Efficient Regioselective Synthesis of Novel Condensed Sulfur–Nitrogen

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

Vladimir A. Potapov * , Roman S. Ishigeev and Svetlana V. Amosova

A. E. Favorsky Irkutsk Institute of Chemistry, Siberian Division of The Russian Academy of Sciences, 1 Favorsky Str., 664033 Irkutsk, Russia; [email protected] (R.S.I.); [email protected] (S.V.A.) * Correspondence: [email protected] or [email protected]; Tel.: +7-3952-426599

Abstract: 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 Citation: Potapov, V.A.; and 1-alkenes was discussed. Ishigeev, R.S.; Amosova, S.V. Efﬁcient Regioselective Synthesis of Novel Keywords: 1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium derivatives; annulation reactions; Condensed Sulfur–Nitrogen 2-quinolinesulfenyl chloride; 2-quinolinesulfenyl bromide; alkenes; cycloalkenes; 2-mercaptoquinoline Heterocyclic Compounds Based on Annulation Reactions of 2-Quinolinesulfenyl Halides with Alkenes and Cycloalkenes. Molecules 1. Introduction 2021, 26, 4844. https://doi.org/ The vast majority of drugs contain heterocyclic fragments in their structures [1]. The 10.3390/molecules26164844 sulfur heterocycles are structural parts of many drugs that are used in modern pharma-

Academic Editors: Oleg A. Rakitin cotherapy [2]. Drugs containing condensed nitrogen and sulfur heterocycles are some of and Andrea Penoni the most commonly used medications [2]. Penicillin and cephalosporin scaffolds contain condensed nitrogen and sulfur heterocycles and represent examples of antibiotics that Received: 30 June 2021 played an outstanding role in the history and development of pharmaceutical chemistry. Accepted: 6 August 2021 The quinoline derivatives exhibit a variety of biological activities, including an- Published: 10 August 2021 tibacterial, antifungal, anticancer, anti-inflammatory, antimalarial and antileishmanial actions [3–9]. The fluoroquinolone antibiotics (ciprofloxacin, levofloxacin, gatifloxacin and Publisher’s Note: MDPI stays neutral moxifloxacin) and antimalarial medications (chloroquine, hydroxychloroquine, amodi- with regard to jurisdictional claims in aquine and primaquine) took an important place in pharmacotherapy. It is worth noting published maps and institutional affil- that some quinoline derivatives (e.g., hydroxychloroquine) have been recently used for the iations. treatment of COVID-19 [10]. The condensed system of quinoline and thiazole heterocycle is very promising in terms of possible manifestation of biological activity. The [1,3]thiazolo[3,2-a]quinolin- 10-ium scaffold derivatives represent an important class of condensed heterocyclic com- Copyright: © 2021 by the authors. pounds exhibiting various types of biological activity including antibacterial [11–21], anti- Licensee MDPI, Basel, Switzerland. tumor [22–24], anti-inflammatory [25] and antitrypanosomal [26] action as well as glycogen This article is an open access article synthase kinase 3 inhibitors properties [24,27] (Figure1). distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https:// creativecommons.org/licenses/by/ 4.0/).

Molecules 2021, 26, 4844. https://doi.org/10.3390/molecules26164844 https://www.mdpi.com/journal/molecules Molecules 2021, 26, 4844 2 of 15 MoleculesMolecules 20212021,, 2626,, 48444844 22 of of 1415

O O O O O O OR O O O O OR O O F F F OH F N S F OH OH F N S OH H2N N H2N N S N N S N N S EtNH N N S EtNFH F

antibarterial antitumor antitrypanosomal antibarterial antitumor antitrypanosomal activity activity activity activity activity activity

NH2 O O O O NH O O O O O O F 2 O O F F OH F F OH OH F OH N OH OH HN N N S N N S HN N S N N S NH N N S F N N S 2 F HN NH2 Me HN Me antibacterial GSK-3 inhibitory antibacterial antibacterial GSK-3 inhibitory antibacterial activity and antitumor activity activity activity and antitumor activity activity Figure 1. Known biologically active compounds containing [1,3]thiazolo[3,2-a]quinolin-10-ium scaffold (antibacterial Figure 1. Known biologically active compounds containing [1,3]thiazolo[3,2-a]quinolin-10-ium scaffold (antibacterial [11,16,21], antitumorFigure [22,24], 1. Known antitrypanosomal biologically active [26] compounds and glycogen containing synthase [1,3]thiazolo[3,2- kinase 3 inhibitora]quinolin-10-ium [24] activities). scaffold (antibacterial [11,16,21], antitumor[11,16,21], [anti22,24tumor], antitrypanosomal [22,24], antitrypanosomal [26] and glycogen [26] and synthase glycogen kinase synthase 3 inhibitor kinase [24 ]3 activities).inhibitor [24] activities). The development of the effective synthesis of novel chalcogen condensed com- The development development of of the the effective effective synthesis synthesis of novel of novel chalcogen chalcogen condensed condensed compounds compounds and heterocycles by regioselective annulation and cyclization reactions of chal- andpounds heterocycles and heterocycles by regioselective by regioselective annulation annulation and cyclization and cyclization reactions reactions of chalcogen- of chalcogen-containing reagents is our favourable area of research [28–39]. The annulation re- containingcogen-containing reagents reagents is our favourable is our favourable area of researcharea of research [28–39]. The[28–39]. annulation The annulation reactions r ofe- actions of 2-pyridinesulfenyl and 2-pyridineselenenyl halides with functionalized al- 2-pyridinesulfenylactions of 2-pyridinesulfenyl and 2-pyridineselenenyl and 2-pyridineselenenyl halides with functionalized halides with alkenes functionalized led to novel alkenes led to novel 2Н,3Н-[1,3]thiazolo[3,2-а]pyridin-4-ium and 2kenesH,3H -[1,3]thiazolo[3,2-led to a]pyridin-4-ium novel 2Н and,3Н 2-[1,3]thiazolo[3,2H,3H-[1,3]selenazolo[3,2--а]pyridina-4]pyridin-4-ium-ium and 2Н,3Н-[1,3]selenazolo[3,2-а]pyridin-4-ium derivatives in high yields [34–39]. derivatives2Н,3Н-[1,3]selenazolo[3,2 in high yields- [а34]pyridin–39]. -4-ium derivatives in high yields [34–39]. Recently we described the annulation reactions of 8-quinolinesulfenyl halides with Recently we describeddescribed thethe annulationannulation reactionsreactions ofof 8-quinolinesulfenyl8-quinolinesulfenyl halideshalides withwith vinylic heteroatom compounds, including vinylic ethers, sulfides, divinyl selenide and vinylic heteroatom compounds, including vinylic ethers,ethers, sulﬁdes,sulfides, divinyldivinyl selenideselenide andand tetravinyl silane [40]. Starting 8-quinolinesulfenyl halides were generated in situ from tetravinyl silane [[40].40]. Starting 8-quinolinesulfenyl8-quinolinesulfenyl halides were generated in situ from from di(8-quinolinyl) disulfide by the action of sulfuryl chloride or bromine and used in fur- di(8-quinolinyl)di(8-quinolinyl) disulﬁdedisulfide byby the the action action of of sulfuryl sulfuryl chloride chloride or or bromine bromine and and used used in furtherin further reactions without isolation (Scheme 1). reactionsther reactions without without isolation isolation (Scheme (Scheme1). 1).

