Synthesis and applications of fluorinated, polyfluoroalkyl- and polyfluoroaryl-substituted 1,2,3-triazoles

Abstract

1,2,3-Triazoles and organofluorine substitutents are both important structural and functional motifs used in a range of applications. This review summarises the confluence of these two important moities and provides a comprehensive account of the methods for synthesising and applying fluorine-, polyfluoroalkyl- and polyfluoroaryl-substituted 1,2,3-triazoles. Focus has been devoted to recent examples and applications where the properties of both the 1,2,3-triazole and organofluorine substituent are proposed to be important in enhancing the compound's functionality.

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Frances E. Bugden

Frances Bugden obtained her integrated MChem in Chemistry with Drug Discovery from the University of Strathclyde, Glasgow in 2020 which included a year in the pharmaceutical industry. She then moved to the University of Warwick to carry out her PhD studies under the supervision of Dr Mark Greenhalgh in the area of chalcogen bonding catalysis using Se- and Te-functionalised triazoles. Since completing her PhD in 2024, she has transitioned from academia into the pharmaceutical industry.

Jason L. Westwood

Jason L. Westwood was born in Birmingham and studied chemistry at the University of Warwick, obtaining a Bachelor of Science degree in 2022. He then completed a Master of Science by Research at the same institution, under the supervision of Dr Mark Greenhalgh. Currently, he is continuing his research for a PhD in organic chemistry in Dr Mark Greenhalgh's group at the University of Warwick.

Henry Stone

Henry Stone is originally from Oxfordshire and obtained an integrated MChem degree from the University of Warwick in 2022. Henry completed his final year Masters research project under the supervision of Dr Stefan Roesner and Prof. Mike Shipman on the stereoselective synthesis of 1,2-diazetidine-3-carboxylic acid derivatives for use in peptidomimetics. Currently, Henry is working as a PhD student in the Greenhalgh group on a project sponsored by GoldenKeys® High-tech Materials Co., Ltd.

Yingjian Xu

Prof. Dr Yingjian Xu CCHEM FRSC is the CEO of GoldenKeys® High-tech Materials Co., Ltd, and an Honorary Professor at the University of Warwick. After his BSc degree at Huaqiao University, he obtained a PhD in organic chemistry at University of Warwick under the supervision of Prof. Martin Wills, during which he developed of a series of patented XuPHOS catalysts. After a postdoctoral position with Prof. John Brown FRS (Oxford), he joined PhosphonicS. In late 2016, he started his own company, which specialises in organometallic catalysts, metal-ligating functionalised materials and molecular purification technologies for pharmaceutical and fine chemical industries.

Mark Greenhalgh

Mark completed his Undergraduate degree at the University of Sheffield before moving to Bristol, and then Edinburgh, to complete a PhD with Stephen Thomas on iron-catalysed hydrofunctionalisation of alkenes and alkynes. Mark then moved to the University of St Andrews to conduct postdoctoral work with Andrew Smith on the development and mechanistic understanding of organocatalytic enantioselective methodologies. In April 2020, Mark moved to the University of Warwick as an Assistant Professor to start his independent research group and was promoted to Associate Professor in 2024. His group work on utilising unconventional non-covalent interactions for catalysis and drug discovery.

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1. Introduction

1,2,3-Triazoles are incredibly important motifs used in a range of fields due to their high thermal, chemical and biological stability. They possess two lone pairs available for bonding and have a relatively high dipole moment of >4 D,¹ leading to triazoles being both good hydrogen bond acceptors/transition metal ligands and good hydrogen bond donors. Based on these various properties, 1,2,3-triazole derivatives have found applications in drug discovery,² bioconjugation,^2a,3 carbohydrate,⁴ peptide,⁵ and DNA chemistry,⁶ supramolecular chemistry,⁷ polymer science⁸ and sensing applications,⁹ amongst others.¹⁰

The widespread application of 1,2,3-triazoles is also due to their ease of synthesis. The thermal azide–alkyne cycloaddition (AAC), originally reported by Michael¹¹ and later formalised and popularised by Huisgen,¹² provides simple access to 1,2,3-triazoles, however often as a mixture of regioisomers (Scheme 1A). In 2002, the groups of Meldal and Sharpless independently reported the use of a copper(I) catalyst that promotes the AAC reaction between azides and terminal alkynes at room temperature, and provides only the 1,4-regioisomer of triazole product (Scheme 1B).¹³ Following this seminal work, a wide range of transition metal catalysts (Ru, Ir, Rh, Ag, Ni, Zn, Au) have been reported for AAC reactions.¹⁴ Depending on the catalyst, selective access to either the 1,4- or 1,5-regioisomer of triazole is now possible with both terminal and internal alkynes (Scheme 1C). The use of strained alkynes has also been used to accelerate the metal-free AAC reaction through strain release,^3b,c with this approach particularly suited to bioconjugation strategies (Scheme 1D). Beyond AAC reactions, organocatalytic and base-mediated approaches to 1,2,3-triazoles have been reported from ketones and azides (Scheme 1E).^14e,15 Finally, a range of azide-free approaches have been developed, which typically use hydrazine, hydrazone or diazo derivatives as the nitrogen-rich substrate.^14e,15b,c,16

Scheme 1 Synthetic approaches to 1,2,3-triazoles.

Organofluorine compounds have also attracted significant interest in a range of fields due to their unique physicochemical, electrochemical and biological properties, which are often distinct from their non-fluorinated analogues.¹⁷ Many of these differences originate from the high electronegativity of fluorine which results in high dipole moments, low polarisability, small size and strong C–F bonds.¹⁸ The main area of application is within medicinal chemistry,¹⁹ where the introduction of fluorine impacts various pharmacological properties of the drug candidate, including membrane permeability, metabolic stability, lipophilicity, and binding affinity. Beyond medicinal chemistry, the unique properties of organofluorine compounds have also resulted in their application in agrochemicals²⁰ and functional materials.^17,21

Combining the unique structural, chemical and biological properties of 1,2,3-triazoles and fluorine therefore provides great potential for applications across a range of fields.

Fluorine may be incorporated directly on the triazole ring at the C(4) (1) or C(5) (2) position, or alternatively polyfluoroakyl/aryl substituents may be incorporated at the N(1) (3), C(4) (4) or C(5) (5) position (Fig. 1). This review will provide a thorough summary of recent advances in the synthesis of these classes of triazoles, in addition to an overview of their applications. Focus has been devoted to applications where the properties of both the 1,2,3-triazole and organofluorine substituent are proposed to play essential roles in the compound's functionality. Several specialised reviews have been released on aspects of the synthesis or applications of fluorinated triazoles,^22–24 however to the best of our knowledge no comprehensive review on the subject currently exists.

Fig. 1 Fluorinated triazole structures covered in this review.

2. Synthesis of C(4) and C(5) fluorinated 1,2,3-triazoles

2.1. Introduction

The introduction of fluorine at the C(4) or C(5) position of a 1,2,3-triazole would ideally be achieved using a fluoroalkyne, however, these substrates are relatively difficult to synthesise and are typically unstable.²⁵ The earliest preparation of fluoroacetylene 8 was reported by Middleton and Sharkey in 1959 through the pyrolysis of monofluoro-maleic anhydride at high temperature (650 °C) and low pressure (5–7 mmHg).²⁶ In 1982, Sauvêtre reported that lithiation of 1,1-difluoroethylene 6 and subsequent β-elimination of LiF gave fluoroacetylene 8 (Scheme 2A). However, both fluoroacetylene 6 and the lithiated intermediate 7 are unstable and explosive.^26,27 In the same year Taylor²⁸ synthesised perfluoropropyne 10 through the debromination of dibromotetrafluoropropene 9 (Scheme 2B). Perfluoropropyne 10 was obtained by condensation at −196 °C. Due to the challenges of synthesising and handling fluoroalkynes, approaches to access 4- and 5-fluorotriazoles that avoid the use of a fluoroalkyne have been pursued.

Scheme 2 Preparation of fluoroalkynes.

Some traction has been gained in the use of fluoroalkyne surrogates to circumvent the use of unstable fluoroalkynes.²⁹ In general, these ‘surrogates’ are fluoroalkenes bearing an electron-withdrawing substituent which serves two purposes; (i) as an activating group to promote the initial reaction with an azide, and (ii) as a leaving group to provide the triazole in the final step (Scheme 3).

Scheme 3 Fluoroalkyne ‘surrogate’ approach.

The first example of this ‘surrogate’ approach was reported by Reck in 2005,^29a using α-fluorovinylsulfone 12 (Scheme 4). A thermal AAC reaction with oxazolidinone-functionalised azide 11 at 110 °C gave a 1 : 7 mixture of the 1,4- and 1,5-regioisomers 13 and 14 in a combined yield of 28%.

Scheme 4 Cycloaddition-elimination using α-fluorovinylsulfone fluoroalkyne surrogate 12.^29a

2.2. 4-Fluoro-1,2,3-triazoles

Building on Reck's initial work, Roy^29b and Nenajdenko^29c showed the efficiency and regioselectivity of these reactions can be improved by using an α-fluoronitroalkene 16 as a fluoroalkyne surrogate in combination with a Brønsted acid catalyst (Schemes 6 and 7). The preparation of α-fluoronitroalkenes 16 was achieved in a ‘one-pot’ process from a benzaldehyde derivative 15via an α-fluorobromoalkene intermediate (Scheme 5A).^29b,30 It is worth noting that this procedure is only applicable for the synthesis of β-aryl α-fluoronitroalkenes 16 as conversion of the α-fluorobromoalkene intermediate to the final nitroalkene product requires stabilisation of a radical intermediate by the aryl substituent. However, Beier has reported an alternative Horner–Wadsworth–Emmons approach using diethyl fluoronitromethylphosphonate 18 (Scheme 5B), which allows access to both β-alkyl- and β-aryl α-fluoronitroalkenes.³¹ However, to the best of our knowledge these β-alkyl α-fluoronitroalkenes have not yet been applied for triazole synthesis.

Scheme 5 Preparation of α-fluoronitroalkenes (A) via an α-fluorobromoalkene intermediate; (B) through a Horner–Wadsworth–Emmons approach.

Scheme 6 Synthesis of 1,5-disubstituted-4-fluoro-triazoles 20 from α-fluoronitroalkenes 16.

Scheme 7 Synthesis of 4-fluoro-NH-1,2,3-triazoles 21.^29c

Roy utilised β-aryl α-fluoronitroalkenes 16 for the regioselective preparation of 1,5-disubstituted-4-fluoro-1,2,3-triazoles 20 in good yields (Scheme 6).^29b Through screening a range of Lewis and Brønsted acids, it was shown that regioselectivity and yield was significantly enhanced by using trifluoroacetic acid (TFA). This can be explained by the mechanism given in Scheme 3, where protonation of the electron-withdrawing nitro group can further promote regioselective product formation. A range of aryl- and alkyl-substituted azides were tolerated, however aryl azides bearing electron-withdrawing groups gave lower yields.^29b α-Fluoronitroalkenes bearing β-aryl groups with para- or meta-substitution were tolerated, with those bearing electron-donating groups providing the highest yields.

Nenadjenko showed the addition of sodium azide to β-aryl α-fluoronitroalkene 16 in the presence of sulfamic acid led to the formation of 4-fluoro-1,2,3-NH-triazoles 21 (Scheme 7).^29c Low nitroalkene concentration was necessary for a successful reaction, with this requirement suggested to minimise the polymerisation of proposed intermediate 22 (Scheme 7). In addition to activating the α-fluoronitroalkene to nucleophilic addition, sulfamic acid was also suggested to promote protonation of intermediate 22 to favour triazole formation over polymerisation. The NH-triazoles were isolated in good yields, and the reaction is tolerant of a variety of aryl substituents, except for those bearing electron-withdrawing groups, which were liable to undergo competitive anionic polymerisation.

Inspired by the work of Sauvêtre (Scheme 2A),²⁷ Ichikawa reported difluorovinylzinc N,N,N′,N′-tetramethylethylenediamine (TMEDA) complex 24 as a thermally stable fluoroacetylene equivalent (Scheme 8).³² Lithiation of 1,1-difluoroethylene 23, followed by addition of zinc chloride and TMEDA gives difluorovinylzinc TMEDA complex 24 in excellent yield. The reagent was reported to be thermally stable, allowing it to be stored and used as a solution in THF/Et₂O. Ichikawa initially used this reagent in palladium-³² and copper-catalysed^32,33 cross-coupling reactions with aryl, alkenyl, alkynyl, allyl, and benzyl coupling partners, before applying it in the formation of 4-fluoro-1,2,3-triazoles in 2020.³⁴

Scheme 8 Preparation of difluorovinylzinc complex 24.

In the presence of CuCl and 1,10-phenanthraline, Ichikawa demonstrated that difluorovinylzinc TMEDA complex 24 could be applied in the copper-catalysed synthesis of a variety of 4-fluoro-triazoles 25 in good yields (Scheme 9).³⁴ A range of substituted benzylic azides were tolerated; however, the application of aryl and allylic azides required the use of 2.5 eq. of 24 to achieve good yields.

Scheme 9 Copper-catalysed synthesis of 4-fluoro-1,2,3-triazoles 25 from difluorovinylzinc TMEDA complex 24.

