SuFEx-enabled, chemoselective synthesis of triflates, triflamides and triflimidates

Abstract

Sulfur(VI) Fluoride Exchange (SuFEx) chemistry has emerged as a next-generation click reaction, designed to assemble functional molecules quickly and modularly. Here, we report the ex situ generation of trifluoromethanesulfonyl fluoride (CF₃SO₂F) gas in a two chamber system, and its use as a new SuFEx handle to efficiently synthesize triflates and triflamides. This broadly tolerated protocol lends itself to peptide modification or to telescoping into coupling reactions. Moreover, redesigning the S^VI–F connector with a S=O → S=NR replacement furnished the analogous triflimidoyl fluorides as SuFEx electrophiles, which were engaged in the synthesis of rarely reported triflimidate esters. Notably, experiments showed H₂O to be the key towards achieving chemoselective trifluoromethanesulfonation of phenols vs. amine groups, a phenomenon best explained—using ab initio metadynamics simulations—by a hydrogen bonded termolecular transition state for the CF₃SO₂F triflylation of amines.

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Introduction

Recent interest in high-valent sulfur species has brought about an increasing number of S^VI–F bond-containing connective hubs. In the framework of Sulfur(VI)–Fluoride Exchange (SuFEx) chemistry—an umbrella term for substitution events replacing fluoride at the electrophilic sulfur center—these ‘molecular plugins’ allow selective and efficient installation of linkages around the S^VI core. Especially in the last seven years, various research groups have demonstrated the potential of SuFEx hubs such as sulfonyl fluorides (R–SO₂F),¹ sulfuryl fluoride (SO₂F₂),² thionyl tetrafluoride (SOF₄),³ ethenesulfonyl fluoride (ESF, CH₂=CH–SO₂F),^2a,4 and others.⁵ The chemoselective and straightforward nature of SuFEx chemistry has enabled a range of applications in synthesis and materials.⁶

A particularly intriguing aspect of SuFEx chemistry is its ability to activate oxygen nucleophiles. Various OH-containing materials of different acidities and nucleophilicities have been shown to react cleanly at the sulfur center, and subsequently transform them into useful electrophiles for further derivatization. For example, through SO₂F-containing reagents, aliphatic alcohols have been converted into alkyl fluorides⁷ or alkylating agents,⁸ carboxylic acids into acyl fluorides,⁹ and silyl ethers into sulfonate esters¹⁰ (Scheme 1B). A unique role in this collection is reserved for aromatic alcohols, which in reaction with SO₂F₂ selectively form the valuable aryl fluorosulfates in the presence of various other nucleophiles.^2a,11 By far, the most commonly employed category of O-based pseudohalides consists of aryl triflates.¹² Even though a number of ways to prepare aryl triflates exist,^{13,14,15,16,17} a broadly applicable protocol that uses an inexpensive and atom-economic [CF₃SO₂] precursor in a chromatography-free and water-tolerable fashion is still missing from the toolbox.

Scheme 1 (A) Selected published SuFEx hubs and new SuFEx handles proposed; (B) complex products derived from SuFEx reactions of O nucleophiles; (C) this work: CF₃SO₂F-mediated and N-substituted triflimidoyl fluoride-mediated SuFEx chemistry.

Herein, we set out to investigate whether SuFEx chemistry can provide this general way of [CF₃SO₂] transfer onto complex organic molecules. Building on our previous work on sulfuryl fluoride,^2b we propose trifluoromethanesulfonyl fluoride gas, CF₃SO₂F (b.p. −22 °C), as a new electrophilic SuFEx hub, easily generated via two-chamber reactor technology and which reacts efficiently with phenols. Other nucleophiles such as carboxylic acids and amines reacted smoothly with the gas under dry conditions, identifying water as a key additive to obtain complete chemoselectivity for aromatic alcohols (Scheme 1C). Moreover, to shed some light on the mechanistic origins of this chemoselectivity, we relied on ab initio metadynamics simulations to gain fundamental insight into the key SuFEx transition state. Finally, we report a general synthesis of aryl trifluoromethanesulfonimidate (triflimidate) esters: the rarely reported aza analogs of the ArOTf scaffold. Triflimidoyl fluorides show potential as weakly electrophilic SuFEx hubs, which could have unexplored applications as covalent warheads.

Results and discussion

Triflyl fluoride gas was first reported in 1956 by Gramstad for the synthesis of trifluoromethanesulfonic acid derivatives.¹⁸ This smallest perfluoroalkanesulfonyl fluoride is gaseous above −22 °C, and its atmospheric chemistry is relatively innocuous.¹⁹ The most relevant industrial preparation consists of the electrolytic fluorination of methanesulfonic acid or methanesulfonyl fluoride, and the resulting gas serves as the precursor to all other [CF₃SO₂]-containing bulk chemicals such as TfOH or Tf₂O.²⁰ Other authors have prepared triflyl fluoride on a semibulk scale, by reacting CF₃SO₂Cl^19,21 or Tf₂O²² with a fluoride source.²³ Recently, Pees and co-workers have developed CF₃SO₂¹⁸F as a carrier gas for nucleophilic [¹⁸F]-fluoride, evolving it from PhNTf₂ as a precursor.²⁴

