride or bromine and involved in further reactions without isolation (Scheme 1). However, di(2-quinolinyl) disulfide is a hard-to-get reagent, whereas 2-mercaptoquinoline is an available compound. It would seem that di(2-quinolinyl) disulfide can be easily prepared by oxidation of 2-mercaptoquinoline. Unfortunately, the oxidation reactions of 2-mercaptoquinoline are complicated by side processes that make it difficult to obtain pure di(2-quinolinyl) disulfide.
We developed a simple and efficient method for the generation of 2-quinolinesulfenyl chloride (2) and bromide (3) by the action of sulfuryl chloride or bromine on 2-mercaptoquinoline (1) in methylene chloride or chloroform.
We found that the reactions of 2-quinolinesulfenyl chloride 2 with 1-hexene, 1-heptene and 1-octene proceeded in a regioselective fashion at room temperature in methylene chloride or chloroform affording 2-alkyl-1,2-dihydro [1,3] Along with the investigation of the chemical properties of sulfenyl chloride 2, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes were studied. The reaction of sulfenyl bromide 3 with 1-heptene also proceeded regioselectively, leading to condensed compound 7 in a 99% yield (Scheme 5). However, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes containing an even number of carbon atoms (1-hexene and 1-octene) occurred with loss of regioselectivity giving along with compounds 8 and 9 (bromide analogues of products 4 and 6) minor regioisomers 10 and 11, which were originated from electrophilic addition of the sulfur atom of 2-quinolinesulfenyl bromide 3 to the terminal carbon atom of the double bond of alkenes (Scheme 6). A ratio of regioisomers, compounds 8/10 and 9/11, was Scheme 3. The simple and efficient method for generation of 2-quinolinesulfenyl chloride 2 and bromide 3 by the action of sulfuryl chloride or bromine on 2-mercaptoquinoline 1 in methylene chloride or chloroform.
We found that the reactions of 2-quinolinesulfenyl chloride 2 with 1-hexene, 1-heptene and 1-octene proceeded in a regioselective fashion at room temperature in methylene chloride or chloroform affording 2-alkyl-1,2-dihydro [1,3] Along with the investigation of the chemical properties of sulfenyl chloride 2, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes were studied. The reaction of sulfenyl bromide 3 with 1-heptene also proceeded regioselectively, leading to condensed compound 7 in a 99% yield (Scheme 5). However, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes containing an even number of carbon atoms (1-hexene and 1-octene) occurred with loss of regioselectivity giving along with compounds 8 and 9 (bromide analogues of products 4 and 6) minor regioisomers 10 and 11, which were originated from electrophilic addition of the sulfur atom of 2-quinolinesulfenyl bromide 3 to the terminal carbon atom of the double bond of alkenes (Scheme 6). A ratio of regioisomers, compounds 8/10 and 9/11, was Along with the investigation of the chemical properties of sulfenyl chloride 2, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes were studied. The reaction of sulfenyl bromide 3 with 1-heptene also proceeded regioselectively, leading to condensed compound 7 in a 99% yield (Scheme 5). The chemical properties of 2-quinolinesulfenyl chloride 2 and bromide 3 are unknown, and we started studies using simple terminal alkenes (1-hexene, 1-heptene and 1-octene) and cycloalkenes (cyclopentene, cyclohexene and cyclooctene).