N 2 S SO2Cl2 (Br2) S N CH Cl (CHCl ,CH CN) N 2 2 3 3 SHal RT

Si N XR Hal N S N Hal CH Cl (CHCl ) CH2Cl2 (CHCl3) SHal 2 2 3 S XR RT RT Si

Hal = Cl, Br; XR = OBu-i, OC2H4Cl. SCH=CH2, SPh, SeCH=CH2

Scheme 1. TheScheme generation 1. The of generation 8-quinolinesulfenyl of 8-quinolinesulfenyl halides from di(8-quinolinyl)halides from di(8-quinolinyl) disulﬁde by the disulfide action of by sulfuryl the ac- chloride or Scheme 1. The generation of 8-quinolinesulfenyl halides from di(8-quinolinyl) disulfide by the action of sulfuryl chloride or bromine followed by the annulation reactions with vinylic ethers, sul- bromine followed by the annulationtion of sulfuryl reactions chloride with vinylic or bromine ethers, followed sulﬁdes, by divinyl the annulation selenide and reactions tetravinyl with silane. vinylic ethers, sulfides, divinyl selenide and tetravinyl silane. fides, divinyl selenide and tetravinyl silane.

Molecules 2021, 26, 4844 3 of 15

Molecules 2021, 26, 4844 3 of 14 The annulation reactions of 8-quinolinesulfenyl halides with vinylic ethers, sulfides and divinyl selenide proceeded in a regioselective manner affording 3-substituted 2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium halides in high yields (Scheme 1) [40]. The The annulation reactions of 8-quinolinesulfenyl halides with vinylic ethers, sulﬁdes andannulation divinyl selenidereaction proceededof 8-quinolinesulfenyl in a regioselective halides manner with tetravinyl affording 3-substitutedsilane was found 2H,3 Hto- [1,4]thiazino[2,3,4-occur withij]quinolin-4-ium opposite halides in highregiochemistry yields (Scheme 1)[ 40leading]. The annulation to reaction2-trivinylsilyl-2 of 8-quinolinesulfenylH,3H-[1,4]thiazino[2,3,4- halides withij]quinolin-4-ium tetravinyl silane halides was in found near to quantitative occur with oppositeyields (Scheme regiochemistry 1). leading to 2-trivinylsilyl-2H,3H-[1,4]thiazino[2,3,4-ij]quinolin-4-ium halidesThe in reactions near quantitative of 8-quinolinesulfenyl yields (Scheme 1halides). with cycloalkenes (cyclopentene, cy- clohexeneThe reactions and ofcyclooctene), 8-quinolinesulfenyl depending halides on with the cycloalkenes nature of (cyclopentene, the halogen, cyclohexene led to and[1,4]thiazino[2,3,4- cyclooctene), dependingij]quinolin-11-ium on the nature of the halogen, ledderivatives to [1,4]thiazino[2,3,4- ij]quinolinor- 11-ium8-[(2-chlorocycloalkyl)sulfanyl]quinolines derivatives or 8-[(2-chlorocycloalkyl)sulfanyl]quinolines in high yields (90–100%) in high (Scheme yields 2). (90–100%) The re- (Schemeactions 2of). 8-quinolinesulfenyl The reactions of 8-quinolinesulfenyl chloride with cycloalkenes chloride with led cycloalkenesto electrophilic led addition to elec- trophilicproducts, addition while condensed products, compounds while condensed were obtained compounds in the were case obtained of 8-quinolinesulfenyl in the case of 8-quinolinesulfenylbromide (Scheme 2) bromide [41]. (Scheme2)[41].

N n n N N Br Cl S Hal = Cl Hal = Br S CH2Cl2 SHal CH2Cl2 ~100% 90-98% n n

Hal = Cl, Br; n = 1, 2, 4

SchemeScheme 2.2. The synthesissynthesis ofof [1,4]thiazino[2,3,4- [1,4]thiazino[2,3,4-ij]quinolin-11-iumij]quinolin-11-ium derivatives derivatives and 8-[(2-and chlorocycloalkyl)sulfanyl]quinolines8-[(2-chlorocycloalkyl)sulfanyl]quinolines by the by reactions the reactions of 8-quinolinesulfenyl of 8-quinolinesulfenyl chloride andchloride bromide and withbromide cycloalkenes. with cycloalkenes.

TheThe aimaim ofof this this research research is is the the development developmen oft of the the efﬁcient efficient regioselective regioselective synthesis synthesis of novelof novel condensed condensed [1,3]thiazolo[3,2- [1,3]thiazolo[3,2-a]quinolin-10-iuma]quinolin-10-ium derivatives derivati withves promisingwith promising biological bio- activitylogical activity basedon based annulation on annulation reactions reactions of 2-quinolinesulfenyl of 2-quinolinesulfenyl halides halides with alkeneswith alkenes and cycloalkenes.and cycloalkenes. The annulation The annulation of 5-membered of 5-membered 1,3-thiazole 1,3-thiazole heterocycle heterocycle to the quinoline to the quino- ring occursline ring in theoccurs reaction in the of 2-quinolinesulfenylreaction of 2-quinolinesulfenyl halides with alkeneshalides andwith cycloalkenes, alkenes and whereas cycloal- thekenes, annulation whereas of the 6-membered annulation 1,4-thiazineof 6-membered heterocycle 1,4-thiazine to the heterocycle quinoline ringto the is observedquinoline inring the is reactions observed of in 8-quinolinesulfenyl the reactions of 8-quinolinesulfenyl halides with cycloalkenes halides with and vinylcycloalkenes heteroatom and compoundsvinyl heteroatom [40,41 ]compounds (Schemes1 and[40,41]2). (Schemes 1 and 2).

2.2. ResultsResults andand DiscussionDiscussion TheThe reactionsreactions ofof 2-quinolinesulfenyl2-quinolinesulfenyl halideshalides areare unknown,unknown, andand thethe preparationpreparation ofof 2-quinolinesulfenyl2-quinolinesulfenyl chloride and and bromide bromide has has no nott yet yet been been described described in the in theliterature literature (the (theSciFinder SciFinder database). database). Previously Previously we generatedgenerated 8-quinolinesulfenyl 8-quinolinesulfenyl halides halides from di(8-from quinolinyl)di(8-quinolinyl) disulfide disulfide by the by action the action of sulfuryl of sulfuryl chloride chloride or bromine or bromine and involved and involved in further in reactionsfurther reactions without isolationwithout (Schemeisolation1 ).(Scheme However, 1). di(2-quinolinyl)However, di(2-quinolinyl) disulfide is adisulfide hard-to-get is a reagent, whereas 2-mercaptoquinoline is an available compound. It would seem that hard-to-get reagent, whereas 2-mercaptoquinoline is an available compound. It would di(2-quinolinyl) disulfide can be easily prepared by oxidation of 2-mercaptoquinoline. seem that di(2-quinolinyl) disulfide can be easily prepared by oxidation of Unfortunately, the oxidation reactions of 2-mercaptoquinoline are complicated by side 2-mercaptoquinoline. Unfortunately, the oxidation reactions of 2-mercaptoquinoline are processes that make it difficult to obtain pure di(2-quinolinyl) disulfide. complicated by side processes that make it difficult to obtain pure di(2-quinolinyl) disul- We developed a simple and efficient method for the generation of 2-quinolinesulfenyl fide. chloride (2) and bromide (3) by the action of sulfuryl chloride or bromine on We developed a simple and efficient method for the generation of 2-mercaptoquinoline (1) in methylene chloride or chloroform. The generated 2-quinolinesulfenyl chloride (2) and bromide (3) by the action of sulfuryl chloride or 2-quinolinesulfenyl halides 2 and 3 were involved in further reactions without isola- bromine on 2-mercaptoquinoline (1) in methylene chloride or chloroform. The generated tion (Scheme3). 2-quinolinesulfenyl halides 2 and 3 were involved in further reactions without isolation (Scheme 3).

