Synthesis of Fluorinated and Fluoroalkylated Heterocycles Containing at Least One Sulfur Atom via Cycloaddition Reactions

Fluorinated heterocycles constitute an important group of organic compounds with a rapidly growing number of applications in such areas as medicinal chemistry, agrochemicals production, polymer chemistry, as well as chemistry of advanced materials. In the latter case, fluorinated thiophenes are considered as a lead class of compounds with numerous spectacular applications. On the other hand, cycloaddition reactions offer a superior methodology for stereo-chemically controlled synthesis of heterocycles with a diverse ring size and a variable number of heteroatoms. A comprehensive review of methods based on cycloaddition reactions and applied for construction of fluorinated and/or fluoroalkylated S-heterocycles has not yet been published. For this reason, the main goal of the presented review was to fill the existing gap and to summarize the results published over last six decades. In this context, the [3+2]- and [4+2]-cycloadditions (Huisgen reactions, and Diels–Alder reactions, respectively) are of special importance. Some questions related to the discussed mechanisms of cycloaddition processes observed in reactions with electron deficient, fluorinated substrates (dipolarophiles and dienophiles), and electron-rich sulfur containing counter partners, are of fundamental importance for the development of interpretations of organic reaction mechanisms.


Introduction
In recent decades, we have witnessed the growing importance of fluorinated organic compounds in practically all areas of organic synthesis, and the elaboration of new methods for the preparation of fluorinated heterocycles belongs to the challenging problems of current organic chemistry [1,2]. It is well known that one of the best methods for the construction of the non-aromatic, heterocyclic compounds are cycloaddition reactions, and those most frequently applied are [2+1]-, [2+2]-, [3+2]-and [4+2]-cycloadditions. Starting with properly designed components containing fluorine (thiocarbonyl compounds, carbenes, 1,3-dipoles, dienes), the synthesis of a fluorinated S-heterocycle can be achieved via a cycloaddition step or by further transformation of the initially obtained cycloadduct. The presence of electron-withdrawing fluoroalkyl groups enhance the reactivity of both dipolarophiles and dienophiles. Similarly, fluorinated 1,3-dipoles display high reactivity towards electron-rich dipolarophiles and [3+2]-cycloadditions performed with thiocarbonyl dipolarophiles are of special importance for the construction of fluoroalkylated sulfur heterocycles. For materials chemistry, the development of methods for the synthesis and studies on the reactivity of fluorinated heterocycles are of great interest. In a recent comprehensive review, the methods applied for syntheses of diverse heterocycles bearing fluorine atoms and/or fluoroalkylated substituents were summarized. However, sulfur-containing heterocycles are inadequately represented, mainly by fluorothiazole and fluorobenzothiazole derivatives [3]. The goal of the present work is an overview of the methods which are of practical importance for the preparation of fluorine-containing sulfur heterocycles upon exploration of cycloaddition reactions as basic tools for the construction of the heterocyclic core.
Heating of perfluoropropenoxide in the presence of difluorothiophosgene (thiocarbonyl fluoride) or trifluorothioacetyl fluoride in a closed reactor under pressure at 175 • C yielded the corresponding perfluorinated thiiranes 2e and 2f, respectively, in fair yields ( Figure 1) [6]. The same method was applied for the preparation of chlorotrifluorothiirane (2g) [6,7].
In the case of trifluoromethyl dithiochloroformate, the thermal reaction with perfluoropropenoxide leads to the corresponding vinyl sulfide 4c, formed via spontaneous desulfurization of the intermediate thiirane [8]. In all of these reactions, thermal decomposition of perfluoropropenoxide leads to difluorocarbene as the reactive intermediate. A superior method for the preparation of fluorinated thiiranes is the 1,3-dipolar electrocyclization (1,3-DE) of transient, fluorinated thiocarbonyl S-methanides 7, generated from the corresponding 1,3,4-thiadiazolines 6 (Scheme 3, Table 1). The latter heterocycles are smoothly formed via [3+2]-cycloaddition of a thiocarbonyl compound as dipolarophile with diazomethane derivatives 5. The fluorine atom or a fluoroalkyl group may originate either from one or from both reaction partners.