A mechanism for this reaction was proposed to begin with transmetallation of 24 to give Cu–fluoroalkene 26, followed by co-ordination of CuCl (Scheme 10). This allows for oxidative cyclisation to 6-membered metallocycle 28 followed by reductive elimination and β-fluoride elimination to give the triazole product 25. The proposal of one σ-bonded Cu and one π-complexed Cu is in line with the mechanism described by Fokin for copper-catalysed alkyne–azide cycloadditions.³⁵ An alternative pathway through initial β-fluoride elimination to give in situ fluoroacetylene was considered but discounted through preliminary mechanistic experiments.³⁴

Scheme 10 Ichikawa's proposed mechanism for the copper-catalysed synthesis of 4-fluoro-1,2,3-triazoles 25 from difluorovinylzinc TMEDA complex 24.

Building on previous work on the reaction of β-ketophosphonates and azides to give 1,5-disubstituted triazoles,³⁶ Chou demonstrated that a range of 1,4,5-trisubstituted triazoles could be produced in the base-mediated reaction of α-substituted-β-ketophosphonates and azides.³⁷ Of the 35 examples reported, two demonstrated the introduction of a fluorine at the C(4) position of the triazole 31, by using the appropriate α-fluoro-β-ketophosphonate 30 (Scheme 11).

Scheme 11 Base-mediated synthesis of 4-fluoro-1,2,3-triazoles 31 from α-fluoro-β-ketophosphonates 30 and azides.

2.3. 5-Fluoro-1,2,3-triazoles

The synthesis of 5-fluoro-1,2,3-triazoles 33 has been exclusively achieved from 5-iodo-1,2,3-triazoles 32 through a so-called “halogen exchange” (Halex) reaction.³⁸ This approach was first reported by Fokin in 2012 using KF at 180 °C under microwave irradiation (Scheme 12A).³⁸ The reaction is tolerant of various functional groups in both the N(1) and C(4) positions, except for alkyl chains at C(4), which led to a complex mixture of products. Additionally, the high temperature required for this reaction led to decomposition over long reaction times. The work was extended to include amide, ketone, nitrile and N-p-toluenesulfonyl functional groups by using the acidic KHF₂ reagent in place of KF (Scheme 12B).³⁸

Scheme 12 Halex reaction reported by Fokin³⁸ using (A) KF; (B) KHF₂.

Neither of the other regioisomers of iodotriazole (34 or 35) could be applied in this methodology, with >98% of the starting iodotriazole recovered in each case (Scheme 13).³⁸

Scheme 13 Alternative iodotriazole regioisomers unreactive under Halex reaction conditions.

Since 5-iodotriazole 32 can undergo a Dimroth-like fragmentation through ring-chain isomerisation,³⁹ it was proposed the reaction may proceed via imidoyl iodide 36, which could undergo iodide–fluoride exchange and ring-chain isomerisation to give 5-fluorotriazole 33 (Scheme 14A). This proposal is consistent with neither of the other regioisomers of iodotriazole being applicable in this reaction (Scheme 13) and is supported by the known reaction of imidoyl halides to give fluoride analogues under similar conditions.⁴⁰ Although this mechanism was favoured by the authors, they could not rule out the possibility of an S_NAr-type pathway (Scheme 14B).

Scheme 14 (A) Fokin's proposed mechanism for Halex reaction; (B) alternative S_NAr mechanism.³⁸

In 2015, Chu further developed the Halex reaction by demonstrating that AgF could be used as the fluoride source in the presence of TMEDA as a solubilising agent in toluene at reflux (Scheme 15).⁴¹ This method was applicable to a wider substrate scope, in particular triazoles bearing C(4) alkyl substituents, which were not tolerated in Fokin's method using KF.³⁸

Scheme 15 Alternative Halex reaction conditions reported by Chu using silver fluoride.

Protodehalogenated triazole side-products were also observed, which prompted mechanistic studies using deuterated solvents. Using d₆-DMSO as solvent provided 63% of the deuterodehalogenated triazole 45 (Scheme 16), whilst the use of D₂O in DMF or MeCN led to 32% and 25% of triazole 45, respectively. These studies indicated that the protodehalogenated side-product may form by intercepting an organometallic intermediate, hence, the need for strict exclusion of water in this transformation.

Scheme 16 Deuteration studies.

Replacing AgF with KF or CsF provided no conversion, indicating that silver is essential for this reaction. It was therefore proposed that, in contrast to Fokin's method using KF, AgF is not simply providing a nucleophilic source of fluoride. Based on a related mechanism proposed by Ritter for the fluorination of stannanes,⁴² Chu suggested that oxidative addition of silver into the carbon–iodine bond of 40 gives a bimetallic silver(II) fluoride intermediate 46, which undergoes reductive elimination to give the triazole product 41 (Scheme 17).

Scheme 17 Mechanistic proposal for Chu's Halex reaction.⁴¹

3. Synthesis of C(4) and C(5) polyfluoroalkyl- and polyfluoroaryl-1,2,3-triazoles

3.1. Introduction

The preparation of C(4) and C(5)polyfluoroalkyl-1,2,3-triazoles would be most easily attempted through the use of polyfluoroalkyl-substituted alkynes, however simple analogues are gaseous and potentially unstable species. In the 1960s, Norris⁴³ and then Moore⁴⁴ used the zinc mediated reduction of dichloroalkenes 47 and 48 for the preparation of 3,3,3-trifluoropropyne 49 and hexafluorobut-2-yne 50, respectively (Scheme 18A). Hamper⁴⁵ also showed it was possible to prepare α-acetylenic esters through the vacuum pyrolysis of α-acylmethylenephosphorane 51 at 150–200 °C and 1–2 torr (Scheme 18B). This procedure specified the need for slow heating to ensure the unstable alkyne product 52 is not formed too quickly. The issues of thermal instability and difficult handling due to their gaseous nature are akin to those encountered with fluoroacetylene derivatives. Despite the challenges, Hamper's method is still used for the preparation of perfluoroalkyl-substituted α-acetylenic esters.⁴⁶

Scheme 18 Preparation of perfluoroalkyl-alkynes.

Shibata has reported the use of fluoroform as a source of difluorocarbene for the preparation of difluoromethyl-substituted alkynes 54 from phenylacetylene derivatives 53 (Scheme 19).⁴⁷ Under basic reaction conditions, fluoroform can be used as a source of the ⁻CF₃ carbanion, or as the more stable difluorocarbene and a fluoride anion.⁴⁸ A range of difluoromethyl-alkynes can be synthesised by this method, including those bearing electron-rich and -poor arenes and heteroarenes.

Scheme 19 Synthesis of CF₂H-substituted phenylacetylene derivatives.

In contrast to polyfluoroalkyl-substituted alkynes, polyfluoroaryl-alkynes are generally more stable and easier to prepare and handle, thus simplifying the synthesis of the corresponding polyfluoroaryl-1,2,3-triazoles. In 1991, Zanardi⁴⁹ showed that polyfluoroaryl-alkynes bearing a CF₃-substituent 56 could be synthesised by base-mediated elimination of HCl from the corresponding chloroalkene 55 (Scheme 20A). Adopting a similar approach to Hamper, Rao showed that β-oxo-alkylidenetriphenylphosphoranes 57 could be transformed to the corresponding polyfluoroaryl-alkynes 58 following just 5 minutes of microwave irradiation (Scheme 20B).⁵⁰ Finally, polyfluoroaryl-substituted alkynes, such as 59, can be prepared from the corresponding polyfluoroaryliodide through a Sonogashira cross-coupling reaction (Scheme 20C).⁵¹

Scheme 20 Preparation of polyfluoroaryl-alkynes. Aryl^F = polyfluoroaryl.

Due to the relative ease with which polyfluoroaryl-substituted alkynes can be accessed, the corresponding triazoles are generally synthesised using well-established metal-catalysed azide–alkyne cycloaddition reactions. As such, these synthetic methods have not been explicitly discussed in this review and the following sections will focus on the synthesis of polyfluoroalkyl-substituted triazoles. Examples of thermal AAC reactions have been reported for the synthesis of polyfluoroalkyl-substituted triazoles,^{23a,b,44,46b,49,52} often giving mixtures of regioisomers. The following sections will therefore focus on a diverse range of specialised approaches that selectively provide access to a single regioisomer of triazole product.

3.2. 4-Polyfluoroalkyl-1,2,3-triazoles

In 2015, Ma reported the silver-catalysed synthesis of 4-CF₃-1,2,3-triazoles 62 from isocyanides 60 and 2,2,2-trifluorodiazoethane 61 (Scheme 21).^52,53 It should be noted that low molecular weight diazo compounds are potentially explosive,⁵⁴ and previous explosions have been reported with 2,2,2-trifluorodiazoethane.⁵⁵ The approach proved to be regioselective and applicable to a variety of aryl isocyanides, bearing electron-donating and -withdrawing substituents in the ortho-, meta-, and para-positions. Adamantyl isocyanide was also tolerated, although cyclohexyl and t-butyl isocyanides gave only modest conversion to the triazole products.

Scheme 21 Synthesis of 4-trifluoromethyl-triazoles from isocyanides and 2,2,2-trifluorodiazoethane.

Interestingly, it was reported that if two or more equivalents of the diazo reagent were used, 1,4,5-trisubstituted triazole 63 was isolated in up to 12% yield (Scheme 22). Treatment of the triazole product 62 with 2,2,2-trifluorodiazoethane 61 under the reaction conditions did not lead to the formation of 1,4,5-trisubstituted triazole 63, indicating that this side-product is most likely formed prior to the formation of triazole 62. Based on in situ¹³C NMR and IR monitoring, it was suggested that the isocyanide co-ordinates to the silver catalyst to give a silver(I) isocyanide complex,⁵⁶ which undergoes cycloaddition with 2,2,2-trifluorodiazoethane 61. This provides a Ag-intermediate, which following protonation gives the product 62. Alternatively, reaction of this Ag-intermediate with 2,2,2-trifluorodiazoethane 61 gives side-product 63.

Scheme 22 Formation of side-product 63 in the presence of excess 2,2,2-trifluorodiazoethane 61.

In 2020, Panja reported an alternative approach to prepare 4-trifluoromethyl-triazoles 65 through the copper-mediated trifluoromethylation of 4-iodotriazoles 64 (Scheme 23A).⁵⁷ The use of CuI, methyl-2,2-difluoro-2-(fluorosulfonyl) acetate (MDFA, also known as Chen's reagent),⁵⁸ and tetrabutylammonium iodide (TBAI) gave the desired trifluoromethyl triazole products 65 in moderate yields. The reaction was proposed to proceed through demethylation of MDFA by iodide to give copper carboxylate complex 66 (Scheme 23B). Decarboxylation results in the loss of CO₂ and SO₂ to give difluorocarbene⁵⁹ and a fluoride ion, which can combine to form Cu–CF₃ intermediate 67. Finally, this intermediate mediates the cross-coupling with iodotriazole 64 to give the trifluoromethylated triazole product 65.^58,60

Scheme 23 Synthesis and proposed mechanism for the copper-mediated formation of 4-trifluoromethyltriazoles 65.

Topczewski reported an interrupted Banert cascade reaction⁶¹ for the preparation of α-fluoro-NH-1,2,3-triazoles 69 (Scheme 24).⁶² Heating propargylic azide 68 at 60 °C was proposed to promote a [3 + 3]-sigmatropic rearrangement to give allene intermediate 70, which undergoes electrocyclisation to triazafulvene 71. Finally, nucleophilic addition of fluoride provides the α-fluoro-NH-1,2,3-triazole product 69 (Scheme 24).^62,63

Scheme 24 Banert cascade approach to α-fluoro-NH-1,2,3-triazoles 69.

Zajc reported the synthesis of fluorinated 1,4-disubtituted-1,2,3-triazoles 73 from novel fluorinated benzothiazole sulfones 72 (Scheme 25).⁶⁴ This transformation involves silyl-deprotection followed by a copper-catalysed AAC reaction with aryl or alkyl azides. The benzothiazole sulfone-substituted triazoles 73 were subsequently applied in Julia–Kocienski olefination reactions (see section 6.2).⁶⁴

Scheme 25 Copper-catalysed synthesis of α-fluoro-benzothiazole sulfone-substituted triazoles.

In 2018, both Moses^65a and Fokin^65b used 1-bromoethenesulfonyl fluoride 76 (known as BESF or Br–ESF) as a synthetic equivalent for acetylenesulfonyl fluoride for the preparation of 4-sulfonyl fluoride-substituted 1,2,3-triazoles 75. Sulfonyl fluorides are commonly applied reagents in SuFEx click reactions, used in a variety of fields and notably as biological probes.⁶⁶ Moses showed this reagent could be formed in situ by reacting 1,2-dibromoethane-1-sulfonyl fluoride 74 (DESF) with Et₃N for 5 minutes. Addition of an azide and heating to 90 °C, in the absence of any catalyst, provides the 4-sulfonyl fluoride-substituted triazole product 75 as a single regioisomer (Scheme 26A).^65a Aryl azides bearing electron-donating and withdrawing groups were tolerated, however, no examples using alkyl azides were demonstrated. It was proposed that following in situ formation of BESF 76, [3 + 2]-cycloaddition of the azide provides triazoline 77, which following elimination of HBr gives triazole 75 (Scheme 26B). Moses also demonstrated the use of in situ generated BESF for the synthesis of isoxazoles and β-sulfams.

Scheme 26 Preparation and proposed mechanism for the formation of 4-sulfonyl fluoride-substituted 1,2,3-triazoles.