MoleculesMolecules 20212021,, 2626,, 48444844 44 ofof 1515 Molecules 2021, 26, 4844 4 of 14 Molecules 2021, 26, 4844 4 of 15

SO Cl (Br ) SO22Cl22 (Br22)

N SH CHSOC2lC l(2C (HBrC2)l ) N SHal N SH CH22Cl22 (CHCl33) N SHal RT N SH CH2CRl2T (CHCl3) N SHal 11 22,, 33 RT 1 2, 3 HHaall == CCll ((22)),, BBrr ((33))

Hal = Cl (2), Br (3) SchemeScheme 3.3. TheThe simplesimple andand efficientefficient methodmethod forfor generationgeneration ofof 22--quinolinesulfenylquinolinesulfenyl chloridchloridee 22 andand bromide 3 by the action of sulfuryl chloride or bromine on 2-mercaptoquinoline 1 in methylene bromideSchemeScheme 3.33. by TheThe the simplesimple action andand of efﬁcientsulfurylefficient methodchloridemethod fororfor bromine generationgeneration on ofof2- 2-quinolinesulfenylmercaptoquinoline2-quinolinesulfenyl 1 chloride chloridin methylenee2 2and and chloride or chloroform. chloridebromidebromide or 33 bychloroform.by thethe actionaction ofof sulfurylsulfuryl chloridechloride oror brominebromine onon 2-mercaptoquinoline2-mercaptoquinoline1 1in in methylene methylene chloridechloride oror chloroform.chloroform. TheThe chemical chemical properties properties of of 2 2--quinolinesulfenylquinolinesulfenyl chloride chloride 22 andand bromide bromide 33 areare u un-n- known,known,TheThe andand chemical chemical wewe startedstarted properties properties studiesstudies of 2-quinolinesulfenylof usingusing 2-quinolinesulfenyl simplesimple terminalterminal chloride chloridealkenesalkenes2 and (1(12 bromide--andhexene,hexene, bromide 311-are-hepteneheptene unknown,3 are and and un- 1and1known,--octene)octene) we started and andand we cycloalkenescycloalkenes studies started using studies (cyclopentene,(cyclopentene, simple using terminal simple cyclohexenecyclohexene alkenesterminal (1-hexene, and andalkenes cyclooctene).cyclooctene). (1 1-heptene-hexene, 1 and-heptene 1-octene) and and1-octene) cycloalkenesWeWe found foundand cycloalkenes that that (cyclopentene, the the reactions reactions (cyclopentene, cyclohexene of of 2 2--quinolinesulfenyl quinolinesulfenylcyclohexene and cyclooctene). and cyclooctene). chloride chloride 22 withwith 1 1--hexene,hexene, 11--heptenehepteneWeWe found found and and that 1 1 --octene thatoctene the reactionsthe proceeded proceeded reactions of 2-quinolinesulfenyl in in of a a 2regioselective regioselective-quinolinesulfenyl chloride fashion fashion chloride2 atwith at room room 1-hexene, 2 tempe tempewith 1-hepteneraturerature 1-hexene, in in methyleneandmethylene1-heptene 1-octene and proceeded 1-octene chloride chloride inproceeded a regioselective in a regioselective or or fashion at room chloroform chloroformfashion temperature at room tempe in methylene affording affordingrature in 2chloride2methylene--alkylalkyl--1,21,2 or--dihydro[1,3]thiazolo[3,2 dihydro[1,3]thiazolo[3,2 chloroform chloride affording 2-alkyl-1,2-dihydro[1,3]thiazolo[3,2---aa]quinolin]quinolin or --1010--iumium chlorides chlorides chloroform 44––66 inina]quinolin-10-ium 95 95––100%100% affording yields yields (Schemechlorides(Scheme2-alkyl-1,2 4).4).4–- 6Thedihydro[1,3]thiazolo[3,2Thein 95–100%electrophilicelectrophilic yields additionaddition (Scheme-a ]quinolin ofof4 the).the The sulfursulfur electrophilic-10- atomiumatom chlorides ofof 22 addition--quinolinesulfenylquinolinesulfenyl 4– of6 in the 95 sulfur–100% chloridechloride atom yields of 22 occurred2-quinolinesulfenyloccurred(Scheme 4). to to The the the electrophilic α α-- chloridecarboncarbon atomatom2 additionoccurred of of the the of to the terminalthe terminal sulfurα-carbon atom double double atom of 2 bond bond- ofquinolinesulfenyl the of of terminal alkenes alkenes double in in chloride an an bond anan- 2 tioftioccurred--MarkovnikovMarkovnikov alkenes into an the anti-Markovnikovfashion.fashion. α-carbon atom fashion. of the terminal double bond of alkenes in an anti-Markovnikov fashion. AAllkk CH AClkl (CHCl ) NN SS NN SSCCll CH22Cl22 (CHCl33) RT CCll N S N SCl CH2CRl2T (CHCl3) 95-100% AAllkk 95-R10T0% Cl 22 44--66 95-100% Alk 2 4-6 AAllkk == BBuu ((44)),, PPeenntt ((55)),, HHeexx ((66))