Thiolanes (Tetrahydrothiophenes)
The thiolane ring constitutes a core fragment in many compounds demonstrating diverse types of biological activities and they have found numerous therapeutic applications [27][28][29]. In spite of numerous commercial offers for their supply in large quantities, there are only a limited number of reports available on efficient laboratory synthesis of the 2-or 3-trifluoromethylated thiolanes. Obviously, in this situation the studies that are focused on the exploration of the cycloaddition methodology for the synthesis of this class of S-heterocycles remain the most relevant.
An unexpected formation of 1,3-dithiolanes 31 was observed upon treatment of perfluoropropene with elemental sulfur in the presence of vinyl O-alkyl ethers in DMF solution at 45-65 • C using CsF as a catalyst. Under the same conditions, dihydrofuran gave the bicyclic 1,3-dithiolane 32 in a 58% yield as a mixture of cisand trans-isomer (Scheme 13) [17].
In a recent publication, an alternative mechanism for the formation of 1,2-dithiole derivatives via sulfurization of 2,3-diarylcyclopropenthiones 37 with elemental sulfur in the presence of catalytic amounts of tetrabutylammonium fluoride (TBAF) was formulated to explain the role of the fluoride anion as an activator. This mechanism corresponds to a formal [2+3]-cycloaddition of elemental sulfur (as S 2 ) with the congested three-membered ring (Scheme 17) [35]. Similar reactions of 2,3-diarylcyclopropenethiones, without explanation of the crucial role of the fluoride anion, have also been published [36,37]. It has to be stressed that the fluoride anion-mediated sulfurization of 2,3-diarylcyclopropenthiones 37 should be considered as a useful method for the synthesis of 1,2-dithiole-3-thiones of type 38. The latter sulfur heterocycles are of importance as biologically active compounds, and in a recent review, the method of their synthesis as well as diverse transformations have been summarized [38]. Analogously, fluorinated nitrile imines 42b react with monomeric aryl/hetaryl substituted thiochalcones yielding 2-styryl-substituted 1,3,4-thiazolidines 45 in a chemo-and regioselective manner (Scheme 19, equation below) [44].

1,3-Oxathiolanes
Remarkably, cycloadditions of non-fluorinated nitrile imines with thiochalcones have not been studied to the date. However, chalcones were reported to react with non-fluorinated nitrile imines upon selective involvement of the C=C bond in [3+2]cycloaddition reactions leading to pyrazole derivatives [45,46].
An interesting and rather unexpected observation was made in the course of studying the [3+2]-cycloaddition of thiocarbonyl ylide 46 to 1,2-bis(trifluoromethyl)-ethene 1,2-dicarbonitrile. Along with the expected five-membered product, i.e., the thiolane 47, formation of a seven-membered thiazepine derivative 48, with a ketenimine fragment incorporated into the heterocyclic ring, occurred predominantly (ratio 87:22) (Scheme 20) [47]. Its reaction with methanol gave the spirocyclic thiazepine derivative 49 as a mixture of two diastereoisomers. Other sterically crowded thiocarbonyl S-methanides that were derived, e.g., from 2,2,6,6-tetramethylcyclohexanethione, reacted with electron deficient, fluorinated ethylenes analogously, yielding seven-membered products. Some of them were isolated as crystalline materials and their structures, as well as that of some products of their further conversions, were unambiguously confirmed by X-ray measurements [48,49]. The formation of these unusual N,S-heterocycles was explained by the non-concertedness of the expected cycloaddition process and formation of stabilized zwitterionic intermediates of type 50, which competitively can undergo either 1,5-or 1,7-cyclization yielding the five-membered thiolane 47 or the seven-membered 1,3-thiazepine 48, respectively. The unusual stability of the heterocumulene (ketenimine) unit -N=C=C-was rationalized by 'the magic effect' of the trifluoromethyl group located at the neighboring C-atom [50]. Some chemical properties of 48 will be described in Section 6.

