Stereospecific SuFEx reactivity of highly enantioenriched sulfondiimidoyl fluorides

Abstract

Sulfondiimidoyl fluorides are established SuFEx platforms, yet their potential in asymmetric synthesis remains largely unexplored. Herein we report stereospecific SuFEx transformations of highly enantioenriched sulfondiimidoyl fluorides to access sulfone diimines, sulfondiimidamides and sulfondiimidates with complete chirality transfer. For sulfone diimine formation, heteroleptic triorganozincates serve as mild and chemoselective carbon nucleophiles, enabling exclusive stereospecific allyl and benzyl transfer with broad functional group tolerance. The accomplished orthogonal deprotection of sulfondiimidoyl scaffolds demonstrates their additional synthetic flexibility. Collectively, this work establishes sulfondiimidoyl fluorides as robust chiral SuFEx building blocks for asymmetric synthesis.

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Introduction

Development of robust transformations, which rapidly assemble complex molecular frameworks, remains a central objective of synthetic chemistry. Initially proposed by Barry Sharpless in 2013, ¹ SuFEx (Sulfur Fluoride Exchange) reactions have emerged as a “click chemistry” approach that meets this challenge. The SuFEx method exploits the high chemical stability of S(VI)–F motifs, which, nonetheless, exhibit controllable and versatile reactivity toward nucleophiles. Moreover, the broad structural diversity of S(VI)–fluorides renders SuFEx a general platform with applications in organic synthesis,² materials science³ and chemical biology.⁴

Among the various S(VI)–fluorides, sulfonyl fluorides have gained most attention (Fig. 1).⁵ The ability to tolerate harsh reaction conditions and to unleash the desired reactivity under an appropriate reaction system has enabled their use as privileged warheads in chemical biology⁶ and as valuable precursors for sulfones and sulfonamides.⁵ The latter constitute a crucial functional group in drug discovery with over 70 FDA-approved drugs containing a sulfonamide.^7,8 The broad application of sulfonyl fluorides invigorated an in-depth investigation of their aza-analogues.

Fig. 1 Sulfonyl fluorides and their aza-analogues.

Mono-aza-analogues – sulfonimidoyl fluorides – retain the high stability and controlled electrophilic reactivity characteristic of S(VI)–F motifs, additionally featuring an N-vector and a stereogenic S-atom. Importantly, the SuFEx reactions with C-, N- and O-nucleophiles proceed with complete inversion of the sulfur stereocenter.⁹ Notably, C- and N-substitution products – sulfoximines and sulfonimidamides – have already become well-established^10,11 bioisosteres of sulfonamides often offering improved solubility and an ADME profile with retention of potency.^12–15

The next O- to N-atom exchange in sulfonimidoyl fluorides affords S-chiral sulfondiimidoyl fluorides introducing yet another N-vector. Despite the potential utility of these novel scaffolds, general synthetic entries toward sulfodiimidoyl fluorides have appeared only recently. While considerable progress has been achieved in the preparation of racemic derivatives,^16–23 stereoselective synthesis remains largely unexplored.²⁴ Herein, we aim to gain a comprehensive insight into stereochemical aspects of the respective SuFEx reactivity with C-, N- and O-nucleophiles in order to exploit the full potential of highly enantioenriched sulfondiimidoyl fluoride building blocks as a SuFEx platform.

Results and discussion

Despite the reliability of the already developed general synthetic access to racemic sulfondiimidoyl fluorides starting from S(IV) precursors,^16–23 similar preparation of the corresponding enantioenriched products was often plagued by various degrees of racemization and turned out to be a task far from trivial. Our study commenced with the synthesis of the key NH₂-sulfinamidine precursor 2 (Scheme 1). Treatment of the conveniently accessible²⁵ sulfinimidate 1 with LiHMDS afforded the desired building block 2 in fair yield and excellent enantiomeric purity after a single recrystallization. As expected, the reaction proceeded with inversion of configuration at stereogenic sulfur as evidenced by X-ray analysis of sulfinamidine 2. Several electron-withdrawing protecting groups were further introduced at the N-atom. The morpholine-4-carbonyl fragment could be installed in high yield without enantiopurity erosion, whereas introduction of Alloc under identical conditions led to diminished yield and partial racemization presumably due to acyl transfer. Nevertheless, lowering the reaction temperature dramatically improved the outcome, enabling the preparation of Cbz and Alloc derivatives 3b and c in high yields and enantiopurities. Interestingly, switching the base counterion to potassium was pivotal for the successful synthesis of Ns derivative 3d.