We envisaged the generation of CF₃SO₂F in a two-chamber reactor as the most convenient way to employ this gas safely on lab scale.²⁵ Even though a higher-MW precursor adds to the process mass intensity of this procedure, the results obtained with ex situ CF₃SO₂F gas remain true on larger scales in which case the precursor would be abandoned for direct use of gas bottles. Inspired by the aforementioned results, we set out to develop a CF₃SO₂F gas generation method using PhNTf₂ as a bench-stable and easily handled solid precursor (for optimization, see ESI Section 3†). To our delight, the final reaction conditions allowed conversion of the model substrate 4-fluoro-4′-hydroxybiphenyl into product 1 in 85% yield after 4 hours at room temperature (Scheme 2A). With optimized conditions of method A in hand, a variety of readily accessible phenol derivates was examined to further explore the scope of this methodology (Scheme 2). First, monosubstituted electron-rich and deficient phenols were successfully transformed into their corresponding triflates (2–8). Sterically hindered triflates 8, 12 and 27 were also formed efficiently. Although ¹⁹F NMR monitoring of catechols showed a high degree of ditriflation at the reaction onset, they nevertheless converged to the monotriflates (14 and 16) after longer reaction times, most likely due to subsequent hydrolysis (see ESI Section 5.1†). With a few experimental adaptations and shorter reaction times, however, it was possible to get the less stable ditriflates 15 and 17 in a fair isolated yield. The triflation of two L-tyrosine derivatives not only offered corresponding products in excellent yields (24 and 25), but also without loss of enantiopurity (25). When it comes to naturally occurring phenols, all afforded the corresponding monotriflates in good to excellent yields (4, 9, 10, 19, 20, 26, 27 and 29). In addition, three heteroaryl triflates were obtained in good to excellent yields (21, 22 and 23). It is worth pointing out that in many cases, the two-chamber reactor method afforded the triflates in sufficiently pure form after extractive work-up, without the need for column chromatography.

Scheme 2 Synthesis of aryl triflates through ex situ generation of CF₃SO₂F gas in a two-chamber reactor. Unless stated otherwise, method A was used. Generation chamber: N-phenyltrifluoromethanesulfonimide (PhNTf₂, 1.5 equiv.), KHF₂ (1.0 equiv.) and MeCN (0.86 M, 1.75 mL) at room temperature. Reaction chamber: (hetero)aryl alcohol (1.0 mmol, 1.0 equiv.), N,N-diisopropylethylamine (DIPEA, 1.5 equiv.) in 3.0 mL of MeCN and 1.0 mL of H₂O. Reaction details see ESI Section 4.† Isolated yield after column chromatography unless stated otherwise. Between brackets is given the ¹⁹F NMR yield using PhCF₃ as internal standard, between parentheses the reaction time. [a] Isolated yield after aqueous work-up. [b] 2.5 equiv. of DIPEA were used in the reaction chamber. [c] 3 mL MeCN was used in the reaction chamber as solvent, and the crude reaction mixture was purified on silica directly without aqueous work-up. [d] 2.5 equiv. of PhNTf₂ and 1.67 equivalents of KHF₂ were used in the generation chamber. [e] The reaction was set under Argon atmosphere. [f] Et₃N (3.5 equiv.) and DMSO (0.25 M, 4.0 mL) were used in the reaction chamber. [g] The corresponding boronic acid was used as the starting material, and protected afterwards with pinacol. [h] Yield corresponds to product isolated as an HCl salt. [i] The assay yield is reported (average over two runs), defined by dividing the [M + 132] peak area by the total AUC of the HPLC-MS TIC chromatogram.

In parallel to this method, a different set of conditions was developed using Tf₂O as the gas precursor,²² a less expensive and commonly available chemical (method B). Even though good results were obtained for simple phenols (1), the unpleasant nature of this fuming and sensitive liquid, and the reduced yields for more complex phenols (3, 8, 9 and 18) make this method less ideal. Next, in order to further assess the validity of CF₃SO₂F as a triflating agent, our method was benchmarked against other known triflation methods (for details, see ESI Section 4.1.3†). Four representative phenols were treated according to three literature triflation protocols: adding Tf₂O to a solution of phenol and organic base (method C);²⁶ adding Tf₂O under Frantz' aqueous conditions (method D)²⁷ and using the PhNTf₂ reagent directly (method E).²⁸ Even though the gas-free methods required a shorter reaction time, the corresponding triflates were almost universally obtained in lower yield than with CF₃SO₂F. Not only did the literature methods require more careful temperature control or moisture exclusion, also the chemoselectivity was usually inferior when the phenol starting materials contained indoles (19), aliphatic amines (24 and 28), carboxylic acids (25) or aliphatic alcohols (27). Moreover, amine 28 did not show any trace of sulfonamide formation, even with 2.5 equivalents of gas (see ESI Section 5.2.1†). To sum up, our CF₃SO₂F gas-based two-chamber system allowed triflation to proceed in a stable, productive and chemoselective fashion.

During the development of this work, it was observed that the aryl triflate synthesis was relatively insensitive towards the choice of solvent or base. To further showcase the versatility of this SuFEx reaction, a series of solvent–base combinations was explored (Scheme 2G). While maintaining the original gas generation using PhNTf₂, a set of 7 bases (organic and inorganic) was screened against a set of 6 commonly used reaction solvents. In almost all cases, the reactions had reached >50% conversion after 20 h, and the majority even >80% under unoptimized conditions. While some of the stronger bases were more prone to cause product degradation, nevertheless this broad compatibility enables a subsequent reaction step without intermediate ArOTf isolation.

Given the variety of allowed solvent/base combinations, we wondered whether the triflation method can reach further synthetic utility in a one-pot Suzuki–Miyaura cross-coupling reaction. Based on a literature protocol,²⁹ we found that the (hetero)aryl triflates underwent efficient cross-coupling by transferring the reaction mixture to a vial with the (hetero)aryl boronic acid, palladium(II) acetate and tricyclohexylphosphine (Scheme 3A). With this protocol, biaryls 33–37 were synthesized under mild conditions with good to near-quantitative isolated yield over two steps. The more challenging bipyridine 35 was prepared in a 1,4-dioxane/H₂O mixture in 63% yield, which was higher than the 42% yield reported in literature.³⁰ In addition, this Suzuki cross-coupling afforded 2-methyl-5-(3-fluoro phenyl) pyridine 36, the pharmacophore of vorapaxar³¹ in 80% yield without purifying the intermediate triflate.

Scheme 3 One-pot reactions enabled by CF₃SO₂F gas generation. (A) One-pot, two-step method of aryl triflate generation followed by Suzuki–Miyaura cross-coupling. (B) Amide synthesis with in situ generated acyl fluorides. The yield corresponds in all cases to the isolated yield after column chromatography without isolation of the intermediates; the enantiomeric excess (ee) was determined by HPLC analysis. [a] DMF was used in the generation chamber instead of MeCN for volatility reasons. [b] NaHCO₃ was used as the only base (1.5 + 2.2 equiv. in step 1 and 2, resp.), with 1,4-dioxane/H₂O 5 : 1 as the solvent, step 2 was heated to 80 °C. [c] Pd(OAc)₂ (2.0 mol%) and PCy₃ (2.4 mol%) were used. [d] The product was isolated as a 92 : 8 mixture of diastereoisomers, which was detected by ¹H NMR.

