Developing Efficient Nucleophilic Fluorination Methods and Application to Substituted Picolinate Esters

Abstract

This report describes nucleophilic fluorination of 3 and 5-substituted picolinate ester substrates using potassium fluoride in combination with additive promoters. Agents such as tributylmethylammonium or tetraphenylphosphonium chloride were among the best additives investigated giving improved fluorination yields. Additionally, the choice of additive promoters could influence the potential formation of new impurities such as alkyl ester exchange. Other parameters explored in this study include additive stoichiometry, temperature influence on additive degradation, solvent selection, product isolation by solvent extraction, and demonstration of additive recycling. ■ INTRODUCTIONAryl fluorides are extremely important structural motifs that are featured prominently in pharmaceuticals, agrochemicals, organic materials, and biological imaging agents. 1 An increasing number of fluorine-containing biologically active molecules have been developed for pharmaceutical and agrochemical applications ( Figure 1). Despite rising pharmaceutical and agrochemical prevalence, the selective fluorination of arenes remains a difficult task. As a result, significant recent efforts have focused on the development of new synthetic procedures for the formation of C Aryl −F bonds. 2,3 Halex reactions are a class of nucleophilic substitutions where a carbon−halogen bond (C−X 1 ) is converted to new and different carbon−halogen (C−X 2 ). For this study, halex reactions specifically refer to the conversion of aryl−Cl bonds to aryl−F bonds using a nucleophilic fluoride source. Halex reactions, typically run in polar aprotic solvents, require extreme temperatures (greater than 150°C) largely due to the poor solubility of metal fluoride salts such as cesium fluoride (CsF) and potassium fluoride (KF). 4 KF is much more economical than CsF but usually less reactive. Traditionally, common halex substrates require an electron-withdrawing group to activate the aryl ring towards nucleophilic attack. These factors often present challenges for developing efficient fluorination methods for aromatic and heteroaromatic motifs.Recently, our efforts have focused on the development of mild, selective methods to fluorinate aromatic systems. One strategy developed in our laboratories utilizes the combination of copper triflate Cu(OTf) 2 and KF to convert a variety of aryl potassium trifluoroborates to the corresponding fluorinated products in good yield. 5 This methodology has a wide range of functional group compatibility (Figure 2). Additionally, we developed methodology for high yielding fluorination of heteroarenes utilizing adaptations to the anhydrous tetrabutylammonium fluoride (TBAF) protocol. 6 Unique to this adaptation was the ability to premix some of the heteroarene substrates with tetrabutylammonium cyanide before adding hexafluorobenzene, thus enabling in situ generation of anhydrous TBAF. This strategy telescoped the fluorination procedure into a single one pot process. Overall, the anhydrous TBAF agent exhibited good solubility in a wide rang...

Expanding the Balz–Schiemann Reaction: Organotrifluoroborates Serve as Competent Sources of Fluoride Ion for Fluoro‐Dediazoniation

“…In nearly all cases, high‐temperature thermolysis (>100 °C) with inorganic “‐ate” salts or demanding conditions (e.g., dry HF) are required. While yields remain variable and highly dependent on specific conditions or a given substrate class, no set of conditions has emerged to be generally applicable for the Balz–Schiemann reaction, a peculiarity typifying many fluorination methodologies of variable scope often accompanied by significant limitations …”

“…While yields remainv ariable and highly dependent on specific conditions or ag iven substrate class, [12] no set of conditions has emerged to be generally applicablef or the Balz-Schiemann reaction, ap eculiarity typifying many fluorination methodologies of variable scope often accompanied by significant limitations. [13] While organotrifluoroborates (RBF 3 À s) have been known since 1940, their use in fluoro-dediazoniation is limited to a singler eport on the decomposition of 4-fluorophenyl-diazonium perfluoroalkyl-BF 3 À salts at 140 8C. [14] Whereas the inductive effecto ft he adjacent difluoromethylene group is known to greatly impede fluoridei on release from perfluoroalkyl-BF 3 À , [15] other RBF 3 À ss olvolyzef luoride ion much more rapidly.…”

Nucleophilic Fluorination of Electron-Deficient Arenes

“…Accordingly, the reactions usually require high temperature and long reaction time to achieve high yields and complete conversion. Moreover, the use of spray-dried KF to increase its surface area [17,18] and the addition of phase transfer catalysts including quaternary ammonium salts, quaternary phosphonium salts, and crown ethers have been shown to be advantageous in increasing the yields (Scheme 5) [14,16,[19][20][21][22][23][24][25][26][27]. A combination of KF, tetraphenylphosphonium bromide, and 18-crown-6 has been successfully used to convert chlorobenzaldehydes to the corresponding fluorobenzaldehydes (Scheme 5, Eq.…”

Reactions of Arylsulfonate Electrophiles with NMe4F: Mechanistic Insight, Reactivity, and Scope

“…S N Ar fluorination reactions typically involve the conversion of an aryl chloride or nitroarene to the corresponding aryl fluoride via treatment with an alkali metal fluoride salt (Figure A). , However, these transformations remain limited by the requirement for high temperatures (generally >100 °C) and long reaction times. These forcing conditions often lead to poor functional group tolerance as well as the formation of side products. , In addition, the scope of S N Ar fluorination reactions is typically restricted to substrates bearing strongly electron-withdrawing substituents, which are needed to stabilize the high energy Meisenheimer intermediates/transition states (Figure A) . Recent work has demonstrated the use of soluble anhydrous tetraalkylammonium fluoride salts to achieve the S N Ar fluorination of aryl chloride and nitroarene substrates under milder conditions. − However, these transformations still remain limited to highly electron-deficient ArX electrophiles.…”

“…These forcing conditions often lead to poor functional group tolerance as well as the formation of side products. 5,6 In addition, the scope of S N Ar fluorination reactions is typically restricted to substrates bearing strongly electron-withdrawing substituents, which are needed to stabilize the high energy Meisenheimer intermediates/transition states (Figure 1A). 3b Recent work has demonstrated the use of soluble anhydrous tetraalkylammonium fluoride salts to achieve the S N Ar fluorination of aryl chloride and nitroarene substrates under milder conditions.…”