Chemistry of Fluorinated Oxadiazoles and Thiadiazoles

Abstract

A literature survey of the chemistry of fluorinated oxadiazoles and thiadiazoles is presented. The core part on synthetic procedures is given by type of heterocycle and includes recent developments up to the end of 2012. Reactivity is discussed when induced by the presence of the fluorinated moiety. Selected examples of bioactive compounds and applications are illustrated.

1 Introduction

Oxadiazoles and thiadiazoles are a subset of heteroaromatic compounds which are widely applied in many fields, and their chemical and physicochemical properties can be appropriately tuned by the introduction of fluorine or fluorinated groups. This is one of the main reasons of the increasing development of synthetic methodologies leading to targeted fluorinated heterocycles. Additionally, the presence of the fluorinated moiety opens the way to new fluorine-induced reactivity with respect to corresponding non-fluorinated systems [1]. Target fluorinated oxadiazoles and thiadiazoles find applications in materials and fluoropolymer science and, in the case of biologically active compounds, their use as agrochemicals or pharmaceuticals is also common. Four types of compounds can be considered under the general classification “fluorinated heterocycles” in this chapter: (i) compounds where the fluorine atom is directly linked to the heterocyclic core; (ii) compounds where the heterocycle is substituted with a mono-, poly- or perfluoroalkyl group; (iii) compounds where the heterocycle is substituted with a mono-, poly- or perfluoroaryl group; (iv) compounds where the fluorine substituent is far from the heterocyclic core. Although the latter category may seem too generally applicable, in several cases the presence of a fluorinated group not directly linked to the heterocyclic core can strongly affect the heterocyclic moiety chemical behaviour. Most of the literature refers to (per)fluoroalkyl and (per)fluoroaryl derivatives and reported examples have been selected on the basis of general interest or major breakthrough. Our efforts have been devoted to present an update until the end of 2012, mainly considering publications appeared in the last two decades. Previous papers have been cited when of general interest for the synthetic approach.

2 Synthetic Routes to Fluorinated Oxadiazoles and Thiadiazoles

2.1 1,2,3-Oxadiazoles

With the exception of mesoionic compounds such as sydnone 1 (Fig. 1) [2], fluorinated 1,2,3-oxadiazole systems are rare and often included as structures in patent’s Markush, without sufficient experimental details [3].

Fig. 1

A reported example of fluorinated 1,2,3-oxadiazole system

2.2 1,2,4-Oxadiazoles

Fluorinated 1,2,4-oxadiazoles find their application in both the pharmaceutical industry and materials science. Recently, 3-substituted 5-pentafluorophenyl-1,2,4-oxadiazoles 2 (Fig. 2) have been used as fluorinated oxadiazole arylating reagents (FOXARs) for the attachment of fluorinated moieties to nucleophilic pendants of polymers [4] and macromolecules [5]. Fluorinated 1,2,4-oxadiazoles 3 (Fig. 2) have been employed as reagents to introduce the difluoromethylene moiety into organic compounds [6]. To date, despite the fact that 3- (or 5-) chloro- or bromo- derivatives are known, there is still no literature on the synthesis of 1,2,4-oxadiazoles bearing a fluorine atom directly linked to the oxadiazole ring.

Fig. 2

Examples of 1,2,4-oxadiazole reagents

The synthesis of fluorinated oxadiazoles can be achieved from open-chain fluorinated precursors through conventional heterocyclization reactions such as the amidoxime route (i in Scheme 1) and the cycloaddition route (ii in Scheme 1), both necessitating of a nitrile precursor [7].

Scheme 1

1,2,4-oxadiazole synthesis by (i) the amidoxime route; (ii) the cycloaddition route

2.2.1 The Amidoxime Route

The historical amidoxime route towards 1,2,4-oxadiazoles is still the most represented in the literature also for fluorinated structures. Oxadiazoles 12, bearing fluorinated groups at both the C(3) and C(5) can be obtained from the appropriate perfluoroalkyl amidoxime 11 and a fluorinated acylating reagent (Scheme 2). Similarly, from suitably fluorinated reagents, one can obtain oxadiazoles bearing the fluorinated group either at the C(3) or at C(5), respectively.

Scheme 2

Synthesis of 1,2,4-oxadiazoles bearing fluorinated groups at both the C(3) and C(5) by the amidoxime route

Pioneering work on this subject [8] reported the preparation of various perfluoro-alkylamidoximes 11 (R_F=CF₃, C₂F₅, C₃F₇, C₇F₁₅) and their acylation with perfluoro-acylchlorides (R_F ¹COCl) followed by cyclodehydration to produce 3,5-bis(perfluoroalkyl)-1,2,4-oxadiazoles 12 either symmetrically (R_F=R_F ¹) or unsymmetrically substituted. By following the same methodology, bis-oxadiazoles 14 (n = 3) could be obtained (Scheme 3) [8, 9].

Scheme 3

Synthesis of perfluoroalkylated bis-oxadiazoles 14 by the amidoxime route

Perfluoroalkyl substituted oxadiazoles joined by the annular 5,5′- positions can be obtained by using the appropriate diacyl chloride. For instance, in the reaction of amidoxime 11 with oxalyl chloride, the 5,5′-bis(1,2,4- oxadiazolyl) compound 15 is produced (Scheme 4) [8]. Furthermore, the corresponding O,O′-hexafluoroglutaryl diamidoxime 17 (n = 3) was isolated in acceptable yields by the reaction of amidoxime 16 and hexafluoroglutaryl chloride [10]. Subsequent dehydration by heating with phosphorus pentoxide gave the corresponding bis-oxadiazole 18 in good yields (Scheme 4).

Scheme 4

Bis-oxadiazoles 15 and 18 obtained by the amidoxime route followed by dehydration step with P₂O₅

Various 5-perfluoroalkyl-3-phenyloxadiazoles have been obtained from the direct reaction of benzamidoxime 16 (R=Ph) with perfluoroacylating reagents [10, 11]. Difluoromalonyl chloride and benzamidoxime directly gave the bis-oxadiazolyl-difluoromethane 18 (n = 1). Similarly, the reaction of difluoroaminodifluoroacetamidoxime 20 with perfluoroalkanoyl chlorides followed by dehydration of the resulting O-perfluoroacylamidoximes with P₂O₅ leads to 5-perfluoroalkyl-oxadiazoles 19. When heating amidoxime 20 with perfluorosuccinic acid and phosphorus pentoxide, the bis-oxadiazole 21 (n = 2) is obtained [12]. The same amidoxime 20 with oxalyl chloride will yield bis-oxadiazole 21 (n = 0) (Scheme 5) [13].

Scheme 5

Synthesis of perfluoroalkyl 1,2,4-oxadiazole 19 and bis-oxadiazole 21

5-Pentafluorophenyl-oxadiazoles of general formula 22 (Fig. 3) can be obtained directly from the reaction of the corresponding amidoximes and pentafluorobenzoyl chloride in refluxing toluene in the presence of pyridine [14].

Fig. 3

Examples of synthetically available FOXARs

Similarly, 3-benzoyl- 24 (R=Ph) [15] and 3-carboxyethyl-5-perfluoroalkyl-oxadiazole 24 (R=OEt) are prepared from amidoximes (23; R=Ph, OEt respectively) and the corresponding perfluoroalkanoyl chlorides (or anhydrides) (Scheme 6).

Scheme 6

Synthesis of 5-perfluoroalkyl 1,2,4-oxadiazole 24

4-(5-Perfluoroheptyl-1,2,4-oxadiazol-3-yl)pyridine or 3-(5-perfluoroheptyl-1,2,4- oxadiazole-3-yl)pyridine 26, have been obtained directly (in 90 and 70 % yields, respectively) from the acylation reaction of the corresponding nicotyl amidoxime and isonicotyl amidoxime (Scheme 7) [16]. From these derivatives, the corresponding N-methyl-pyridinium salts have been prepared for possible applications as Self-Organized Functional Organic Salts (SOFOS) [16].