Alk = Bu (4), Pent (5), Hex (6) SchemeScheme 4. 4. TheThe synthesis synthesis of of 2 2-alkyl-1,2-dihydro[1,3]thiazolo[3,2-2--alkylalkyl--1,21,2--dihydro[1,3]thiazolo[3,2dihydro[1,3]thiazolo[3,2--aa]quinolin]quinolin-10-ium]quinolin --1010--iumium chlorides chlorides 44––66 byby the reactions of sulfenyl chloride 2 with 1-hexene, 1-heptene and 1-octene. thetheScheme reactions reactions 4. The of sulfenyl synthesis chloride of 2-alkyl 2 with-1,2- dihydro[1,3]thiazolo[3,2 1-hexene,1-hexene, 1-heptene1-heptene and- a 1-octene.1]quinolin-octene. -10-ium chlorides 4–6 by the reactions of sulfenyl chloride 2 with 1-hexene, 1-heptene and 1-octene. AlAlongAlongong with with the the investigation investigation of of the the chemical chemical properties properties of of sulfenylsulfenyl chloridechloride 22,, thethe reactionsreactionsAlong of of with 22-quinolinesulfenyl 2--quinolinesulfenylquinolinesulfenyl the investigation bromide bromide of the 3chemical3 withwith alkenes alkenes properties were were of studied. studied. studied. sulfenyl The The chloride reaction reaction 2, the of of sulfenylsulfenylreactions bromide bromide of 2-quinolinesulfenyl 33 withwith 1 1-heptene1--hepteneheptene bromide also also proceeded proceeded 3 with regioselectively, alkenesregioselectively, were studied. leadingleading The toto condensedcondensed reaction of compoundcompoundsulfenyl bromide 77 inin a a 99% 99% 3 with yield yield 1- heptene (Scheme (Scheme also 5 5).5).). proceeded regioselectively, leading to condensed compound 7 in a 99% yield (Scheme 5). C H C55H1111 N CHCCHl (CHCl ) N SS NN SSBBrr CH22C5l22 1(C1 HCl33) BBrr N CH ClR T(CHCl ) S N SBr 2 R2T 3 C H 99% Br C55H1111 3 9R9%T 3 77 C H 99% 5 11 3 7 SchemeScheme 5.5. TheThe synthesis synthesissynthesis of ofof 2-pentyl-1,2-dihydro[1,3]thiazolo[3,2- 22--pentylpentyl--1,21,2--dihydro[1,3]thiazolo[3,2dihydro[1,3]thiazolo[3,2a]quinolin-10-ium--aa]quinolin]quinolin-- 1010--iumium bromide bromidebromide7 by 77 the byby reactionsthe reactions of sulfenyl of sulfenyl bromide bromide3 with 3 with 1-heptene. 1-heptene. theScheme reactions 5. The of sulfenyl synthesis bromide of 2-pentyl 3 with-1,2 1-dihydro[1,3]thiazolo[3,2heptene. -a]quinolin-10-ium bromide 7 by the reactions of sulfenyl bromide 3 with 1-heptene. However,However, the the reactions reactions ofof 2-quinolinesulfenyl22--quinolinesulfenylquinolinesulfenyl bromidebromide 33 withwith alkenesalkenes containingcontaining anan even number of carbon atoms (1-hexene and 1-octene) occurred with loss of regioselectivity eveneven numberHowever,number ofof the carboncarbon reactions atomsatoms of (1 (12--quinolinesulfenylhexenehexene andand 11--octene)octene) bromide occurredoccurred 3 with withwith alkenes lossloss ofofcontaining regioseleregiosele c-anc- giving along with compounds 8 and 9 (bromide analogues of products 4 and 6) minor tivitytivityeven givingnumbergiving alongalong of carbon withwith atomscompoundscompounds (1-hexene 88 andand and 99 (bromide(bromide1-octene) analoguesoccurredanalogues with ofof productsproducts loss of regiosele 44 andand 66c-)) regioisomers 10 and 11, which were originated from electrophilic addition of the sulfur minorminortivity regioisomersgivingregioisomers along 10with10 andand compounds 1111,, whichwhich werewere8 and originatedoriginated 9 (bromide fromfrom analogues electrophilicelectrophilic of products addadditionition 4 ofandof thethe 6 ) atom of 2-quinolinesulfenyl bromide 3 to the terminal carbon atom of the double bond of sulfursulfurminor atom atomregioisomers ofof 22--quinolinesulfenylquinolinesulfenyl 10 and 11, which bromidebromide were 33originated toto thethe terminalterminal from electrophilic carboncarbon atomatom add ofof thetheition doubledouble of the alkenes (Scheme6). A ratio of regioisomers, compounds 8/10 and 9/11, was found to be bondbondsulfur of of atom alkenes alkenes of 2 - (Schemequinolinesulfenyl (Scheme 6). 6). A A ratio ratio bromide of of regioisomers regioisomers 3 to the terminal,, compoundscompounds carbon 88 atom//1010 andand of the9/119/11 double,, was was approximately 3:1. The total yields of regioisomers 8 + 10 and 9 + 11 are quantitative. bond of alkenes (Scheme 6). A ratio of regioisomers, compounds 8/10 and 9/11, was

Molecules 2021,, 26,, 48444844 5 of 15

Molecules 2021, 26, 4844 5 of 14 found to be approximately 3:1. The total yields of regioisomers 8 + 10 and 9 + 11 are quantitative.

Allk N S N S N SBr CH2Cll2 (CHCll3) Br Br Br RT Allk Allk 3 8,, 9 10,, 11 74-75% Allk = Bu (8,, 10),, Hex (9,, 11) 24-26%

SchemeScheme 6. 6. TheThe reactionsreactions ofof 2-quinolinesulfenyl2-quinolinesulfenyl bromidebromide 33 withwith 1-hexene1-hexene andand 1-octene1-octene affordingaffording compoundscompounds 88––1111...

TheThe reactions reactions of of 2-quinolinesulfenyl 2-quinolinesulfenyl chloride chloride2 and 2 and bromide bromide3 with 3 cycloalkeneswith cycloalkenes were alsowere studied. also studied. PreviouslyPreviously we found found that that the the reactions reactions of of 8- 8-quinolinesulfenylquinolinesulfenyl bromide bromide with with cyclo- cy- cloalkenesalkenes led led to tocondensed condensed compounds, compounds, while while in in the the case case of of 8 8-quinolinesulfenyl-quinolinesulfenyl chloridechloride electrophilicelectrophilic addition, addition, products products were were obtained obtained (Scheme (Scheme2). Unlike 2). Unlike this this trend, trend, the reactions the reac- oftions cyclopentene of cyclopentene with both with sulfenyl both sulfenyl chloride chloride2 andbromide 2 and bromide3 at room 3 at temperature room temper ina methy-ture in lenemethylene chloride chloride afforded afforded condensed condensed tetracyclic tetracyclic products products12 and 1213 andin 81% 13 in and 81% quantitative and quan- yields,titativerespectively yields, respectively (Scheme (Scheme7). 7).

N S N SHall CH Cll , RT 2 2 Hall Hall = Cll, 81% Hall = Br, ~100% 12, 13 Hall = Cll (12), Br (13)

SchemeScheme 7.7. The reactions ofof 2-quinolinesulfenyl2-quinolinesulfenyl chloridechloride 22 andand bromidebromide 33 withwith cyclopentenecyclopentene leadingleadinging toto condensedcondensed tetracyclictetracyclic compoundscompounds 1212 andand 1313...

TheThe reactionsreactions ofof cyclohexenecyclohexene withwith bothboth 2-quinolinesulfenyl2-quinolinesulfenyl chloridechloride 22 and and bromidebromide 33 werewere accompaniedaccompanied byby thethe formationformation ofof by-products,by-products, andand itit waswas difﬁcultdifficult toto separateseparate thethe desireddesired condensedcondensed compounds.compounds. UnlikeUnlike thethe reactionsreactions of cyclopentene with with both both 2 2-quinolinesulfenyl-quinolinesulfenyl halides halides 2 2andand 3 3givinggiving condensed condensed tetracyclic tetracyclic products products 1212 andand 1313,,, t thehe reaction reaction of of 2-quinolinesulfenyl 2-quinolinesulfenyl chloridechloride 22 with with cyclooctenecyclooctene at at room room temperature temperature led led to to electrophilic electrophilic addition addition product product14 in14 quantitative yield (Scheme8). When sulfenyl bromide 3 was involved in the reaction with Molecules 2021, 26, 4844 in quantitative yield (Scheme 8). When sulfenyl bromide 3 was involved in the reaction6 of 15 cyclooctenewith cyclooctene under under similar similar conditions, conditions, tetracyclic tetracyclic condensed condensed compound compound15 was obtained15 was o inb- quantitativetained in quantitative yield (Scheme yield8 ).(Scheme 8).

N N S S Cl Hal = Cl N SHal Hal = Br Br CH2Cl2 CH2Cl2 ~100% 2, 3 ~100% 14 15

Hal = Cl (2, 14), Br (3, 15)

Scheme 8. The reactionsreactions ofof 2-quinolinesulfenyl2-quinolinesulfenyl chloride chloride2 2and and bromide bromide3 with3 with cyclooctene cyclooctene affording affording compounds compounds14 and14 and15. 15.

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).

HO N S N S Me Cl Cl CH Cl 2 2 N SCl CH2Cl2 Me ~100% 80% 2 HO OMe

16 17

Scheme 9. The reactions of 2-quinolinesulfenyl chloride 2 with styrene and isoeugenol giving compounds 16 and 17.

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).

Molecules 2021, 26, 4844 6 of 15

N N S S Cl Hal = Cl N SHal Hal = Br Br CH2Cl2 CH2Cl2 ~100% 2, 3 ~100% 14 15

Hal = Cl (2, 14), Br (3, 15)

MoleculesScheme2021, 268., The 4844 reactions of 2-quinolinesulfenyl chloride 2 and bromide 3 with cyclooctene affording compounds 14 and6 of 14 15.

