Tetramethylammonium Fluoride Alcohol Adducts for S_NAr Fluorination

Abstract

Nucleophilic aromatic fluorination (S N Ar) is among the most common methods for the formation of C(sp 2 )−F bonds. Despite many recent advances, a long-standing limitation of these transformations is the requirement for rigorously dry, aprotic conditions to maintain the nucleophilicity of fluoride and suppress the generation of side products. This report addresses this challenge by leveraging tetramethylammonium fluoride alcohol adducts (Me 4 NF•ROH) as fluoride sources for S N Ar fluorination. Through systematic tuning of the alcohol substituent (R), tetramethylammonium fluoride tert-amyl alcohol (Me 4 NF•t-AmylOH) was identified as an inexpensive, practical, and bench-stable reagent for S N Ar fluorination under mild and convenient conditions (80 °C in DMSO, without the requirement for drying of reagents or solvent). A substrate scope of more than 50 (hetero) aryl halides and nitroarene electrophiles is demonstrated. * sı Supporting InformationThe Supporting Information is available free of charge at https://pubs.acs.org/doi/10.1021/acs.orglett.1c01490.Experimental procedures, characterization data, and NMR spectra (PDF) FAIR data, including the primary NMR FID files, for

Unbalanced-Ion-Pair-Catalyzed Nucleophilic Fluorination Using Potassium Fluoride

“…The tolerance to water is a significant advantage compared to most nucleophilic fluorination protocols . The beneficial properties of t -BuOH solvent are consistent with the literature reports on the bulk alcohol effect. − Moreover, the water effect is consistent with Song and Chi’s observation of fluorination using aqueous ionic liquids …”

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

“…Nurturing from that scientific milieu, the use of TMAF in C(sp 2 )-F bond-forming reactions has experienced a vertiginous progression that has culminated in the emergence of synthetic methods capable of fluorinating a wide range of halide and pseudohalide (hetero)arene systems with unparalleled efficiency (even compared to anhydrous TBAF), atom-economy, and often upon reactions conditions mild enough to enable high site-selectivities that are unprecedented in nucleophilic S N Ar fluorinations. Moreover, the refinement in the methods to generate in situ TMAF [97], even catalytically [98], and the development of non-hygroscopic TMAF adducts [132], allows tuning the reactivity of the reagent in solution, and further expands its synthetic utility and versatility (Section 3.2). 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).…”

“…Up to date, the most recent report on the utilization of TMAF for S N Ar fluorinations was published in May 2021 by the Sanford group [132]. This report directly builds on the work of Kim et al [133], who discovered that the combination of t-BuOH with TBAF forms the crystalline adduct (Bu 4 N + F -•(t-BuOH) 4 with attenuated basicity compared to anhydrous TBAF but rather less hygroscopic, and thus operationally simpler to handle (Scheme 12a).…”

“…Scheme 12. Sanford's S N Ar fluorination of halo-and nitro-(hetero)arenes with alcohol adducts of TMAF: (a) Precedent: Preparation of TBAF alcohol adducts[133,134], (b) Sanford's preparation of non-hygroscopic TMAF alcohol adducts, and initial screening[132], and (c) Substrate scope.…”

Hydrogen Bonding Phase-Transfer Catalysis with Alkali Metal Fluorides and Beyond

“… 25 While H-bonding interactions lowered fluoride’s nucleophilicity, the solubility of CsF was improved, 25a and the selectivity for S N 2 vs E2 ( 4a vs 4b ) increased, 25c even when TBAF was used instead of CsF ( Scheme 3 A-ii). 26 The same group also reported the single-crystal X-ray structure of the TBAF( t BuOH) 4 complex and its use for fluorination. 27 The same reagent was successfully employed by our group in Tsuji–Trost-type allylic fluorination of p -NO 2 -benzoates and proved to be superior to both CsF and TBAF due to adequate nucleophilicity combined with low basicity and hygroscopicity ( Scheme 3 B).…”