Scheme 7

Synthesis of 3- and 4-(5-perfluoroheptyl-1,2,4-oxadiazol-3-yl)pyridine 26

The amidoxime route has been used for the synthesis of derivatives differently functionalized at C(5). Amidoxime 11 treated with trichloroacetic anhydride in hot trichloroacetic acid, lead to the corresponding 5-trichloromethyl- 1,2,4-oxadiazole 27. The latter, in the presence of nitrogen nucleophiles (ammonia, primary or secondary amines), undergoes an aminolysis reaction leading to 28 (Scheme 8) [17].

Scheme 8

Synthesis of 5-trichloromethyl- 1,2,4-oxadiazole 27 and its aminolysis leading to 28

Amidoximes also react with ethyl bromodifluoroacetate to give 5-(bromodifluoro-methyl)oxadiazoles 29 [18]. A series of difluoro alcohols such as 30 were obtained by an electron transfer process in the presence of aromatic aldehydes starting from compounds 29 (Scheme 9). The reactions occurs through an initial formation of a red colored charge-transfer complex between TDAE (donor) and bromo derivative 29 (acceptor). A temperature increase from −20 °C to rt allows to complete an electron transfer process producing difluoromethylene anion 31, which is stable enough to react with aromatic aldehydes, finally leading to the corresponding alcohols 30 [19].

Scheme 9

Synthesis of 5-(bromodifluoro-methyl)oxadiazoles 29 and difluoro alcohols 30

Nitriles themselves can be also used as acylating reagent for amidoximes in some cases. Subsequent heterocyclization involves loss of ammonia in the final step (Scheme 10). For this purpose, the reaction is carried out in the presence of an ammonia acceptor reagent (e. g. the perfluorocarboxylic acid, or an excess of the nitrile). For example, from the reaction of benzamidoxime with perfluoroalkylnitriles, a series of 5-perfluoroalkyl-1,2,4-oxadiazoles 35 can be obtained [20].

Scheme 10

Synthesis of 5-perfluoroalkyl-1,2,4-oxadiazoles 35

2.2.2 The Cycloaddition Route

Another general approach to the synthesis of fluorinated 1,2,4-oxadiazoles is based on the [3 + 2] cycloaddition between nitriles and nitrile oxides (each component of the reaction can contain the fluorinated moiety). Cycloaddition of the trifluoroacetonitrile oxide 37 produced the 3-trifluoromethyl-5-phenyl derivative 38 (Ar=Ph) (Scheme 11) [21]. Unfortunately, aliphatic nitriles such as the butyronitrile do not undergo cycloaddition into the oxadiazole derivative [21].

Scheme 11

Synthesis of 3-trifluoromethyl-5-phenyl derivative 38 by the Cycloaddition Route

The method involving cycloaddition between nitriles and nitrile oxides has also been employed for the synthesis of complex systems precursors of polymeric materials. For example, terephthaldinitrile oxide 39 was reacted with R_FCN (Scheme 12) to give representative oxadiazole 40. In the case of R_F=nitrile-terminated polyperfluoroalkylether chain, the presence of several nitrile pendants as curing sites can lead to further functionalized oligomers 41 [22].

Scheme 12

Synthesis of functionalized oligomers 41

2.2.3 The Ring-Rearrangement Route

More than a decade from our laboratories demonstrated how heterocyclic rearrangements can be fruitfully implemented for the synthesis of fluorinated heterocycles. ANRORC-like reactions, which consists of the Addition of a Nucleophile to a electron deficient heterocycle, followed by Ring-Opening and Ring- Closure steps [23], represent a valuable strategy to transform an easily accessible fluorinated heterocycle into a different one containing the heteroatoms originally belonging to the nucleophilic reagent. The reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles 42 with hydroxylamine in DMF at room temperature gave excellent yields of 3-perfluoroalkyl-1,2,4-oxadiazoles 43, resulting in a virtual C(5)-C(3) annular switch (Scheme 13) [24].

Scheme 13

ANRORC-like reactions: the C(5)-C(3) annular switch

The ring-degenerate ANRORC rearrangement has been successfully applied also for the synthesis of perfluoroalkylated 1,2,4-oxadiazolyl-pyridines 43 (R_F=C₇F₁₅; R=3- or 4-pyridyl), suitable precursors of the corresponding N-methylated salts [16].

The ring-rearrangement approach is an efficient methodology also for the synthesis of 3-amino-5-polyfluoroaryl-1,2,4-oxadiazoles. Following the Boulton-Katritzky rearrangement pattern, the ring-degenerate thermal equilibration of 47 (easily accessible from the reaction of 3-amino-5-methyl-1,2,4-oxadiazole with pentafluorobenzoyl chloride) gave a mixture of both the ring degenerate isomers 47 and 48 in a 80:20 ratio as a result of the electron-withdrawing character of the pentafluorophenyl moiety (Scheme 14) [25]. Interestingly, acidic hydrolysis of this thermally equilibrated mixture gave the expected 3-amino compound 49 in about 60 % yield because of the acid induced shift of the ring-degenerate equilibrium. By the same procedure, different 3-amino-5-polyfluorophenyl-1,2,4-oxadiazoles have also been prepared [25]. These results appear of some significance, since attempts to synthesize the same fluorinated oxadiazoles by conventional procedures (e. g., by the acylcyanamide method) were reported to be unsuccessful.

Scheme 14

The Boulton-Katritzky ring-degenerate thermal equilibration of 47

Unfortunately, because of the structure-dependent reactivity of 3-acylamino oxadiazoles towards ring- degenerate interconversions, this procedure is not applicable to the synthesis of 5-perfluoroalkyl derivatives [25]. Nevertheless, these compounds can be obtained through photo-induced rearrangements of O-N bond containing azoles [26] involving the photo-fragmentation of 3-perfluoroalkanoylamino furazans 50 at λ = 313 nm in methanol and in the presence of ammonia or primary aliphatic amines giving the corresponding 3-amino- or 3-N-alkylamino-5- perfluoroalkyl-1,2,4-oxadiazoles 51 as a result of the involvement of the added amine in the reaction of photofragmented intermediates (Scheme 15) [27].

Scheme 15

Synthesis of 3-N-alkylamino-5- perfluoroalkyl-1,2,4-oxadiazoles 51 by photo-fragmentation of 3-perfluoroalkanoylamino furazans 50

In order to maximize yields, the irradiated solution needs to stand in the dark overnight, to complete the final cyclization step of 53 into 51. Although yields are not optimal due to the subsequent photoreactivity of compounds 51 at the used irradiation wavelength (see Sect. 2.3.3), this route appears to be the most accessible synthetic method for the synthesis of 3-(alkyl) amino-5-perfluoroalkyl-1,2,4-oxadiazoles.

2.3 1,3,4-Oxadiazoles

There are several reports in the literature concerning 1,3,4-oxadiazoles bearing a fluorinated group at either or both positions 2 and 5 of the ring. Some trifluoromethyl-1,3,4-oxadiazoles are also commercially available. As for oxadiazoles with a fluorine atom directly bond to the ring, although some patents actually claim such derivatives [28], no description of experimental detail has been reported.

Recently, the direct trifluoromethylation of 1,3,4-oxadiazoles has been achieved by reaction with trifluoromethyltrimethylsilane through direct C-H activation of oxadiazole 54 using copper acetate as catalyst under oxidative conditions (Scheme 16) [29].