The formation of an intermediate bromine analogue of compound 14 is accompanied The by intramolecularformation of an cyclization intermediate at bromine room temperature analogue of with compound the formation14 is accompanied of a con- densedby intramolecular product 15,cyclization while chloro at derivative room temperature 14 is less withreactive the under formation these of conditions a condensed and productremains 15uncyclized., while chloro It is derivativeknown that14 theis less bromine reactive atom under is leaving these conditions group better and than remains the chlorineuncyclized. atom It isin known nucleophilic that the substitution bromine atom reactions, is leaving and group intramolecular better than the cyclization chlorine atomwith in nucleophilic substitution reactions, and intramolecular cyclization with the bromine the bromine analogue of compound 14 proceeds easier than with chloro derivative 14. analogue of compound 14 proceeds easier than with chloro derivative 14. Finally, we obtained condensed compounds from 2-quinolinesulfenyl chloride 2 and Finally, we obtained condensed compounds from 2-quinolinesulfenyl chloride 2 and alkenes containing a benzene ring (Scheme 9). The reactions of 2-quinolinesulfenyl chlo- alkenes containing a benzene ring (Scheme9). The reactions of 2-quinolinesulfenyl chloride 2 with styrene and natural product isoeugenol proceeded at room temperature in ride 2 with styrene and natural product isoeugenol proceeded at room temperature in methylene chloride in a regioselective manner but with opposite regiochemistry com- methylene chloride in a regioselective manner but with opposite regiochemistry compared pared to the reactions of sulfenyl chloride 2 with terminal alkenes (Scheme 4). The elec- to the reactions of sulfenyl chloride 2 with terminal alkenes (Scheme4). The electrophilic trophilic addition of the sulfur atom of sulfenyl chloride 2 occurred to the β-carbon atom addition of the sulfur atom of sulfenyl chloride 2 occurred to the β-carbon atom of the of the double bond of styrene and isoeugenol in a Markovnikov fashion. Condensed double bond of styrene and isoeugenol in a Markovnikov fashion. Condensed products products 16 and 17 based on styrene and isoeugenol were obtained in quantitative and 16 and 17 based on styrene and isoeugenol were obtained in quantitative and 80% yields, 80%respectively yields, respectively (Scheme9). (Scheme 9).

HO N S N S Me Cl Cl CH Cl 2 2 N SCl CH2Cl2 Me ~100% 80% 2 HO OMe

16 17

Scheme 9. The reactio reactionsns of 2-quinolinesulfenyl2-quinolinesulfenyl chloride 2 with styrene andand isoeugenolisoeugenol givinggiving compoundscompounds 1616 andand 1717..

Why dodo annulationannulation reactionsreactions of of quinolinesulfenyl quinolinesulfenyl chloride chloride2 with2 with styrene, styrene, isoeugenol isoeuge- noland terminaland terminal alkenes alkenes proceed proceed with opposite with opposite regiochemistry? regiochemistry? Supposed Supposed reaction pathways reaction pcanathways be regarded can be inregarded order to in explain order to this explain trend this (Scheme trend 10 (Scheme). The reactions10). The reactions of sulfenyl of sulfenylchloride chloride2 with compounds 2 with compounds containing containing a double a bond double conjugated bond conjugated with the with benzene the ben- ring (styrene,zene ring isoeugenol) (styrene, isoeugenol proceeded) proceeded regioselectively regioselectively via electrophilic via electrophilic addition of addition the sulfur of theatom sulfur to the atomβ-carbon to the atom β-carbon of the atom double of the bond. double The bond. regioselectivity The regioselectivity is due to the is due formation to the Molecules 2021, 26, 4844 7 of 15 formationof intermediate of intermediate linear carbocation linear carbocationA, which is stabilizedA, which byis stabilized the benzene by ring the (thebenzene relatively ring (thestable relatively benzyl cation) stable benzyl (Scheme cation) 10). (Scheme 10).

N S Alk N S Cl N SCl Cl Alk 2 A B

N S N S Cl Cl Alk

4-6 16 Alk = Bu (4), Pent (5), Hex (6) SchemeScheme 10. 10.The The supposed supposed pathways pathways of of the the reactions reactions of of sulfenyl sulfenyl chloride chloride2 2with with styrene styrene and and 1-alkenes. 1-alkenes.

Addition reactions of sulfenyl halides to alkenes are well understood [42–53], 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 afforded predominantly anti-Markovnikov products, and thiiranium cations were regarded as intermediates in these reactions [44–47]. 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 1H and 13C-NMR spectroscopy (see Supplementary Materials), including proton-coupled 13C-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 13C-NMR spectra of the obtained compounds (the number of protons is determined by NMR experiments). The CHS moiety and the CH2N+ methylene group manifest themselves in the regions of 44–48 ppm and 58–62 ppm, respectively, in 13C-NMR spectra of compounds 4–9 (the products derived from anti-Markovnikov addition of the sulfur electrophile to the double bond). Signals of the CH2S group and containing one proton CHN+ moiety are observed in the regions of 31–38 ppm and 66–71 ppm, respectively, in 13C-NMR spectra of compounds 10, 11 and 16 (the products derived from Markovnikov addition of the sulfur electrophile to the double bond). Stereochemistry of compound 17 is determined based on the value of the spin–spin coupling constant (3JH-H = 8.2 Hz) of protons in the N-(Ar)CH-CH(Me)-S fragment. This value corresponds to the trans-disposition of methyl and aryl groups relative to the plane of the ring (trans-configuration) [39,54,55].

Molecules 2021, 26, 4844 7 of 14

Addition reactions of sulfenyl halides to alkenes are well understood [42–53], 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 afforded predominantly anti-Markovnikov products, and thiiranium cations were regarded as intermediates in these reactions [44–47]. 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 1H and 13C-NMR spectroscopy (see Supplementary Materials), including proton-coupled 13C-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 13C-NMR spectra of the obtained compounds (the number of protons is determined + by NMR experiments). The CHS moiety and the CH2N methylene group manifest themselves in the regions of 44–48 ppm and 58–62 ppm, respectively, in 13C-NMR spectra of compounds 4–9 (the products derived from anti-Markovnikov addition of the sulfur electrophile to the double bond). Signals of the CH2S group and containing one proton CHN+ moiety are observed in the regions of 31–38 ppm and 66–71 ppm, respectively, in 13C-NMR spectra of compounds 10, 11 and 16 (the products derived from Markovnikov addition of the sulfur electrophile to the double bond). Stereochemistry of compound 17 is determined based on the value of the spin–spin 3 coupling constant ( JH-H = 8.2 Hz) of protons in the N-(Ar)CH-CH(Me)-S fragment. This value corresponds to the trans-disposition of methyl and aryl groups relative to the plane of the ring (trans-conﬁguration) [39,54,55].

3. Experimental Section 3.1. General Information 1H (400.1 MHz) and 13C (100.6 MHz) NMR spectra were recorded on a Bruker DPX-400 spectrometer (Bruker BioSpin GmbH, Rheinstetten, Germany) in 2–5% solution in D2O. 1H and 13C chemical shifts (δ) are reported in parts per million (ppm), relative to tetram- ethylsilane (external) or to the residual solvent peaks of D2O(δ = 4.79), acetone-d6 (δ = 2.05 1 13 and 29.84 ppm) and DMSO-d6 (δ = 2.50 and 39.52 ppm for H and C NMR, respectively). 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.

