Installation of -SO2F groups onto primary amides

A protocol of SO2F2-mediated installation of sulfonyl fluoride onto primary amides has been developed providing a new portal to sulfur(VI) fluoride exchange (SuFEx) click chemistry. The generated molecules contain pharmaceutically important amide and -SO2F moieties for application in the discovery of new therapeutics.

Phenols (or alcohols) and amines as the most common nucleophiles have been found to react with different S(VI) connectors (SO 2 F 2 , CH 2 =CH-SO 2 F, SOF 4 etc.) to provide diversified sulfonyl fluoride derivatives. The reactions of phenols (or alcohols) with SO 2 F 2 [29] or the fluorosulfuryl imidazolium salt were developed for mild and effective formation of the corresponding fluorosulfates to act as biological probes in chemical proteomics studies (Scheme 1, (1)) [1,30]. On the other hand, the reactions of aliphatic or aromatic amines with SO 2 F 2 or the fluorosulfurylimidazolium salt have been achieved for assembly of N-sulfonyl fluorides [1,30], which have served as important active precursors for the development of noncovalent inhibitors (Scheme 1, (1)) [1,30,31]. Amides are the key connections in proteins, amides, and a vast number of synthetic structures, such as polymers, biologically active compounds and pharmaceutical products [32][33][34][35]. However, the installation of sulfonyl fluoride (SO 2 F) onto nitrogen atoms of amides has not been achieved, which, if accomplished, would provide a very important class of sulfonyl fluorides, namely, N-fluorosulfonyl amides, for the development of potential covalent inhibitors . The Roesky group described a pioneering protocol for the synthesis of N-fluorosulfonyl amides from fluorosulfonyl isocyanate (Scheme 1, (2)) [36]. The available procedures for the preparation of N-fluorosulfonyl amides are very limited which relied on using either the isocyanate approach, or the amidosulfofluoride (FSO 2 NH 2 ) (Scheme 1, (2)) [37][38][39]. Therefore, the development of a new method for the assembly of N-fluorosulfonyl amides from cheap and abundant reagent is highly desirable. Herein, we report the first, to the best of our knowledge, SO 2 F 2 -mediated N-fluorosulfonylation [40][41][42] of amides by using DBU as base for the constructions of a series N-fluorosulfonyl amides (Scheme 1b).

Results and Discussions
Initially, benzamide (1a) was selected as model substrate to test the feasibility of this proposed N-fluorosulfonylation reaction in the presence of Cs 2 CO 3 in DMSO under SO 2 F 2 atmosphere (balloon) at 50 °C, and excitingly, the desired product benzoylsulfamoyl fluoride (2a) was obtained in 25% yield (Table 1, entry 1). Encouraged by this preliminary success, several common bases were evaluated, among which, 1,8-diazabicycloundec-7-ene (DBU) catalysed the proposed transformation most effectively to provide the desired product 2a in nearly quantitative yield ( With the optimized conditions in hand, we next turned our efforts to investigate the scope of substrates. Under the standard conditions, a variety of substituted amides were examined which were smoothly converted to their corresponding substituted benzoylsulfamoyl fluoride derivatives (Scheme 2) in moderate to excellent isolated yields. Both electron-withdrawing groups, such as halogen atoms (1b-d, 1j, 1m, and 1n), NO 2 (1e, 1k) and CF 3 (1f), and electron-donating groups, such as Me (1g, 1l, and 1o), tert-butyl (1h) and 2-naphthyl (1i) on the aromatic rings, were well tolerated under the optimized conditions. It was

Scheme 2:
Screening of the substrate scope of amides. Reaction conditions: a mixture of amides 1 (1.0 mmol), DBU (5.0 mmol, 5.0 equiv), and DMSO (1.0 mL) was added to a reaction flask before SO 2 F 2 was introduced into the stirred reaction mixture by slowly bubbling from a balloon, and the mixture was allowed to stir at 50 °C for 12 h. Isolated yields. a 50 °C, 18 h.
worth noting that not only para-(1b-h) but also meta-(1j-l) and ortho-(1m-o) substituted benzamides afforded the desired products in generally good yields. Arylcarboxylic amides (1p and 1q) bearing bis-substitutions also behaved well under the standard conditions. Heterocyclic aromatic carboxylic amides (1r-u) were well-tolerated and afforded the target products in 56-90% yields. In addition, alkyl carboxylic amides were also smoothly transformed into the corresponding products (2v-z). However, primary amides bearing an amino group or a phenolic hydroxy group were not successfully converted to the corresponding N-fluorosulfonyl amides and only a mixture of undesired products were observed.
Interestingly, during the work-up process of drying 2e with Na 2 SO 4 , a colourless crystal 4e was observed and its structure was confirmed by XRD analysis (Scheme 3). We speculate that the tautomerism of amides [43] may occur in the reaction process and the tautomer 3e could react with Na 2 SO 4 to generate 4e, which indicated that N-H connected with two electron-withdrawing groups (carbonyl, and SO 2 F) can behave as an acid to donate a proton for chemical transformations. This property of fluorosulfonyl amides 2 with nucleophilicity may attract significant attention for further applications.
As depicted in Scheme 4, a plausible reaction mechanism is proposed for SO 2 F 2 -mediated transformation of amides to N-fluorosulfonyl amides. The reaction was initiated by the deprotonation of amide 1 with the base (DBU) to generate an intermediate A, which subsequently went through a SuFEx process with SO 2 F 2 to deliver the final product 2.

Scheme 4:
The proposed reaction mechanism.

Conclusion
In conclusion, we have developed a novel method for N-fluorosulfonylation of amides. This simple, convenient, and mild protocol provides a portal to a class of novel sulfonyl fluorides for SuFEx click chemistry with great potential to be applied in the development of covalent inhibitors. Further studies of this class of molecules in chemical biology and drug discovery are underway in our laboratory.