Fokin showed it was possible to synthesise and isolate BESF 76 on a 68 g scale by elimination of HBr from 1,2-dibromoethane-1-sulfonyl fluoride at −78 °C (Scheme 27A).^65a,67 In the absence of a catalyst, the reaction of BESF 76 with both aryl and alkyl azides gave a wide range of 4-sulfonyl fluoride-substituted 1,2,3-triazoles 78 in good yields (Scheme 27B).

Scheme 27 (A) Large-scale synthesis and isolation of BESF 76; (B) preparation of 4-sulfonyl fluoride-substituted triazoles 78 using BESF 76.

In 2020, Moses extended and improved on this approach with the development of alkynyl sulfonyl fluoride reagents 79 that were applied for the synthesis of 12 different classes of heterocycle.⁶⁸ Within this broad scope, the synthesis of 4-sulfonyl fluoride-substituted triazoles 80 was demonstrated through a Rh-catalysed AAC reaction (Scheme 28).

Scheme 28 Synthesis of alkynyl sulfonyl fluoride reagents 79 and application for synthesis of 4-sulfonyl fluoride-substituted triazoles 80.

3.3. 5-Polyfluoroalkyl-1,2,3-triazoles

Beyond the use of thermal AAC reactions, efforts have been made to selectively install trifluoromethyl groups in the C(5) position of 1,2,3-triazoles, resulting in various methods published in recent years. An approach that is comparable to Panja's work⁵⁷ above was reported by Cao in 2013.⁶⁹ The copper-mediated transformation of 1,4-diaryl-5-iodo-1,2,3-triazole derivatives 81 to the trifluoromethylated analogue 82 was achieved using TMSCF₃ (Ruppert–Prakash reagent)⁷⁰ as the trifluoromethyl source (Scheme 29). The method provides triazoles 82 in good yields and was demonstrated with both electron-neutral and -rich aromatics at the C(4) position and a range of N-benzylic and N-alkyl substituents.

Scheme 29 Copper-mediated synthesis of 5-trifluoromethyl-substituted 1,2,3-triazoles 82.

Tsui published a related interrupted copper-catalysed AAC reaction to prepare 5-trifluoromethyl-1,2,3-triazoles 85 (Scheme 30).^71a The cycloaddition of a range of alkynes with azides was achieved using a combination of CuI, 1,10-phenanthroline, TMSCF₃, Ag₂CO₃, and Et₃N. Alkynes bearing a range of aryl and ester substituents were tolerated, however only the use of benzylic azides was demonstrated. Improved yields were obtained when TMSCF₃ was added at 0 °C before warming the reaction to room temperature, with this approach proposed to slow down the decomposition of the reagent.

Scheme 30 Interrupted copper-catalysed azide–alkyne cycloaddition for the synthesis of 5-trifluoromethyl-substituted 1,2,3-triazoles 85.

A catalytic cycle was proposed based on literature⁷² with control reactions showing that formation of a CF₃-substituted internal alkyne 89 or the protonated triazole 91 prior to CF₃ substitution were not relevant for the productive catalytic cycle (Scheme 31). Following formation of copper acetylide 87, in the absence of azide, formation of both diyne 88 and CF₃-alkyne 89 can occur. However, when an azide is present, cycloaddition with the copper acetylide gives cuprated triazole 90, which can be protonated by water or protic solvent to form protonated triazole 91 as a side-product. Alternatively, reaction of cuprated triazole intermediate 90 with TMSCF₃ in combination with Ag₂CO₃-mediated oxidation, gives proposed copper(III) intermediate 92. This copper(III) species can undergo reductive elimination to form the product and regenerate catalyst 86.^71a Zhu and Li reported a related process, where the silver oxidant used by Tsui was omitted, and the reaction was simply run in the presence of air.^71b Of note, a specific glycinamide bis-triazole ligand was required to obtain good selectivity for the trifluoromethylated triazole product over the protonated triazole side-product. The method was also demonstrated with longer chain perfluoroalkylsilanes and applied to a wider range of azides and alkynes than reported by Tsui.

Scheme 31 Proposed catalytic cycle of interrupted CuAAC reaction.

Building on their previous work,^71a Tsui published an interrupted copper-mediated AAC reaction for the preparation of 5-C₂F₅-substituted triazoles 95 (Scheme 32A).^71c This method requires the preparation of [CuC₂F₅] from gaseous HCF₂CF₃, CuCl, t-BuOK and Et₃N·HF in a glovebox, however once the fluorinating agent has been prepared it can be used under aerobic conditions. Following a series of control experiments, it was proposed that the reaction proceeds in a similar manner to other interrupted copper-catalysed AAC reactions through formation of a 5-cuprated-triazole intermediate, which undergoes reductive elimination to install the C₂F₅ group. Interestingly, applying Et₃SiC₂F₅ under the conditions reported in their previous methodology for the synthesis of 5-trifluoromethyl-substituted 1,2,3-triazoles (see Scheme 30)^71a led to only 16% yield of the C₂F₅-substituted triazole 96, demonstrating the advantage of using CuC₂F₅ in this approach (Scheme 32B).

Scheme 32 Copper-mediated synthesis of 5-C₂F₅-substituted triazoles 95.

Beyond the use of copper-mediated couplings and cycloadditions, Zhu reported the formal [3 + 2] cycloaddition between tertiary enamines 97 and azides 98 ¹⁵ to give 5-polyfluoroalkyl substituted triazoles 99 (Scheme 33A).^73a High temperatures and long reaction times were required, and the reactions were generally performed neat, with an excess of azide used as solvent. When benzyl azides were used the addition of sodium carbonate was also required. In a related base-mediated approach,¹⁵ Bakulev showed that a range of 5-trifluoromethyl substituted triazoles 102 could be access from trifluoromethyl 1,3-diketones and β-ketoesters 100 in the presence of triethylamine as a Brønsted base (Scheme 33B).^73b A range of 1,3-dicarbonyls were applicable, however only azides bearing electron-withdrawing groups gave good yields (for example p-MeOC₆H₄N₃: 12%; BnN₃: 9%).

Scheme 33 Enamine and base-mediated synthesis of C(5)-polyfluoroalkyl-substituted triazoles.

In 2013, Cao reported a combined copper- and piperidine-catalysed reaction of (hetero)aryl boronic acids 104, ketones 103 and sodium azide for the preparation of 1,4,5-trisubstituted-1,2,3-triazoles 105 (Scheme 34).^73c In this method, the aryl boronic acids 102 are converted to the corresponding aryl azides in situ via a copper-catalysed Chan–Lam coupling with sodium azide. Triazole synthesis can then take place through enamine catalysis.^15,74 The ketones used all required an anion-stabilising substituent in the β-position, such as another ketone, an ester or a nitrile. Of relevance to this review, trifluoromethyl and difluoromethyl ketones were applied to give CF₃ and CF₂H substituents in the C(5) position, in addition to fluorinated aryl N(1) substituents.^73c

Scheme 34 Copper- and piperidine-catalysed synthesis of triazoles, through Chan–Lam coupling followed by CuAAC.

Tverdekhlebov has also demonstrated the preparation of 1-alkyl-5-trifluoromethyl-1,2,3-triazoles 107 through the reaction of secondary enamines 106 with mesyl azide in the presence of DBU (Scheme 35A).⁷⁵ Calculation of frontier orbital energies by Kascheres in 1993,⁷⁶ coupled with experimental data led to the following proposed mechanism (Scheme 35B). The nucleophilic enamine 106 reacts with electrophilic mesyl azide, which, following tautomerisation, gives intermediate triazine 108. The electron-withdrawing methanesulfonyl group is necessary to lower the LUMO of the azide and promote this initial reaction.⁷⁶ An ‘anti-Baldwin’ 5-endo-trig cyclisation of the enamine nitrogen onto the triazine gives intermediate 109, which following DBU-mediated elimination of methanesulfonamide provides triazole product 107.

Scheme 35 Use of enamines 106 and mesyl azide for triazole synthesis (A) and proposed mechanism (B).

In 2021, Bi reported an alternative route to 5-polyfluoroalkyl triazoles 112 through the reaction of perfluoroalkyl N-mesylhydrazones 110 with amines 111 (Scheme 36).⁷⁷ This reaction was proposed to proceed by defluorinative condensation of the amine 111 with the perfluoroalkyl N-mesylhydrazone 110, followed by cyclisation and elimination of methanesulfinic acid. A very large scope was reported, with triazoles 112 generally obtained in excellent yields. In addition to simple aryl and alkyl amines, complex natural products and bioactive molecules containing primary amines were also applied. The perfluoroalkyl N-mesylhydrazone substrates 110 were reported to be bench-stable solids that can be synthesised through the condensation of methanesulfonohydrazide and perfluoroalkyl aldehyde hydrates.

Scheme 36 Defluorinative [4 + 1] annulation of perfluoroalkyl N-mesylhydrazones 110 with primary amines 111.

Wu has also reported an alternative approach to C(5)-polyfluoroalkylated triazoles 115 using diazo compounds 113 and polyfluoroalkyl-imidoyl chlorides 114 (Scheme 37).⁷⁸ A wide range of different polyfluoroalkyl substituents on the imidoyl chloride were demonstrated. While the N-substituent was generally aromatic, an example of an N-alkyl-substituted imidoyl chloride was also successfully applied. Ethyl diazoacetate was generally used, however other stabilised diazo compounds were demonstrated, including those bearing aryl ketones, phosphonates and a trifluoromethyl group. Although some diazo compounds are relatively unstable, this method provides access to triazoles that would be difficult to access through other routes, such as the example with CF₃ groups in both the C(4) and C(5) positions.

Scheme 37 Synthesis of C(5)-polyfluoroalkylated triazoles 115 from diazo compounds 113 and polyfluoroalkyl-imidoyl chlorides 114.

Interrupted copper-mediated AAC reactions have also been used for the synthesis of (5)-SCF₃-substituted triazoles 118 (Scheme 38).⁷⁹ A combination of Cu(I) iodide, elemental sulfur, AgCO₃ and TMSCF₃ was proposed to generate a CuSCF₃ reagent in situ, which can intercept the copper–triazole intermediate formed through the CuAAC reaction. The use of a range of both aryl and alkyl azides and alkynes was demonstrated to provide triazoles 118 in good yields.

Scheme 38 Copper-mediated synthesis of 5-SCF₃-1,2,3-triazoles 118.

Xu reported an interrupted CuAAC that allowed for the isolation of stable 5-stannyl-1,2,3-triazoles 119, which could be reacted with a range of electrophiles and applied in cross-coupling reactions.⁸⁰ The reaction of these 5-stannyl-1,2,3-triazoles 119 with Togni reagent II 120 or N-trifluoromethylthiosaccharin 122 provided access to a range of 5-CF₃ and 5-SCF₃ triazoles 121 and 122, respectively (Scheme 39).⁸⁰

Scheme 39 Electrophilic fluorination of 5-stannyl-triazoles 119 with (A) Togni reagent II 120; (B) N-trifluoromethylthiosaccharin 122.

Billard reported an alternative approach to the synthesis of 5-SCF₃-triazoles 125 through the direct reaction of NaN₃ with a SCF₃-substituted alkyne 124 (Scheme 40).⁸¹ A one-pot two-step cycloaddition–alkylation process was also demonstrated to give ring-fused triazole 127.

Scheme 40 Synthesis of 5-SCF₃-triazoles utilising NaN₃.

More general access to 5-SCF₃-triazoles from SCF₃-substituted alkynes has been reported by Guo and Song using ruthenium and rhodium catalysis, respectively (Scheme 41).⁸² Guo reported the use of both trifluoroethyl- and (trifluoromethyl)thiosubstituted alkynes (128 and 129) for the synthesis of 1,2,3-triazoles bearing a CH₂CF₃ or SCF₃ substituent in the C(5) position (Scheme 41A).^82a The majority of examples focused on the use of trifluoroethyl-substituted alkynes 128, with a range of both aryl and alkyl azides and aryl alkynes demonstrated. A significantly lower yield was obtained using an enyne substrate and no examples of alkyl-substituted alkynes were reported. Three examples of 5-SCF₃-triazoles 132 were also synthesised under analogous conditions with good yields obtained. The regioselectivity of the 5-CF₃CH₂-triazoles 131 was confirmed for several products by X-ray crystallography.

Scheme 41 Preparation of 5-CH₂CF₃ and 5-SCF₃-1,2,3-triazoles.

Song reported a complementary rhodium-catalysed AAC reaction of SCF₃-substituted alkynes 133, where once again a range of alkyl and aryl azides were utilised, but only aryl-substituted alkynes were demonstrated (Scheme 41B).^82b The only alkyl-substituted alkyne attempted (R¹ = t-Bu) gave no reaction, however Song also reported an extended scope of thio- and seleno-alkynes bearing alkyl and aryl substituents (i.e. not CF₃) where examples of alkynes bearing linear alkyl chains were also successfully demonstrated.

4. Synthesis of N-polyfluoroalkyl- and -aryl-1,2,3-triazoles

4.1. Introduction

Whilst N-fluorinated 1,2,3-triazoles are known, their low stability means few syntheses or applications have been reported.^23a The synthesis of N-polyfluoroalkyl- and aryl triazoles is much more common and is usually achieved through transition metal-catalysed AAC reactions (Scheme 42),^13,14 however other methods will also be discussed in this section. The main challenge therefore often lies in the synthesis of the polyfluoroalkyl- and aryl azides required for use in these AAC reactions.