We found that the reactions of 2-quinolinesulfenyl chloride 2 with 1-hexene, 1-heptene and 1-octene proceeded in a regioselective fashion at room temperature in methylene chloride or chloroform affording 2-alkyl-1,2-dihydro [1,3] Along with the investigation of the chemical properties of sulfenyl chloride 2, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes were studied. The reaction of sulfenyl bromide 3 with 1-heptene also proceeded regioselectively, leading to condensed compound 7 in a 99% yield (Scheme 5). However, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes containing an even number of carbon atoms (1-hexene and 1-octene) occurred with loss of regioselectivity giving along with compounds 8 and 9 (bromide analogues of products 4 and 6) minor regioisomers 10 and 11, which were originated from electrophilic addition of the sulfur atom of 2-quinolinesulfenyl bromide 3 to the terminal carbon atom of the double bond of alkenes (Scheme 6). A ratio of regioisomers, compounds 8/10 and 9/11, was However, the reactions of 2-quinolinesulfenyl bromide 3 with alkenes containing an even number of carbon atoms (1-hexene and 1-octene) occurred with loss of regioselectivity giving along with compounds 8 and 9 (bromide analogues of products 4 and 6) minor regioisomers 10 and 11, which were originated from electrophilic addition of the sulfur atom of 2-quinolinesulfenyl bromide 3 to the terminal carbon atom of the double bond of alkenes (Scheme 6). A ratio of regioisomers, compounds 8/10 and 9/11, was found to be approximately 3:1. The total yields of regioisomers 8 + 10 and 9 + 11 are quantitative. found to be approximately 3:1. The total yields of regioisomers 8 + 10 and 9 + 11 are quantitative. The reactions of 2-quinolinesulfenyl chloride 2 and bromide 3 with cycloalkenes were also studied.
Previously we found that the reactions of 8-quinolinesulfenyl bromide with cycloalkenes led to condensed compounds, while in the case of 8-quinolinesulfenyl chloride electrophilic addition, products were obtained (Scheme 2). Unlike this trend, the reactions of cyclopentene with both sulfenyl chloride 2 and bromide 3 at room temperature in methylene chloride afforded condensed tetracyclic products 12 and 13 in 81% and quantitative yields, respectively (Scheme 7). The reactions of cyclohexene with both 2-quinolinesulfenyl chloride 2 and bromide 3 were accompanied by the formation of by-products, and it was difficult to separate the desired condensed compounds.
Unlike the reactions of cyclopentene with both 2-quinolinesulfenyl halides 2 and 3 giving condensed tetracyclic products 12 and 13, the reaction of 2-quinolinesulfenyl chloride 2 with cyclooctene at room temperature led to electrophilic addition product 14 in quantitative yield (Scheme 8). When sulfenyl bromide 3 was involved in the reaction with cyclooctene under similar conditions, tetracyclic condensed compound 15 was obtained in quantitative yield (Scheme 8). The reactions of 2-quinolinesulfenyl chloride 2 and bromide 3 with cycloalkenes were also studied.
Previously we found that the reactions of 8-quinolinesulfenyl bromide with cycloalkenes led to condensed compounds, while in the case of 8-quinolinesulfenyl chloride electrophilic addition, products were obtained (Scheme 2). Unlike this trend, the reactions of cyclopentene with both sulfenyl chloride 2 and bromide 3 at room temperature in methylene chloride afforded condensed tetracyclic products 12 and 13 in 81% and quantitative yields, respectively (Scheme 7). The reactions of 2-quinolinesulfenyl chloride 2 and bromide 3 with cycloalkenes were also studied.
Previously we found that the reactions of 8-quinolinesulfenyl bromide with cycloalkenes led to condensed compounds, while in the case of 8-quinolinesulfenyl chloride electrophilic addition, products were obtained (Scheme 2). Unlike this trend, the reactions of cyclopentene with both sulfenyl chloride 2 and bromide 3 at room temperature in methylene chloride afforded condensed tetracyclic products 12 and 13 in 81% and quantitative yields, respectively (Scheme 7). The reactions of cyclohexene with both 2-quinolinesulfenyl chloride 2 and bromide 3 were accompanied by the formation of by-products, and it was difficult to separate the desired condensed compounds.
Unlike the reactions of cyclopentene with both 2-quinolinesulfenyl halides 2 and 3 giving condensed tetracyclic products 12 and 13, the reaction of 2-quinolinesulfenyl chloride 2 with cyclooctene at room temperature led to electrophilic addition product 14 in quantitative yield (Scheme 8). When sulfenyl bromide 3 was involved in the reaction with cyclooctene under similar conditions, tetracyclic condensed compound 15 was obtained in quantitative yield (Scheme 8). The reactions of cyclohexene with both 2-quinolinesulfenyl chloride 2 and bromide 3 were accompanied by the formation of by-products, and it was difficult to separate the desired condensed compounds.
