Deoxyfluorination of (Hetero)aryl Aldehydes Using Tetramethylammonium Fluoride and Perfluorobutanesulfonyl Fluoride or Trifluoromethanesulfonic Anhydride

Abstract

This Communication describes the conversion of (hetero)aryl aldehydes into the corresponding (hetero)aryl difluoromethyl products using anhydrous NMe 4 F in combi-nation with perfluorobutanesulfonyl fluoride or trifluoromethanesulfonic anhydride.

Tetramethylammonium Fluoride: Fundamental Properties and Applications in C-F Bond-Forming Reactions and as a Base

“…More recently, TMAF has been also shown capable of promoting other C(sp 2 )-F bond-forming reactions on important building blocks such as the deoxyfluorination of phenols via aryl fluorosulfonates with a performance comparable to the better existing methods for this task [138], and improved atom-economy [111,139] (Section 3.3). To that end, TMAF has also been utilized for the relatively understudied deoxyfluorination reaction of (hetero)aromatic aldehydes that yields the corresponding difluoromethylated products [142,143], with better results than DAST-the only reagent hitherto known to render this transformation.…”

“…In the aftermath of their report on the deoxyfluorination of phenols via aryl fluorosulfonates, the Sanford group swiftly described two approaches to transform (hetero)aryl aldehydes and α-ketoester substrates into the corresponding difluoromethylated (hetero)arene products (Scheme 16) [142,143]. The deoxyfluorination of aldehydes was already known for other reagents, such as DAST [73] or Deoxofluor [144] but is relatively less studied than the deoxyfluorination of other types of substrates.…”

“…However, they also inferred that the implementation of this method at laboratory scale may be limited by safety concerns related to the toxicity profile of SO 2 F 2 . Consequently, the second approach reported by the Sanford group on the deoxyfluorination of (hetero)aryl aldehydes dealt with the search of suitable liquid sulfur-based reagents that may replace SO 2 F 2 gas as the electrophile that reacts with TMAF at room temperature, thus improving the possible applicability at the laboratory scale [143]. Based on their previous mechanistic proposal for this transformation, Sanford and co-workers devised that such liquid sulfur-based electrophiles should simultaneously contain a good leaving group and a strong electron-withdrawing group to enhance the electrophilicity-both attached to sulfur.…”

“…Other Types of C-F Bond Formation with TMAF 3.5.1. Nucleophilic Additions to C=X bonds with TMAF Formally, Sanford's method to deoxyfluorinate aromatic aldehydes and α-ketoesters substrates (Section 3.3.3, Scheme 16) [142,143] constitutes the only example in the literature involving the use of TMAF for the nucleophilic addition of fluorine to multiple C=X bonds in organic molecules. Conversely, there is a larger number of examples of such a transformation in inorganic molecules.…”

Sulfonyl Fluorides and Their Analogs Deoxofluorination

“…Besides, PBSF has also been used as an alternative to SO 2 F 2 for deoxofluorination of (hetero) aryl aldehydes, but with somewhat lower yields [23].…”