Scheme 1 Synthesis of enantioenriched sulfondiimidoyl fluorides: ^a LiHMDS serves as the amine source; ^b after single recrystallization; and ^c KHMDS instead of LiHMDS.

Subsequently, we found that the nature of the N-substituent strongly influenced the final S-fluorination. While the 4-morpholine-carbonyl derivative 4a was obtained in quantitative yield and with a minor erosion of enantiopurity under standard conditions, noticeable racemization occurred in the case of Alloc and Cbz derivatives 4b and 4c, respectively. Control experiments with 4b implicated fluoride ions present in the reaction medium as a probable cause of stereochemical erosion.²⁶ Addition of oxysilanes such as tetramethyldisiloxane or diethoxymethylsilane as fluoride-ion scavengers²⁷ improved the stereoselectivity on a small scale, but failed to resolve the problem upon attempted scale-up. In the case of less nucleophilic 3d, a noticeable decrease in the reaction rate was observed, leading to longer reaction times. Importantly, the X-ray crystal structure of fluoride 4d confirmed the stereoretentive character of both sulfonation and fluorination.

Relying on the stereospecific approach elaborated above, we targeted the p-Br-functionalized sulfondiimidoyl fluoride 4′ (Scheme 2). Unexpectedly, the reaction of sulfinimidate 1′ with LiHMDS led to significant racemization even at cryogenic temperatures. This behavior is consistent with the increased susceptibility of the p-Br-substituted sulfinimidate 1′ toward racemization induced by liberated lithium isopropoxide.²⁵ The racemization was fully suppressed upon addition of TMSCl, in line with the in situ silylation of the expelled isopropoxide. Downstream carbamoylation and fluorination proceeded smoothly to afford sulfondiimidoyl fluoride 4′ in 74% yield over two steps and with 99 : 1 er.

Scheme 2 Synthesis of p-Br-functionalized sulfondiimidoyl fluoride.

The reactivity of sulfondiimidoyl fluorides 4a–d was initially assessed using representative C- and N-nucleophiles (Scheme 3). PhMgBr was chosen as a simple model C-nucleophile owing to the widespread use of aryl-Grignard reagents across various SuFEx transformations.^{18,21,28–30} While the stable morpholine-4-carbonyl moiety was preserved, substitution reactions of Alloc- and Cbz-protected substrates 4b and c under identical conditions led to selective removal of carbamates, affording N–H sulfone diimines 6 in high yields without racemization. Not unexpectedly, the Ns-substituted fluoride 4d formed a complex mixture of products due to the sensitivity of the nitro group to reduction.³¹

Scheme 3 SuFEx reactivity of sulfondiimidoyl fluorides toward C- and N-nucleophiles. Reaction conditions for PhMgBr: sulfondiimidoyl fluoride (1 equiv.), PhMgBr (2.5 equiv.), THF (0.1 M), −30 °C, and 1.5 h. Reaction conditions for morpholine: sulfondiimidoyl fluoride (1 equiv.), Ca(NTf₂)₂ (1.1 equiv.), morpholine (2.2 equiv.), DCE (0.2 M), 60 °C, and 2 h. ^a er of 4b: 99 : 1; ^b er of 4b > 99 : 1; and ^c 18 h at RT.

The SuFEx reactivity toward N-nucleophiles was evaluated next. Morpholine was selected as a model nucleophile owing to its high nucleophilicity and well-documented^{16–18,21,28,31} compatibility with SuFEx chemistry. While morpholine-4-carbonyl and Ns-substituted fluorides 4a and d readily engaged in Ca(NTf₂)₂-promoted³² substitution,³³ mixtures of products were obtained using Alloc- and Cbz-derivatives 4b and c, presumably due to competitive cleavage of the respective protecting groups. Nevertheless, in all cases examined, the substitution reactions proceeded stereospecifically. The strong electron-withdrawing nature of the Ns group enabled fluoride 4d to react with morpholine even without a promoter, albeit with nearly complete stereochemical erosion. Other fluorides did not deliver the desired substitution product in the absence of Ca(NTf₂)₂. On the basis of combined C- and N-nucleophile screening studies, the most versatile 4a was selected as a platform electrophile for further investigation of the scope of nucleophiles.