Scheme 42 Common approach to synthesise N-polyfluoroalkyl- and aryl-substituted 1,2,3-triazoles. TM = transition metal.

4.2. Synthesis of polyfluoroaryl and -alkyl azides

Polyfluoroaryl azides 136 are readily accessed in several ways,⁸³ including from polyfluoroaryl amines 137 (via the diazonium salt 138),⁸⁴ boronic acids 139 (through Cu(II)-catalysed Chan Lam coupling)⁸⁵ and halides 140 (through either S_NAr⁸⁶ or Cu(I)-catalysed Ullmann-type coupling)⁸⁷ (Scheme 43).

Scheme 43 General procedure for synthesis of polyfluoroaryl (Aryl^F) azides 136.

The synthesis of polyfluoroalkyl azides is significantly more challenging.⁸⁸ Alkyl azides are most conveniently synthesised by S_N2 substitution of a (pseudo)halide leaving group by azide,^83,89 however introduction of fluorine substituents on the alkyl chain severely inhibits nucleophilic substitution. Dolbier Jr has studied in detail the effect of fluorine substitution on the nucleophilic substitution of alkyl halides by sodium azide (Scheme 44A).⁹⁰ Comparing a simple alkyl bromide to γ- and β-fluorinated alkyl bromides revealed a significant deceleration in S_N2 rate upon introduction of fluorine close to the reaction centre [relative rates: n-C₇H₁₅Br (1); n-R^FCH₂CH₂Br (0.14); n-R^FCH₂Br (0.00002)]. Whilst introduction of single α-fluorine substituent on an alkyl chain is tolerated [relative rates: n-C₇H₁₅Br (1); n-C₈H₁₇CHFBr (0.14)], α,α-difluorinated substrates do not undergo substitution in MeOH and only undergo E2 elimination in DMSO. The reduction in the rate of substitution was proposed to originate from two main effects: (1) the inductive electron-withdrawing effect of fluorine destabilising the developing partial positive charge in the S_N2 transition state; and (2) electrostatic repulsion of the approaching nucleophile due to the lone pairs/electron density on fluorine.

Scheme 44 Kinetic studies on the nucleophilic substitution of fluorinated alkyl bromides by azide.

In line with Dolbier Jr's kinetic studies, the synthesis of monofluoromethyl azide 142 is relatively simple to achieve from bromofluoromethane 141 and sodium azide in NMP at room temperature (Scheme 45).⁹¹ The azide was obtained in quantitative yields and could be isolated by co-distillation with THF in 82%.

Scheme 45 Synthesis of monofluoromethyl azide 142.

The preparation of 2-fluoroethyl azide 144 is also relatively simple through displacement of the respective tosylate 143 with sodium azide (Scheme 46).⁹² Alternatively these azides can be accessed through displacement of a β-tosylated azide 145 by fluoride. This approach has been widely exploited for the synthesis of ¹⁸F-labelled azide [¹⁸F]-144 using ¹⁸F isotopically enriched KF (Scheme 46).^92,93

Scheme 46 Synthesis of isotopic 2-fluoroethyl azide.

As shown in Dolbier Jr's kinetic studies, the synthesis of β,β-difluorinated alkyl azides is considerably more difficult, with high temperatures and long reaction times often required. Wu and Chen have shown the synthesis of long chain polyfluoroalkyl azides 147 can be synthesised from the reaction of the corresponding alkyl mesylate 146 and sodium azide for 20 h at 110 °C in the presence of 18-crown-6 (Scheme 47A).⁹⁴ Koroniak-Szejn subsequently investigated the use of both alkyl mesylates and tosylates 148, with the latter providing higher yields (Scheme 47B).⁹⁵ Shorter reaction times and reaction temperatures of 85 or 120 °C were achieved by using sodium azide in HMPA. Notably, the tosylate of hexafluoroisopropanol (HFIP) was applicable under these conditions to give a secondary alkyl azide. Koroniak-Szejn also reported a smaller range of alkyl iodides 150 were applicable when using sodium azide and Aliquot 336 (phase transfer catalyst) in a water/Et₂O mixture in a sealed tube at 90–100 °C (Scheme 47C).⁹⁵ The yields obtained were generally lower, suggesting the methods from mesylate of tosylate substrates are the best option for the synthesis of these polyfluorinated azides.

Scheme 47 General procedure for synthesis of 1,1-dihydro-fluroalkyl azides.

The only examples of α,α-difluorinated azides that can be synthesised through nucleophilic substitution are those bearing other activating groups, such as benzylic and α-carbonyl substrates (Scheme 48).^90,96 In these examples it is possible they may operate through a radical rather than S_N2 mechanism. Dolbier Jr reported the kinetics for the substitution of α,α-difluorobenzyl bromide with azide, with the relative rates for PhCH₂Br and PhCF₂Br measured as 1 and 0.000005, respectively (Scheme 44B).⁹⁰ As such, high reaction temperatures and times are required for this reaction (Scheme 48A).^96a The original synthesis of ethyl 2-azido-2,2-difluoroacetate 155 (R = Et) was first reported at 50 °C in DMSO,^96b however it has since been noted that these conditions can lead to an alternative substitution pathway to give ethyl azide and sodium bromodifluoroacetate.^96c,f Alternative conditions in DMF or MeCN have also been reported,^96g,h without the side-reaction being noted (Scheme 48B). Although yields have been reported, the α-azido ester is often simply used as a crude product in the next step of the synthesis. The use of sodium azide in DMSO at 50 °C has however been successfully used for the synthesis of the tert-butyl ester and amide analogues, where the same dealkylation side-reaction is not possible (Scheme 48B and C).^96c,e,f α-Azido-α,α-difluoro amides 157 have also been synthesised by amidation of the corresponding ethyl or methyl ester.^96e,97 Finally, two examples of α-azido-α,α-difluoroketones 159 have been reported, in both cases starting from the corresponding α-chloroacetophenone derivative 158 (Scheme 48D).⁹⁸

Scheme 48 Preparation of α,α-difluorinated benzylic and α-carbonyl azides.

The apparent nucleophilic substitution of vicinal dibromo- and diiodofluoroalkanes (160 and 162) by sodium azide was reported by Knunyants in 1986 (Scheme 49A).⁹⁹ Based on previous work,¹⁰⁰ an ionic chain mechanism was proposed, in which the reaction is initiated by the attack of azide on bromine to form BrN₃, elimination of bromide and formation of alkene intermediate 164 (Scheme 49B). Addition of azide to alkene 164 forms anionic intermediate 165, which can abstract another bromine from the substrate to propagate the chain mechanism.¹⁰¹ Evidence for this mechanism was provided by similar yields being achieved through the reaction of one of the proposed alkene intermediates 166 with sodium azide and bromine, giving addition product 167 in 70% yield (Scheme 49C). This provides a general approach to the synthesis of fluorinated alkyl azides 169 from polyfluoroalkenes 168 by the addition of sodium azide in the presence of an electrophile (Scheme 50). This method has been applied using a range of electrophiles, including sodium dihydrogen phosphate (acid),¹⁰² ICl,¹⁰³ aryl thiocyanates,¹⁰⁴ carbon dioxide¹⁰⁵ and perfluoroalkanoates¹⁰⁶ for the synthesis of diversely functionalised polyfluoroalkyl azides (Scheme 50).

Scheme 49 Synthesis of β-bromo- and β-iodo-fluoroalkylazides through an ionic chain mechanism.

Scheme 50 General approach for the synthesis of β-functionalised fluoroalkylazides.

In addition to fluorinated alkenes, difluorocarbene is a suitable electrophile for reaction with sodium azide (Scheme 51). Originally described in a 1973 patent,¹⁰⁷ and again in 1985 by Bock,¹⁰⁸ base mediated decomposition of chlorodifluoromethane 170 in the presence of sodium azide provides difluoromethyl azide 171 in 54% yield (Scheme 51A). More recently, Beier has shown that difluoromethyl azide 171 can also be accessed in a similar way via quaternary salt Bu₃N⁺(HCF₂)Cl⁻172 (Scheme 51B).¹⁰⁹

Scheme 51 Methods for the synthesis of difluoromethyl azide 171.

Beier has reported a series of relatively simple methods for the synthesis of fluoroalkyl azides 174 through the nucleophilic fluoroalkylation of electrophilic azide sources. Treatment of the commercially available Ruppert–Prakash reagent 173 (R^F = CF₃) with caesium fluoride in DMF in the presence of tosyl azide provides trifluoromethyl azide 174 (R^F = CF₃) in high yield (Scheme 52).¹¹⁰ The crude reaction product mixture has been applied in subsequent reactions, or the azide can be co-distilled with THF to produce a THF solution of the fluoroalkylazide product 174. Trifluoromethyl azide is significantly more thermally stable than methyl azide, with explosive decomposition only reported over 330 °C.¹¹¹ Longer chain perfluoroalkyl azides could be prepared in a similar way, however in some cases the more electrophilic nonaflyl azide (F₉C₄SO₂N₃) was required as the azide source (Scheme 52).^110,112

Scheme 52 Synthesis of azidoperfluoroalkanes 174 through nucleophilic fluoroalkylation of sulfonyl azides.

As an alternative to using trimethylsilyl-substituted polyfluoroalkanes 173, polyfluoroalkyl azides can also be synthesised by formation of a polyfluoroalkyl carbanion equivalent through deprotonation (Scheme 53A and B),^110,113 or magnesium–halogen exchange (Scheme 53C),¹¹² followed by reaction with tosyl or nonaflyl azide.

Scheme 53 Synthesis of azidoperfluoroalkanes 177, 179 and 182 through nucleophilic fluoroalkylation of sulfonyl azides.

4.3. Synthesis of N-polyfluoroaryl-1,2,3-triazoles

N-Polyfluoroaryl triazoles are most often synthesised through a thermal or transition metal catalysed azide–alkyne cycloadditions (Scheme 54). Whilst thermal methods usually give mixtures of regioisomers, high regioselectivity can be achieved for one regioisomer by using a transition metal catalyst.^12–14 When using a terminal alkyne 183, the vast majority of examples in the literature involving polyfluoroaryl azides 184 focus on the copper-catalysed synthesis of the 1,4-regioisomer 185;¹³ however there are also reports on using silver¹¹⁴ and ruthenium¹¹⁵ catalysts giving 1,4- and 1,5-regioselectivity (185 and 186), respectively (Scheme 54A). The use of internal alkynes 187 provides access to trisubstituted triazoles 188, with examples of polyfluoroaryl azides 184 being used in copper (specifically for iodo- and telluro-alkynes),¹¹⁶ rhodium,¹¹⁷ ruthenium^82a,118 and iridium¹¹⁹ catalysed AAC reactions (Scheme 54B).

Scheme 54 Transition metal-catalysed azide–alkyne cycloaddition approaches for the synthesis of N-polyfluoroaryl triazoles.

As previously outlined, aryl azides can be synthesised from aryl boronic acids and aryl iodides through copper-catalysed Chan Lam and Ullmann-type couplings, respectively (Scheme 43).^85,87 The telescoped copper-catalysed synthesis of triazoles through in situ generation of aryl azides from aryl boronic acids 190 or iodides 191 and subsequent CuAAC has therefore been developed,^85a,120 with a range of examples including polyfluorinated aryl groups (Scheme 55).^121,122 This approach is convenient to avoid the synthesis and isolation of the aryl azide and is particularly suited to library synthesis where a large range of aryl boronic acids and iodides are commercially available.

Scheme 55 Telescoped copper-catalysed synthesis of N-polyfluoroaryl triazoles 192 from aryl boronic acids 190 and iodides 191.

Polyfluoroaryl azides 194 have also been applied in base- and secondary amine-catalysed synthesis of triazoles from 1,3-diketones, β-keto esters, amides and nitriles 193 (Scheme 56A).^73a,74,123 These reactions proceed via an enolate or enamine (in the case of secondary amines) intermediate that reacts with the electrophilic azide, followed by ring closing and elimination of water.¹⁵ The electron-withdrawing nature of the polyfluoroaromatic group can therefore have a beneficial effect by increasing the electrophilicity of the azide. The ester-functionalised products 196 are particularly useful as hydrolysis followed by decarboxylation provides access to the less usual 1,5-disubstituted 197 triazole regioisomer (Scheme 56B).

Scheme 56 Base- and amine-catalysed synthesis of triazoles 195 from α-activated ketone derivatives 193.

Other α-substituted ketones, where the α-substituent provides an acidifying effect can also be applied in these reactions, such as α-aryl and α-thioalkyl/aryl ketones 198 (Scheme 57A).^123h,124 The 4-thio-substituted triazoles 201 can also be converted into 1,5-disubstituted triazoles 202 through desulfurisation using RANEY® nickel (Scheme 57B).^124a

Scheme 57 Base-catalysed synthesis of triazoles 200 from α-substituted ketones 198.

Another approach to access 1,5-disubstituted triazoles 206 is through the addition of in situ-generated magnesium acetylides to azides (Scheme 58).^125–127 The azide acts as an electrophile in this reaction and therefore the use of azides bearing electron-withdrawing groups (such as polyfluorinated azides 204) accelerate the reaction and provides high yields of triazole product. This is evidenced by the reaction with azides bearing electron-withdrawing groups being complete within an hour at room temperature, whereas azides bearing neutral or electron donating groups required 24–48 h to reach completion. This method also allows for the magnesiated triazole intermediate 205 to be trapped by a range of electrophiles to provide access to 1,4,5-trisubstituted triazoles 207.