3.2. Synthesis of Compounds 4–11 by the Reactions of 2-Quinolinesulfenyl Chloride 2 and Bromide 3 with Alkenes

2-Butyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium chloride (4). 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 (0.089 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 1-hexene (0.093 g, 1.1 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 CCl4 and dried in vacuum, giving product 4 (0.146 g, 95% yield) as a yellow oil. 1 H–NMR (400 MHz, D2O): δ 0.81 (t, J 7.1 Hz, 3H, CH3), 1.25–1.40 (m, 4H, CH2), 1.77–1.88 (m, 1H, CH2), 1.89–1.99 (m, 1H, CH2), 3.79 (tt, J 8.7, 6.4 Hz, 1H, SCH,), 5.00 (dd, J 13.0, 6.4 Hz, 1H, NCH2), 5.25 (dd, J 13.0, 8.7 Hz, 1H, NCH2), 7.66–7.72 (m, 2H, Cquino), 7.86–7.88 (m, 1H, Cquino), 7.93–7.98 (m, 1H, Cquino), 8.00–8.02 (m, 1H, Cquino), 8.50–8.52 (m, 1H, Cquino). Molecules 2021, 26, 4844 8 of 14

13 C–NMR (101 MHz, D2O): δ 11.82 (CH3), 20.27, 27.17, 32.72 (CH2), 45.44 (SCH), 59.82 (NCH2), 116.27 (Cquino), 116.84 (Cquino), 124.96 (Cquino), 127.06 (Cquino), 128.85 (Cquino), 133.87 (Cquino), 136.51 (Cquino), 143.49 (Cquino), 163.60 (Cquino). Anal. Calcd for C15H18NClS: C 64.38, H 6.48, Cl 12.67, N 5.01, S 11.46. Found: C 64.67, H 6.71, Cl 12.00, N 5.29, S 11.89. 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 CCl4 and dried in vacuum, giving product 5 (0.120 g, 100% yield) as a yellow oil. 1 H–NMR (400 MHz, D2O): δ 0.79–0.82 (m, 3H, CH3), 1.22–1.30 (m, 4H, CH2), 1.37–1.46 (m, 2H, CH2), 1.80–1.89 (m, 1H, CH2), 1.90–1.97 (m, 1H, CH2), 4.49 (ddd, J 14.8, 8.7, 6.2 Hz, 1H, SCH), 5.05 (dd, J 13.0, 6.2 Hz, 1H, NCH2), 5.30 (dd, J 13.0, 8.7 Hz, 1H, NCH2), 7.72–7.77 (m, 2H, Cquino), 7.91–7.93 (m, 1H, Cquino), 7.98–8.3 (m, 1H, Cquino), 8.06–8.08 (m, 1H, Cquino), 8.56–8.58 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O): δ 11.92 (CH3), 20.44, 24.66, 29.18, 32.99 (CH2), 45.46 (SCH), 59.82 (NCH2), 116.27 (Cquino), 116.85 (Cquino), 125.03 (Cquino), 127.07 (Cquino), 128.89 (Cquino), 133.88 (Cquino), 136.59 (Cquino), 143.54 (Cquino), 163.60 (Cquino). Anal. Calcd for C16H20NClS: C 65.40, H 6.86, Cl 12.06, N 4.77, S 10.91. Found: C 65.57, H 7.02, Cl 12.57, N 4.93, S 11.42. 2-Hexyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium chloride (6). A solution of sulfuryl chloride (0.052 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 chloride 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 CCl4 and dried in vacuum, giving product 6 (0.097 g, 100% yield) as a light-yellow oil. 1 H–NMR (400 MHz, D2O): δ 0.79–0.82 (m, 3H, CH3), 1.21–1.24 (m, 4H, CH2), 1.29–1.32 (m, 2H, CH2), 1.40–1.45 (m, 2H, CH2), 1.82–1.89 (m, 1H, CH2), 1.92–1.99 (m, 1H, CH2), 4.49–4.53 (m, 1H, SCH), 5.00 (dd, J 13.0, 6.3 Hz, 1H, NCH2), 5.25 (dd, J 13.0, 8.7 Hz, 1H, NCH2), 7.74–7.79 (m, 2H, Cquino), 7.94–7.96 (m, 1H, Cquino), 8.00–8.03 (m, 1H, Cquino), 8.09–8.11 (m, 1H, Cquino), 8.59–8.61 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O): δ 12.03 (CH3), 20.55, 24.90, 26.60, 29.49, 33.03 (CH2), 45.47 (SCH), 59.86 (NCH2), 116.31 (Cquino), 116.87 (Cquino), 124.98 (Cquino), 126.61 (Cquino), 128.94 (Cquino), 133.79 (Cquino), 137.84 (Cquino), 143.59 (Cquino), 165.00 (Cquino). Anal. Calcd for C17H22NClS: C 66.32, H 7.20, Cl 11.52, N 4.55, S 10.42. Found: C 66.58, H 7.39, Cl 11.88, N 4.72, S 10.90. 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 CCl4 and dried in vacuum, giving product 7 (0.114 g, 99% yield) as an orange oil. 1 H–NMR (400 MHz, D2O): δ 0.73 (t, J 6.8 Hz, 3H, CH3,), 1.15–1.24 (m, 4H, CH2), 1.30– 1.42 (m, 2H, CH2), 1.77–1.92 (m, 2H, CH2), 4.40–4.47 (m, 1H, SCH), 5.02 (dd, J 12.9, 6.3 Hz, 1H, NCH2), 7.34 (d, J 12.9, 8.8 Hz, 1H, NCH2), 7.65–7.71 (m, 2H, Cquino), 7.86–7.89 (m, 1H, Cquino), 7.92–7.96 (m, 1H, Cquino), 8.01–8.03 (m, 1H, Cquino), 8.51–8.53 (m, 1H, Cquino). Molecules 2021, 26, 4844 9 of 14

