Concise and Additive‐Free Click Reactions between Amines and CF₃SO₃CF₃

Abstract

Trifluoromethyl trifluoromethanesulfonate has proved to be an excellent reservoir of difluorophosgene and a promising click ligation for amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under metal‐ and additive‐free conditions. The reactions are rapid, efficient, selective, and versatile, and can be performed in benign solvents, giving products in excellent yields with minimal efforts for purification. The characteristics of the reactions meet the requirements of a click reaction. The use of trifluoromethyl trifluoromethanesulfonate as a click reagent is advantageous over other “CO” sources (e.g., TsOCF3, PhCO2CF3, CsOCF3, AgOCF3, and triphosgene) because this reagent is readily accessible; easy to scale up; and highly reactive, even under metal‐ and additive‐free conditions. It is anticipated that CF3SO3CF3 will be increasingly as important as SO2F2 as a click agent in future drug design and development.

Tertiary‐Amine‐Initiated Synthesis of Acyl Fluorides from Carboxylic Acids and CF3SO2OCF3

“…The nucleophilic trifluoromethoxy anion, derived from the breakage of the S−OCF 3 bond of CF 3 SO 2 OCF 3 by diverse fluorides, represents the most prevalent trifluoromethoxylation reagent, which reacted with organic halides, metal complexes, α‐diazo compounds, and alkenes under transition‐metal‐catalyzed or ‐free conditions to form a variety of useful trifluoromethoxylated compounds [8] . Moreover, CF 3 SO 2 OCF 3 can be employed as a promising click ligation for primary and secondary amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under additive‐free conditions [10] . In addition to these achievements, application of CF 3 SO 2 OCF 3 in other reactions has rarely been explored.…”

“…The − OCF 3 anion originated in situ from CF 3 SO 2 OCF 3 is thermally unstable and quickly decomposes to form fluorophosgene and fluoride ion at room temperature. In this regard, CF 3 SO 2 OCF 3 can be considered as a convenient and efficient reservoir of O=CF 2 and − F anions [10] . Furthermore, fluorophosgene and anhydrous fluorine anions have been evidenced to be important condensation and nucleophilic fluorination reagents, respectively [11] .…”

“…[8] Moreover,C F 3 SO 2 OCF 3 can be employed as ap romising click ligation for primary and secondary amines in the preparation of urea derivatives, heterocycles, and carbamoyl fluorides under additive-free conditions. [10] In addition to these achievements, application of CF 3 SO 2 OCF 3 in other reactions has rarely been explored. It was known that CF 3 SO 2 OCF 3 is al ow-cost, modest, bench-stable, air-and moisture-insensitiver eagent, and resistant to hydrolysis even in an aqueous NaOH solutiona talow temperature.…”

“…In this regard,C F 3 SO 2 OCF 3 can be considereda s ac onvenient and efficient reservoir of O=CF 2 and À Fa nions. [10] Furthermore, fluorophosgene and anhydrous fluorinea nions have been evidenced to be important condensation and nucleophilic fluorination reagents, respectively. [11] We envisioned that decompositiono fC F 3 SO 2 OCF 3 by an appropriate initiator would result in av iable condensation/fluorinationr eagent for organic synthetic chemistry.I nt his article, the reactiono fc arboxylic acids with CF 3 SO 2 OCF 3 in the presence of at ertiary amine was explored, which providede xclusivelya cyl fluorides as the products via deoxyfluorination.…”

Modern synthesis of carbamoyl fluorides

“…The group of Zhang used trifluoromethyl trifluoromethanesulfonate (TFMT) as difluorophosgene (O=CF2) precursor in conjunction with amines to generate very quickly (within 2 min of reaction at room temperature) the desired carbamoyl fluorides in excellent yields using acetonitrile (ACN) as solvent (Scheme 3). 22 The substrate scope encompasses complex structures without alteration in the reaction outcome. The functional group tolerance was also very interesting since carboxylic acids, amides as well as nitriles are tolerated under the reaction conditions.…”