Scheme 58 Synthesis of 1,5-di- and 1,4,5-trisubstituted triazoles 206 and 207 from magnesium acetylides.

The magnesiated triazole intermediate 205 is apparently stable at high temperatures for long reaction times, however metalated triazoles of the other triazole regioisomer are known to be unstable when bearing electron-withdrawing N-substituents. 1,4-Disubstituted triazoles bearing N-polyfluoroaryl groups 208 were shown to undergo rapid deprotonation with lithium diisopropylamide (LDA) at −78 °C, with the lithiated intermediate 209 subsequently trapped at −78 °C with a variety of electrophiles (Scheme 59A).¹²⁸ However if the lithiated intermediate 209 was left for extended times or allowed to warm above −78 °C, rapid decomposition led to over 15 compounds, including amidine 211. Based on related literature on N-phenyl- and N-sulfonyl triazoles,¹²⁹ it was believed that the electron-withdrawing N-substituent accelerates nitrogen extrusion through stabilisation of the intermediate acetylenamide 212 (Scheme 59B). Protonation, followed by nucleophilic attack by LDA provides the amidine product 211 upon protonation during reaction work-up.

Scheme 59 Formation, trapping and decomposition of lithiated triazoles 209 bearing N-polyfluoroaryl groups.

Avoiding the use of azides,¹⁶ the cyclocondensation of α-diazoketones and amines provides access to triazoles.¹³⁰ This approach is sometimes referred to as the Wolff triazole synthesis.¹³¹ Typically, an α-electron-withdrawing group and a Lewis or Brønsted acid is required to promote condensation of the amine and ketone. In 2019, Krasavin reported an example of this approach using sulfonyl-substituted α-diazoketones 215 and anilines 216, in which examples using fluorinated aniline derivatives were demonstrated (Scheme 60).¹³² Presumably fluorinated aniline derivatives could also be applied in other Wolff triazole syntheses,¹³⁰ however to the best of our knowledge this has not been reported.

Scheme 60 Triazole synthesis via Wolff cyclocondensation.

4.4. Synthesis of N-polyfluoroalkyl-1,2,3-triazoles

Thermal azide–alkyne cycloaddition (AAC) reactions between polyfluoroalkyl azides and terminal and internal alkynes have been reported at 90–140 °C to give N-polyfluoroalkyl triazoles.¹³³ In the case of terminal alkynes, low regioselectivity was generally reported. The most common method to synthesise N-polyfluoroalkyl triazoles is through CuAAC reactions, with nearly all examples in the literature synthesised this way. There is also a single example of a RuAAC reaction between thioalkynes and polyfluoroalkyl azides,¹³⁴ demonstrating that this metal/fluorinated azide combination is tolerated.

Beier has demonstrated that perfluoroethyl azide reacts twice as fast as ethyl azide with a terminal alkyne in a CuAAC reaction.¹¹⁰ As previously mentioned, short-chain perfluoroalkyl azides can be co-distilled with THF to allow isolation as a THF solution, however Beier also demonstrated that the crude perfluoroalkyl azide can be directly applied in a CuAAC reaction (Scheme 61).¹¹⁰ This method significantly simplifies their application for the synthesis of N-polyfluoroalkyl triazoles 218 and removes any operational concerns about azide distillation; however in some cases the regioselectivity of triazole formation was slightly lower than when using the purified azide.

Scheme 61 One-pot synthesis of N-trifluoromethyl triazoles 218.

In addition to applications in CuAAC reactions,^{91,101,102,109,110,112,113,135} Beier has demonstrated the use of polyfluoroalkyl azides 220 in an enamine-catalysed synthesis of triazoles 221 from 1,3-diketones and β-keto esters, sulfones, phosphonates, nitriles and α-nitroketones 219 (Scheme 62A).¹³⁶ The hydrolysis and decarboxylation of a select number of 4-ester-substituted products 222 was demonstrated to provide access to 1,5-disubstituted triazoles 223 (Scheme 62B). This approach is therefore complementary to the 1,4-disubstituted products obtained through CuAAC reactions.

Scheme 62 Preparation of 1,4,5-trisubstituted N-polyfluoroalkyl triazoles 221 and subsequent decarboxylation to access 1,5-trisubstituted N-polyfluoroalkyl triazoles 223.

The direct fluoroalkylation of triazoles and benzotriazoles has been reported through a range of approaches.^23b The difluoromethylation of triazole and benzotriazole derivatives has been reported using a range of difluorocarbene precursors.¹³⁷ Although the alkylation of benzotriazole 224 is regioselective (Scheme 63A), the alkylation of triazole derivatives 226 generally provides a mixture of the 1- and 2-difluoromethylated products 227 and 228 (Scheme 63B).

Scheme 63 Difluoromethylation of triazoles using difluorocarbene precursors.

N-Trifluoromethylation of a range of azoles has been reported by Togni using Togni reagent I 229.¹³⁸ Examples of benzotriazole and triazole N-trifluoromethylation was included in the reaction scope (Scheme 64). The in situ N-silylation of the azole substrate was achieved using hexamethyldisilazane (HMDS) and catalytic silica-supported sulfuric acid (SSA) at reflux. Following removal of excess HMDS, the addition of Togni reagent I 229 and sub-stoichiometric HNTf₂ and LiNTf₂ gave high N(1) regioselectivity for the trifluoromethylation of benzotriazole 224 (Scheme 64A), however when using triazoles 231 a mixture of both the N(1)- and N(2)-trifluoromethylated triazoles 232 and 232 was obtained (Scheme 64B).

Scheme 64 N-Trifluoromethylation of triazoles using Togni reagent I 229.

Wang has also reported the use of hypervalent iodine-mediated trifluoromethylation for the synthesis of N–CF₃ azoles.¹³⁹ Inspired by earlier work from Togni,¹⁴⁰ Wang showed that trifluoromethylation of nitriles 234 could be efficiently achieved using PhICF₃Cl 235,¹⁴¹ with the nitrilium intermediates trapped and isolated as DMAP salts 236.¹³⁹ Wang has subsequently applied this strategy in a range of applications,¹⁴² including formal [3 + 2] cycloadditions with diazo compounds 237 to give a range of N–CF₃ triazole products 238 (Scheme 65).¹³⁹

Scheme 65 Synthesis of N-CF₃ triazoles 238 from DMAP-stabilised nitrilium salts 236 and diazo compounds 237.

5. Applications of C(4) and C(5) fluorinated 1,2,3-triazoles

5.1. Pharmaceutical applications

Two recent patents have been published concerning the use of 5-fluoro-1,2,3-triazoles within drugs for cancer treatment. In 2017, Gilead Sciences prepared compounds such as 239 (Fig. 2)¹⁴³ to test against the cancer Osaka thyroid (COT) protein, which is involved in the formation of tumour necrosis factor α: a cytokine also involved in inflammatory diseases such as diabetes, sepsis and multiple sclerosis. Interestingly, the triazole C(5) substituent was shown to be important, as changing from a proton to either an iodine or fluorine atom improved the IC₅₀ value by a factor of ∼10⁴. The C(5)-fluorinated triazole was synthesised from the iodine analogue using Fokin's Halex methodology.³⁸

Fig. 2 5-Fluoro-triazole-containing COT treatments.

In 2019, Idorsia Pharmaceuticals prepared drug candidates 240 to inhibit two key dioxygenases (Fig. 3),¹⁴⁴ which are involved in catalysing the kynurenine pathway causing tryptophan degradation. This pathway is prevalent in various cancers to create an immunosuppressed environment which is key to their growth. In this example, Chu's Halex reaction conditions⁴¹ were used to prepare the fluorinated derivative, and whilst the addition of a C(5)-fluorine did not reduce the IC₅₀ value compared to the iodinated or protonated analogues, the value is in the low nanomolar range and thus still represents a good candidate for the inhibition of these enzymes.

Fig. 3 5-Fluoro-triazole-containing dioxygenase inhibitors.

A patent from Dogma therapeutics was released in 2020 using fluorinated-1,2,3-triazoles in compounds targeting proprotein convertase subtilisin/kexin 9 (PCSK9), which is important in cholesterol metabolism.¹⁴⁵ Inhibiting PCSK9 is important in treating conditions such as cardiovascular disease and sepsis/septic shock. Triazole containing candidate 241 (Fig. 4) was one of the promising compound scaffolds, giving good K_D values for the C(5) protonated and fluorinated analogues. Again, Fokin's Halex reaction³⁸ was used for late-stage fluorination of the iodinated analogue.

Fig. 4 5-Fluoro-triazole-containing PCSK9 inhibitors.

In 2018, Abell reported the use of 5-fluoro-1,2,3-triazoles for the inhibition of biotin protein ligases (BPL) present in Staphylococcus aureus bacteria.¹⁴⁶ It was found that the presence of a fluorine atom in inhibitor compound 242 decreased the minimum inhibitory concentration (MIC) drastically to within clinical levels (>100 μM to 16 μM, Fig. 5). Further cell studies determined the likely reason for this was increased uptake of the compound into the cell meaning a higher concentration was present allowing for greater inhibition of BPL across the whole cell. Importantly, this did not affect the cytotoxicity against healthy HepG2 liver cells indicating this compound would be an ideal drug candidate. Abell also demonstrated that N-benzyl-5-fluoro-1,2,3-triazoles 243 were also effective against S. aureus whilst not being cytotoxic to human cells.

Fig. 5 5-Fluoro-triazole-containing BPL inhibitors.

Fluorinated triazole motifs have also been incorporated into anaesthetics by Chengdu MFS Pharma Co. as alternatives to the more well-known imidazole-based Etomidate and cyclopropyl–methoxycarbonate metomidate (CPMM) (Fig. 6).¹⁴⁷ In the examples shown below, the ED₅₀ and therapeutic index (TI) values are improved with both C(4)–H and C(4)–F triazole derivates 244. A higher TI value indicates better efficacy of the drug.

Fig. 6 4-Fluoro-triazole-containing anaesthetics.

As well as their use in pharmaceuticals, fluorinated triazoles have also been applied in other medicinal applications. Crousse reported that incorporating 5-fluoro-1,2,3-triazoles into peptides 245 altered their electronic properties (Fig. 7).¹⁴⁸ It was shown through X-ray crystallography and a series of calculations that the fluorine atom within model compound 246 could act as a hydrogen bond acceptor with N–H and C–H contacts from nearby amino acid residues. Furthermore, the dipole moment induced by the fluorine caused a negative potential surface on one side of the peptide, resulting in a folded conformation in solution. The properties gained from the presence of fluorine include improved stability, hydrophobicity, and acidity which may be important for biological applications. A patent released in 2023 also showed the use of 5-fluoro-triazoles in polymeric materials for biological implant devices, for use in the slow release of a pharmaceutical agents.¹⁴⁹

Fig. 7 5-Fluoro-triazoles in peptides.

Zhang demonstrated in 2021 a modification of Fokin's Halex conditions³⁸ in the preparation of ¹⁸F labelled-1,2,3-triazoles 248 for use in positron emission tomography (PET) imaging.¹⁵⁰ The method was developed without the need to dry [¹⁸F]-HF, which, in combination with K₂CO₃ was presumed to form the required [¹⁸F]-KF in situ (Scheme 66). A probe targeting thiamine-dependant enzymes 249 was prepared using this method in 10–16% radiochemical yield (RCY).

Scheme 66 Radiolabelled synthesis of 5-¹⁸F-triazoles and use in thiamine-dependant enzyme inhibitor 249.

5.2. Use as synthetic intermediates

Regioselective alkylation of NH-triazoles in the N(2) position is typically difficult to achieve, requiring the use of directing¹⁵¹ or bulky¹⁵² groups to form the N(2) alkylated product as the major regioisomer. Nenajdenko demonstrated that a C(4)–fluorine substituent allows for complete N(2) regioselectivity when using primary and secondary alkyl halides (Scheme 67A).³⁰ X-ray crystallography and DFT showed the 2H tautomer of 251 is energetically favoured the over the 1H and 3H tautomers.³⁰ In the case of methyl iodide, ∼80% selectivity for the 2-methylated product was obtained, with small amounts of the 1- and 3-methylated products also observed. N(2)-Selective functionalisation, including arylation, acylation, tosylation, hydroxymethylation and Michael addition reactions were used to demonstrate the versatility of this method (Scheme 67B).

Scheme 67 Selected examples of N(2) substitutions of 4-fluoro-triazoles 250. (A) Alkylations; (B) arylation: ArylB(OH)₂, Cu(OAc)₂ (10 mol%), O₂, DMSO, 100 °C, 2 h; or (S_NAr) aryl–F, K₂CO₃, DMSO, 70 °C, 1 h; acylation: Ac₂O, Et₃N, CH₂Cl₂, rt, 3 h; Michael addition: CH₂=CHCN, Et₃N, DMF, rt, 20 h.³⁰

Nenajdenko noted that the 2,5-diaryl-4-fluoro-triazoles possessed fluorescence properties, with their synthesis and application further expanded by Nenajdenko and Tabolin in 2018 (Scheme 68A).¹⁵³ All triazoles 256 were found to absorb light in the near-middle UV range with maxima at 300–325 nm. Emission was recorded in near-UV to violet/blue range, demonstrating the compounds to be blue light emitting fluorophores. Incorporation of a p-methoxybenzene substituent in N(2) position (Aryl²) led to a red shift in the emission spectrum, whilst electron-withdrawing p-cyanobenzene caused a red shift in the absorption and emission spectra. Furthermore, a p-bromobenzene derivative diminished nearly all activity due to the heavy atom effect. When comparing the C(4) fluorinated triazole 258 with proto- (257) other halo-triazoles (259, 260), the fluorinated derivative 258 was shown to most significantly increase the emission maximum (359 nm, Scheme 68B). These fluorinated-triazoles may therefore have applications in medicine or materials.