13 C–NMR (101 MHz, D2O): δ 14.14 (CH3), 22.65, 26.89, 31.38, 35.20 (CH2), 47.67 (SCH), 62.09 (NCH2), 118.56 (Cquino), 119.56 (Cquino), 127.30 (Cquino), 129.20 (Cquino), 131.09 (Cquino), 136.00 (Cquino), 145.72 (Cquino). Anal. Calcd for C16H20NBrS: C 56.80, H 5.96, Br 23.62, N 4.14, S 9.48. Found: C 57.02, H 6.21, Br 23.98, N 4.40, S 9.91. 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 CCl4 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. 1 2-Butyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium bromide (8). H–NMR (400 MHz, D2O): δ 0.80–0.87 (m, 3H, CH3), 1.28–1.52 (m, 4H, CH2), 1.83–1.92 (m, 1H, CH2), 1.94–2.01 (m, 1H, CH2), 4.52 (dd, J 8.3, 6.4 Hz, 1H, SCH), 5.05 (dd, J 13.0, 6.4 Hz, 1H, NCH2), 5.30 (dd, J 13.0, 8.3 Hz, 1H, NCH2), 7.71–7.79 (m, 2H, Cquino), 7.91–7.93 (m, 1H, Cquino), 7.97–8.02 (m, 1H, Cquino), 8.05–8.07 (m, 1H, Cquino), 8.54–8.56 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O) (multiplicities are given based on the proton-coupled 13 C-NMR spectrum): δ 10.36 (q, CH3), 18.80, 25.69, 31.25 (t, CH2), 43.97 (d, SCH), 58.35 (t, NCH2), 114.80 (d, Cquino), 115.37 (d, Cquino), 123.40 (d, Cquino), 125.58 (s, Cquino), 127.34 (d, Cquino), 132.40 (d, Cquino), 134.97 (s, Cquino), 141.99 (d, Cquino), 162.08 (s, Cquino). 1 1-Butyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium bromide (10). H–NMR (400 MHz, D2O): δ 0.80–0.87 (m, 3H, CH3), 1.28–1.52 (m, 4H, CH2), 1.58–1.67 (m, 1H, CH2), 1.94–2.01 (m, 1H, CH2), 3.79 (d, J 12.1 Hz, 1H, SCH2), 5.02 (dd, J 12.1, 8.3 Hz, 1H, SCH2), 5.96 (t, J 9.4 Hz, 1H, NCH), 7.71–7.79 (m, 2H, Cquino), 8.00–8.04 (m, 2H, Cquino), 8.05–8.07 (m, 1H, Cquino), 8.54–8.56 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O) (multiplicities are given based on the proton-coupled 13 C-NMR spectrum): δ 10.36 (q, CH3), 18.95, 24.13, 26.85 (t, CH2), 30.99 (t, SCH2), 66.61 (d, NCH), 115.10 (d, Cquino), 115.55 (d, Cquino), 123.42 (d, Cquino), 125.60 (s, Cquino), 127.67 (d, Cquino), 132.39 (d, Cquino), 134.98 (s, Cquino), 141.97 (d, Cquino), 161.66 (s, Cquino). Anal. Calcd for C15H18NBrS: C 55.56, H 5.59, Br 24.64, N 4.32, S 9.89. Found: C 55.89, H 5.78, Br 24.91, N 4.60, S 10.25. 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 CCl4 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. 2-Hexyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium bromide (9). 1H–NMR (400 MHz, DMSO- d6): δ 0.80–0.84 (m, 3H, CH3), 1.26–1.32 (m, 6H, CH2), 1.36–1.51 (m, 2H, CH2), 1.84–1.99 (m, 2H, CH2), 4.59–4.63 (m, 1H, SCH), 5.30–5.34 (m, 1H, NCH2), 5.45–5.49 (m, 1H, NCH2), 7.85–7.89 (m, 1H, Cquino), 8.12–8.15 (m, 1H, Cquino), 8.20–8.25 (m, 1H, Cquino), 8.28–8.30 (m, 1H, Cquino), 8.32–8.37 (m, 1H, Cquino), 8.96–8.98 (m, 1H, Cquino). 13 C–NMR (101 MHz, DMSO-d6): δ 13.93 (CH3), 21.99, 26.40, 28.23, 31.02, 34.21 (CH2), 46.57 (SCH), 61.17 (NCH2), 118.80 (Cquino), 119.03 (Cquino), 126.28 (Cquino), 128.16 (Cquino), 130.06 (Cquino), 134.78 (Cquino), 137.90 (Cquino), 144.62 (Cquino), 164.46 (Cquino). Molecules 2021, 26, 4844 10 of 14

1-Hexyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium bromide (11). 1H–NMR (400 MHz, DMSO-d6): δ 0.80–0.84 (m, 3H, CH3), 1.26–1.32 (m, 4H, CH2), 1.36–1.51 (m, 2H, CH2), 1.59–1.76 (m, 2H, CH2), 3.84–3.97 (m, 2H, CH2), 4.18–4.22 (m, 1H, SCH2), 4.36–4.42 (m, 1H, SCH2), 6.21–6.25 (m, 1H, NCH,), 8.12–8.15 (m, 1H, Cquino), 8.20–8.25 (m, 1H, Cquino), 8.28–8.32 (m, 2H, Cquino), 8.32–8.37 (m, 1H, Cquino), 8.96–8.99 (m, 1H, Cquino). 13 C–NMR (101 MHz, DMSO-d6): δ 24.70 (CH3), 26.35, 27.88, 28.38, 29.96, 31.02 (CH2), 35.96 (SCH2), 68.74 (NCH), 118.70 (Cquino), 119.05 (Cquino), 126.30 (Cquino), 126.73 (Cquino), 130.52 (Cquino), 135.06 (Cquino), 136.76 (Cquino), 144.84 (Cquino), 164.30 (Cquino). Anal. Calcd for C17H22NBrS: C 57.95, H 6.29, Br 22.68, N 3.98, S 9.10. Found: C 58.16, H 6.46, Br 23.01, N 4.24, S 9.49.

3.3. Synthesis of Compounds 12–15 by the Reactions of Quinolinesulfenyl Chloride 2 and Bromide 3 with Cycloalkenes

8,9,10,10a-Tetrahydro-7aH-cyclopenta[4,5][1,3]thiazolo[3,2-a]quinolin-11-ium chloride (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 CCl4 and dried in vacuum, giving the product 12 (0.153 g, 81% yield) as a brown oil. 1 H–NMR (400 MHz, D2O): δ 1.83–1.90 (m, 2H, CH2), 2.06–2.17 (m, 2H, CH2), 2.23–2.31 (m, 1H, CH2), 2.47–2.57 (m, 1H, CH2), 4.91–4.95 (m, 1H, SCH), 6.03–6.07 (m, 1H, NCH,), 7.62–7.65 (m, 1H, Cquino), 7.69–7.73 (m, 1H, Cquino), 7.88–7.90 (m, 1H, Cquino), 7.94–7.99 (m, 1H, Cquino), 8.02–8.04 (m, 1H, Cquino), 8.47–8.50 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O): δ 23.77, 34.60, 34.76 (CH2), 49.78 (SCH), 75.12 (NCH), 117.67 (Cquino), 118.06 (Cquino), 126.76 (Cquino), 128.28 (Cquino), 130.42 (Cquino), 134.90 (Cquino), 137.50 (Cquino), 144.69 (Cquino), 165.39 (Cquino). Anal. Calcd for C14H14NClS: C 63.74, H 5.35, Cl 13.44, N 5.31, S 12.16. Found: C 63.91, H 5.59, Cl 13.79, N 5.52, S 12.52. 8,9,10,10a-Tetrahydro-7aH-cyclopenta[4,5][1,3]thiazolo[3,2-a]quinoli-11-ium bromide (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 CCl4 and dried in vacuum, giving product 13 (0.117 g, 100% yield) as a light-yellow oil. 1 H–NMR (400 MHz, D2O): δ 1.76–1.82 (m, 2H, CH2), 1.90–1.95 (m, 1H, CH2), 2.07–2.12 (m, 1H, CH2), 2.19–2.27 (m, 1H, CH2), 2.41–2.51 (m, 1H, CH2), 4.85–4.89 (m, 1H, SCH), 5.92–5.96 (m, 1H, NCH), 7.55–7.64 (m, 2H, Cquino), 7.78–7.80 (m, 1H, Cquino), 7.86–7.94 (m, 2H, Cquino), 8.38–8.40 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O): δ 23.79, 34.67, 34.81 (CH2), 49.82 (SCH), 75.02 (NCH), 117.72 (Cquino), 118.03 (Cquino), 126.50 (Cquino), 128.29 (Cquino), 130.32 (Cquino), 134.94 (Cquino), 137.02 (Cquino), 144.54 (Cquino), 165.33 (Cquino). Anal. Calcd for C14H14NBrS: C 54.55, H 4.58, Br 28.92, N 4.54, S 10.40. Found: C 54.69, H 4.82, Br 26.34, N 4.71, S 10.86. 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, Molecules 2021, 26, 4844 11 of 14

