Rapid access to sulfinyl fluorides for the preparation of sulfonimidoyl fluorides

Abstract

Herein, we report a new thionyl fluoride-based method that rapidly converts sulfinic acids into the corresponding sulfinyl fluorides in 62–97% yield. The unstable sulfinyl fluorides can be directly treated with chloramine-T to afford sulfonimidoyl fluorides, an important class of sulfur(VI)-fluoride exchange (SuFEx) hubs, in 56–92% isolated yields.

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The past two decades have witnessed a surge in new methods for efficiently accessing sulfur(VI) fluoride motifs, driven by their valuable biological properties and distinctive balance of stability and reactivity.¹ Among these, sulfonyl fluorides (Fig. 1a, 1) have emerged as key motifs in pharmaceutical drug development² and chemical biology,³ and are widely used as SuFEx reagents.⁴ In contrast, studies of sulfur(IV) fluorides have largely focused on their use as reagents, such as DAST⁵ and XtalFluor-E®,⁶ with relatively few investigations exploring these motifs as synthetic intermediates.

Fig. 1 Sulfinyl fluorides: background, preparation, and novel synthesis and application.

An intriguing class of sulfur(IV) fluoride motifs are sulfinyl fluorides (Fig. 1b, 2) as they have the potential to be used as intermediates for the formation of important sulfur(IV) or (VI) motifs. Despite the synthetic potential of sulfinyl fluorides, reports of their successful isolation are rare, as they are typically unstable during purification.⁷ The preparation and use of sulfinyl fluorides as reactive intermediates in one-pot processes would, therefore, be a versatile strategy. Unfortunately, existing methods for the preparation of sulfinyl fluorides are not readily adaptable to these protocols.^8,9 The only one-pot method reported thus far involves the deoxyfluorination of trifluoromethylsulfinate (3), where the resulting sulfinyl fluoride (4) is a gas at room temperature and can be readily separated from the reaction mixture.¹⁰ Beyond this isolated example, there are currently no general, one-pot methods available for the preparation and use of these sulfur(IV) motifs.

We hypothesized that a general and expedited strategy (Fig. 1d) could be achieved using ex situ-generated thionyl fluoride (SOF₂, 7). This reagent has been shown to enable rapid deoxyfluorination of other motifs, and one-pot processes were readily be achieved¹¹ as the byproducts had minimal impact on downstream reactions. Unlike previous methods, this approach would not be limited to gaseous sulfinyl fluoride intermediates.

For the second step in the one-pot process, we targeted the synthesis of sulfonimidoyl fluorides. This important class of fluorinated motifs serve as sulfur(VI) fluoride exchange (SuFEx) hubs and are particularly valuable because of their enhanced stability relative to sulfonyl fluorides.¹² Existing approaches to these compounds typically require at least two synthetic steps, and the intermediates require isolation.¹³ A subsequent transformation of the sulfinyl fluoride intermediate (2), such as a novel oxidation to the corresponding sulfonimidoyl fluoride (8) would serve as a useful application toward an important class of molecules.

We began our investigation with the deoxyfluorination of para-fluorophenyl sodium sulfinate (Table 1, 5a), which enabled analysis of the crude reaction mixture by ¹⁹F NMR spectroscopy. For these experiments, an acetonitrile solution of thionyl fluoride was readily generated from thionyl chloride using our ex situ method (Scheme 1).¹⁴ Acetonitrile was used for the optimization¹⁵ as it was observed to efficiently solubilize the starting salts (entry 1). Even though some heterogeneity persisted, the desired sulfinyl fluoride 2a was formed in 30% yield by ¹⁹F NMR spectroscopy. Increasing the amount of thionyl fluoride to 3 equivalents resulted in a modest improvement in the yield (entry 2, 38%). The addition of pyridine led to a substantial increase in yield (entry 3, 69%), consistent with previous observations regarding the beneficial effect of amine bases in thionyl fluoride-promoted reactions.¹⁶

Table 1 Optimization experiments for the deoxyfluorination of sodium sulfinate 5a and sulfinic acid 6a

Entry^a	X	SOF2 (equiv.)	Base^b	Additive	^19F NMR yield^c (%)
a Reaction conditions: To a vial containing 5a or 6a and additive under argon was added a solution of base and SOF2 in acetonitrile (0.20 M, see SI for SOF2 generation). The mixture was stirred at rt for 30 min and then analyzed by ^19F NMR spectroscopy. Reactions were performed on 0.25 mmol scale.b 1.0 equiv. of base was used.c Conversion was determined by ^19F NMR spectroscopy using trifluorotoluene as the internal standard.
1	Na	1	—	None	30
2	Na	3	—	—	38
3	Na	3	Pyridine	—	69
4	Na	3	Pyridine	15-crown-5	83
5	Na	3	DIPEA	15-crown-5	75
6	Na	3	Piperidine	15-crown-5	51
7	Na	3	DMAP	15-crown-5	60
8	Pyr	3	—	—	73
9	H (6a)	3	Pyridine	—	97