Scheme 68 Synthesis and fluorescence properties of 2,5-diaryl-4-fluoro-triazoles.

Following the development of the Halex reaction, Fokin demonstrated the use of 5-fluoro-triazoles 261 as substrates for S_NAr reactions (Scheme 69).³⁸ This worked well for N-, O-, and S-based nucleophiles in the presence of sodium hydride. The methodology was also applicable to relatively complex examples including stereocentres with no epimerisation observed during either the Halex reaction or the subsequent S_NAr reaction.

Scheme 69 S_NAr of 5-fluoro-triazoles 261 using N-, O-, and S-based nucleophiles.

Beer utilised this approach for the synthesis of C(5)-tellurated bis-triazole 264 from the corresponding C(5)-fluoro bis-triazole 263 using in situ formed MeTeLi as a nucleophile (Scheme 70).¹⁵⁴ The tellurated bis-triazole compound 264 was used as a heteroditopic receptor for binding sodium halide salts. NMR, X-ray crystallography, and DFT calculations indicated the crown ether substituents bound the sodium ion, whilst the tellurated triazoles acted as Lewis acidic chalcogen bond donors to bind the halide anion.

Scheme 70 S_NAr of 5-fluoro-triazoles 263 for the synthesis of chalcogen bond donor 5-telluro-triazoles 264.

Finally, Ichikawa used 4-fluoro-triazoles 265 and 266 in rhodium catalysed C–H activation-[4 + 2] annulations¹⁵⁵ with diarylalkynes 267 to give tricyclic systems 268 and 269 (Scheme 71).³⁴ The triazoles were proposed to act as directing groups for the C–H activation.

Scheme 71 Rhodium-catalysed C–H activation-[4 + 2] annulation using 4-fluoro-triazoles 265 and 266 and diarylalkynes 267.

6. Applications of N(1), C(4) and C(5) polyfluoroalkyl- and polyfluoroaryl-1,2,3-triazoles

6.1. Pharmaceutical applications

In 2011, Chen studied the efficacy of triazole-containing inhibitors 270 of the dipeptidyl peptidase IV enzyme, which is implicated in type 2 diabetes. The introduction of CF₃ and CF₂H substituents at the C(4) position of the triazole was shown to significantly increase the potency of the inhibitor in comparison to C(4)–H and C(4)–Me analogues (Fig. 8).¹⁵⁶ It was assumed this effect was due to the electronegativity of the fluorinated groups as other aromatics bearing electron-withdrawing groups also improved the IC₅₀ values to <50 nM. Out of 25 derivatives tested, the C(4)–CF₃-susbtituted triazole showed the best pharmacokinetic profile and in vivo efficacy and hence was selected for further studies.

Fig. 8 4-Polyfluoroalkyl-triazole-containing dipeptidyl peptidase IV inhibitors.

Also targeting type 2 diabetes, Al-Harrasi reported compounds containing 4-fluorophenyl-triazoles 271 as α-glucosidase inhibitors (Fig. 9).¹⁵⁷ The triazoles were installed in the penultimate step of the synthesis via standard CuAAC conditions from 1-ethynyl-4-fluorobenzene and the appropriate azide. The IC₅₀ values show these compounds are all potent inhibitors of this enzyme, outperforming the marketed oligosaccharide-based drug Acarbose (IC₅₀ = 942 μM). Through structure–activity relationship docking studies, it was suggested that the triazole could form a hydrogen bond to an asparagine residue in the active site.

Fig. 9 4-Fluorophenyl-triazole containing α-glucosidase inhibitors.

In 2022, Maze therapeutics released a patent targeting the glycogen synthase 1 enzyme with compounds containing fluorinated 1,2,3-triazoles 272 (Fig. 10).¹⁵⁸ This enzyme is responsible for the conversion of glucose to glycogen; hence inhibition of this enzyme can be used to treat diseases related to glycogen accumulation. The installation of a CF₃ group on the triazole dramatically reduced the IC₅₀ value, with similar trends also observed with other derivatives of this scaffold.

Fig. 10 CF₃-substituted triazole-based glycogen synthase 1 inhibitors.

Tang and Zheng reported the use of fluorinated-1,2,3-triazoles in a scaffold for use as kinase inhibitors to treat cancer in 2016.¹⁵⁹ SAR studies determined that the electronegativity of the fluorinated groups was key in increasing the potency of the inhibitor structure 273 (Fig. 11). Substituting CH₃ for CF₃ had the largest impact, with a decrease in electron-density within the triazole ring proposed to have a significant effect on inhibitory ability. Based on docking studies, it was also proposed that CF₃ group can act as a hydrogen bond acceptor to provide additional hydrogen bonding contacts in the binding site. The addition of an electron-withdrawing group in the R² position further increasing potency to bring the IC₅₀ value down to 1.68 nM, below that of Foretinib (IC₅₀ = 1.92 nM), a kinase inhibitor that progressed to Phase II clinical trials.¹⁶⁰

Fig. 11 CF₃-substituted triazole-based kinase inhibitors.

Wu reported the use of 4-trifluoroacetyl-1,2,3-triazoles as potential anticancer agents in 2018.¹⁶¹ A solvent- and catalyst-free synthesis of these triazoles was reported by the thermal [3 + 2]-cycloaddition of trifluoroacetyl-substituted alkynes 274 and azides 275 (Scheme 72). The 4-trifluoroacetyl regioisomer 276 was favoured over the 5-fluoroacetyl regioisomer 277 in all cases (≥83 : 17 C4 : C5). These compounds were tested against six cancer cell lines, with some showing comparable or improved activity relative to Erianin, a natural product with anticancer properties. Triazole 278 had the greatest potency against HepG2 cells, with an IC₅₀ value of 0.03 μM.

Scheme 72 4-Trifluoroacetyl-triazole anticancer agents.

Teixeira reported the ability of fluorinated-triazole compounds to act as anti-fungal agents in 2022,¹⁶² for the treatment of papaya crops, which are prone to fungal growth. Derivatives of compound 279 (Fig. 12) were prepared and tested against the Colletotrichum pathogen which is responsible for this fungus. The EC₉₀ values were shown to be between 1 and 5 mg mL⁻¹, with the effect of the fluorinated aryl derivatives having a clear effect in reducing this value. Unfortunately, these were not as effective as eugenol, the fungicide used currently (<0.05 mg mL⁻¹), however, this eugenol is prone to degradation via heat, light and oxygen, hence further modifications on these triazole compounds could provide a solution.

Fig. 12 C(4)-(Poly)fluoroaryl-triazole fungicide candidates.

Fluorinated benzylic groups are the most commonly used N-polyfluoroalkyl substituents in medicinal chemistry applications. The phenyl ring is often modified with differing numbers of fluorine or trifluoromethyl groups. A notable example of this is the anticonvulsant Rufinamide 280, where the introduction of one or two fluorines on the N-benzyl substituent was shown to improve activity (Fig. 13).¹⁶³

Fig. 13 Structure of Rufinamide 280.

Another anticonvulsant bearing the 1,2,3-triazole moiety was reported by Kelley.¹⁶⁴ The authors examined fused pyridine-1,2,3-triazoles, where pyridine is fused at the C(4) and C(5) positions of the triazole ring (Fig. 14). The o-fluorobenzyl analogue 281 showed strong anticonvulsant effects but also caused nausea. By modifying the structure to 282, the authors maintained a similar oral administration MES ED₅₀, while eliminating the nausea side-effect.

Fig. 14 Anticonvulsants 281 and 282. ip = intraperitoneal injection; po = oral administration.

N-Polyfluoroalkyl-1,2,3-triazoles 283 have also been investigated for use as anti-inflammatory drug candidates. Xu studied triazole-based inhibitors of the NLRP3 inflammasome:¹⁶⁵ an important target for treating inflammatory diseases.¹⁶⁶ Generally however, the addition of substituents on the benzyl group reduced the potency of the drug candidates, demonstrating that adding fluorine substituents to triazoles is not always beneficial to activity (Fig. 15).

Fig. 15 Fluorinated benzyl derivatives of a NLRP3 inhibitor and their IC₅₀ values.

Fluorinated triazoles are often incorporated into the structures of known drugs to produce drug hybrids. For example, 28 triazole hybrids 284 derived from the antiretroviral drug Cabotegravir were recently explored by Mao, Li and Wang (Fig. 16).¹⁶⁷ Some of the synthesised 1,2,3-triazole hybrids were effective against the human cancer cell lines tested, with fluorinated compounds 286 and 287 reported to be the most active. 287 was active against all tested cell lines, while 286 was strongly active against two cell lines. By comparison, the non-fluorinated analogue 285, in addition to the other 25 derivatives tested, displayed significantly lower activity.

Fig. 16 IC₅₀ values for activity of 1,2,3-triazole-cabotegravir hybrids 284 against several cancer cell lines. HuH-7 = human hepatocellular carcinoma; MCF-7 = human breast cancer; SKOV3 = human ovarian cancer; HCT-116 = human colon cancer.

Fluorinated 1,2,3-triazole hybrids have also been investigated as anticancer drug candidates by Liu, who reported a series of novel 1,2,3-triazole-containing dithiocarbamates 289. These were evaluated against human esophageal, cervical, prostate, lung and breast cancer cell lines.¹⁶⁸ Fluorinated triazole-containing dithiocarbamates 289 compared favourably to dithiocarbamate 288 hybrids reported previously by Liu (Fig. 17).¹⁶⁹

Fig. 17 IC₅₀ values for activity of fluorinated 1,2,3-triazole dithiocarbamate 289, and previously reported dithiocarbamate hydrid 288, against several cancer cell lines.

In 1988, Kadaba reported an early example of N-polyfluorophenyl 1,2,3-triazoles in medicinal chemistry.¹⁷⁰ The authors described promising anti-convulsant properties of aryl- and pyridyl-functionalised triazolines and 1,2,3-triazoles. Of the triazoles tested, chlorinated and fluorinated derivatives showed promising activity in combination with relatively high toxic doses compared to the non-halogenated analogues.

The antibacterial activity of 1,2,3-triazoles-functionalised tetrahydroisoquinolinium-salts 290 has been reported by Ung.^85d Screening a range of N-aryl triazoles revealed that the incorporation of hydrophobic groups resulted in increased activity against both S. aureus and B. subtilis (Fig. 18). p-tert-Butyl substitution of the aryl ring resulted in a large increase in activity, and whilst substitution with CF₃ groups resulted in a smaller increase in activity, the combination of a p-OBn-substituent and either an o- or m-fluorine resulted in the same effect as tert-butyl substitution. This was suggested to reflect the combination of hydrophobicity of the OBn group, as well as synergistic electron donation from OBn and withdrawal by fluorine.

Fig. 18 Select examples of 1,2,3-triazoles-functionalised tetrahydroisoquinolinium-salts 290 investigated for antibacterial activity.

6.2. Use as synthetic intermediates

The α-fluorosulfone-substituted triazoles 291 synthesised by Zajc (section 2.3, Scheme 25),⁶⁴ were used as Julia–Kocienski olefination reagents for the stereoselective formation of fluoro-alkenes 293.⁶⁴ By varying the reaction conditions, formation of either the E- or Z-fluoro-alkene could be favoured (Scheme 73).^64b Both aliphatic and aryl aldehydes 292 bearing electron-withdrawing or -donating substituents were successfully applied, with higher yields and stereoselectivities typically achieved for the synthesis of the Z-alkene products (Z)-293. Five examples involving symmetric and unsymmetric ketones were also demonstrated for the synthesis of tetra-substituted alkenes.^64b

Scheme 73 Use of α-fluorosulfone-substituted triazoles 291 as Julia–Kocienski olefination reagents. BT = benzo[d]thiazole.

The applicability of 4-sulfonyl fluoride substituted triazoles 294 in SuFEx click reactions was demonstrated by Fokin and Moses (Scheme 74).⁶⁵ Reaction with phenolates 295 or amines 297 provided access to sulfonates 296 (Scheme 74A) and sulfonamides 298 (Scheme 74B) in moderate to high yields, including biologically relevant examples, including amino acids, steroids and N-heterocycles. Furthermore, base hydrolysis of 299 provided sodium sulfonate 300 in high yield (Scheme 74C). The direct sulfonation of triazoles is not possible using standard sulfonation conditions, thus this route provides a useful alternative approach to access these potentially useful compounds.

Scheme 74 Example SuFEx applications of 4-sulfonyl fluoride substituted triazoles.

N-Polyfluoroalkyl-1,2,3-triazoles have also been used as synthetic intermediates and reagents for a range of transformations. For example, in 1997, Katritzky reported the use of (trifluoroacetyl)benzo-1,2,3-triazole 302 to trifluoroacetylate amines 301 and alcohols 304 in good to excellent yields (Scheme 75).¹⁷¹ Previously reported reagents for trifluoroacetylation were unstable or produced difficult to remove byproducts, however this reagent was both simple to prepare (from benzotriazole and triflic anhydride), bench-stable and convenient to use. Katritzky extended this methodology for the polyfluoroacetylation of primary and secondary amines by using polyfluoroacetylated benzo-1,2,3-triazoles.¹⁷²

Scheme 75 Trifluoroacetylation of amines and alcohols.