Thiopyran Derivatives
Synthetic methodologies based on the hetero-Diels-Alder reaction are widely employed in organic chemistry. Using heterodienes or heterodienophiles in the [4+2]-cycloaddition reaction makes it possible to construct complex natural products or their analogues containing a six-membered heterocyclic framework. Thiocarbonyl compounds are well-known representatives of heterodienophiles which, for example, found applications for the preparation of thioglycoside derivatives [53] or thiashikimic acid [54]. Electron-withdrawing groups in α-position to the thiocarbonyl group lower the LUMO energy of the heterodienophile and facilitate the cycloaddition. Therefore, the polyfluoroalkyl thiocarbonyl compounds are excellent dienophiles and can be used for the preparation of diverse sulfurcontaining heterocycles.
The pioneering works of W. Middleton described the first examples of the Diels-Alder reactions of trifluoroacetyl fluoride [64] and perfluorinated thioketones [65] with 1,3-dienes. These reactions were studied in more detail much later. The cycloaddition of the chloride and fluoride of polyfluoroalkane thiocarboxylic acids with 1,3-dienes proceeded rapidly at 0 • C. The stability of the cycloadducts formed depended on the length of the polyfluoroalkyl chain. Trifluorothioacetyl chloride afforded a relatively stable adduct 66, which was isolated and characterized spectroscopically (Scheme 25). Chlorides with longer chains gave directly 2H-thiopyrans 67 after the evaporation of the reaction mixture. Dehydrochlorination of the CF 3 -substituted thiopyran was achieved only after heating at 100 • C [66]. The thiopyrans obtained turned out to be convenient starting compounds for the 2H-thiopyrans 67 preparation of the first 2-polyfluoroalkyl-substituted thiopyrylium salts, which in turn can efficiently be used for the synthesis of fluorinated thiopyranosides and nucleosides [66]. Over the past two decades, the factors affecting the reactions of polyfluoroalkane thiocarboxylic acid esters with 1,3-dienes of various structures have been studied in detail and diverse synthetic applications of the obtained derivatives of dihydrothiopyrans have been considered [32,[68][69][70]. As a result of these reactions, at least one new stereogenic center was generated by the Diels-Alder addition. Therefore, the application of a proper chiral thionoester could influence the stereochemical outcome of the cycloaddition and could be used in the construction of optically active compounds.
The preparation of a series of thionoesters 72 with various optically active substituents, which can serve as chiral auxiliaries in asymmetric syntheses, allowed the observation of the first examples of asymmetric induction in the thia-Diels-Alder cycloaddition involving polyfluoroalkane thionocarboxylates, which provided 2-fluoroalkyl-2-alkylsulfanyl-3,6dihydro-2H-thiopyrans 73 in good yields but a low to modest de of 6-60% (Scheme 27, Table 2) [70]. The influence of the nature of the diene and dienophile and the reaction conditions on the asymmetric induction of the cycloaddition have been examined. It has been found that electronic factors have a minimal effect on the stereoselectivity of the cycloaddition. Quantum chemistry (DFT) calculations indicate that the differences in the activation energies are larger than the relative energies of the cyclic adducts. This result allows the conclusion that the stereoselectivity of the formation of thiopyrans 73 is kinetically driven: the observed de refers to different free-activation energies inherent to the corresponding transition states.
Much less is known about the reactions of derivatives of polyfluoroalkane thionocarboxylic acid such as the O-esters and amides. However, even the available data allow a conclusion to be drawn about the significant effect of the nature of the heteroatom in the Alk F C(S)XR (X = S,O,N) on the rate of the cycloaddition reaction. Thus, in the case of dithioethers 72a-d, the reaction with 2,3-dimethylbuta-1,3-diene proceeds at room temperature, while a similar reaction with the ester 72e requires vigorous heating [70]. Alkylamides of polyfluoroalkane thiocarboxylic acids 74a-d do not react with 1,3dienes even after many hours of heating in a sealed ampoule. A successful reaction to give 3,6-dihydro-2H-thiopyrans 75a-d was ensured only by microwave activation in Nmethylpyrrolidone (NMP) solution [71] or using an N-acylated thioamide derivative 76 (Scheme 28) [69]. The positive results observed in the last cases, leading to products 77, was explained by the electron-withdrawing influence of the amide substituent on the thio-carbonyl group. The high activity of hexafluorothioacetone in cycloaddition reactions with 1,3-dienes is explained by the influence of the electron-withdrawing trifluoromethyl groups. In the case of thioacid derivatives, the opposite effect is observed. The electronegativity of the nitrogen and oxygen atoms is significantly higher than that of sulfur, but the rates of cycloaddition reactions are lower. Perhaps the reason for this unexpected effect may be the interaction of the sulfur-carbon multiple bond orbitals with the orbitals of oxygen or nitrogen heteroatoms, which is not so significant in the case of the sulfur atom due to the larger size of the latter. The thermal reaction of bis(trifluoromethyl)sulfine (85) with thiophosgene at 110 • C leads to 3,3,6,6-tetrakis(trifluoromethyl)-1,2,4,5-tetrathiane (86) as a minor product (3%) resulting from the thermal decomposition of the initially formed sulfenylchloride 87, which in this case was isolated as the major product (Scheme 31) [74]. The decomposition of 2-diazohexafluoropropane (88) in carbon disulfide at 150-175 • C produced the tetrathiane 89 in trace amounts, presumably formed via the addition of bis(trifluoromethyl)carbene to carbon disulfide and the subsequent dimerization of the adduct (Scheme 31) [26].