Scheme 16

Synthesis of trifluoromethyl-1,3,4-oxadiazole 55 by copper acetate catalysis

Beside this direct approach, the most widely used methodologies to obtain fluorinated 1,3,4-oxadiazole derivatives are: (i) the cyclodehydration of fluorinated diacylhydrazines 58 (Scheme 17); (ii) the ring-transformation of fluorinated 2-acyl-tetrazoles 56 (Huisgen reaction) [30] involving the loss of a nitrogen molecule of the acylated tetrazole ring leading to a nitrilimine intermediate which will finally produce 1,3,4-oxadiazoles 57 (Scheme 17). Besides these general methodologies, some syntheses of particular 1,3,4-oxadiazoles through photoinduced ring-rearrangements have been reported as well (see Scheme 26 in Sect. 2.3.3).

Scheme 17

Synthesis of perfluoroalkylated 1,3,4-oxadiazoles 57 by cyclodehydration of fluorinated diacylhydrazines 58 and Huisgen reaction of fluorinated 2-acyltetrazoles 56

2.3.1 The Diacylhydrazine Route

Historical examples of syntheses by cyclodehydration of bis-perfluoro-acylhydrazines with P₂O₅ were reported by Brown et al. [31] as well as by Chambers and Coffman [32]. By using the same approach, a series of symmetrically and asymmetrically substituted 2,5-bis(polyfluoroaryl)-1,3,4-oxadiazoles 60 can be prepared in excellent yields (Scheme 18) [33].

Scheme 18

Synthesis of 2,5-bis(polyfluoroaryl)-1,3,4-oxadiazoles 60 by cyclodehydration of bis-perfluoro-acylhydrazines with P₂O₅

Chloromethyl derivative 63, a useful precursor for other trifluoromethylated heterocycles [34] can be obtained by reaction of 61 with chloroacetylchloride followed by cyclization of the resulting diacylhydrazide with phosphorus oxychloride 62 (Scheme 19) [35].

Scheme 19

Synthesis of chloromethyl derivative 63

An interesting application of the cyclodehydration approach is the synthesis of bis-oxadiazoles 65 by dehydration of bis-diacylhydrazines 64 [36, 37]. Similarly, reaction of perfluoroanhydride 66 leading to 67 is also reported [38]. Bis-oxadiazoles 69, which have a good thermal stability, are prepared by cyclodehydration of the corresponding tetrafluoroisophthaloyl bis(perfluoroacyl-hydrazines) 68 (Scheme 20) [39].

Scheme 20

Synthesis of bisoxadiazoles 65 and 69 and oxadiazoles 67 by the cyclodehydration approach

More recently, the synthesis of 1,3,4-oxadiazoles 73, including fluorinated derivatives, from 1,2-diacylhydrazines was reported by using [Et₂NSF₂]BF₄ as a convenient cyclodehydration agent (Scheme 21) [40].

Scheme 21

Synthesis of 1,3,4-oxadiazoles 73 by using [Et₂NSF₂]BF₄ as a cyclodehydration agent

2.3.2 The Acyl-Tetrazole Rearrangement Route

Some of the previously illustrated fluorinated 1,3,4-oxadiazoles, such as 57 (R_F=CF₃, C₃F₇) and 65 (R=C₃F₇; n = 3), can be alternatively obtained by the Huisgen reaction approach [41]. Both 5-perfluoroalkyl-2-phenyl-1,3,4-oxadiazoles 76 and the diheterocyclic compound 1,3-bis(2-phenyl-1,3,4-oxadiazol-5- yl)hexafluoropropane 78 (n = 3) can be obtained by reaction of 5-phenyltetrazole 77 with perfluoroacyl chloride or perfluoroglutaryl chloride respectively (Scheme 22) [10].

Scheme 22

The Acyl-Tetrazole Rearrangement Route in the synthesis of fluorinated 1,3,4-oxadiazoles 65, 5-perfluoroalkyl-2-phenyl-1,3,4-oxadiazoles 76 and 1,3-bis(2-phenyl-1,3,4-oxadiazol-5- yl)hexafluoropropane 78

Bifunctional reagents have been considered for the construction of polymeric structures. The reaction of α,ω-bis(tetrazol-5-yl)perfluoroalkane 75 with ω-cyanoperfluoroanhydrides 79 (at 150 °C) produces bis-oxadiazoles 80 from which further functionalization may be added on the two terminal nitriles (Scheme 23) [42, 43].

Scheme 23

Bifunctional reagents in the construction of polymeric structures

By the use of the same methodology, the N,N-difluoroaminodifluoromethyl-tetrazole 82 reacts with perfluoroacyl chlorides or oxalyl chloride leading to the corresponding oxadiazoles 81 or bis-oxadiazole 83, respectively (Scheme 24) [13].

Scheme 24

Synthesis of perfluoroalkyl oxadiazoles 81 and bis-oxadiazole 83

Overall, the tetrazole transformation methodology is a quite general approach. Almost any nitrile can be transformed into the corresponding tetrazole precursor which can lead to a perfluoroalkyl-1,3,4-oxadiazole. One example is represented in Scheme 25 for sugar-linked system 85 obtained from the corresponding D-glucose tetrazole derivative (Scheme 25) [44].

Scheme 25

Sugar-linked system 85 obtained by the tetrazole transformation methodology

2.3.3 The Photoinduced Ring-Rearrangement

Although simple derivatives such as the 2-amino-5-trifluoromethyl-1,3,4-oxadiazole 87 (R_F=CF₃) can be prepared by reaction of trifluoroacetylhydrazine with BrCN, an interesting alternative is represented by the photorearrangement of the corresponding 1,2,4-oxadiazoles [26, 45].

As far as functional groups are concerned, in solution this approach is restricted to 1,2,4-oxadiazoles bearing a tautomerizable group at C(3) [7]. For instance, 3-amino-5-pefluoroalkyl-1,2,4-oxadiazoles 86 produced the corresponding 2-amino-5- perfluoroalkyl-1,3,4-oxadiazoles 87 (53–61% of yields) upon UV irradiation at 313 nm in methanol and in the presence of triethylamine (TEA). The reaction followed the typical ring contraction-ring expansion route [46]. In the same reaction, amounts of 5-amino-1,2,4-oxadiazole derivatives 88 are formed also through a competing process following the internal cyclization-isomerization route (Scheme 26) [46].

Scheme 26

Competing photoinduced ring-rearrangement: the ring contraction-ring expansion route and the internal cyclization-isomerization route

Very recent unpublished studies from our laboratories showed also the possibility to exploit the intrazeolite photorearrangement of 1,2,4-oxadiazoles [45] for the preparation of fluorinated diaryl-1,3,4-oxadiazole derivatives 90 (Scheme 27).

Scheme 27

Intrazeolite photorearrangement of 1,2,4-oxadiazoles

2.4 1,2,5-Oxadiazoles

There are not many examples regarding the synthesis of fluorinated 1,2,5-oxadiazole (furazan) systems in the literature. Furazans bearing fluoro atoms were easily obtained by nucleophilic displacement of a nitro group at the furazan ring by using a fluoride source and a ionic liquid (IL) as a medium [47]. Treatment of dinitro derivatives 91 and 93 with triethylamine hydrofluoride (TEAHF), by using butylmethylimidazolium salts (IL) as solvent, gave monofluorinated furazans 92 and 94 in 50–58 % yields (Scheme 28). Unfortunately, formation of the corresponding difluoro derivatives was observed in traces, with the double substitution of the nitro groups, just obtained in the case of diazo-derivative 96 (47 % yield) from the corresponding dinitro derivative 95.

Scheme 28

Synthesis of furazans bearing fluoro atoms by nucleophilic displacement in ionic liquids

The synthesis of trifluoromethyl furazans 98 was described by Kamitori through the dehydration of dioximes 97 in the presence of silica (Scheme 29) [48]. Since the presence of silica is fundamental for this process, the author suggests that an interaction between the substrate and the silanol groups assists the cyclization reaction. The final products were obtained in higher yields (77 %) in presence of electron-withdrawing p-nitrophenyl group which facilitated reaction more effectively than the p-tolyl group in favoring the cyclization step.