The scope of C-nucleophiles was examined first (Scheme 4). The resulting sulfone diimines represent valuable aza-analogues of medicinally relevant sulfones and sulfoximines. The phenyl group was introduced in fair yield simply using PhMgBr. More sensitive ester- and indole-containing Grignard reagents were generated by magnesium-iodine exchange and similarly readily engaged in the substitution reaction, affording sulfone diimines 5ab and 5ac in 95% and 79% yield, respectively. Notably, cyclopropylmagnesium bromide proved exceptionally efficient, forming the substitution product 5ad quantitatively.

Scheme 4 Scope of alkyl and aryl C-nucleophiles. Reaction conditions: sulfondiimidoyl fluoride (1 equiv.), Ar/Alk-MgX (2.5 equiv.), THF (0.1 M), −30 °C, and 1.5 h. ^a NMR yield.

Linear alkyl derivatives 5ae–5ag were obtained from the respective alkylmagnesium chlorides in fair yields and configurational inversion at the stereogenic sulfur was confirmed by X-ray analysis of S-methyl sulfone diimine 5ae (Scheme 4). Unexpectedly, i-PrMgCl failed to engage in substitution, delivering the reduced sulfinamidine 3a instead.^34,35 Nevertheless, productive substitution was achieved using the i-PrMgCl-derived zincate reagent 9h, again proceeding with inversion of configuration as established by X-ray analysis. Prompted by this divergence in reactivity, we undertook a more detailed examination of the SuFEx reaction with various organometallic species (Table 1).

Table 1 Optimization of conditions for alkyl and benzyl nucleophiles

No.	[M]-R	From	T, °C	NMR yield, %			er of 5
				5	3a	4a
1	n-BuMgCl		−30	74	4	0	99 : 1
2	n-BuMgBr		−30	60	23	3	N.D.
3	(MgCl)Zn(n-Bu)3	ZnCl2 + 3 n-BuMgCl	−30	75	5	8	99 : 1
4	n-BuLi		−78	15	0	0	N.D.
5	LiCu (n-Bu)2	CuBr·LiBr + 2 n-BuLi	−78	7	76	0	N.D.
6	LiZn(n-Bu)3	ZnBu2 + n-BuLi	−78	8	0	88	N.D.
7	LiZn(n-Bu)3	ZnBu2 + n-BuLi	−30	84	0	0	99 : 1
8	LiZnMe2Bn	BnZnCl + 2 MeLi	−30	70	4	0	N.D.
9	LiZnMe2Bn	BnZnCl + 2 MeLi	−78	80	5	0	N.D.
10	(MgBr)ZnMe2Bn	BnZnCl + 2 MeMgBr	−78	84	13	0	N.D.
11	(MgCl)ZnMe2Bn	BnZnCl + 2 MeMgCl	−78	90	4	0	99 : 1

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In the case of Grignard reagents, the nature of magnesium halide exerted an unexpectedly pronounced effect on the reaction outcome: switching from n-BuMgBr to n-BuMgCl suppressed the formation of sulfinamidine byproduct (Table 1, entries 2 vs. 1). Based on control experiments, we attribute this effect to dealkylation of the alkyl-sulfone diimine product by the respective halide ion. Generation of a triorganozincate nucleophile from n-BuMgCl led to no improvement over the use of the Grignard reagent itself (entry 3). While Gilman cuprate selectively reduced fluoride 4a to sulfinamidine 3a (entry 5), the use of highly reactive n-BuLi resulted in an intractable product mixture containing little of the desired substitution product (entry 4). In contrast, the use of n-BuLi-derived triorganozincate LiZn(n-Bu)₃ enabled productive substitution. Although low conversion was observed at −78 °C, the substitution proceeded smoothly at −30 °C, delivering sulfone diimine 5af in high yield and with complete stereospecificity (entries 6 and 7).

Considering the high performance of organolithium-derived trialkylzincates and our previous experience³⁶ in organozincate chemistry, we next evaluated easily accessible heteroleptic dimethyl benzylzincates (Table 1). Thus, LiZnMe₂Bn generated in situ from BnZnCl and MeLi readily engaged in the substitution reaction (entries 8 and 9) and analogous MeMgBr-derived zincate exhibited comparable reactivity (entry 10). Switching the halide from bromide to chloride (entry 11) further suppressed the formation of sulfinamidine byproduct, affording the corresponding substitution product 5ai in a very high yield without racemization. Complete selectivity of Bn vs. Me transfer was observed with no trace of methyl-substituted derivative 5ae detected.