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Scheme 1 Ex situ method of thionyl fluoride generation.^11a

To further improve the solubility profile of the reaction mixture, we evaluated the use of 15-crown-5,¹⁷ which provided sulfinyl fluoride 2a in 83% yield (entry 4). Use of this crown ether in combination with other bases, including diisopropylethyl amine (DIPEA, entry 5), piperidine (entry 6), and N,N-dimethylaminopyridine (DMAP, entry 7), resulted in diminished yields. The corresponding pyridinium sulfinate salt was also evaluated as a starting material to improve solubility, affording 2a in 73% yield (entry 8). Treatment of sulfinic acid 6a with 3 equivalents of both pyridine and thionyl fluoride proved highly effective, delivering the sulfinyl fluoride (2a) in near quantitative yield (entry 9, 97%).¹⁸ Other sulfur(IV)- and sulfur(VI)-fluoride reagents were also examined, but the yields were either poor or the byproducts narrowed the scope of subsequent transformations.¹⁹

With the optimized conditions established (Table 1, entry 9), we next explored the scope of this new method (Table 2) with a focus on substrates that lack viable preparative methods.²⁰ Consistent with prior reports,²¹ significant degradation was observed upon attempted isolation of the sulfinyl fluorides (2). To evaluate the efficiency of the deoxyfluorination step, we therefore used ¹⁹F NMR spectroscopic yields of the substrates.²²

Table 2 Sulfinyl fluoride scope

a Reaction conditions: To a vial containing sulfinic acid 6 (0.25 mmol) under argon was added a solution of pyridine (1 equiv.) and SOF₂ in acetonitrile (0.20 M, see SI for SOF₂ generation method). The mixture was stirred at rt for up to 45 min, and the conversion was determined by ¹⁹F NMR spectroscopy using fluorobenzene or trifluorotoluene as the internal standard.

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Electron-withdrawing groups in the para-position were tolerated, with the corresponding sulfinyl fluorides formed in 77 to 97% yield (2a–2c). Likewise, meta- and ortho-substituted substrates, as well as napthyl sulfinyl fluoride were obtained in good to excellent yields (2d–2f, 81–96%). While there are methods that can access aryl sulfinyl fluorides, there are only a few literature examples of non-fluorinated aliphatic products.^9a,c Our new method also proved to be effective for these non-aromatic substrates (2g–2j). Vinyl- and benzyl-substituted sulfinic acids proved to be suitable substrates, affording 2g and 2h in 62% and 94% yield, respectively. Finally, the protocol was successfully extended to aliphatic sulfinyl fluorides, delivering 2i and 2j in 88% and 91% yield.

To ensure the method is compatible with one-pot processes, we next sought an effective strategy to remove excess thionyl fluoride. Initial attempts focused on sparging sulfinyl fluoride solutions with a dry inert gas, such as nitrogen or argon. However, extended sparging consistently resulted in lower yields of the corresponding sulfinyl fluorides (2). Moreover, sparged solutions exhibited significantly faster degradation compared with solutions that retained residual thionyl fluoride. To better understand this unexpected behavior, we first synthesized sulfinyl fluoride 2a using our optimized protocol (Scheme 2), and then analyzed the reaction mixture every 2 minutes over a 10-minute degassing period using ¹⁹F NMR spectroscopy.²³ Over the 10 minutes, sulfinyl fluoride 2a was depleted and several new sulfur species increased in concentration. ¹⁹F NMR spectroscopic analysis suggested that these species corresponded to sulfinic anhydride 9 and sulfinyl sulfone 10. These structures are also consistent with previously reported decomposition pathways.²⁴ Aqueous workup of the reaction mixture afforded thiosulfonate 11 as the major byproduct, along with sulfonic acid 12 and sulfonyl fluoride 13, which are known to form from 9 and 10.²⁶ To minimize formation of these side products, we found it advantageous to leave trace thionyl fluoride present in the reaction mixture (the reaction was sparged for approximately 5 minutes).²⁵

Scheme 2 Side reactions of sulfinyl fluorides after prolonged sparging with argon.

