Site‐Selective Late‐Stage Aromatic [¹⁸F]Fluorination via Aryl Sulfonium Salts

Abstract

Site‐selective functionalization of C−H bonds in small complex molecules is a long‐standing challenge in organic chemistry. Herein, we report a broadly applicable and site‐selective aromatic C−H dibenzothiophenylation reaction. The conceptual advantage of this transformation is further demonstrated through the two‐step C−H [18F]fluorination of a series of marketed small‐molecule drugs.

18F-Fluorination: Challenge and Opportunity for Organic Chemists

“… 60 The most practical reaction with promise for fluorine-18 translation was obtained when we switched from the thianthrene scaffold to the dibenzothiophene scaffold. 61 The substituent can be readily introduced into a variety of molecules through C–H functionalization, although not quite as generally and selectively as thianthrene, and the resulting aryl sulfonium salts react with simple [ 18 F]fluoride ( Scheme 10 ), presumably by reductive elimination from a triarylfluoro sulfur(IV) intermediate. The approach can quickly access a variety of suitable reaction precursors, does not require a transition metal, is simple in its execution, and employs a simple fluoride source for the C–F bond formation.…”

High Site Selectivity in Electrophilic Aromatic Substitutions: Mechanism of C–H Thianthrenation

“…In parallel, the groups of Procter and Alcarazo have reported the use of dibenzothiophene S -oxide ( DBTO ) to access the corresponding sulfonium salts ( Ar–DBT + ). 42 , 43 With the aim of introducing 18 F via nucleophlic substitution, 44 we have also used Ar–DBT + salts as linchpins, finding site selectivities somewhat lower than those observed for Ar–TT + in their preparation from arenes (>50:1 in ethylbenzene). While the synthetic utility of aryl sulfonium salts is currently well recognized, 45 − 51 the reasons behind the high selectivity on their formation from arenes still remain largely unexplored and are not well understood.…”

Studies on the Synthesis of Perfluoroaryl Sulfides and their Application in Desulfurative Nickel-Catalyzed Reductive Cross-Coupling

“…The concept of C−S bond activation has also been exploited for the functionalization of C−H /C−X bonds (X = halide). Organosulfur reagents like thianthrene sulfoxide, [60][61][62][63] dibenzothiophene S-oxide, [64][65] xanthate [66][67] , thiocarbamate, [68][69] and tetrafluoropyridinyl disulfide [48][49][50][51][52] can be added to arenes or organohalides to obtain sulfonium salts or sulfides, which contain a weak C−S bond that can be easily replaced in a reductive C−S bond cleavage step. Despite the success of the above methods, which are all based on C−S bond activation, one still lacks a generally applicable tool for the efficient conversion of mercapto groups into other functionalities.…”