Unlike the reactions of cyclopentene with both 2-quinolinesulfenyl halides 2 and 3 giving condensed tetracyclic products 12 and 13, the reaction of 2-quinolinesulfenyl chloride 2 with cyclooctene at room temperature led to electrophilic addition product 14 in quantitative yield (Scheme 8). When sulfenyl bromide 3 was involved in the reaction with cyclooctene under similar conditions, tetracyclic condensed compound 15 was obtained in quantitative yield (Scheme 8). The formation of an intermediate bromine analogue of compound 14 is accompanied by intramolecular cyclization at room temperature with the formation of a condensed product 15, while chloro derivative 14 is less reactive under these conditions and remains uncyclized. It is known that the bromine atom is leaving group better than the The formation of an intermediate bromine analogue of compound 14 is accompanied by intramolecular cyclization at room temperature with the formation of a condensed product 15, while chloro derivative 14 is less reactive under these conditions and remains uncyclized. It is known that the bromine atom is leaving group better than the chlorine atom in nucleophilic substitution reactions, and intramolecular cyclization with the bromine analogue of compound 14 proceeds easier than with chloro derivative 14.
Finally, we obtained condensed compounds from 2-quinolinesulfenyl chloride 2 and alkenes containing a benzene ring (Scheme 9). The reactions of 2-quinolinesulfenyl chloride 2 with styrene and natural product isoeugenol proceeded at room temperature in methylene chloride in a regioselective manner but with opposite regiochemistry compared to the reactions of sulfenyl chloride 2 with terminal alkenes (Scheme 4). The electrophilic addition of the sulfur atom of sulfenyl chloride 2 occurred to the β-carbon atom of the double bond of styrene and isoeugenol in a Markovnikov fashion. Condensed products 16 and 17 based on styrene and isoeugenol were obtained in quantitative and 80% yields, respectively (Scheme 9). The formation of an intermediate bromine analogue of compound 14 is accompanied by intramolecular cyclization at room temperature with the formation of a condensed product 15, while chloro derivative 14 is less reactive under these conditions and remains uncyclized. It is known that the bromine atom is leaving group better than the chlorine atom in nucleophilic substitution reactions, and intramolecular cyclization with the bromine analogue of compound 14 proceeds easier than with chloro derivative 14.
Finally, we obtained condensed compounds from 2-quinolinesulfenyl chloride 2 and alkenes containing a benzene ring (Scheme 9). The reactions of 2-quinolinesulfenyl chloride 2 with styrene and natural product isoeugenol proceeded at room temperature in methylene chloride in a regioselective manner but with opposite regiochemistry compared to the reactions of sulfenyl chloride 2 with terminal alkenes (Scheme 4). The electrophilic addition of the sulfur atom of sulfenyl chloride 2 occurred to the β-carbon atom of the double bond of styrene and isoeugenol in a Markovnikov fashion. Condensed products 16 and 17 based on styrene and isoeugenol were obtained in quantitative and 80% yields, respectively (Scheme 9). Why do annulation reactions of quinolinesulfenyl chloride 2 with styrene, isoeugenol and terminal alkenes proceed with opposite regiochemistry? Supposed reaction pathways can be regarded in order to explain this trend (Scheme 10). The reactions of sulfenyl chloride 2 with compounds containing a double bond conjugated with the benzene ring (styrene, isoeugenol) proceeded regioselectively via electrophilic addition of the sulfur atom to the β-carbon atom of the double bond. The regioselectivity is due to the formation of intermediate linear carbocation A, which is stabilized by the benzene ring (the relatively stable benzyl cation) (Scheme 10). Why do annulation reactions of quinolinesulfenyl chloride 2 with styrene, isoeugenol and terminal alkenes proceed with opposite regiochemistry? Supposed reaction pathways can be regarded in order to explain this trend (Scheme 10). The reactions of sulfenyl chloride 2 with compounds containing a double bond conjugated with the benzene ring (styrene, isoeugenol) proceeded regioselectively via electrophilic addition of the sulfur atom to the β-carbon atom of the double bond. The regioselectivity is due to the formation of intermediate linear carbocation A, which is stabilized by the benzene ring (the relatively stable benzyl cation) (Scheme 10). Addition reactions of sulfenyl halides to alkenes are well understood [42][43][44][45][46][47][48][49][50][51][52][53], and it is known that the reactions of arylsulfenyl halides with styrene and its derivatives also afforded Markovnikov adducts [42,43].