Another class of oxygen nucleophiles that was subjected to CF₃SO₂F-enabled post-transformations, consists of carboxylic acids. In line with Moses'^9c and Qin's^9b work on SuFEx-mediated carboxylic acid activation, we aimed to develop a new method based on generating acyl fluoride intermediates via CF₃SO₂F gas (Scheme 3B). Without isolating the acyl fluorides, they were reacted immediately to build amides with various degrees of steric congestion. Where the biphasic conditions developed in Scheme 2A left carboxylic acids untouched (products 7 and 25), simply shifting to a pure organic solvent led to smooth deoxofluorination. To explore the substrate scope and functional group tolerance of the amidation process, a variety of aromatic and aliphatic carboxylic acids were examined for coupling with different kinds of amines, including anilines, primary and secondary alkylamines and azoles. All coupling reactions proceeded in fair to excellent yields (Scheme 3, 38–44). This work could be extended to peptide formation, and dipeptide 45 was obtained in 98% isolated yield, while retaining 84% diastereomeric ratio. Especially noteworthy is the procedure's tolerance of bulky coupling partners, a known feature of acyl fluorides.³²

After investigating the chemistry of CF₃SO₂F with oxygen nucleophiles, we were curious to see whether S=N analogs uphold the same substitution reactions. By replacing a single oxo-group with a substituted nitrogen in the S^VI–F hub, trifluoromethanesulfonimidoyl (triflimidoyl) fluorides are obtained. These chiral molecules are characterized by a milder electrophilicity compared to CF₃SO₂F, due to the increased electron density around the sulfur atom. Since the first description of triflimidoyl fluorides in 2002,³³ the recent report by Oehlrich and co-workers is the only example of triflimidoyl fluorides reacting with phenols to form trifluoromethanesulfonimidate (triflimidate) esters.³⁴ Given that only two examples were made under strongly basic conditions, we surmised that an improved synthesis under mild SuFEx conditions should be possible.^3b,35 We synthesized three different triflimidoyl fluoride compounds containing N-aryl or N-alkyl substituents (for preparation, see ESI Section 4.5†). These electrophiles were engaged in SuFEx reactions with various phenols to generate a small library of triflimidate esters. The N-aryl substituted triflimidoyl fluorides reacted efficiently under mild conditions to afford the corresponding products in moderate to excellent yields (Scheme 4, 46–51). The N-alkyl counterparts, which are less electrophilic,^3b,36 required DBU as a stronger base and an elevated reaction temperature of 50 °C. Naturally occurring phenols such as vanillin (47), eugenol (50), L-tyrosine methyl ester (53), raspberry ketone (54), as well as sterically hindered 2-bromophenol (51) and thiophen-2-ol (48) were all well tolerated (Scheme 4).

Scheme 4 SuFEx-enabled synthesis of aryl triflimidate esters from triflimidoyl fluorides. Reactions were carried out at a 0.2 mmol scale. [a] 1.1 equiv. of ArOH was used. [b] 1.2 equiv. of ArOH used, reaction time was 3 h. [c] Reaction was carried out at a 2.0 mmol scale.

After the transformation of various oxygen nucleophiles into reactive handles with CF₃SO₂F, we also wanted to investigate nitrogen nucleophiles. To this end, a range of aliphatic amines, anilines and azoles was engaged in a triflylating reaction to form the trifluoromethanesulfonamides (triflamides) (Scheme 5). Based on a literature SuFEx reaction between SO₂F₂ and secondary amines,^2a we selected DMAP as a stoichiometric base, although we found later that Et₃N furnishes the same products in equal reaction times and yields with the dry MeCN served as the solvent.

Scheme 5 Synthesis of triflamides by reaction of CF₃SO₂F with amines and azoles. Reaction was carried out on 1.0 mmol scale and reported yields are after column chromatography unless noted otherwise. Between brackets is given the ¹⁹F NMR yield using PhCF₃ as internal standard, between parentheses the reaction time. [a] Isolated yield of pure material after aqueous work-up. [b] 3.0 equiv. of base was used. [c] 2.5 equiv. of CF₃SO₂F gas was used. [d] 3.5 equiv. of base was used. [e] 2.0 equiv. of CF₃SO₂F was generated. [f] K₂CO₃ was used as the base. [g] 2.5 equiv. of base was used.

Under these conditions, secondary amines (55–60, 62) reacted efficiently to form the tertiary sulfonamides. Also, primary amines (61, 63–65) were suitable reaction partners to form N-monosubstituted triflamides, an interesting contrast with monosubstituted sulfamoyl fluorides, which cannot be formed under basic conditions.^2a Finally, except for a few unsuccessful substrates (see ESI Section 7.7†), various N-triflyl heterocycles were prepared in the same manner in fair to good yields (66–70). It is worth noting that the N,O-bis(trifluoromethanesulfonyl) compound 60 was formed in high yield using 2.5 equivalents of the generated gas. This stands in contrast to the reaction leading to 28, where no trace of N-triflyl product was observed. The same discrepancy was observed for 70vs.19. It was also verified that N-triflyl compounds 60 and 70 were not hydrolysed by water (see ESI Section 5.3 and 5.4†). Since the only difference between these reaction conditions is the presence or absence of water, it seems that water influences the mechanism in such a way that it plays a decisive role in the reaction outcome. Ultimately, a direct reactivity comparison of phenol and amine groups in compound 60 was evaluated using only 1.0 equiv. of CF₃SO₂F gas. Regardless of choice of base, the product mixtures resulting from trifluoromethanesulfonation in anhydrous MeCN invariably lacked N–SO₂CF₃ monotriflylated product, indicating highest reactivity for the phenol group (see ESI Section 5.2.2†).