Based on these results, we decided to exploit the discovered utility of triorganozincate derivatives for the preparation of benzylic sulfone diimines (Scheme 5). Notably, the organozincate approach enabled efficient incorporation of functional groups that are typically incompatible with more reactive organometallic reagents. Accordingly, the yield of sulfone diimines 5aj–al was unaffected by the presence of nitrile, methyl ester and aryl iodide functionalities. Aryl bromide and benzyl-protected aryl moieties were likewise introduced with high efficiency. Dimethylallylzincates generated from allylZnBr and MeLi smoothly engaged in the substitution reaction with stereochemical inversion, as confirmed by X-ray analysis of 5ao. Analogous to benzylic zincates, complete allyl vs. methyl transfer selectivity was observed.

Scheme 5 Scope of benzyl and allyl C-nucleophiles. Reaction conditions: sulfondiimidoyl fluoride (1 equiv.), Bn/allyl-ZnCl (2.5 equiv.), MeMgCl (5 equiv.), THF (0.1 M), −78 °C, and 1.5 h. ^a MeLi instead of MeMgBr.

Having established stereospecific SuFEx with C-nucleophiles, we next explored the scope of N-nucleophiles to access sulfondiimidamides, di-aza analogues of sulfonamides. Under the optimized conditions,³⁷ fluoride 4a was reacted with a diverse set of representative amines (Scheme 6). Anilines as well as primary and secondary amines smoothly afforded the corresponding sulfondiimidamides with high stereoselectivity. The configurational inversion at stereogenic sulfur was confirmed by X-ray analysis of the cyclopropylmethylamine derivative 7ae. The transformation proved compatible with strained alicycles (10e and f), a terminal alkyne (10g) and a Boc-protected primary amine (10h). Interestingly, the substitution with NaN₃ resulted in complete racemization of the sulfur stereocenter.

Scheme 6 Scope of N-nucleophiles. Reaction conditions: sulfondiimidoyl fluoride (1 equiv.), Ca(NTf₂)₂ (1.1 equiv.), amine (2.2 equiv.), DCE (0.2 M), 60 °C, and 2–18 h. ^a Yield on 1.0 mmol scale; ^b 60 °C, 18 h; and ^c at RT, 18 h, in DMF as a solvent.

To complete the exploration of SuFEx substitution reaction, we investigated the scope of O-nucleophiles using a range of phenols³⁸ (Scheme 7). Variation of para-substitution revealed broad applicability of the SuFEx reaction across a wide pK_a range. High yields and stereospecificity were observed for p-OMe-, p-Me-, p-CF₃- and p-CN-substituted phenols (11a–d), whereas a higher temperature was required for the strongly deactivated p-nitrophenol 11e. Introduction of ortho-substituents (phenols 11f and g) led to slightly prolonged reaction times, while yields and stereoselectivity remained high. Notably, SuFEx reactions with biologically relevant estrone (11h), the tyrosine derivative 11i and paracetamol 11j revealed excellent compatibility with functional groups.

Scheme 7 Scope of O-nucleophiles. Reaction conditions: sulfondiimidoyl fluoride (1 equiv.), phenol (1.2 equiv.), NaHMDS (1.2 equiv.), THF (0.05 M), RT, and 1–3 h. ^aRT, 3 h and ^b60 °C, 2 h.

Having established the scope of SuFEx reactivity, we next turned our attention to the possibility of orthogonal deprotection of the obtained scaffolds (Scheme 8). Morpholine-4-carbonyl and Piv-protected sulfone diimine 5aa was chosen as a model substrate. While the selective pivaloyl deprotection was readily achieved using DIBAL, removal of the urea fragment proved more challenging. Following a preliminary screening of conditions, CSA/HFIP-promoted cleavage³⁰ was found to deliver the N–H sulfone diimine 6 with complete stereoselectivity, albeit in a moderate yield.

Scheme 8 Orthogonal deprotection of the obtained scaffolds. ^a enantiomer ratio measured for isolated 15.