More recently, Beier has reported a range of synthetic applications of N-polyfluoroalkyl triazoles 306,^23c which all take advantage of the electron-withdrawing nature of the N-polyfluoroalkyl group. Taking inspiration from the formation of rhodium–carbenoids from N-sulfonyl-triazoles with concomitant extrusion of N₂,¹⁷³ Beier has demonstrated analogous reactivity can be achieved from N-polyfluoroalkyl-substituted triazoles 306 (Scheme 76). Heating the triazole substrates 306 with a Rh(II) catalyst provides access to the key Rh–carbenoid intermediate 307, which has been exploited for the synthesis of imidazoles, pyrroles, azepines, oxazoles and indoles (Scheme 76).^101,174

Scheme 76 Synthetic use of the Rh-carbenoid intermediates generated from N-polyfluoroalkyl triazoles.

The reaction of N-polyfluoroalkylated triazoles 314 with both Brønsted and Lewis acids has also been investigated (Scheme 77). In these reactions, loss of N₂ was proposed to generate a vinyl cation intermediate 315, which, depending on the identity of the Brønsted or Lewis acid could, following hydrolysis, result in the formation of (Z)-vinyl triflate enamides 316,^101,175 β-(Z)-enamido fluorides 317,¹⁷⁶ and β-(Z) imidoyl chlorides, bromides and iodides 318 (Scheme 77).^135b Beier also demonstrated the use of these products in subsequent transformations, such as cross-coupling and displacement reactions.

Scheme 77 Treatment of N-polyfluoroalkyl-triazoles 314 with Brønsted or Lewis acids followed by hydrolysis leads to β-(Z)-enamido triflates 316, fluorides 217 or β-(Z) imidoyl halides 318.

Extending this reactivity, Beier demonstrated that the vinyl cation intermediate could be trapped through an intramolecular alkene insertion when N-polyfluoroalkylated triazoles bearing a C(5) allylic substituent 319 were used (Scheme 78).^135a The cyclopentenyl imidoyl halides 320 formed could be further transformed into a range of products, including tetrazoles 321, isoquinolines 322, N-alkenyl amides 323, amidines 324 and cyclopentenones 325 (Scheme 78).

Scheme 78 Formation and synthetic versatility of cyclopentenyl imidoyl halides 320.

Beier has also reported the formation of ketenimine intermediates 327 from the thermal aza-Wolff rearrangement of N-polyfluoroalkyl-triazoles 326 (Scheme 79).¹⁷⁷ Treatment of the ketenimine intermediate 327 with oxygen-, sulfur- and nitrogen-based nucleophiles provides access to N-polyfluoroalkylated imidates, thioimidates and amidines 328, whilst treatment with alkenes or alkynes results in iminocyclobutanes and -butenes 329, respectively.

Scheme 79 Formation and synthetic applications of ketenimine intermediate 327 from the aza-Wolff rearrangement of N-polyfluoroalkyl-triazoles 326.

N-Fluoroalkyl-triazoles have been applied for the formation of foldamers (Scheme 80). The conformation of peptides is essential to their biological function, and whilst peptides can be highly active pharmaceuticals their poor in vivo stability can be an obstacle to their application. The introduction of triazoles into peptides increases their stability, and the fluorinated triazole–peptide hybrid 330 was reported by Crousse in 2017 (Scheme 80).^96e DFT studies of the peptide indicated the presence of hydrogen bonding between the amide and fluorine as well as non-classical hydrogen bonding from the methylene group to fluorine. The authors concluded that these interactions involving the CF₂ group could help the structure adopt a single, rigid conformation. Ongeri reported the synthesis of triazole–peptide hybrid 331 with stereogenic CF₃ substituents on the backbone (Scheme 80).^96h These two triazole–peptide hybrids were found to adopt unique conformations, with the more rigid 330 forming long β-strands, whilst 331 formed short multistrand β-sheets.^96h Olsen has also reported a selection of triazole–peptide dipeptide mimics that utilise an N–CF₂ functionalised triazole 332. The authors synthesised Fmoc- and Boc-protected dipeptide mimics, which were used for the synthesis of Leu-enkephalin analogues (Scheme 80).^96f

Scheme 80 Fluorinated triazole–peptide hybrid foldamers. Pbf = 2,2,4,6,7-pentamethyldihydrobenzofuran-5-sulfonyl.

6.3. Materials applications

Shreeve has reported the use of 4-CF₃ and SF₅-triazoles 335 as energetic materials,¹⁷⁸ where the fluorinated group is proposed to impart increased thermal stability, chemical resistance, electronegativity, and hydrophobicity (Scheme 81). The preparation of these triazoles is procedurally challenging due to the use of gaseous, relatively unstable acetylene substrates 334, which must be condensed into the reaction mixture at −195 °C. A range of triazole products 335 were obtained however in good yields and as single regioisomers. These compounds were tested for their density, detonation pressure (P), and detonation velocity (D) which were found to be comparable to TNT. Furthermore, the SF₅-contained triazoles were found to have higher densities and more favourable detonation properties relative to the CF₃ analogues. Due to these detonation properties, extreme caution should be taken if preparing these triazoles.

Scheme 81 Synthesis and application of 4-CF₃ and SF₅-triazoles 335 as energetic materials.

6.4. Anion binding and catalysis

N-Polyfluoroaryl 1,2,3-triazoles have seen considerable application within anion binding and catalysis due to the numerous non-covalent interactions these motifs can engage in. For example, the triazole and N-aryl substituents can engage in π-π stacking; the triazole proton can act as a hydrogen bond donor (where this ability may be enhanced by the electron withdrawing nature of the N-polyfluorophenyl group); and the fluorines on the N-polyfluorophenyl group can act as hydrogen bond acceptors.

Several groups have reported the use of polyfluorinated N-aryl triazoles within anion binding, as either anion binding catalysts or as anion transporters. The earliest of these studies was performed by Mancheño where the chloride ion binding ability of a range of bis-triazoles 336a–c was evaluated (Scheme 82A).¹⁷⁹

Scheme 82 Mancheño's first generation 1,2,3-triazole chloride anion binding catalyst 336c.

The chloride binding association constant for bis-triazole 336c, bearing N-3,5-CF₃-phenyl groups, was significantly improved relative to the use of a simple N-phenyl substituent 336b (K_a = 458 M⁻¹vs. K_a = 342 M⁻¹). In contrast, the use of an N-pentafluorophenyl substituent 336a led to a decrease in chloride binding (K_a = 111 M⁻¹). It was suggested that the stronger chloride binding observed for the bis-CF₃-phenyl triazole 336c was due to the ortho-protons present on the bis-CF₃-phenyl ring, which provide an additional non-classical hydrogen bond to the chloride anion. DFT studies suggested that the bis-CF₃-phenyl ring of 336c sits co-planar with the triazole, thus facilitating the formation of this additional non-classical hydrogen bond. In contrast, the pentafluorophenyl group of 336a sits at an angle due to its inability to engage in any additional non-covalent interactions with the chloride anion. The bis-triazoles synthesised in this work (two additional structures in addition to those in Scheme 82) were applied as catalysts for the tritylation of amines 337 (Scheme 82B). The trend in kinetic performance of the bis-triazole catalysts matched the trend of chloride binding ability, hence demonstrating a useful proof-of-concept study.

Mancheño applied the knowledge from this fundamental study to design chiral analogues, by incorporating a trans-1,2-cyclohexane linkage in place of a phenyl bis CF₃ group in order to obtain a chiral tetra-triazole anion binder 340 (Scheme 83A).¹⁸⁰ Due to the relatively rigid structure of 340, it is proposed to form a chiral helix and thus was employed as an enantioselective catalyst for anion abstraction reactions through asymmetric counterion-directed catalysis.¹⁸¹ Initially reported for the asymmetric dearomatisation of quinolines 341 (Scheme 83B),¹⁸⁰ the catalyst has since been applied for further studies into the dearomatisation of quinolines, isoquinolines, pyridines, diazarenes and pyryliums.¹⁸² In addition, investigations into the spatial folding of the catalyst¹⁸³ and in-depth NMR studies on the effects of changing the anion have been reported.¹⁸⁴

Scheme 83 Mancheño's point, and helically chiral tetratriazole anion binding catalyst 340.

Based on Mancheño's work, Feringa developed an asymmetric anion-binding catalyst 344 which incorporated a molecular motor functionality (Scheme 84A).¹⁸⁵ The authors described a unidirectional motor which, upon irradiation with light, transitions from a racemic trans-form of the catalyst into a helical pseudochiral cis-form, from which the configuration can be switched by heating. The catalyst was applied for chloride abstraction to promote the addition of a silyl ketene acetal 346 to 1-chloroisochromene 345 (Scheme 84B). The (M,M)- and (P,P)-pseudoenantiomers of the catalyst provided the (R)- and (S)-product 347, respectively, thus stereodivergent access to both enantiomers was achieved with the same catalyst.

Scheme 84 Molecular motor-based anion binding catalysis.

Beyond the use of polyfluoroaryl-substituted triazoles in hydrogen bonding applications, more recent interest has focused on their use in halogen and chalcogen bonding applications. Mancheño showed that modification of their helically-chiral tetra-triazole 340 by substitution of the C(5)–proton of the triazole with iodine created chiral halogen bond donors 348 (Scheme 85A).^116c,k Chiral halogen bond donor 348a was found to bind halide and acetate anions more strongly than the hydrogen bond donor analogue 340 (for example, 348a: K_a (Cl⁻) = 1125 M⁻¹; 340: K_a (Cl⁻) = 99 M⁻¹). Conversely, lower association constants were observed for the binding between halogen bond donor 348a and bisulphate, hydrogen phosphate and nitrate, relative to the hydrogen bonding donor analogue 340. Whilst no rationale was provided for this change in selectivity, similar observations have previously been reported for multi-dentate triazole-based halogen bond donors.¹⁸⁶ Interestingly, the halogen and hydrogen bond donor analogues 340 and 348a displayed opposite selectivities for binding mandelic acid salts, with halogen bond donor 348a binding more strongly with (R)-mandelic acid (K_a(R)/K_a(S) = 1.41) and hydrogen bond donor 340 binding more strongly with (S)-mandelic acid (K_a(R)/K_a(S) = 0.78). This divergence in enantiomeric preference was also observed when halogen bond donor 348a was applied as a catalyst. Using the asymmetric dearomatisation of quinoline as a benchmark reaction, the use of halogen bond donor 348a as a catalyst provided the (S)-enantiomer of product with moderate enantioselectivity (65 : 35 er (R : S)) (Scheme 85B). Under analogous conditions, hydrogen bond donor 340 provided the (R)-enantiomer of product with higher enantioinduction (78 : 22 er (S : R)). This intriguing switch in enantioselectivity between the seemingly analogous halogen and hydrogen bond donors 340 and 348a was investigated through DFT studies and was suggested to originate from distortion of the helicity of 348a due to the additional steric hindrance imposed by the large iodine groups. Mancheño subsequently demonstrated that through slight modulation of the catalyst and substrate structures, enantioselectivities of up to 76% ee were achieved for the dearomatisation of quinolines 351 (Scheme 85C), and up to 90% ee for the dearomatisation of isoquinolines.^116k

Scheme 85 Helically chiral halogen bond catalyst 348.

In 2017, Philp reported the design of bifunctional phosphine oxide–iodotriazole compounds 354, which were shown to undergo halogen bond-induced dimerisation in solution (Scheme 86).^116a An N-polyfluorinated substituent was used to enhance the strength of halogen bonding, with a long-chain para-ester substituent required to increase solubility.

Scheme 86 Halogen bond-induced dimerisation of 354.

Beer has reported a series of studies on the use of N-polyfluorophenyl-1,2,3-triazoles for applications in anion binding and transport. As part of a study into the utility of halogen bonding to template [2]rotaxane synthesis, Beer investigated the anion binding ability of a range of pyridinium bis-iodotriazole halogen bond donors 355a–d (Fig. 19).¹⁸⁷ Modulating the triazole N-substituent revealed that the polyfluorophenyl derivate 355d provided significantly enhanced anion binding for chloride in particular. Based on this finding, a related cyclodextrin-capped ‘thread’ was synthesised to investigate chloride anion-templated [2]rotaxane synthesis. The importance of chloride anion binding for [2]rotaxane templating was demonstrated with the optimal halogen bond donor providing a 91% yield of a [2]rotaxane, whilst a non-fluorinated analogue gave the [2]rotaxane in only 45%.

Fig. 19 Anion association constants for pyridinium bis-iodotriazole halogen bond donors 355a–d.