Having established a robust procedure for installing a triflyl group through our CF₃SO₂F SuFEx hub, we turned towards the mechanism of this reaction. More specifically, we investigated the base-mediated triflylation of secondary amines, aiming to elucidate the reaction pathway and the specific role of the base. As a result, we hope to shed light on the observed chemoselectivity, by comparing our simulations for secondary amines with the better-studied mechanism of phenol SuFEx reactions.^35,37 To achieve this goal, we use ab initio metadynamics (AIMtD) to retrieve the mechanism as well as quantify the associated activation barriers.³⁸ In contrast to static DFT computations, AIMtD usually includes all molecules in the simulation box, meaning explicit interactions between reactants and additives or solvents are accurately modelled, with the trade-off of a significant increase in computational workload (for theoretical background, see ESI Section 8.1†). We, among others, have previously shown the ability of AIMtD to elucidate reaction mechanisms, quantify reaction barriers and unveil solvation effects.³⁹ Here, piperidine served as a case study for the computationally modelled CF₃SO₂F triflylation reaction (Fig. 1A). In parallel, a series of experimental studies was performed, to complement the in silico findings (Fig. 1B).⁴⁰ Initially, three different systems were considered. A single CF₃SO₂F and one piperidine molecule were placed in the simulation box together with explicit acetonitrile (I), or with DMAP (II) or Et₃N (III) included as a base (Fig. 1A). All simulations in this study followed the Born–Oppenheimer molecular dynamics scheme at the DFT level of theory, with the GGA PBE functional and DZVP-MOLOPT-GTH plane wave basis set.⁴¹ Additionally, the description of long-range dispersion interactions was improved by Grimme's D3 dispersion correction.⁴² The CP2K code (version 6.1) was used together with the Quickstep implementation (for full computational details see ESI Section 8.1†).⁴³

Fig. 1 (A) Transition states obtained through metadynamics simulations for: (I) the non-activated CF₃SO₂F-triflylation of piperidine in acetonitrile, (II) the DMAP-activated CF₃SO₂F-triflylation of piperidine in acetonitrile, (III) the Et₃N-activated CF₃SO₂F-triflylation of piperidine in acetonitrile and (IV) the non-activated CF₃SO₂F-triflylation of piperidine in acetonitrile including two molecules of piperidine. In all cases, electron displacement is schematically illustrated using green arrows. During the simulations, Gaussian shaped potentials were placed along two coordination numbers, resulting in a free energy surface and Helmholtz free energy of activation (ΔF^‡). Simulations were performed in triplicate. (B) Triflylation of phenylpiperazine as model reaction varying the base, solvent and relative amounts of substrate and CF₃SO₂F. Isolated yields are provided unless stated otherwise. [a] ¹⁹F NMR yield relative to int. std. after 72 h reaction time. (C) NCI analyses were performed on the transition states of the DMAP-mediated CF₃SO₂F triflylation (II, green) and Et₃N-mediated CF₃SO₂F triflylation (III, red). Analyses were performed in absence of the solvent to focus on the noncovalent interactions present in and between the reactive species. Top; 3D NCI isosurfaces (s = 0.5) visualized for both reactive systems. An RGB-scale is used to differentiate between repulsive (red) and attractive (green) interactions, set from −0.005 a.u. to 0.005 a.u. For the DMAP-mediated triflylation, a non-classical CH⋯O hydrogen bond is observed as an attractive blue surface, which connects DMAP with CF₃SO₂F (purple arrow). Bottom; an overlay plot of s against ρ sign(λ₂) is presented for both NCI analyses.

From analysing the trajectory obtained for the non-activated CF₃SO₂F-triflylation of piperidine (I), a concerted bimolecular reaction mechanism was observed, akin to an S_N2-type pathway (see ESI Movie†). Indeed, bond length analysis shows a simultaneous S–F bond breaking and S–N_pip bond formation (see ESI Section 8.1†) and the free energy surface displays a reactant and product phase, without an additional intermediate basin (Fig. 1A, I). Notably, without a base, the piperidine nucleophile attacks the sulfur-center from the frontside, which for most S_N2 reactions would be less favourable compared to the corresponding backside pathway.⁴⁴ Herein, frontside attack allows F⁻ to directly scavenge the amine hydrogen of piperidine.

While this mechanism coincides with the findings of Luy and Tonner, the AIMtD simulations result in a Helmholtz free energy of activation (ΔF^‡) of 29 ± 4 kcal mol⁻¹, which exceeds a barrier that can readily be crossed at ambient conditions.³⁷ As the non-activated triflylation of 55 yielded 49% of product at room temperature after 18 hours (Fig. 1B, entry 1), the obtained high activation barrier raises questions on the validity of this mechanism. When adding a base such as DMAP (A, II) or Et₃N (A, III) to the simulation box, a significantly reduced ΔF^‡ is observed (13 ± 1 kcal mol⁻¹ and 22.1 ± 0.05 kcal mol⁻¹, respectively, Fig. 1A). These activation barriers are reasonable, given the high experimental yields obtained for the base-mediated triflylation of 55 (entries 2–3). Mechanistically, the reaction occurs concertedly when DMAP or Et₃N are used, similar to the non-activated CF₃SO₂F-triflylation of piperidine (see ESI Section 8.1 and Movie†). Moreover, the trajectory indicates that the base forms a Lewis adduct with piperidine through a hydrogen bond, enhancing the nucleophilicity of N_pip. Collectively, these observations indicate that the transition state has a termolecular nature, meaning the reaction follows an S_N3-type pathway. While initially these findings might seem surprising, such S_N3 pathways have previously been proposed as mechanisms for substitution reactions on sulfonyl substrates.⁴⁵ Moreover, when the reaction is activated by DMAP or Et₃N, backside attack of the nucleophile is preferred.