Scheme 29

Synthesis of trifluoromethyl furazans 98 through the dehydration of dioximes 97 in the presence of silica

Furazan-N-oxides (furoxanes) 104 (Scheme 30) are isolated as a result of the nitrile oxide dimerization when chloro-oximes 101 are treated with bases in the absence of dipolarophiles [21, 49, 50]. Oxidation of aldoxime 99 with nitric acid gives furoxan 104 [R_F=H(CF₂)₈] in 50 % yield [51]. Similarly, furoxane 104 (R_F=C₆F₅) can be also formed from lead tetraacetate oxidation of the pentafluorobenzaldehyde oxime [49]. The involvement of nitrile oxide dimerization has been also suggested in the formation of furoxanes 104 by reaction of perfluoroalkyldiazomethanes 100 (R_F=CF₃, C₂F₅, C₃F₇) with nitrogen dioxide [52], and in the formation of the 3,4-bis(trifluoromethyl) derivative 104 (R_F=CF₃) from the dehydration reaction of trifluoromethylnitromethane 103 with trifluoroacetic anhydride (Scheme 30) [53]. More recently, the unstable trifluoroacetonitrile N-oxide molecule, CF₃CNO, has been generated in high yield in the gas phase from the corresponding bromo-oxime [54]. Cold trapping of this molecule followed by slow warming forms the stable bis (trifluoromethyl)furoxan 104 (R_F=CF₃), and the mechanism of the dimerization process to the furoxan ring was studied with density functional theory.

Scheme 30

Synthesis of the 3,4-bis(trifluoromethyl) furoxan 104

2.5 1,2,3-Thiadiazoles

The synthesis of fluorinated 1,2,3-thiadiazole was not widely investigated and is essentially related to the general scheme of the Hurd-Mori reaction [55], i.e. the treatment of hydrazone derivatives with thionyl chloride (Scheme 31).

Scheme 31

Hurd-Mori reaction to 1,2,3-thiadiazole

By applying this method some representative fluorinated 1,2,3-thiadiazoles were obtained from the corresponding hydrazone derivatives (Scheme 32) [56].

Scheme 32

Synthesis of fluorinated 1,2,3-thiadiazole by the Hurd-Mori reaction

Concerning benzocondensated derivatives, despite the largely cited use of fluorinated 2,1,3-benzothiadiazoles 115 in electronic devices [57], due also to the redox properties and anion stability of 2,1,3-benzothiadiazole systems such as 115 (Fig. 4) [58], the preparation of fluorinated 1,2,3-benzothiadiazoles such as 116 (Fig. 4), used for application as agrochemical, are rarely reported [59].

Fig. 4

Structure of fluorinated benzothiadiazoles

2.6 1,2,4-Thiadiazoles

When aminoderivatives such as 117 or 120 are available, the introduction of a fluorine atom directly bonded to the ring can be achieved by the generally applied decomposition of diazoniumtetrafluoroborates 118 and 121 leading to 3-fluoro-5-phenyl- 119 (67 %) or the regioisomer 5-fluoro-3-phenylthiadiazole 122 (18 %), respectively [60] (Scheme 33). The same methodology has been utilized for the preparation of 3-fluoro-5-methylthiothiadiazole 125 which can be obtained in a 33 % yield [61]. In turn, this 5-methylthio derivative 125 can be oxidized to the 5-sulfonylthiadiazole 126 which is a precursor of a series of compounds of industrial interest (of the general type 127) obtained through nucleophilic substitution reactions with appropriate reagents (NuH in the Scheme 33).

Scheme 33

Introduction of a fluorine atom directly bonded to the 1,2,4-thiadiazole ring

The introduction of fluorine has also been described through nucleophilic substitutions or fluorination of functional groups already bonded to the ring. For instance, 5-chloro-3-trichloromethylthiadiazole 128 can be fluorinated with different reagents (Scheme 34) [62]. By the use of the SbF₃/SbCl₃ fluorinating mixture, only the trichloromethyl group is fluorinated to yield the trifluoromethyl derivative 129. The annular 5-chloro moiety undergoes substitution and partial fluorination of the 3-trichloromethyl moiety is also observed with AgF. Further reactions of derivatives 129 and 131 with AgF lead to perfluorinated compound 130.

Scheme 34

Introduction of fluorine in 1,2,4-thiadiazole systems through nucleophilic substitution or fluorination of functional groups already bonded to the ring

With regard to the syntheses from fluorinated acyclic precursors, an approach to fluorinated 1,2,4-thiadiazoles utilized the oxidative heterocyclization of fluorinated thioacyl-amidines. For example, trifluoroacetamidine and ethyl chlorothiocarbonate will form the open-chain intermediate 132 which, upon oxidation with bromine, leads to 5-ethoxy-3-trifluoromethyl-1,2,4-thiadiazole 133 (Scheme 35) [63]. A direct heterocyclization into the thiadiazole 137 takes places from the reaction of the fluorinated N-bromotrifluoroacetamidine 134, prepared by selective bromination of the corresponding trifluoroacetamidine 135, with ethyl xanthate [64]. In addition, the 3-perfluoropropyl-5-chlorothiadiazole 137 is obtained in 52 % yield from the reaction of heptafluorobutyramidine hydrochloride 136 with trichloromethylsulfenyl chloride in the presence of a base (Scheme 35) [62].

Scheme 35

Synthesis of fluorinated 1,2,4-thiadiazole from fluorinated acyclic precursors

Due to their reactivity towards both O- and N- nucleophiles, 5-chlorothiadiazole derivatives 138 are used as precursors for the synthesis of various compounds such as 139 [65]. Further reactions of 5-amino-3-trifluoromethyl-1,2,4-thiadiazole 141 into target compounds 140 and 142 are also patented (Scheme 36) [66].

Scheme 36

5-chlorothiadiazole derivatives 138 as precursors for the synthesis of fluorinated 1,2,4-thiadiazoles

Reaction of polyfluoroalkylthioamide 144, prepared by sulfur insertion on the appropriate polyfluoroalkylcarboxamide, give rise to 1,2,4-thiadiazoles 145 in 54–62% yields (Scheme 37) [67, 68].

Scheme 37

Synthesis of 3,5-perfluoroalkyl-1,2,4-thiadiazoles 145

Another convenient strategy for the synthesis of 3,5-diaryl-1,2,4-thiadiazoles is the oxidative dimerization of arylthioamides by using 2,4,6-trichloro-1,3,5-triazine and dimethylsulfoxide in polyethylene glycol 400 (PEG-400) as solvent at ambient temperature. This methodology can be applied to various fluoroarylated systems (Ar_F=mono-, poly-, or perfluorophenyl). The reaction give rise to 4-fluoro substituted derivatives 147 during 8 min in yields of 96 % (Scheme 38) [69]. The same reaction has been recently reported by using 1-butyl-3-methylimidazolium tetrafluoroborate as eco-friendly reaction medium at room temperature [70].

Scheme 38

Synthesis of 3,5-diaryl-1,2,4-thiadiazoles 147 by oxidative dimerization of arylthioamides

Concerning perfluoroaryl-1,2,4-thiadiazoles synthesis, C₆F₅CN reacts with Sn(AsF₆)₂ (n = 4,8) in liquid SO₂ to give 3,5-bis(perfluorophenyl)-1,2,4-thiadiazole 150 in mixture with its precursor 149 (Scheme 39) [71].

Scheme 39

Synthesis of 3,5-diaryl-1,2,4-thiadiazoles 150 by oxidative dimerization of arylnitriles

A new and efficient method for the synthesis of the 3,5-diaryl-1,2,4-thiadiazole system including fluorophenyl and trifluoromethylphenyl derivatives was investigated. The appropriate aryl thioamide 152a, b, undergo a very rapid condensation in the presence of methyl bromocyanoacetate 151 in methanol to provide the corresponding fluorinated 3,5-diaryl-1,2,4-thiadiazoles 153a, b with yields from low to quantitative (Scheme 40) [72].