We then examined the orthogonal deprotection of sulfondiimidamides, promising di-aza-analogues of sulfonamides. The Ns- and Piv-protected derivative 7da served as a model substrate. Analogous to the sulfone diimine case, the Piv group was selectively cleaved with DIBAL in high yield and with minor erosion of enantiopurity. Notably, no reduction of the sensitive nitro group was observed. In contrast, removal of the Ns group proved troublesome due to pronounced hydrolytic instability of the deprotected derivative even in mildly acidic media. While near-complete erosion of enantiopurity was observed upon isolation of N–H diimidamide 15, in situ trapping with an isocyanate furnished the corresponding urea 16 in high yield and with complete stereoselectivity.³⁹

Conclusions

In the present work, a stereoselective SuFEx platform was established using highly enantioenriched sulfondiimidoyl fluoride building blocks. Systematic investigation of their reactivity toward C- and N-nucleophiles revealed consistent inversion of configuration at the stereogenic sulfur atom. The configurational lability of the sulfur center encountered at various synthetic stages was investigated and resolved through rational control of reaction conditions. Heteroleptic triorganozincates were identified as mild and chemoselective C-nucleophiles, enabling exclusive stereospecific allyl or benzyl group transfer with broad functional group tolerance. Orthogonal protecting group cleavage further demonstrates synthetic versatility of the obtained scaffolds and provides a synthetic entry toward enantioenriched di-aza-analogues of sulfones and sulfonamides. Collectively the obtained results demonstrate the broad applicability of sulfondiimidoyl fluorides as chiral SuFEx hubs and provide a foundation for their application in asymmetric synthesis and medicinal chemistry.

Author contributions

Conceptualization: G. J., P. A. D., and E. S.; investigation G. J., A. J. P., J. B., and V. K.; supervision: P. A. D. and E. S.; writing – original draft: G. J. and P. A. D.; writing – review & editing: G. J., P. A. D., J. B., V. K., and E. S.; funding acquisition: E. S. All authors have given approval for the final version of the manuscript.

Conflicts of interest

There are no conflicts to declare.

Data availability

Supplementary information (SI): experimental details, characterization data, HPLC/CSP chromatograms, and NMR spectra. See DOI: https://doi.org/10.1039/d6qo00230g.

CCDC 2531871–2531876 (2, 4d, 5ae, 5ah, 5ao, and 7ae) contain the supplementary crystallographic data for this paper.^40a–f

Acknowledgements

This work was financially supported by EU Recovery and Resilience Facility (RRF) grant no. 02/OSI/ZG (RRF project no. 5.2.1.1.i.0/2/24/I/CFLA/001). The authors thank Dr Sergey Belyakov from the Latvian Institute of Organic Synthesis for X-ray crystallographic analyses.

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36. V. Kovada, T. Pulle and E. Suna, Chiral Epoxy-Imine Building Block for Diversity-Oriented Synthesis of Peptidomimetic Aspartic Protease Inhibitors, J. Org. Chem., 2025, 90, 10771–10785.
37. See SI page S36 for details.
38. Although aliphatic alcohols can serve as O-nucleophiles in reactions with sulfondiimidoyl fluorides, the resulting O-alkyl sulfondiimidoates are highly unstable, owing to the electrophilic nature of the O-alkyl group and excellent leaving group ability of sulfonimidamide; see, for example E. Friedrich, P. Freund, C. Lorenz, T. Heinrich, D. Didier and M. Reggelin, Synthesis of Sulfondiimidoates by Desoxychlorination of Sulfonimidamides, Org. Lett., 2025, 27, 11673–11677 Consistent with these observations, attempts to isolate the corresponding sulfondiimidate ester from the reaction of sodium or lithium menthoxide with fluoride 4a were unsuccessful.
39. Racemization likely occurs during isolation on silica gel. The high yield and complete stereoretention observed in the in situ trapping experiment indicate that Ns deprotection proceeds without loss of stereochemical integrity. As no workup precedes chromatographic purification, the racemization is attributed to the configurational instability of NH-diimidamide 15 on silica gel.
40. (a) CCDC 2531871: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qzm8m; (b) CCDC 2531872: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qzm9n; (c) CCDC 2531873: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qzmbp; (d) CCDC 2531874: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qzmcq; (e) CCDC 2531875: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qzmdr; (f) CCDC 2531876: Experimental Crystal Structure Determination, 2026,  DOI:10.5517/ccdc.csd.cc2qzmfs.

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