Another intriguing observation was the difference between ΔF^‡ of the DMAP and Et₃N activated triflylation. One would expect that a stronger base would activate the nucleophile more efficiently and thus further decrease the activation barrier. Nevertheless, our AIMtD simulations resulted in a value for ΔF^‡ of 13 ± 1 kcal mol⁻¹ and 21.9 ± 0.5 kcal mol⁻¹ for DMAP and Et₃N, respectively. In other words, the activating role of Et₃N is significantly less effective compared to DMAP, notwithstanding Et₃N is the stronger base. To further study the differences between the DMAP-mediated and Et₃N-mediated triflylation of piperidine, NCI analyses were performed on their transition states (for theoretical background, see ESI Section 8.2†).⁴⁶ Remarkably, the 3D NCI isosurface of the DMAP-mediated transition state and bond length analysis reveals an attractive non-classical CH⋯O hydrogen bond connecting DMAP with CF₃SO₂F (Fig. 1C, purple arrow and ESI Section 8.1†). The synergy between this CH⋯O hydrogen bond and Lewis adduct formation between DMAP and piperidine favourably align both reactants in the transition state. Furthermore, the isosurface of the Et₃N-mediated transition state is characterized by larger repulsive (red) surfaces compared to the DMAP-mediated transition state, especially between Et₃N and CF₃SO₂F. From the number of peaks present in the plot of s against ρ sign(λ₂), it can also be inferred that the Et₃N-mediated transition state contains considerably more noncovalent interactions (Fig. 1C). Based on these results, we believe that the activating role of the base in the CF₃SO₂F-triflylation of piperidine transcends beyond deprotonation of the amine. Clearly, intricate non-covalent interactions such as hydrogen bonding or steric repulsion due to the bulkiness of all reactants involved play an important role in the stability of the termolecular transition state.

After establishing plausible reaction pathways for the activated triflylation of piperidine, we reconsidered the mechanism for the non-activated reaction (A, I). We reasoned that, besides acting as the nucleophile, a second equivalent of piperidine could activate the reaction, similar to an added base. Such a mechanistic picture would also coincide with the non-activating triflylation of 55 yielding 49% of product (Fig. 1B entry 1). Indeed, a maximum of 50% would be expected when the substrate acts as its own base. To our delight, we obtained an energetically more reasonable mechanism for the non-activated triflylation of piperidine when a second piperidine molecule was added to the simulation box, resulting in a ΔF^‡ of 18 ± 4 kcal mol⁻¹ (A, IV). In this mechanism, a second equivalent of piperidine forms a Lewis adduct with the piperidine nucleophile and a termolecular transition state is observed. A notable difference with the activated pathways (A, II and III), is that herein substitution preferably proceeds through frontside attack of the nucleophile. To further strengthen our hypothesis, the relative amount of phenylpiperazine with respect to CF₃SO₂F was increased (2 : 1 ratio). As expected, the experimental yield of the reaction increased to 79% (entry 4), suggesting that indeed a second equivalent of piperidine plays an active part in the reaction. Intriguingly, when the water content is gradually increased, as little as 1.5 equivalent shuts down the reaction completely (entries 5–7).

Based on these mechanistic insights, we propose an explanation for the observed chemoselectivity when comparing the triflylation of amines and phenols. When performing the reaction in MeCN : H₂O (3 : 1), phenols are selectively triflylated, while amines remain unaffected (compounds 19 and 28). On the other hand, in dry MeCN (0.33 M), both phenols and amines are converted (compounds 60 and 70). We believe that the influence of H₂O on chemoselectivity can be explained through the difference in mechanism. A trialkylamine (pK_aH ∼11) will partially deprotonate the phenol (pK_aH ∼10) towards the phenolate, which is likely to undergo triflylation via a bimolecular S_N2 type mechanism, as shown by Zuilhof and co-workers.³⁵ In contrast, our simulations showed that under the same conditions, amines would undergo an S_N3 type mechanism, in which a hydrogen bond driven Lewis adduct between the nucleophile and the base is formed (Scheme 6). We assume H₂O to disrupt these essential hydrogen bonds, explaining why the reaction in MeCN : H₂O is selective towards phenols, while in dry MeCN both phenols and amines showcase a high reactivity towards triflylation.

Scheme 6 The CF₃SO₂F triflylation of phenols (phenolate as reactive species) and amines occurs through different pathways.

Conclusions

To summarize, we designed a two-chamber procedure for the safe and efficient ex situ handling of triflyl fluoride gas (CF₃SO₂F) as a new type of SuFEx connector. Herewith, a diverse library of triflates and triflamides was built straightforwardly, often without the need for further purification. Comparing with literature triflation methods, CF₃SO₂F consistently furnished higher yields and selectivities. A particularly interesting finding was the lack of reactivity of carboxylic acids and amines in the presence of water, allowing a completely chemoselective triflation of phenolic nucleophiles. In a more in-depth study of this phenomenon, ab initio metadynamics (AIMtD) simulations offered insight into the reactivity of the CF₃SO₂F triflylation with secondary amine nucleophiles. In contrast to phenolates reacting in a bimolecular fashion, the simulations for amines suggested a formal S_N3 mechanism with a termolecular transition state that relies on hydrogen bond formation between base and nucleophile. Due to the absence of such H-bonds in aqueous media, we believe this mechanism explains the observed difference in reaction outcome. The formation of aryl triflates proved amenable to peptide functionalization and reaction telescoping into one-pot Suzuki–Miyaura cross-coupling. In addition, the sulfonylation chemistry developed for triflyl fluoride CF₃SO₂F was found to be fully translatable to triflimidoyl fluorides CF₃SO(NR)F. These aza-analogous SuFEx hubs provided an efficient route to aryl triflimidate esters, a barely reported class of compounds with three-dimensional, potentially chiral character and unknown biological properties. Overall, we believe that the ex situ gas generation method will lead to increased use of CF₃SO₂F in chemoselective, lab-scale synthesis of valuable aryl triflates and triflamides. Also, process chemistry may benefit from the clean reaction profiles demonstrated here, when using gaseous CF₃SO₂F directly as a low-MW progenitor to current standard Tf₂O. Ultimately, we believe the insights derived from high-quality ab initio calculations form the next step in understanding the fundamental interactions during S^VI–F chemistry, and provide a better-informed basis for future applications.