To evaluate whether the newly developed sulfinyl fluoride synthesis is compatible with one-pot protocols, we targeted the preparation of sulfonimidoyl fluorides (Fig. 1, 8). We hypothesized that we could access these important motifs in a sequence involving initial formation of the sulfinyl fluoride, followed by oxidation using chloramine-T. While nitrene additions to sulfinyl chlorides have been reported,²⁶ there are no examples of analogous transformations using sulfinyl fluorides.

We investigated the scope of this one-pot procedure for accessing sulfonimidoyl fluorides (8) using a wide range of aryl, vinyl, and aliphatic sulfinic acids (Table 3).²⁷ Electron-deficient sulfinic acids were amenable to this process, affording fluoro- (8a), trifluoromethyl- (8b), and nitro-substituted sulfonimidoyl fluoride (8c) in 63–80% yield. Chloride and iodide substituents in the para-position (8k and 8l) provided comparable yields (79–80%) to the fluoride derivative (8a). para-Alkyl substituted sulfinic acids were successfully converted to the corresponding sulfonimidoyl fluorides (8m–8p) in good to excellent yields (56–85%). para-Phenyl substrate 2q was also a viable substrate, affording 8q in 72% yield. The reaction also proved to be effective for strongly electron-donating arenes, such as para-methoxy sulfinic acid (8r, 92% yield). meta-Substitution was also tolerated (8d, 57% yield). The reaction was largely tolerant of both electron-donating and withdrawing group in the ortho position, with sulfonimidoyl fluorides 8e, 8s, and 8t all furnished in comparable yields (78–84%). Naphthyl-substituted sulfonimidoyl fluoride 8f was obtained in 92% yield.

Table 3 Scope of sulfonimidoyl fluorides via one-pot procedure from sulfinyl fluorides^a

a Reaction conditions: To a vial containing sulfinic acid 6 (1.0 mmol) under argon was added a solution of pyridine (1 equiv) and SOF₂ in acetonitrile (0.20 M, see SI for SOF₂ generation method). The mixture was stirred at rt for up to 45 min, upon which it was sparged with argon for 5 min. Chloramine-T (3 equiv.) and anhydrous toluene (0.38 M) were then added, and the mixture was stirred at 80 °C for 18 h. Purification by flash column chromatography yielded the corresponding sulfonimidoyl fluoride.b The yields of sulfonimidoyl fluorides 8h–8j were low, and are reported using ¹⁹F NMR spectroscopy with fluorobenzene as the internal standard.

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This method could also be extended to access vinyl sulfonimidoyl fluoride 8g in 58% yield. Benzyl-substituted sulfonimidoyl fluoride 8h could be obtained, albeit in a low yield (10%). Likewise, aliphatic sulfonimidoyl fluorides 8i and 8j were generated under these conditions in 24% (8i) and 14% (8j) yield. Products 8h–8j were formed in poor yields and decomposition was observed.²⁸ Thus, they were not isolated and the yields were determined by quantitative ¹⁹F NMR spectroscopy.

Overall, we have developed a novel method for synthesizing sulfinyl fluorides using thionyl fluoride via the deoxyfluorination of sulfinic acids. This approach rapidly generates aromatic and aliphatic sulfinyl fluorides in situ (≤45 min, 62–97% yield), and represents the most general method for preparing sulfinyl fluorides reported to date. Importantly, the reaction produces relatively unreactive byproducts, which enables a second transformation in the same reaction pot. We have leveraged this feature to demonstrate that sulfinyl fluorides generated by our method can be converted to sulfonimidoyl fluorides through reaction with chloramine-T in a one-pot process. This transformation represents one of the most efficient routes to sulfonimidoyl fluorides and constitutes the first example of nitrene addition to sulfinyl fluorides. The extension of this methodology to access additional sulfur(IV) and sulfur(VI) motifs from sulfinyl fluorides is currently under investigation.

The project was conceptualized by B. J. T., T. G. B., N. D. B., and G. M. S. B. J. T., R. P., T. G. B., M. S., C. B., and W. Y. conducted the experiments. M. S., C. L. J., R. P., N. D. B., and G. M. S. wrote and edited the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

The data supporting this article have been included as part of the supplementary information (SI). Supplementary information is available. See DOI: https://doi.org/10.1039/d6cc02993k.

Acknowledgements

Financial support for this work was provided by the University of British Columbia (UBC), the Natural Sciences and Engineering Resource Council of Canada (2020-RGPIN-04653), and Pomona College (N. D. B.). Student support was provided in the form of a NSERC CGSD (T. G. B.) and a MITACS Accelerate fellowship (C. L. J.).

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27. See the SI for details of the optimization.
28. See the SI for details.

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Footnote

† These authors contributed equally.

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