It is worth noting that electrophilic addition of arylsulfenyl halides to linear 1-alkene Scheme 10. The supposed pathways of the reactions of sulfenyl chloride 2 with styrene and 1-alkenes.
It is worth noting that electrophilic addition of arylsulfenyl halides to linear 1-alkene afforded predominantly anti-Markovnikov products, and thiiranium cations were regarded as intermediates in these reactions [44][45][46][47]. Taking into account these data, we suppose that the reactions of quinolinesulfenyl chloride 2 with terminal alkenes proceeded via intermediates thiiranium cation B and nucleophilic attack of the nitrogen atom of the quinoline ring occurred at the least substituted carbon atom of thiiranium ion B leading to the formation of products 4-6 in an anti-Markovnikov fashion (Scheme 10).
The structural assignments of synthesized compounds were made using 1 H and 13 C-NMR spectroscopy (see Supplementary Materials), including proton-coupled 13 C-NMR spectra, and confirmed by elemental analysis.
The products of opposite regiochemistry exhibit characteristic signals of the carbon atoms bonded with charged nitrogen (N + ), sulfur atom and with one or two protons in 13 C-NMR spectra of the obtained compounds (the number of protons is determined by NMR experiments). The CHS moiety and the CH 2 N + methylene group manifest themselves in the regions of 44-48 ppm and 58-62 ppm, respectively, in 13    2-Pentyl-1,2-dihydro [1,3]thiazolo[3,2-a]quinolin-10-ium chloride (5). A solution of sulfuryl chloride (0.062 g, 0.46 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.074 g, 0.46 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. The obtained solution of 2-quinolinesulfenyl chloride was added dropwise to a solution of 1-heptene (0.09 g, 0.92 mmol) in methylene chloride (5 mL), and the reaction mixture was stirred for 20 h at room temperature. The solvent was removed by a rotary evaporator. The residue was washed with CCl 4 and dried in vacuum, giving product 5 (0.120 g, 100% yield) as a yellow oil. 2-Pentyl-1,2-dihydro [1,3]thiazolo[3,2-a]quinolin-10-ium bromide (7). A solution of bromide (0.055 g, 0.34 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.055 g, 0.34 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. The obtained solution of 2-quinolinesulfenyl bromide was added dropwise to a solution of 1-heptene (0.067 g, 0.68 mmol) in methylene chloride (5 mL), and the reaction mixture was stirred for 20 h at room temperature. The solvent was removed by a rotary evaporator. The residue was washed with CCl 4 and dried in vacuum, giving product 7 (0.114 g, 99% yield) as an orange oil.  2-Butyl-1,2-dihydro [1,3]thiazolo [3,2-α]quinolin-10-ium bromide (8) and 1-butyl-1,2-dihydro [1,3] thiazolo [3,2-α]quinolin-10-ium bromide (10). A solution of bromide (0.048 g, 0.30 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.048 g, 0.30 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. The obtained solution of 2-quinolinesulfenyl bromide was added dropwise to a solution of 1-hexene (0.050 g, 0.60 mmol) in methylene chloride (5 mL), and the reaction mixture was stirred for 20 h at room temperature. The solvent was removed by a rotary evaporator. The residue was washed with CCl 4 and dried in vacuum, giving a mixture (0.097 g) of products 8 (0.073 g, 75% yield) and 10 (0.024 g, 24% yield) as a yellow oil. 2-Hexyl-1,2-dihydro [1,3]thiazolo[3,2-a]quinolin-10-ium bromide (9) and 1-hexyl-1,2-dihydro [1,3] thiazolo[3,2-a]quinolin-10-ium bromide (11). A solution of bromide (0.063 g, 0.39 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.063 g, 0.39 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. The obtained solution of 2-quinolinesulfenyl bromide was added dropwise to a solution of 1-octene (0.096 g, 0.78 mmol) in methylene chloride (5 mL), and the reaction mixture was stirred for 20 h at room temperature. The solvent was removed by a rotary evaporator. The residue was washed with CCl 4 and dried in vacuum, giving a mixture (0.12 g) of products 9 (0.089 g, 74% yield) and 11 (0.031 g, 26% yield) as a yellow oil.  (12). A solution of sulfuryl chloride (0.074 g, 0.55 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.088 g, 0.55 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. The obtained solution of 2-quinolinesulfenyl chloride was added dropwise to a solution of cyclopentene (0.075 g, 1.1 mmol) in methylene chloride (5 mL), and the reaction mixture was stirred for 94 h at room temperature. The solvent was removed by a rotary evaporator. The residue was washed with CCl 4 and dried in vacuum, giving the product 12 (0.153 g, 81% yield) as a brown oil. 1 (13). A solution of bromide (0.060 g, 0.38 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.061 g, 0.38 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. The obtained solution of 2-quinolinesulfenyl chloride was added dropwise to a solution of cyclopentene (0.052 g, 0.76 mmol) in methylene chloride (5 mL), and the reaction mixture was stirred for 20 h at room temperature. The solvent was removed by a rotary evaporator. The residue was washed with CCl 4 and dried in vacuum, giving product 13 (0.117 g, 100% yield) as a light-yellow oil. 1  2-(2-Chlorocyclooctylsulfanyl)quinoline (14). A solution of sulfuryl chloride (0.059 g, 0.44 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.070 g, 0.44 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. A solution of vinyl isobutyl ether (0.098 g, was added dropwise to a solution of 2-mercaptoquinoline (0.093 g, 0.57 mmol) in methylene chloride (5 mL), and the mixture was stirred for 15 min at room temperature. The obtained solution of 2-quinolinesulfenyl chloride was added dropwise to a solution of isoeugenol (0.189 g, 1.15 mmol) in methylene chloride (5 mL), and the reaction mixture was stirred for 20 h at room temperature. After filtration, the solvent was removed by a rotary evaporator, and the residue was washed with CCl 4 and dried in vacuum, giving product 17 (0.166 g, 80% yield) as an orange oil. 1

Conclusions
Novel reagents 2-quinolinesulfenyl chloride and bromide have been involved in the preparation of condensed heterocyclic sulfur-nitrogen compounds. The simple and efficient method for generation of 2-quinolinesulfenyl chloride and bromide is based on the action of sulfuryl chloride or bromine on available 2-mercaptoquinoline. Regioselective synthesis of novel 2-alkyl-1,2-dihydro [1,3]thiazolo[3,2-a]quinolin-10-ium derivatives in 95-100% yields has been developed by annulation reactions of 2-quinolinesulfenyl chloride and bromide with 1-alkenes. Condensed tetracyclic products have been obtained by the reactions of 2-quinolinesulfenyl chloride and bromide and cycloalkenes.
The reactions of cyclopentene with both 2-quinolinesulfenyl chloride and bromide at room temperature afforded condensed tetracyclic products in high yields. The reaction of 2-quinolinesulfenyl chloride with cyclooctene led to an electrophilic addition product in quantitative yield. When 2-quinolinesulfenyl bromide was involved in the reaction with cyclooctene under similar conditions, the tetracyclic condensed compound was obtained in quantitative yield.
The reactions of 2-quinolinesulfenyl chloride with styrene and natural compound isoeugenol proceeded in a regioselective manner but with opposite regiochemistry compared to the reactions of 2-quinolinesulfenyl chloride with terminal alkenes. The electrophilic addition of the sulfur atom of 2-quinolinesulfenyl chloride occurred to the β-carbon atom of the double bond of styrene and isoeugenol in a Markovnikov fashion.
The reaction of 2-quinolinesulfenyl chloride with terminal alkenes was supposed to proceed via intermediate thiiranium cation, and nucleophilic attack of the nitrogen atom of the quinoline ring occurred at the least substituted carbon atom of thiiranium ion, leading to the formation of condensed products in an anti-Markovnikov fashion.
The obtained condensed sulfur-nitrogen heterocycles are novel water-soluble functionalized compounds with potential biological activity.

Acknowledgments:
The authors thank Baikal Analytical Centre SB RAS for providing the instrumental equipment for structural investigations.