Seven-Membered, Sulfur-Containing Heterocycles
Information on the syntheses of sulfur-and fluorine-containing seven-membered heterocycles via a stepwise [4+3]-cycloaddition reaction is fragmentary. The first example of such a reaction, leading to a trifluoromethylated, seven-membered N,S-heterocycle, was discussed in Section 4.6 (Scheme 20).
A surprising dimerization of the ketenimine 48b occurred in acetonitrile at room temperature in the presence of KF as a catalyst. The formation of two diastereoisomers of product 104 in a ratio of 1:1 was explained by the fluoride ion-initiated reaction mechanism via intermediate 105 (Scheme 36) [78]. Scheme 36. Base-catalyzed dimerization of the seven-membered, cyclic ketenimine 48b initiated by fluoride anion-assisted, heterocyclic ring-opening.

Conclusions and Outlook
The biological utility of fluorinated organic compounds [80], including sulfur heterocycles, e.g., thiolanes [32,81] and benzothiazoles [82], is demonstrated by recently published reviews and original works. Without a doubt, fluorinated and fluoroalkylated thio-phenes are the most prominent S-heterocycles, widely applied in diverse areas of materials chemistry [83][84][85][86]. On the other hand, some fluorinated S-heterocycles, e.g., S-(trifluoromethyl)dibenzothiophenium salts (so called "Umemoto reagents"), are of great importance for the current organic synthesis as fluorinating/fluoroalkylating reagents [87]. In general, fluorine-containing S-heterocycles have rarely been prepared by the direct fluorination/fluoroalkylation of the parent systems and one of the important issues is the regioselectivity of these processes, which complicates the preparation of pure products. For all these reasons, the exploration of highly selective cycloaddition reactions, based on thiocarbonyl dipolarophiles or dienophiles, known as superdipolarophiles [88] and superdienophiles [60], respectively, offer a perfect methodology for the solution of this problem. Thiocarbonyl compounds are also perfect trapping reagents for carbenes in [2+1]-cycloadditions leading to fluorinated thiiranes or their desulfurized derivatives [4]. Remarkably, difluorocarbene reacts with the C=S bond via carbophilic attack, and in these reactions, it resembles the nucleophilic dimethoxycarbene [89] and not the electrophilic dichloro-or dibromocarbene [90].
The present review is aimed at presenting for the first time the synthetic potential of diverse cycloaddition reactions in practical applications for the selective preparation of fluorinated and fluoroalkylated S-heterocycles from three-membered thiiranes to sevenmembered N,S-rings. In addition, the review should be considered as a supplement to the two, recently published reviews on the [4+2]-cycloadditions performed with fluorinated dienes or dienophiles leading, via multi-step mechanisms, to aromatic/heteroaromatic six-membered carbo-and heterocyclic products [91], as well as on the thia-Diels-Alder reactions based on the exploration of sulfur-containing reagents [92]. preparation of the manuscript. Y.S. thanks the Rector of the University of Lodz for financial support within a special stipend for Ukrainian researchers (2022).

Conflicts of Interest:
Authors declare no conflict of interest.