Data availability

All experimental data, procedures for data analysis and pertinent data sets are provided in the ESI.†

Author contributions

J. D., W. M. D. B., S. H. L. V., and B.-Y. L conceived the formulation and evolution of overarching research goals and aims. B.-Y. L, L. V, F. H and J. D. performed the experiments. R. V. L and M. A performed computational calculations. J. D., B.-Y. L and R. V. L wrote the original draft. All the authors discussed the results and contributed to edit the manuscript.

Conflicts of interest

There are no conflicts to declare.

Acknowledgements

We are grateful to Bart Van Huffel and Luc Baudemprez for the assistance with NMR measurements and to Bart Van Huffel for the elemental analysis. We kindly acknowledge Marcus Frings for HPLC analyses. B.-Y. L thanks the CSC (Chinese Scholarship Council) for her fellowship received. J. D., L. V, R. V. L, M. A and W. M. D. B. thank FWO Vlaanderen (Research Foundation – Flanders) for fellowships and grants received (12ZL820N, 1SA1121N, 1185221N, 12F4416N, G0D6221N). M. A. thanks Vrije Universiteit Brussel (VUB) for financial support. W. M. D. B. thanks KU Leuven for financial support via Project DOA/2020/013. S. H. L. V. acknowledges financial support from the Ministerium für Kultur und Wissenschaft des Landes Nordrhein-Westfalen, the Regierende Bürgermeister von Berlin-inkl. Wissenschaft und Forschung, and the Bundesministerium für Bildung und Forschung. Mass spectrometry was made possible by the support of the Hercules Foundation of the Flemish Government (grant 20100225–7). Tier2 computational resources and services were provided by the Shared ICT Services Centre funded by the VUB, the Flemish Supercomputer Center (VSC) and FWO. Tier1 computational resources and services that were used in this work were provided by the VSC, funded by the FWO and the Flemish Government-department EWI.