Extending this work, Beer reported an in-depth study into the use of neutral halogen and chalcogen bond donors based on a 3,5-bis-triazole pyridine scaffold for anion binding (Fig. 20).^116b Systematic variation of the electron-withdrawing nature of the aryl substituents on both the nitrogen of the triazole and the Te substituent of the chalcogen bond donors allowed modulation in the Lewis acidity of the halogen and chalcogen bond donors, which was assessed through halide anion binding. Increasing the degree of fluorination of N-aryl substituents resulted in a systematic increase in the anion binding ability of the chalcogen bond donor 356 (Fig. 20A). Introduction of an N-pentafluorophenyl substituent provided an association constant ∼30 times greater than the analogous chalcogen bond donor bearing a simple N-phenyl substituent (18 500 M⁻¹vs. 590 M⁻¹). Similarly, modulation of the Lewis acidity of the chalcogen bond donor through the introduction of polyfluorinated aryl groups on Te led to a similar magnitude increase in anion binding for chalcogen bond donor 357 (Fig. 20B). Davis and Beer built on this work to show that the incorporation of a ferrocene substituent on Te provided redox-switchable chalcogen-bond donors, where oxidation to the ferrocenium derivative resulted in three orders of magnitude stronger anion binding.^116g

Fig. 20 Binding affinity (K_a) for halide anions with chalcogen bond donors 356 and 357.

Beer and Langton applied related neutral bis-triazoles, incorporating the optimal N-pentafluorophenyl substituent for anion binding and transport (Fig. 21).^116fN-Polyfluorophenyl-1,2,3-triazoles 358a–c were synthesised with halogen, chalcogen and hydrogen bond donor groups at the C(5) position, and were assessed for their chloride binding affinity and lipid bilayer transport selectivity. The halogen bond donor 358a had the strongest binding affinity toward chloride (>10⁵ M⁻¹), followed by chalcogen bond donor 358b (18 540 M⁻¹), and finally the hydrogen bond donor 358c (1010 M⁻¹). The anion transport capability of anionophores 358a–c was assessed using large unilamellar vesicles. The chloride vs. hydroxide transport selectivity was assessed using an adapted pH-gradient dissipation assay using N-methyl-D-glucamine chloride (NMDG–Cl) as the chloride source and incorporation of proton channel gramicidin D to investigate the relative rates of Cl⁻ and H⁺/⁻OH transport.¹⁸⁸ Whilst hydrogen bond donor 358c displayed minimal selectivity for chloride (S = 1.6), halogen bond donor 358a showed good selectivity (S = 5) and however chalcogen bond donor 358b showed excellent selectivity (S = 70). Based on the strong anion binding obtained with the neutral N-pentafluorophenyl substituted bis-iodotriazole 358a, Beer subsequently reported the use a related halogen bonding motif for chloride anion templated [2]rotaxane synthesis.^116h The [2]rotaxane products exhibited enhanced binding affinities for hydrophilic Cl⁻ and Br⁻ and diminished affinity for hydrophobic I⁻, relative to the non-interlocked axle counterparts. This binding selectivity opposes Hofmeister bias and was proposed to originate from the effect of the mechanical bond in the [2]rotaxane.

Fig. 21 Chloride anion binding and transport in lipid bilayer vesicles. Selectivity (S) is defined as EC^NMDG₅₀/EC^Gramicidin₅₀. S values >1 indicate chloride transport is faster than H⁺/⁻OH transport.

Langton built on this work to develop stimuli-responsive anion transporters based on N-pentafluorophenyl substituted bis-iodotriazole halogen bond donors attached to a photo-cleavable linker 359 (Fig. 22A).^116j The incorporation of long alkyl chains was used to anchor the halogen bond donor within the lipid bilayer.¹⁸⁹ Irradiation with 365 nm light promoted photo-triggered cleavage of the ortho-nitrobenzyl motif to release the mobile ion carrier and switch on the anion-transport ability of the halogen bond donor. In an alternative approach, Langton reported a halogen bonding ion relay in which transport is facilitated by the exchange of ions between lipid-anchored receptors 360 on opposite sides of the membrane (Fig. 22B).^116m Once again, an N-pentafluorophenyl substituted bis-iodotriazole halogen bond donor was chosen for this application. The inclusion of polyfluorinated phenyl groups was proposed to serve two purposes: (i) to enhance halogen bond donor ability; and (ii) to make the receptor more lipophilic. In line with earlier work, high chloride vs. hydroxide transport selectivity was observed using the halogen bond donor.

Fig. 22 Lipid bilayer anion transporters based on N-pentafluorophenyl substituted bis-iodotriazole halogen bond donors.

Building on the exceptional chloride binding discovered from N-pentafluorophenyl substituted chalcogen bond donors, Beer has demonstrated that incorporation of 15-crown-5 motifs has allowed realisation of a selective KCl receptor 361 (Fig. 23).¹¹⁶ⁱ The binding of the potassium cation to the crown ether was proposed to enhance the chalcogen bond donor ability of the tellurium substituents. The chalcogen bond donor 361 was highly selective toward KCl over lighter alkali metal chlorides, however some binding was also observed for RbCl and CsCl. Preliminary studies also demonstrated the ability of 361 to promote extraction of KCl under solid–liquid and liquid–liquid extraction conditions, in addition to selective transmembrane transport of KCl over NaCl. Beer and Félix subsequently reported a related approach to potassium halide binding, using a fullerene-supported heteroditopic ion-pair receptor in which a crown ether and bis-iodotriazole halogen bond donor were spatially separated at opposite sides of the fullerene scaffold.^116l In this example, an N-3,5-bis(trifluoromethyl)phenyl substituent was used on the triazole.

Fig. 23 Chalcogen bond donor KCl receptor 361.

Beer and Langton also demonstrated the use of tetraphenylethene-based iodotriazole halogen bond donors for anion sensing and as photoswitchable halogen bond donor anion receptors (Fig. 24).^116e Tetrakis-iodotriazole 362 was shown to undergo anion-induced aggregation, driven by halogen bond-mediated anion binding. The nanoscale aggregates displayed luminescent properties, providing a sensory mechanism for different anions. Of the anions tested chloride provided by far the largest response, followed by sulfate, nitrite, bromide, iodide, nitrate and acetate. An N-phenyl analogue of 362 displayed essentially no aggregation or luminescence, highlighting the importance of the polyfluorinated N-aryl substituent for promoting halogen bonding. Bis-iodotriazole 363 was synthesised as both the (E)- and (Z)-isomer, with the (Z)-isomer displaying a significantly higher chloride association constant [(E) = 4970 M⁻¹; (Z) = 23 200 M⁻¹]. When irradiated with 405 nm light, (E)-363 isomerises to give a photostationary state of 48 : 52 (E) : (Z). Repeating the photoisomerism in the presence of 10 equivalents of chloride however resulted in a photostationary state of 32 : 68 (E) : (Z), indicating that the position of equilibrium is biased by the greater chloride binding ability of (Z)-363.

Fig. 24 Tetraphenylethene-based tetrakis-iodotriazole halogen bond donor fluorescent chloride anion sensor 362 (A) and bis-iodotriazole halogen bond donor photoswitch 363 (B).

Han and Zhang exploited the controlled (E)/(Z)-photoisomerisation of azobenzene¹⁹⁰ to design photoswitchable chalcogen bond donors, containing polyfluoroaryltellurium-functionalised triazoles (Scheme 87).¹⁹¹ Whilst the (E)-isomer (E)-364 displayed a relatively small association constant for chloride binding (807 M⁻¹), isomerisation to (Z)-364 resulted in a significant increase in chloride affinity (3769 M⁻¹; K_a(Z)/K_a(E) ≈ 5) (Scheme 87A). This effect was proposed to originate from the (Z)-isomer's ability to bind chloride in a bidentate fashion as a result of the two chalcogen bond donors being in closer proximity to each other. The cationic analogue 365 (Scheme 87B), provided larger association constants, as would be expected for a charge-assisted chalcogen bond donor,^7h,i with the (Z)-isomer (Z)-365 once again providing significantly higher anion binding affinities than the (E)-isomer (E)-365. The neutral and cationic chalcogen bond donors were then applied as stoichiometric activators for chloride abstraction from benzhydryl chloride 367. Only the cationic chalcogen bond donor (E)/(Z)-365 displayed appreciable activity, with (Z)-365 providing significantly better activity than (E)-365 (58% vs. 9% conversion after 24 h), in line with the higher chloride anion affinity of (Z)-365 (Scheme 87B).

Scheme 87 (E)/(Z) Photo-switchable chalcogen bond donors (A) chloride anion binding affinities for neutral chalcogen bond donors (E)- and (Z)-364; (B) anion abstraction using cationic chalcogen bond donors (E)- and (Z)-365.

Langton reported a similar approach for the design of photoswitchable halogen bond donors (Scheme 88).¹⁹² In this case, an electron-withdrawing 3,5-bis(trifluoromethyl)aryl group was included at the C(4) position of the triazole to enhance the Lewis acidity, and hence anion binding ability, of the iodine-based halogen bond donor. In line with Han and Zhang's work, the (Z)-isomer (Z)-369 provided a higher chloride anion binding association constant, however in this case the difference in binding for the (E)- and (Z)-isomer was even more pronounced [(E)-369: 590 M⁻¹; (Z)-369: 31 600 M⁻¹; K_a(Z)/K_a(E) ≈ 54] (Scheme 88A), suggesting a more optimal relative arrangement of the two Lewis acidic halogen bond donor sites. Once again, the cationic analogue (E)/(Z)-370 displayed higher chloride anion binding affinity, however in this case the differentiation between (E)- and (Z)-370 was significantly diminished [K_a(Z)/K_a(E) ≈ 3]. Both isomers of the cationic halogen bond donor were effective stoichiometric activators for chloride and bromide anion abstract, with the (Z)-isomer (Z)-370 providing ∼2-fold rate enhancement, relative to the (E)-isomer (Scheme 88B). The cationic halogen bond donor was also applied as a catalyst for a Mukaiyama aldol reaction (0.5 mol% catalyst loading) and the Michael addition of 1-methylindole to an enone (10 mol% catalyst loading). The (Z)-isomer (Z)-370 provided approximately twice as much of the aldol product 373 as the (E)-isomer (E)-370, whilst both isomers provided similar activity for the Michael addition. This last result was proposed to indicate that both isomers operate as mono-dentate halogen bond donors in this case.

Scheme 88 (E)/(Z) Photo-switchable halogen bond donors (A) chloride anion binding affinities for neutral halogen bond donors (E)- and (Z)-369; (B) anion abstraction and catalysis using cationic halogen bond donors (E)- and (Z)-370.

Fukuzawa reported the use of 1,3,4-triaryl-5-iodotriazolium iodides 376 as halogen bond donor catalysts (Scheme 89).¹⁹³ The triazoliums were prepared via a previously reported method by Bertrand and Grubbs¹⁹⁴ from the corresponding triazene and terminal alkyne, followed by iodination of the triazolium ion through deprotonation with t-BuOK and electrophilic trapping with I₂. Varying the electronics of the C(4)–aryl substituent of the triazolium catalyst 376 revealed that an electron-withdrawing p-CF₃ group provided the highest yield for the cyanosilylation of p-chlorobenzaldehyde 374 over a standard 1 h reaction time (Scheme 89). It was proposed this effect could be attributed to the enhanced Lewis acidity of the halogen bond donor. The halogen bonding catalyst was also applied for the formation of cyclic carbonates from carbon dioxide and epoxides.¹⁹³

Scheme 89 Effect of different C(4)–aryl substituents within triazole-based halogen bonding catalyst 376 for the cyanosilylation of aldehydes.

7. Conclusions

This review has highlighted the diversity of fluorinated 1,2,3-triazoles present in the literature, and has briefly described their synthesis and application.

Methods to access N(1), C(4) and C(5) polyfluoroalkyl- and aryl-substituted 1,2,3-triazoles have been summarised, in addition to methods to access 4- and 5-fluoro-1,2,3-triazoles. Although many of these triazoles can be synthesised through transition metal-catalysed azide–alkyne cycloaddition (AAC) reactions, a wide variety of other transition metal-catalysed, organocatalytic and stoichiometric approaches have been utilised. Generally, polyfluoroaryl-substituted 1,2,3-triazoles are the most straightforward to synthesise due to simple access to polyfluoroaryl-substituted azides, alkynes and other required substrates. Polyfluoroalkyl-substituted azides and alkynes are more challenging to access, however Beier has made significant recent progress in the synthesis of short-chain polyfluoroalkyl azides. In contrast, there are significantly fewer methods to synthesise 4- and 5-fluoro-1,2,3-triazoles. 5-Fluoro-1,2,3-triazoles are generally only synthesised through the so-called Halex reaction from the corresponding 5-iodo triazole;^38,41 whilst 4-fluoro-1,2,3-triazoles have recently been synthesised through a small selection of alternative routes. All current approaches have limitations and thus represents an area where more advances could be made.

Fluorinated 1,2,3-triazoles have also found extremely widespread applications in drug discovery, materials chemistry, anion binding and catalysis and as use as synthetic intermediates. In many of these applications the unique structural, chemical and biological properties of both the 1,2,3-triazole and organofluorine group have been exploited.

Overall, this review has showcased the versatility and potential of fluorinated 1,2,3-triazoles in many fields of research. We believe that this summary will assist both academic and industrial practitioners in finding appropriate methods and provide inspiration for future advances in both the synthesis and application of fluorinated 1,2,3-triazoles.

Data availability

As this is a review we have not generated any new data.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

This research was funded in part by the EPSRC, grant number EP/R513374/1 (FEB), EP/W524645/1 (JLW). We thank GoldenKeys High-Tech Materials Co., Ltd (91520900MA6DL1ER7N) and the University of Warwick for funding (HS). We also thank Mr Songlin Liu from Wengfu Co., Ltd for providing basic industrial knowledge of nitrogen- and fluorine-based bulk chemicals.

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