Scheme 40

Synthesis of fluorinated 3,5-diaryl-1,2,4-thiadiazoles 153a, b by condensation of the aryl thioamide

A similar approach has been exploited by Cushman and coworkers to obtain a series of thiadiazole 154, for pharmaceutical applications as analogues of resveratrol, in quantitative yields (Fig. 5) [73].

Fig. 5

Fluorinated thiadiazoles used as pharmaceutical analogues of resveratrol

Alternatively, a simple and fast route reported for the preparation of 3,5-bis(fluoroaryl)-1,2,4-thiadiazoles 157, consists in the reaction of benzothioamides 155 and 2-bromo-2-phenylacetamide derivatives 156 at 60 °C in DMSO (Scheme 41) [74].

Scheme 41

Synthesis of 3,5-bis(fluoroaryl)-1,2,4-thiadiazoles 157

2.7 1,3,4-Thiadiazoles

In the case of 1,3,4-thiadiazoles, a fluorine atom can be directly introduced on the ring through nucleophilic substitution of other halogens. An example of this approach is represented by the reaction of the 2,5-dibromo derivative 158 with AgF, leading to the monofluorinated compound 159 (although in low yield; 16 %) and the perfluorinated open-chain compound 160. The latter probably originated from the ring-cleavage of the unisolated 161 (Scheme 42) [62], although any attempts to obtain the difluoro derivative 161 through the diazotization of the 2,5-diaminothiadiazole were unsuccessful. A relatively recent Japanese patent reports the synthesis of a series of derivatives, having the fluorine atom bonded to an annular carbon, through substitution reactions. Inter alia, the reaction of 2-chloro-1,3,4-thiadiazole 162 with KF (in the presence of 18-crown-6 ether at 150 °C) leading to the 2-fluoro derivative 163 (15 %) is claimed [75].

Scheme 42

Introduction of a fluorine atom on the 1,3,4-thiadiazole ring through nucleophilic substitution

In analogy to what was observed in the case of 1,3,4-oxadiazoles, the sulfuration of N,N'-diacylhydrazines 58 with P₂S₅ represent a general methodology for the synthesis of 2,5-bis(perfluoroalkyl)-1,3,4-thiadiazoles 164 which, in the reported examples, are obtained in 56–75 % yields depending on the nature of R_F (Scheme 43) [32]. Quantitative yields were observed in the synthesis of 2,5-bis(trifluoromethyl)-1,3,4-thiadiazoles 164 (R_F=CF₃) by the reaction of dichloroazine 165 with P₂S₅ (Scheme 43) [76]. More recently, Lawesson’s reagent has been also employed for the obtainment of 2-phenyl-5-trifluoromethyl-1,3,4-thiadiazole in moderate yield (54 %) [77].

Scheme 43

Synthesis of 2,5-bis(perfluoroalkyl)-1,3,4-thiadiazoles 164 by sulfuration with P₂S₅

Particular importance has been payed to fluorinated thiadiazoles which contain functionalities such as amino or methylthio groups due to their industrial production. The synthesis of aminothiadiazoles 168 is based on the heterocyclization of acylthiosemicarbazides 167 with yields depending on experimental conditions (Scheme 44). In some cases the heterocyclization into the thiadiazole derivative occurs directly during the acylation reaction. In this manner, the reaction of thiosemicarbazide with trifluoroacetic anhydride lead to the formation of 2-amino-5-trifluoromethylthiadiazole 168 (R_F=CF₃, R=H) in a 30 % yield [78]. However, reaction carried out in the presence of POCl₃ permitted to obtain the yield increased to 93% [79]. Reactions between thiosemicarbazides 166 and trifluoroacetic acid or anhydride in the presence of PPA were also used for the synthesis of 2-amino and 2-methylamino derivatives 168 (R_F=CF₃) [80].

Scheme 44

Synthesis of aminothiadiazoles 168 by heterocyclization of acylthiosemicarbazides 167

Several patents report the synthesis (or in some cases just a purification methodology) of 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole 171 which can be prepared through the reaction of 169 with trifluoroacetic acid or anhydride (Scheme 45) [81]. The same compound 171 can also be obtained from the 2-bromo derivative 172 [82].

Scheme 45

Synthesis of 2-methylthio-5-trifluoromethyl-1,3,4-thiadiazole 171

Very recently, direct trifluoromethylation of the pre-formed 1,3,4-thiadiazole ring has been reported. In all the cases the trifluoromethyl radical is involved as electrophilic species attacking the ring. Generation of the reactive radical could be achieved from CF₃I in the presence of ferrocene (Cp₂Fe) and hydrogen peroxide [83] or by using CF₃SO₂Na (Langlois reagent) in the presence of t-BuOOH [84]. This quite interesting reactivity was just evidenced for the obtainment of 2-amino-5-tryfluoromethyl-1,3,4-thiadiazole 168 from the corresponding 2-amino derivative 173 and unfortunately in low yields. Similarly, radical fluoroalkylation of amine 173 was also achieved by using the new difluoromethylating agent Zn(SO₂CF₂H)₂ (DFMS) [85] or BrCF₂CO₂Et [86] as CF₂R radical sources (Scheme 46).

Scheme 46

Synthesis of fluorinated 1,3,4-thiadiazoles by radical fluoroalkylation of amine 173

2.8 1,2,5-Thiadiazoles

Similarly to other thiadiazoles, the direct introduction of fluorine on the 1,2,5-thiadiazole can be achieved via substitution reactions on the corresponding chloro derivatives. Thus, reaction of the commercially available 4,5-dichloro-thiadiazole 176 with KF in sulfolane at 180ºC allow to obtain both the monofluoro compound 177 (24%) and difluorothiadiazole 178 (48%) (Scheme 47) [87]. Similarly, 3-aryl-4-fluoro-1,2,5-thiadiazoles 180 have been prepared by treating the corresponding 4-chloro derivatives 179 with KF at high temperatures (Scheme 47) [88]. A synthesis of fluorinated 1,2,5-thiadiazoles from acyclic precursors utilizes the reaction of particular fluorinated substrates with tetrasulfur tetranitride (S₄N₄) in a (3 + 2) synthetic pattern. For instance, trifluorobutynonitrile 181 (R=CN) and ethyl 4,4,4-trifluoro-2-butynoate 181 (R=COOEt) treated with S₄N₄ in dichloromethane at 150ºC produced trifluoromethyl substituted thiadiazoles 183 (30–55 %) (Scheme 47)[89]. Interestingly, the reaction was accompanied by the formation of trithiadiazepine 184. In the case of the reaction with hexafluorobutyne 182, only the corresponding trithiadiazepine derivative 184 (R=CF₃) was isolated, although the authors assumed that the bis(trifluoromethyl)thiadiazole 185 was formed also and lost during the reaction work-up because of its volatility. The formation of 185 was claimed in 58 % yield from the reaction of hexafluorobutyne 182 with the more electrophilic trithiazyl trichloride (S₃N₃Cl₃) reagent.[90] In this case, the addition of two NSCl moieties to the triple bond and the loss of SCl₂ during the heterocyclization is suggested. The same bis(trifluoromethyl) derivative 185 had been suggested to be involved in the reaction of 182 with thiazyl fluoride (NSF) [91]. Bis(trifluoromethyl)thiadiazole 185 was also obtained from the photochemical decomposition of bis(trifluoromethyl)-1,3,2-dithiazol-2-yl radical [92].