Notes and references

1. (a) J. C. Brendel, L. Martin, J. Zhang and S. Perrier, Polym. Chem., 2017, 8, 7475–7485; (b) H. Wang, F. Zhou, G. Ren, Q. Zheng, H. Chen, B. Gao, L. Klivansky, Y. Liu, B. Wu, Q. Xu, J. Lu, K. B. Sharpless and P. Wu, Angew. Chem., Int. Ed., 2017, 56, 11203–11208; (c) T. Hmissa, X. Zhang, N. R. Dhumal, G. J. McManus, X. Zhou, H. B. Nulwala and A. Mirjafari, Angew. Chem., Int. Ed., 2018, 57, 16005–16009; (d) S. Park, H. Song, N. Ko, C. Kim, K. Kim and E. Lee, ACS Appl. Mater. Interfaces, 2018, 10, 33785–33789; (e) B. Yang, H. Wu, P. D. Schnier, Y. Liu, J. Liu, N. Wang, W. F. DeGrado and L. Wang, Proc. Natl. Acad. Sci. U. S. A., 2018, 115, 11162–11167; (f) G. Laudadio, A. d. A. Bartolomeu, L. M. H. M. Verwijlen, Y. Cao, K. T. de Oliveira and T. Noël, J. Am. Chem. Soc., 2019, 141, 11832–11836; (g) W. Liu, S. Zhang, S. Liu, Z. Wu and H. Chen, Macromol. Rapid Commun., 2019, 40, 1900310.
2. (a) J. Dong, L. Krasnova, M. G. Finn and K. B. Sharpless, Angew. Chem., Int. Ed., 2014, 53, 9430–9448; (b) C. Veryser, J. Demaerel, V. Bieliūnas, P. Gilles and W. M. De Borggraeve, Org. Lett., 2017, 19, 5244–5247; (c) J. D. Randall, D. J. Eyckens, F. Stojcevski, P. S. Francis, E. H. Doeven, A. J. Barlow, A. S. Barrow, C. L. Arnold, J. E. Moses and L. C. Henderson, ChemPhysChem, 2018, 19, 3176–3181; (d) J. Kwon and B. M. Kim, Org. Lett., 2018, 21, 428–433; (e) C. Lee, N. D. Ball and G. Sammis, Chem. Commun., 2019, 55, 14753–14756; (f) Q. Zheng, J. L. Woehl, S. Kitamura, D. Santos-Martins, C. J. Smedley, G. Li, S. Forli, J. E. Moses, D. W. Wolan and K. B. Sharpless, Proc. Natl. Acad. Sci. U.S.A., 2019, 116, 201909972.
3. (a) S. Li, P. Wu, J. E. Moses and K. B. Sharpless, Angew. Chem., Int. Ed., 2017, 56, 2903–2908; (b) B. Gao, S. Li, P. Wu, J. E. Moses and K. B. Sharpless, Angew. Chem., Int. Ed., 2018, 57, 1939–1943.
4. (a) Q. Chen, P. Mayer and H. Mayr, Angew. Chem., Int. Ed., 2016, 55, 12664–12667; (b) Q. Zheng, J. Dong and K. B. Sharpless, J. Org. Chem., 2016, 81, 11360–11362; (c) H. L. Qin, Q. Zheng, G. A. Bare, P. Wu and K. B. Sharpless, Angew. Chem., Int. Ed., 2016, 55, 14155–14158; (d) J. Leng and H.-L. Qin, Chem. Commun., 2018, 54, 4477–4480; (e) J. Chen, B. Q. Huang, Z. Q. Wang, X. J. Zhang and M. Yan, Org. Lett., 2019, 21, 9742–9746; (f) Y.-P. Meng, S.-M. Wang, W.-Y. Fang, Z.-Z. Xie, J. Leng, H. Alsulami and H.-L. Qin, Synthesis, 2020, 52, 673–687.
5. (a) C. J. Smedley, M.-C. Giel, A. Molino, A. S. Barrow, D. J. D. Wilson and J. E. Moses, Chem. Commun., 2018, 54, 6020–6023; (b) B. Moku, W.-Y. Fang, J. Leng, L. Li, G.-F. Zha, K. P. Rakesh and H.-L. Qin, iScience, 2019, 21, 695–705; (c) H. Zhou, P. Mukherjee, R. Liu, E. Evrard, D. Wang, J. M. Humphrey, T. W. Butler, L. R. Hoth, J. B. Sperry, S. K. Sakata, C. J. Helal and C. W. am Ende, Org. Lett., 2018, 20, 812–815; (d) M. F. Khumalo, E. D. Akpan, P. K. Chinthakindi, E. M. Brasil, K. K. Rajbongshi, M. M. Makatini, T. Govender, H. G. Kruger, T. Naicker and P. I. Arvidsson, RSC Adv., 2018, 8, 37503–37507.
6. (a) T. A. Fattah, A. Saeed and F. Albericio, J. Fluorine Chem., 2018, 213, 87–112; (b) A. S. Barrow, C. J. Smedley, Q. Zheng, S. Li, J. Dong and J. E. Moses, Chem. Soc. Rev., 2019, 48, 4731–4758.
7. (a) H. Vorbrüggen, Synthesis, 2008, 1165–1174,  DOI:10.1055/s-2008-1067006; (b) M. K. Nielsen, D. T. Ahneman, O. Riera and A. G. Doyle, J. Am. Chem. Soc., 2018, 140, 5004–5008; (c) M. K. Nielsen, C. R. Ugaz, W. Li and A. G. Doyle, J. Am. Chem. Soc., 2015, 137, 9571–9574.
8. (a) M. Epifanov, J. Y. Mo, R. Dubois, H. Yu and G. M. Sammis, J. Org. Chem., 2021, 86, 3768–3777; (b) J. Y. Mo, M. Epifanov, J. W. Hodgson, R. Dubois and G. M. Sammis, Chem. –Eur. J., 2020, 26, 4958–4962; (c) P. J. Foth, F. Gu, T. G. Bolduc, S. S. Kanani and G. Sammis, Chem. Sci., 2019, 10, 10331–10335; (d) M. Epifanov, P. J. Foth, F. Gu, C. Barrillon, S. S. Kanani, C. S. Higman, J. E. Hein and G. M. Sammis, J. Am. Chem. Soc., 2018, 140, 16464–16468; (e) C. Zhao, G.-F. Zha, W.-Y. Fang, N. S. Alharbi and H.-L. Qin, Tetrahedron, 2019, 75, 4648–4656.
9. (a) P. J. Foth, T. C. Malig, H. Yu, T. G. Bolduc, J. E. Hein and G. M. Sammis, Org. Lett., 2020, 22, 6682–6686; (b) S.-M. Wang, C. Zhao, X. Zhang and H.-L. Qin, Org. Biomol. Chem., 2019, 17, 4087–4101; (c) C. J. Smedley, A. S. Barrow, C. Spiteri, M.-C. Giel, P. Sharma and J. E. Moses, Chem. –Eur. J., 2017, 23, 9990–9995.
10. V. Gembus, F. Marsais and V. Levacher, Synlett, 2008, 1463–1466,  DOI:10.1055/s-2008-1078407.
11. A. Ishii, T. Ishimaru, T. Yamazaki and M. Yasumoto, Process for Producing Fluorosulfuric Acid Aromatic-ring Esters, US Pat., 9040745B2, 2015.
12. A concise literature discussion can be found in ESI Section 15.†.
13. Examples using triflic anhydride as a [Tf] source: A. G. Martínez, L. R. Subramanian, M. Hanack, S. J. Williams and S. Régnier, Journal, 2016, 1–17,  DOI:10.1002/047084289X.rt247.pub3.
14. Examples using triflyl imidazole as a [Tf] source: F. Effenberger and K. E. Mack, Tetrahedron Lett., 1970, 11, 3947–3948.
15. Examples using PhNTf₂ as a [Tf] source: (a) J. B. Hendrickson and R. Bergeron, Tetrahedron Lett., 1973, 14, 4607–4610; (b) J. E. Mc Murry and W. J. Scott, Tetrahedron Lett., 1983, 24, 979–982; (c) W. E. Zeller and R. Schwörer, N-Phenyltrifluoromethanesulfonimide, in Encyclopedia of Reagents for Organic Synthesis, 2009,  DOI:10.1002/047084289X.rp142.pub2.
16. Examples using Comins' reagent as a [Tf] source: D. L. Comins and A. Dehghani, Tetrahedron Lett., 1992, 33, 6299–6302.