0.98 mmol) in methylene chloride (5 mL) was added dropwise, and the reaction mixture was stirred for 100 h at room temperature. The solvent was removed by a rotary evaporator. The residue was washed with CCl4 and dried in vacuum, giving product 14 (0.119 g, 100% yield) as a light-yellow oil. 1 H–NMR (400 MHz, acetone-d6): δ 1.53–1.72 (m, 4H, CH2), 1.76–1.87 (m, 3H, CH2), 1.93–1.99 (m, 1H, CH2), 2.08–2.16 (m, 2H, CH2), 2.28–2.41 (m, 2H, CH2), 4.51–4.54 (m, 1H, SCH), 4.73–4.78 (m, 1H, CHCl), 7.44–7.45 (m, 1H, Cquino), 7.55–7.57 (m, 1H, Cquino), 7.75–7.79 (m, 1H, Cquino), 7.92–7.94 (m, 1H, Cquino), 8.09–8.13 (m, 1H, Cquino), 8.25–8.27 (m, 1H, Cquino). 13 C–NMR (101 MHz, acetone-d6): δ 24.10 (CH2), 26.00 (CH2), 26.80 (CH2), 27.87 (CH2), 32.14 (CH2), 32.73 (CH2), 53.10 (SCH), 66.44 (CHCl), 122.16 (Cquino), 127.03 (Cquino), 128.02 (Cquino), 128.99 (Cquino), 130.77 (Cquino), 131.17 (Cquino), 131.64 (Cquino), 138.50 (Cquino), 159.57 (Cquino). Anal. Calcd for C17H20NClS: C 66.76, H 6.59, Cl 11.59, N 4.58, S 10.48. Found: C 66.93, H 6.71, Cl 11.93, N 4.79, S 12.00. 7a,8,9,10,11,12,13,13a-Octahydrocyclocta[4,5][1,3]thiazolo[3,2-a]quinolin-14-ium bromide (15). A solution of bromide (0.074 g, 0.46 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.075 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 bromide was added dropwise to a solution of cyclooctene (0.102 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 CCl4 and dried in vacuum, giving product 15 (0.120 g, 77% yield) as a light-yellow oil. 1 H–NMR (400 MHz, D2O): δ 1.24–1.39 (m, 3H, CH2), 1.59–1.71 (m, 3H, CH2), 1.81–1.91 (m, 3H, CH2), 1.99–2.08 (m, 1H, CH2), 2.11–2.25 (m, 1H, CH2), 2.35–2.44 (m, 1H, CH2), 4.61–4.67 (m 1H, SCH), 5.87–5.92 (m, 1H, NCH), 7.66–7.72 (m, 2H, Cquino), 7.80–7.83 (m, 1H, Cquino), 7.96–8.01 (m, 1H, Cquino), 8.03–8.06 (m, 1H, Cquino), 8.50–8.52 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O): δ 23.20, 23.76, 24.10, 25.66, 26.11, 27.75 (CH2), 50.93 (SCH), 71.74 (NCH), 117.64 (Cquino), 117.72 (Cquino), 126.78 (Cquino), 127.96 (Cquino), 130.37 (Cquino), 134.98 (Cquino), 136.63 (Cquino), 144.54 (Cquino), 162.63 (Cquino). Anal. Calcd for C17H20NBrS: C 58.28, H 5.75, Br 22.81, N 4.00, S 9.15. Found: C 58.61, H 6.02, Br 23.14, N 4.31, S 9.71.

3.4. Synthesis of Compounds 16 and 17 by the Reactions of Quinolinesulfenyl Chloride 2 with Styrene and Isoeugenol

1-Phenyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium chloride (16). A solution of sulfuryl chloride (0.047 g, 0.34 mmol) in methylene chloride (5 mL) was added dropwise to a solution of 2-mercaptoquinoline (0.056 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 chloride was added dropwise to a solution of styrene (0.072 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 CCl4 and dried in vacuum, giving product 16 (0.104 g, 100% yield) as a yellow oil. 1 H–NMR (400 MHz, D2O): δ 3.50–3.54 (m, 1H, SCH2), 4.31–4.36 (m, 1H, SCH2), 6.89–6.95 (m, 2H, Ar), 6.93–6.97 (m, H, NCH), 7.04–7.12 (m, 3H, Ar), 7.40–7.44 (m, 1H, Cquino), 7.49–7.56 (m, 2H, Cquino), 7.78–7.82 (m, 1H, Cquino), 7.85–7.90 (m, 1H, Cquino), 8.52–8.56 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O): δ 37.87 (SCH2), 71.06 (NCH), 118.10 (Cquino), 118.30 (Cquino), 125.39 (Ar), 126.73 (Cquino), 128.42 (Cquino), 129.51 (Ar), 129.65 (Ar), 130.47 (Cquino), 135.07 (Cquino), 135.21 (Cquino), 137.12 (Ar), 145.88 (Cquino), 166.15 (Cquino). Anal. Calcd for C17H14NClOS: C 68.10, H 4.71, Cl 11.82, N 4.67, S 10.70. Found: C 68.34, H 4.97, Cl 12.12, N 4.81, S 11.20. trans-1-(Hydroxy-3-methoxyphenyl)-2-methyl-1,2-dihydro[1,3]thiazolo[3,2-a]quinolin-10-ium chloride (17). A solution of sulfuryl chloride (0.078 g, 0.57 mmol) in methylene chloride (5 mL) Molecules 2021, 26, 4844 12 of 14

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 CCl4 and dried in vacuum, giving product 17 (0.166 g, 80% yield) as an orange oil. 1 H–NMR (400 MHz, D2O): δ 1.70 (d, J 7.0 Hz, 3H, CH3), 3.76 (s, 3H, O;CH3), 4.07–4.12 (m, 1H, SCH), 6.21 (d, J 8.2 Hz, 1H, NCH), 6.56–6.60 (m, 1H, Ar), 6.66 (s, 1H, Ar), 6.91 (s, 1H, Ar), 7.62–7.66 (m, 1H, Cquino), 7.74–7.79 (m, 2H, Cquino), 7.93–7.96 (m, 1H, Cquino), 8.08–8.11 (m, 1H, Cquino), 8.72–8.75 (m, 1H, Cquino). 13 C–NMR (101 MHz, D2O): δ 22.38 (CH3), 50.80 (SCH), 55.77 (OCH3), 77.37 (NCH), 109.61 (Ar), 115.50 (Ar), 117.48 (Ar), 118.08 (Cquino), 118.51 (Cquino), 126.83 (Cquino), 126.94 (Ar), 128.42 (Cquino), 130.42 (Cquino), 134.97 (Cquino), 137.59 (Cquino), 145.78 (Ar), 145.86 (Cquino), 148.07 (Ar), 164.96 (Cquino). Anal. Calcd for C19H18NClO2S: C 63.41, H 5.04, Cl 9.85, N 3.89, S 8.91. Found: C 63.63, H 5.21, Cl 10.17, N 4.00, S 9.27.

4. 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.

Supplementary Materials: The following are available online. Supporting Information ﬁle: examples of 1H- and 13C-NMR spectra of the obtained compounds. Author Contributions: Conceptualization and the paper preparation, V.A.P.; methodology and research experiments, R.S.I.; data curation and supervision, S.V.A. All authors have read and agreed to the published version of the manuscript. Funding: This research received no external funding. Institutional Review Board Statement: Not applicable. Informed Consent Statement: Not applicable. Molecules 2021, 26, 4844 13 of 14

Data Availability Statement: Data is available in this article and Supplementary Materials. Acknowledgments: The authors thank Baikal Analytical Centre SB RAS for providing the instru- mental equipment for structural investigations. Conﬂicts of Interest: The authors declare no conﬂict of interest. Sample Availability: Samples of the compounds are not available from the authors.

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