Scheme 47

Synthesis of fluorinated 1,2,5-thiadiazole by direct introduction of fluorine on the ring through nucleophilic substitution or starting from fluorinated acyclic precursors

Cyclization with tetrasulfur tetranitride has been employed with the 1-aryl-2,2-dihaloethanone oximes 186. From the reaction carried out in refluxing dioxane, 3-aryl-4-fluorothiadiazoles 180 have been obtained in fair yields (32–65%) and the mechanistic aspects which involve the species 188 have been discussed (Scheme 48) [93]. It has to be noted that the same reaction performed on 1-aryl-2,2,2-trifluoroethanone oximes 187 does not result in cyclization to thiadiazole [94].

Scheme 48

Mechanistic aspects of the synthesis of fluorinated 1,2,5-thiadiazole by cyclization with tetrasulfur tetranitride

The reaction of benzyl ketones with tetrasulfur tetranitride provided a method for the synthesis of 3,4-diaryl- and 3-alkyl-4-aryl-1,2,5-thiadiazoles [95]. Similarly, in the case of fluorinated substrates, 3-aroyl-4-trifluoromethylthiadiazoles 191 have been obtained in 40–50 % yields from the reaction of aroyltrifluoroacetylmethanes 190 with S₄N₄ in refluxing toluene [96]. Enaminones 192 have also been utilized as suitable substrates for the cyclization into 1,2,5-thiadiazoles 191 (21–51 %) [97]. The reaction has been realized using S₄N₄/SbCl₅ complex in toluene at 100 ºC and 193 as a key intermediate has been suggested (Scheme 49).

Scheme 49

Synthesis of 3-aroyl-4-trifluoromethylthiadiazoles 191

3 Fluorine-Induced Reactivity of Fluorinated Oxadiazoles and Thiadiazoles

3.1 Ring-Fluorinated Derivatives

Few examples are reported in the literature regarding the reactivity of fluorinated 1,2,5-oxadiazoles. As for many azoles, the nucleophilic substitution of a fluorine atom is relatively easy and provided high yields. Fluorofurazans A react with bisfurazanopyrazine dianion 194 yielding a disubstituted compound 195 (73 %) containing two tris (furazanyl)-amino moieties [98]. The same reaction performed on fluoro-derivative B gave compound 196 (85 %), the precursor of macrocycle 197 synthesised by oxidative cyclization with dibromoisocyanurate (DBI) (Scheme 50).

Scheme 50

Reactivity of fluorinated 1,2,5-oxadiazoles: the nucleophilic substitution of a fluorine atom

Displacement of fluoride from furazan 199 is the initial step of a new ring cleavage/ring closure reactions of tetrazole which provides a route to the new furazano[3,4-e]-1-oxa-3,4-diazine system 200 [99]. Interestingly, the nucleophilic substitution on a second molecule of fluorinated furazan 199 is one of the key steps of the suggested mechanism outlined in Scheme 51.

Scheme 51

Suggested mechanism for a route to furazano[3,4-e]-1-oxa-3,4-diazine system 200

Concerning the reactivity of fluorinated 1,2,5-thiadiazoles, the only reported examples are related to the 3,4-difluoro-1,2,5-thiadiazole 178. This compound show nucleophilic displacement by fluoride ion-induced condensation with (Me₃SiN=)₂S, giving [1, 2, 5]thiadiazolo[3,4-c][1, 2, 5]thiadiazole 205 in 62 % yield [100]. Electrochemical generation of 205 radical anion might be of interest to materials science as a building block for molecular ion-based conductors and/or magnets. Ring-opening reactions of 178 were performed with molecular chlorine and/or bromine in the presence of HgF₂ giving open-chain compounds F₂S=NCF₂CF₂NX₂ 206 (X=Cl, Br) (Scheme 52) [101].

Scheme 52

Ring-opening reactions of 178

The gas-phase generation and spectroscopic identification of nitrile sulfides by thermolysis of 1,2,5-thiadiazole precursors was attempted, but in all cases the thiadiazoles were found to produce sulfur and the corresponding nitrile [102]. Interestingly, compound 178 was indicated as the most stable derivative, giving not decomposition up to 900 °C.

3.2 Ring-Fluoroalkylated Derivatives

The C(5) position is the most electrophilic site of the heterocycle in perfluoroalkyl-1,2,4-oxadiazoles due to the electron- withdrawing effect of both O(1) and N(4) [7]. In the presence of a perfluoroalkyl group linked at the C(5) of the oxadiazole the first step of the addition of a nucleophile–ring opening–ring closure (ANRORC) reaction of 5-perfluoroalkyl-1,2,4-oxadiazoles is strongly favoured (Scheme 53). Depending on the nature of the 3-substituent, the cyclization step of the open-chain intermediate can involve either the C(3) or an electrophilic site of the original C(3)-linked side-chain, leading to other five- 207 or six-membered ring 208 heterocycles, respectively [15, 16, 24, 103, 104]. Besides ring-degenerate rearrangement leading to regioisomeric 1,2,4-oxadiazoles (Scheme 13 in Sect. 2.2.3), this ANRORC reactivity has been exploited for the synthesis of fluorinated triazoles 209 and triazines 211 (Scheme 53) [103].

Scheme 53

The ANRORC reactivity in the synthesis of fluorinated triazoles 209 and triazines 211

The reaction of the 2,5-bis-trifluoromethyl-1,3,4-oxadiazole 212 with oxanorbornene derivatives has been recently re-evaluated for its stereoselectivity aspects, through a combination of experimental and computational studies [105]. In particular, the theoretical model was able to explain the origin of stereoselectivity towards the bent product 214 caused by repulsive lone pair interactions between oxygen bridges in the transition state of the 1,3-dipolar addition (Scheme 54).

Scheme 54

Stereoselectivity towards the bent product 214 in the reaction of the 2,5-bis-trifluoromethyl-1,3,4-oxadiazole 212 with oxanorbornene derivatives

An interesting photochemical ring contraction has been reported for trifluoromethylated 1,2,3-thiadiazoles. Thiirene 217 was obtained by the argon matrix photolysis at 265 nm of 1,2,3-thiadiazoles 215 at 8 K. Interestingly, trifluoromethyl group exert a stabilizing effect on the highly unstable 4π-electron ring system (Scheme 55) [56b].

Scheme 55

Thiirene 217 by photochemical ring contraction of trifluoromethylated 1,2,3-thiadiazoles

Regarding the reactivity of fluorinated 1,3,4-thiadiazoles, rare examples of peculiar reaction due to the presence of fluorinated moieties are reported in the literature, and all involve the thiadiazole ring-opening. Beside the above discussed obtainment of perfluorinated open-chain compound 160[62] the only example is related to the treatment 2-amino-5-trifluoromethyl-1,3,4-thiadiazole 218 with an alcoholate, causing dimerization with opening of a thiadiazole ring and formation of 219 in 34 % yield (Scheme 56) [106].

Scheme 56

Reactivity of fluorinated 1,3,4-thiadiazoles: dimerization with opening of a thiadiazole ring and formation of 219

On the other hand, reactivity of other functionalities linked to the thiadiazole ring is not affected by the presence of fluorinated moieties, therefore fluorinated 1,3,4-thiadiazoles behave as unfluorinated congeners. Also in this case, particular attention to fluorinated thiadiazoles which contain amino or methylthio groups has been given, due to their the industrial importance.

It is worth noting that 2-amino-5-trifluoromethylthiadiazole 218 is a commercial product which is widely employed to link the fluorinated thiadiazole to several targets through its amino group by means, for example, of an acylation reaction, as in the case of 220. Several patents on the synthesis of pharmaceuticals and agrochemicals take advantage of this of type of reaction [107]. In some cases, the amino group is involved in a diazotation reaction followed by a coupling reaction (leading to 221) [108] or a nucleophilic substitution [109]. For example, 2-halo derivatives 222 can be prepared via diazonium salts from 2-amino-5-trifluoromethylthiadiazole 218 (Scheme 57) [109]. Also 2-arylthio derivatives 223 are obtained through a nucleophilic substitution reaction [110].

