Recent Advances in the Synthesis of Difluorinated Architectures from Trifluoromethyl Groups

Abstract

Fluorine-containing moieties are widely used in the pharmaceutical, agrochemical, and material fields. Thus, these structures are of immense interest in the fields of organic synthesis and medicinal chemistry. Among various fluorinated groups, the difluoromethyl unit has drawn increasing attention due to its unique pharmaceutical properties. In recent years, several methods for the synthesis of difluoromethylated compounds have been rapidly developed. However, most of these methods treat aromatic compounds with excess difluoromethylating reagents, which often contain organometallic compounds, so these transformations are generally less environmentally friendly and atom-economical. In this review, we summarize the recent development of new methods for the synthesis of difluoromethyl motifs or difluoroalkenes from trifluoromethylated aromatic compounds or trifluoromethyl alkenes via single C(sp 3 )À F bond cleavage.1.

Electrosynthetic C–F bond cleavage

“…For example, such a strategy can enable the use of trifluoromethyl groups as precursors for difluoromethyl (CF 2 H) groups that have received significant attention for medicinal chemistry applications. 10 Despite the low reactivity of C–F bonds, synthetic strategies are available for their cleavage. The most common approach relies on elimination through an E1cB mechanism, including nucleophilic aromatic substitutions.…”

“…transition metal catalysis, 12 Lewis acids based on main group elements, 6 ,13 early transition metals and lanthanides 13 ,14 and low-valent metal reagents. 10 ,15 Recent developments in radical synthesis have also delivered new methods for C–F bond cleavage, including photo- and electrochemical strategies. 16 The latter is becoming an increasingly popular synthetic approach, due to the prospects of new reactivity and selectivity, as well as resource friendly synthesis that follows with electricity as terminal reagent.…”

2‐Bromo‐3,3,3‐Trifluoropropene: A Versatile Reagent for the Synthesis of Fluorinated Compounds

“…Different from the normal S N 2 reaction, S N 2’‐type reaction involves concerted allylic rearrangement, in which the nucleophile attacks an unsaturated C1 and the leaving group departs from the saturated C3 [54] . α‐(trifluoromethyl)styrenes are reactive substrates for S N 2’‐type reactions, which have been successfully utilized for the activation of a single C−F bond [1n–p] . However, BTP has been rarely utilized for S N 2’‐type reactions.…”

Defluorinative Alkylation of Trifluoromethylbenzimidazoles Enabled by Spin-Center Shift: A Synergistic Photocatalysis/Thiol Catalysis Process with CO2•–

“…Due to the inert reactivity of the C–F bond, and because exhaustive defluorination usually occurs during the defluorinative process, selective functionalization of the single C–F bond in the perfluoro group remains challenging . Very recently, several research groups reported photoredox-catalyzed processes to functionalize a range of aryl-CF 3 groups, including hydrodefluorination, defluoroarylation, defluoroallylation, and defluorocarboxylation …”