SuFExable NH-Pyrazoles via 1,3-Dipolar Cycloadditions of Diazo Compounds with Bromoethenylsulfonyl Fluoride

Abstract

“Click” reactions have transformed the molecular sciences. Augmenting cycloaddition reactions, sulfur­(VI) fluoride exchange (SuFEx) chemistry has diversified the landscape of molecular assembly. Herein, we report a facile strategy to access SuFExable NH-pyrazoles via strain and catalyst-free 1,3-dipolar cycloadditions of stabilized diazo compounds under mild conditions. Subsequent SuFEx proceeds efficiently with various N- and O-nucleophiles. Access to SuFExable NH-pyrazolesa class of compounds containing two common pharmacophoresenables future opportunities within drug discovery, chemical biology, materials chemistry, and related fields.

The 1,3‐Dipolar Cycloaddition: From Conception to Quantum Chemical Design

“…[61] 1,3-dipoles had shown to undergo the 1,3-DCA reaction with ethenylsulfonyl (ESF) or 1-bromoethene-1-sulfonyl fluoride (Br-ESF) yielding sulfonyl fluoride-substituted pyrazoles and pyrazolines. [62] Furthermore, diazoacetamide reacts at ambient temperatures while azides do not, thus broadening the scope and diversity of potential substrates for this reaction. [63] Relative to the azido, diazo compounds feature a higher HOMO 1,3-dipole that could engage in more favorable NED HOMO 1,3-dipole -LUMO dipolarophile interaction.…”

“…In recent years, the thermal 1,3‐DCA reaction had been used in the context of sulfur(VI) fluoride exchange (SuFEx) click chemistry, which could be relevant for sulfonyl linkage in biologically active compounds and late‐stage diversification [61] . 1,3‐dipoles had shown to undergo the 1,3‐DCA reaction with ethenylsulfonyl (ESF) or 1‐bromoethene‐1‐sulfonyl fluoride (Br‐ESF) yielding sulfonyl fluoride‐substituted pyrazoles and pyrazolines [62] . Furthermore, diazoacetamide reacts at ambient temperatures while azides do not, thus broadening the scope and diversity of potential substrates for this reaction [63] .…”

Recent advances in pyrazole synthesis employing diazo compounds and synthetic analogues

“…In the biological arena, diazo compounds have served as chemical probes and are widely used in the novel modifications of proteins and nucleic acids, thereby acting as an excellent tool in chemical biology. 5 They can be easily accessed via several methods starting from the corresponding active methylene compounds, amines, and carbonyl compounds (Fig. 3).…”

Cyclobutane Formation by the Reaction of Ethenesulfonyl Fluoride with Dimethyl Diazomalonate

“…Analogously, reactions of ESF with aryldiazomethanes gave 5‐arylpyrazolines that carried an SO 2 F group at position 3 (Scheme 1b) [20] . Very recently, ESF was reported by Gold and coworkers to undergo an uncatalyzed 1,3‐dipolar cycloaddition with N ‐benzyl‐2‐diazoacetamide to deliver a 3,5‐disubstituted pyrazoline (Scheme 1c) [21] . Copper(II) fluoride catalysis was used by Tang and coworkers to synthesize the (3+2)‐cycloadducts of ESF with α‐keto‐stabilized diazoalkanes, hydrolysis of which led to HF/SO 3 elimination with formation of pyrazoles that underwent a Michael addition to a second equivalent of ESF (Scheme 1d) [22]…”

“…[20] Very recently, ESF was reported by Gold and coworkers to undergo an uncatalyzed 1,3-dipolar cycloaddition with N-benzyl-2-diazoacetamide to deliver a 3,5-disubstituted pyrazoline (Scheme 1c). [21] Copper(II) fluoride catalysis was used by Tang and coworkers to synthesize the (3 + 2)-cycloadducts of ESF with α-keto-stabilized diazoalkanes, hydrolysis of which led to HF/SO 3 elimination with formation of pyrazoles that under-went a Michael addition to a second equivalent of ESF (Scheme 1d). [22] During our ongoing studies to quantify the reactivities of diazo compounds, [20,23] we envisioned the cycloaddition of ESF with dimethyl diazomalonate to furnish fluorosulfonyl substituted pyrazolines without the need for metal catalysis, in analogy to the reports summarized in Scheme 1.…”