Scheme 57

Reactivity of fluorinated thiadiazoles which contain amino groups

The methylthiothiadiazole 224 can be oxidized easily to the corresponding sulfonyl derivative 225 (Scheme 58). Some patents have also focused on the optimization of this oxidation which usually is carried out with hydrogen peroxide in acetic acid and in the presence of different catalytic species (boric acid, metal salts, etc.) [111]. The importance of this oxidation is related to the possibility to obtain the sulfonyl derivative system, due the ability of such a group to undergo nucleophilic substitution with several nucleophiles (NuH in the Scheme 58). In this way, it is possible to introduce the trifluoromethylthiadiazole moiety into target compounds for potential industrial applications [112]. Similar reactions are reported for the chlorodifluoromethyl derivative 227, which is used as a precursor for the preparation of herbicides such as 228 [113]. The latter showed very strong preemergent and strong postemergent herbicidal activity.

Scheme 58

Reactivity of fluorinated methylthiothiadiazoles

3.3 Ring-Fluoroarylated Derivatives

As mentioned above, the 1,2,4-oxadiazole is one of the most electron-withdrawing azole having a very activated C(5) position. In turn, when the electronic demand can be distributed over conjugated aromatic rings, the 1,2,4-oxadiazoles can activate the nucleophilic aromatic substitution. Indeed, 5-fluoroaryl-1,2,4-oxadiazoles are ideal examples for this concept. Due to the electron deficient character of the oxadiazole [which is more evident at the C(5) position], the p-fluoro moiety of the pentafluorophenyl ring is activated towards aromatic nucleophilic substitution by nucleophiles such as amines or alkoxides. Such a reactivity has great potential for the development of other synthetic applications and for the functionalization of macromolecules with nucleophilic pendants (Scheme 59) [5, 7]. In fact, a series of variously substituted 5-pentafluorophenyl-1,2,4-oxadiazoles have been used for the arylation of polymers, calixarenes, and tripodal ligands such as highly fluorinated system 231 [5b].

Scheme 59

Fluoroaryl 1,2,4-oxadiazoles in the functionalization of macromolecules with nucleophilic pendants

3.4 Systems Containing Fluorine Far from the Heterocyclic Core

Due to the presence of labile O-N bonds, the furazan system possess also an interesting photochemical reactivity. As discussed previously (Scheme 15 in Sect. 2.2.3 and Scheme 26 in Sect. 2.3.3), 3-perfluoroacylamino-1,2,5-oxadiazoles 50 are useful precursor for the obtainment of fluorinated 3-amino-1,2,4-oxadiazoles [27]. However, differently from non-fluorinated analogues 233 (R=alkyl) which are stable at the irradiation wavelength, perfluoroalkylated 1,2,4-oxadiazoles can undergo a subsequent photorearrangement into the corresponding 1,3,4-oxadiazole system [46]. Due to this peculiar reactivity of fluorinated derivatives, synthesis of fluorinated heterocycles involving photochemical steps must be carefully monitored in order to avoid unwanted reactivity not evidenced in unfluorinated substrates (Scheme 60).

Scheme 60

Photorearrangements in the perfluoroalkylated oxadiazole series

4 Biological Activity of Fluorinated Oxadiazoles and Thiadiazoles

A series of 5-trifluoromethyl-1,2,4-oxadiazoles are patented as potential pesticides [114] and tested for biological activity [115]. More recently, trifluoromethyl-1,2,4-oxadiazole derivatives such as 235 have been evaluated as cannabinoid antagonists [116] Besides these recent reports, one of the major debated bioactivity concerning fluorinated azoles is the efficiency of PTC124, also known with the name of Ataluren 236, which was claimed to promote the readthrough of nonsense premature stop codons (Fig. 6) [117, 118].

Fig. 6

Examples of fluorinated biologically active 1,2,4-oxadiazoles

Fluorinated 1,2,5-oxadiazoles have also been considered as important fragments in the field of medicinal chemistry, but only very recently compounds with considerable activity have been discovered. Some fluoroaryl substituted furoxans derivatives (Fig. 7), developed in the frame of SAR studies on Furoxan, were reported as inhibitors of thioredoxin glutathione reductase (TGR), with nitric oxide (NO) donor ability, acting as efficacious antischistosomal agents [119]. In particular, compounds 238 and 239 displayed an inhibition activity comparable to that of lead compound, while fluorinated bis-furoxan 240 is a better TGR inhibitor than Furoxan 237 (IC₅₀ = 0.48 μM vs 6.3 μM) with improved NO donation and ADME (solubility, Caco-2 permeability) properties.

Fig. 7

Examples of fluorinated biologically active 1,2,5-oxadiazoles

Fluorinated 4,5-diaryl thiadiazoles 241 and 242 were evaluated as cyclooxygenase-2 (COX-2) inhibitors (Fig. 8). They showed good cell viability but poor inhibitor activity [120].

Fig. 8

Examples of fluorophenyl thiadiazoles as potential COX-2 inhibitors

Difluorophenyl derivatives 243 were synthesized and tested in the frame of a SAR study on 1,2,3-Thiadiazole thioacetanilides as HIV non-nucleoside reverse transcriptase inhibitors. They showed the ability to protect MT-4 cells from viral cytopathogenicity in the low-micromolar range, but resulted less active than the chlorinated analogues to be further considered (Fig. 9) [121].

Fig. 9

Example of an anti-HIV fluoroarylated thiadiazole

During the discovery of a series of pyrrolidine-2,4-dicarboxylic acid amides, which have 1-(sulfur-containing hetero-aryl)piperazin-4-yl carbonyl as a substituent of the L-prolyl moiety, and are novel and stable DPP-IV inhibitors, the 1,2,4-thiadiazole 244 (Fig. 10) was found to be acceptable in the desired enzyme pocket, but its inhibitory activity in plasma decreased along with an increase of lipophilicity [122]. In a series of pyrimidine benzamide-based thrombopoietin receptor agonists [123], in which the lead molecule contains a 2-amino-5-unsubstituted thiazole (a group that has been associated with idiosyncratic toxicity), the potential for metabolic oxidation at C-5 of the thiazole, the likely source of toxic metabolites, was removed by substitution at C-5 or by replacing the thiazole with a thiadiazole. In particular, the 4-F-3-CF₃ analog 245 (Fig. 10) is active and only slightly less potent than the corresponding 2-amino-4-arylthiazole lead.

Fig. 10

Examples of fluorinated biologically active 1,2,4-thiadiazoles

Recently, several fluorinated 1,3,4-thiadiazoles have been considered as Drugs. Through a highthroughput biochemical screening of more than 340,000 synthetic compounds, the thiadiazole derivative XCT790 (246 in Fig. 11) has been identified as an estrogen-related receptor α (ERRα)−specific inverse agonist, validating ERRα as a promising therapeutic target in the treatment of metabolic disorders, including diabetes and obesity [124]. This compound could also be used in pathologies such as breast cancer [125], enhancing the efficacy of Fulvestrant 247 – an estrogen receptor antagonist with no agonist effects, already clinically used for the treatment of metastatic breast cancer in postmenopausal women [126]. Moreover, XCT790 itself is a perspective drug for the treatment of hormone-related tumors such as prostate and breast cancer [127].