17. Apart from phenolic starting materials, aryl triflates have also been made using triflic acid (TfOH) in diazonium or benzyne chemistry, or using metal triflate salts in cross coupling chemistry: (a) O. Planas, V. Peciukenas and J. Cornella, J. Am. Chem. Soc., 2020, 142, 11382–11387; (b) C. Picherit, F. Wagner and D. Uguen, Tetrahedron Lett., 2004, 45, 2579–2583; (c) T. Pages and B. R. Langlois, J. Fluorine Chem., 2001, 107, 321–327; (d) C. Ge, G. Wang, P. Wu and C. Chen, Org. Lett., 2019, 21, 5010–5014; (e) A. Pialat, B. Liégault and M. Taillefer, Org. Lett., 2013, 15, 1764–1767.
18. T. Gramstad and R. N. Haszeldine, J. Chem. Soc., 1956, 173–180,  10.1039/JR9560000173.
19. Y. Wang, Z. Gao, B. Wang, W. Zhou, P. Yu and Y. Luo, Ind. Eng. Chem. Res., 2019, 58, 21913–21920.
20. (a) L. Conte, G. Gambaretto, G. Caporiccio, F. Alessandrini and S. Passerini, J. Fluorine Chem., 2004, 125, 243–252; (b) M. Kobayashi, T. Inoguchi, T. Iida, T. Tanioka, H. Kumase and Y. Fukai, J. Fluorine Chem., 2003, 120, 105–110; (c) T. J. Brice and P. W. Trott, Fluorocarbon Sulfonic Acids and Derivatives, US. Pat., US2732398A,. 1956.
21. T. Kume, T. Morinaka, T. Nanmyo and S. Sakai, Process for Preparation of Trifluoromethanesulfonyl Fluoride, European Patent, EP2216325A1, 2010.
22. Y. Morino and Y. Tateishi, Method for Producing Trifluoromethanesulfonyl Fluoride, Japan Patent, 2008285419A, 2008.
23. For applications of CF₃SO₂F in synthetic chemistry, see: (a) D. M. Barnes, V. S. Chan, T. B. Dunn, T. S. Franczyk, A. R. Haight and S. Shekhar, Process for Preparing Antiviral Compounds, US Pat., 20130224149A1, 2013; (b) I. Akihisa, U. Koji and Y. Manabu, Method for Producing Acid Fluorides, Japan Patent, 2009155248A, 2009; (c) N. Masashi and N. Satoshi, Method for Producing Perfluoroalkanesulfonic Acid Ester, JP2007119355A, 2007; (d) I. Akihiro, U. Mikio, K. Yokusu and T. Mitsuru, Process for Producing Binaphthol Bistriflate, US Pat., 6399806B1, 2002.
24. A. Pees, C. Sewing, M. J. W. D. Vosjan, V. Tadino, J. D. M. Herscheid, A. D. Windhorst and D. J. Vugts, Chem. Commun., 2018, 54, 10179–10182.
25. J. Demaerel, C. Veryser and W. M. De Borggraeve, React. Chem. Eng., 2020, 5, 615–631.
26. Y. Zou, L. Qin, X. Ren, Y. Lu, Y. Li and J. Zhou, Chem. –Eur. J., 2013, 19, 3504–3511.
27. D. E. Frantz, D. G. Weaver, J. P. Carey, M. H. Kress and U. H. Dolling, Org. Lett., 2002, 4, 4717–4718.
28. T. Avullala, P. Asgari, Y. Hua, A. Bokka, S. G. Ridlen, K. Yum, H. V. R. Dias and J. Jeon, ACS Catal., 2019, 9, 402–408.
29. A. F. Littke, C. Dai and G. C. Fu, J. Am. Chem. Soc., 2000, 122, 4020–4028.
30. A. S. Voisin-Chiret, A. Bouillon, G. Burzicki, M. Célant, R. Legay, H. El-Kashef and S. Rault, Tetrahedron, 2009, 65, 607–612.
31. J. Liu, B. Sun, X. Zhao, J. Xing, Y. Gao, W. Chang, J. Ji, H. Zheng, C. Cui, A. Ji and H. Lou, J. Med. Chem., 2017, 60, 7166–7185.
32. H. Wenschuh, M. Beyermann, E. Krause, M. Brudel, R. Winter, M. Schuemann, L. A. Carpino and M. Bienert, J. Org. Chem., 2002, 59, 3275–3280.
33. R. Y. Garlyauskayte, A. V. Bezdudny, C. Michot, M. Armand, Y. L. Yagupolskii and L. M. Yagupolskii, J. Chem. Soc. Perkin Trans. 1, 2002, 1887–1889,  10.1039/B205169A.
34. M. Wright, C. Martínez-Lamenca, J. E. Leenaerts, P. E. Brennan, A. A. Trabanco and D. Oehlrich, J. Org. Chem., 2018, 83, 9510–9516.
35. D. D. Liang, D. E. Streefkerk, D. Jordaan, J. Wagemakers, J. Baggerman and H. Zuilhof, Angew. Chem., Int. Ed., 2020, 59, 7494–7500.
36. H. Mukherjee, J. Debreczeni, J. Breed, S. Tentarelli, B. Aquila, J. E. Dowling, A. Whitty and N. P. Grimster, Org. Biomol. Chem., 2017, 15, 9685–9695.
37. J.-N. Luy and R. Tonner, ACS Omega, 2020, 5, 31432–31439.
38. A. Laio and M. Parrinello, Proc. Natl. Acad. Sci. U.S.A., 2002, 99, 12562–12566.
39. (a) R. Van Lommel, J. Bock, C. G. Daniliuc, U. Hennecke and F. De Proft, Chem. Sci., 2021, 12, 7746–7757; (b) G. Bussi and A. Laio, Nat. Rev. Phys., 2020, 2, 200–212; (c) K. M. Bal, S. Fukuhara, Y. Shibuta and E. C. Neyts, J. Chem. Phys., 2020, 153; (d) R. VanLommel, S. L. C. Moors and F. De Proft, Chem. –Eur .J., 2018, 24, 7044–7050.
40. N-Phenylpiperazine was chosen a higher-MW substrate for the mechanistic experiments because N-triflyl piperidine (the product in the simulations) is volatile and less suited for isolated yield determination.
41. (a) J. VandeVondele and J. Hutter, J. Chem. Phys., 2007, 127, 114105; (b) J. P. Perdew, K. Burke and M. Ernzerhof, Phys. Rev. Lett., 1996, 77, 3865–3868.
42. S. Grimme, J. Antony, S. Ehrlich and H. Krieg, J. Chem. Phys., 2010, 132, 154104.
43. (a) J. Hutter, M. Iannuzzi, F. Schiffmann and J. VandeVondele, Wires Comput. Mol. Sci., 2014, 4, 15–25; (b) J. VandeVondele, M. Krack, F. Mohamed, M. Parrinello, T. Chassaing and J. Hutter, Comp. Phys. Commun., 2005, 167, 103–128.
44. T. A. Hamlin, M. Swart and F. M. Bickelhaupt, ChemPhysChem, 2018, 19, 1315–1330.
45. (a) M. Iazykov, M. Canle, J. A. Santaballa and L. Rublova, Int. J. Chem. Kinetics, 2015, 47, 744–750; (b) S. Yamabe, G. Zeng, W. Guan and S. Sakaki, J. Comput. Chem., 2014, 35, 1140–1148; (c) T. W. Bentley, R. O. Jones, D. H. Kang and I. S. Koo, J. Phys. Org. Chem., 2009, 22, 799–806.
46. E. R. Johnson, S. Keinan, P. Mori-Sánchez, J. Contreras-García, A. J. Cohen and W. Yang, J. Am. Chem. Soc., 2010, 132, 6498–6506.

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Footnote

† Electronic supplementary information (ESI) available. See DOI: 10.1039/d1sc06267k

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