Fig. 11

Examples of fluorinated biologically active 1,3,4-thiadiazoles

A patent from Janssen Pharmaceutica disclosed compound 248, and other trifluoromethyl-1,3,4-thiadiazole derivatives, as fast dissociating dopamine 2 receptor antagonists with a pIC₅₀ value > 5.0 when tested for in vitro binding affinity for human D2L receptor [128]. Compound 248 should be useful for treating or preventing central nervous system disorders, for example schizophrenia, by exerting an antipsychotic effect without motor side effects. Also in the field of non-steroidal anti-inflammatory drugs (NSAIDs) fluorinated thiadiazoles appear. Compound 249 showed appreciable cyclooxygenase-2 (COX-2) selective inhibitory activity [129]. This compound also exhibited significant in vivo anti-inflammatory activity, comparable to that of the reference compound Celecoxib. 5-Trifluoromethyl-1,3,4-thiadiazolyl-amide 250 has been considered for anti-parasitic activity against Sarcocystis neurona [130], an obligate intracellular parasite that causes equine protozoal myeloencephalitis (EPM), and Cryptosporidium parvum [131], responsible for diarrhea in immunocompetent children and adults (cryptosporidiosis). Compound 250 is more active than reference compound nitazoxanide (NTZ) and seems promising for the treatment of both threats. In the field of anti-fungal compound, derivative 251 has been recently highlighted as a chitinase inhibitor for the fungal pathogen Aspergillus fumigates [132]. Despite the weak inhibitory activity, it could represent an interesting lead for future inhibitor development.

Regarding biological applications of fluorinated 1,2,5-thiadiazoles, compounds 180 were investigated for their nematocidal activity [88], while compound 252 was highlighted as antiviral agent, showing an EC₅₀ of 0.008 μg/mL in vitro, protecting HIV-infected MT-4 cells from death [133] (Fig. 12).

Fig. 12

Examples of fluorinated biologically active 1,2,5-thiadiazoles

5 Applications of Fluorinated Oxadiazoles and Thiadiazoles

Potential artificial oxygen carriers, based on new water-soluble fluorinated polymers, were obtained by using FOXARs (see also Scheme 59 in Sect. 3.3) to introduce fluorinated pendants in the α,β-poly(N-2-hydroxyethyl)-DL-aspartamide (PHEA) and polyethylenglycol–PHEA (PHEA– PEG) biocompatible polymers. The introduction of the fluorinated moiety increased the polymer’s oxygen-dissolving ability without compromising its biocompatibility which was checked by an in vitro viability assay[4].

Fluorinated ionic liquid crystals (ILC) were synthesized by quaternization of pyridyl-1,2,4-oxadiazoles with CH₃I [134]. Interestingly, replacing the rigid perfluoroalkyl moiety with a more disordered alkyl chain resulted in a dramatic change of the salt’s physico-chemical properties. In the field of supramolecular interactions involving fluorinated heterocyclic systems, a very recent study was performed on a series of perfluoroalkyl-1,2,4-oxadiazolyl-pyridines as H-bond acceptors in protic ionic liquids [135]. Interestingly, self-assembling capability of 1,3,4-oxadiazoles 256 (Fig. 13) allowed the obtainment of tubular crystals of size controllable through sublimation protocols [136].

Fig. 13

Examples of fluorinated oxadiazoles for sensoring and optoelectronics

Other examples regarding applications of fluorinated oxadiazoles in the field of sensoring and optoelectronics are illustrated in Fig. 13. In some cases the luminescent properties of a system can be designed to be a function of a measure such as the concentration of a given species in solution. For example, the fluorescence of the star-shaped molecule similar to 253 (Fig. 13) is self-quenched by the tertiary amino moiety of its core and is strongly dependant on the medium’s acidity [5b] Additionally, the derivative 253 has been recently developed as fluorescent sensor for mercuric ion in aqueous media [137]. Starburst oxadiazole 254 is a precursor of dendritic emitter [138]. Finally, compound 255 represents the simplest oligomer of highly fluorinated polyarylene systems with fluoride anion sensing ability [139].

The application of fluorinated furazan is rather limited for synthesis and reactivity. Most studied derivative is 3-amino-4-trifluoromethyl-1,2,5-oxadiazole, which is commercially available. Nevertheless, in recent years, some perspective applications have been envisaged. In the agrochemical field a large library (more than 300 derivatives) of N-(4-trifluoromethyl-1,2,5-oxadiazol-3-yl)benzamides 257 has been prepared and considered for herbicidal activity [140], while 1-(4-fluoro-1,2,5-oxadiazol-3-yl)pyrazole derivatives 258 were claimed as herbicides and plant growth regulators (Fig. 14) [141].

Fig. 14

Examples of fluorinated 1,2,5-oxadiazoles agrochemicals

Many fluorinated thiadiazoles have been applied as agrochemicals. For instance, thiadiazole 259 is an antidote for acetanilide herbicides, protecting sorghum and wheat against phytotoxicity without affecting green foxtail control by these herbicides (Fig. 15) [142].

Fig. 15

A fluorinated 1,2,3-thiadiazole herbicide

As outlined above, fluorinated 1,3,4-thiadiazoles are widespread applied in many fields as agrochemicals, drugs and materials. It is noteworthy that in the agrochemical field some 1,3,4-thiadiazole derivatives have reached the market, in particular, Flufenacet 260 and Thiazafluron 261 (Fig. 16).

Fig. 16

Examples of commercial fluorinated 1,3,4-thiadiazole agrochemicals

Flufenacet (brand names: Artist®, Axiom®, Cadou®, Define®, Liberator®, Radius®, Tiara®, Terano®) was introduced by Bayer AG and is an oxyacetanilide herbicide applied before crops have emerged [143]. Is an inhibitor of cell division acting on very-long-chain-fatty-acid (VLCFA) synthesis. Applied for crop protection (Corn, Rice, Wheat, Potatoes, Soybeans) presents a spectrum of activity on infesting annual grasses like Alopecurus myosuroides, Apera spica-venti, Digitaria spp., Echinochloa crus-galli, Poa annua, Setaria spp.

Thiazafluron (other names: Erbotan® GS 29696, Thiazfluron) is an herbicide introduced by Ciba-Geigy AG [144]. Thiazafluron is believed to be obsolete for use as pesticides is one of 320 pesticides to be withdrawn in July 2003. Recently, other trifluoromethyl-1,3,4-thiadiazole derivatives such as 262 (Fig. 16) have been claimed useful for fighting or controlling invertebrate pests in agricultural as well as veterinary applications [145].

In the field of materials for photography, metal complexes containing fluoro-thiadiazoles as monodentate ligand have been used. Emulsion layer contains Ag halide and the iridium complex 263 provides high-speed development method with high-quality images free from pressure-derived fogs [146], while the emulsion containing the iridium complex 264 showed high sensitivity and contrast, preventing reciprocity law failure in broader exposure range (Fig. 17) [147].

Fig. 17

Examples of fluorinated 1,3,4-thiadiazoles applied in materials science

Also in the field of reagents for materials characterization fluorinated 1,3,4-thiadiazoles have found some applications. In fact, the couple 5-trifluoromethyl-2-mercapto-1,3,4-thiadiazolate/5,5′-bis(2-trifluoromethyl-1,3,4-thiadiazole) disulfide 265 was employed as organic redox couple in nonaqueous media to perform capacitance measurements through Electrochemical Impedance Spectroscopy (EIS) on semiconductive materials (Fig. 17) [148].

6 Concluding Remarks

Due to the peculiar features introduced by fluorinated moieties, the synthesis, the reactivity, and the application of fluorinated oxadiazoles and thiadiazoles still are challenging research topics. Therefore, the updated synthetic guidelines reported in this chapter will represent a useful tool for both the experienced synthetic chemists and those willing to embrace the study of fluorinated azoles. For this reason, it is the authors’ opinion that synthetic information organized by kind of heterocycle is better approached by the reader for faster consultation. On the other hand, reactivity has been presented by focusing on the type and position of the fluorinated moiety, in the attempt to provide general concepts transferable also to other heterocyclic systems. Finally, examples of fluorinated oxadiazoles and thiadiazoles used in materials chemistry or as bioactive compounds have been briefly illustrated to suggest the potential application of newly synthesized compounds.