Development of S_NAr Nucleophilic Fluorination: A Fruitful Academia-Industry Collaboration

Abstract

Conspectus The identification of reliable, general, and high yielding methods for the formation of C­(sp2)–fluorine bonds remains a major challenge for synthetic organic chemists. A very common approach involves nucleophilic aromatic fluorination (SNAr fluorination) reactions of aryl chlorides or nitroarenes. Despite being known for more than a century, traditional SNAr fluorination reactions suffer from significant limitations, particularly on a process scale. These include the high cost of common reagents [e.g., cesium fluoride (CsF)], a requirement for elevated temperatures and long reaction times, poor functional group tolerance, and the need for rigorous exclusion of water. This Account summarizes our collaboration with Corteva Agriscience (previously Dow Agrosciences) to address many of these challenges. This collaboration has provided a platform for fundamental scientific advances involving the development of new methods, reagents, and substrates for mild and high yielding nucleophilic fluorination reactions. Our early studies established that the combination of potassium fluoride (KF) and superstoichiometric tetrabutylammonium chloride (Bu4NCl) serves as a cost-effective alternative to CsF for the SNAr fluorination of chloropicolinate substrates. However, these reactions still require elevated temperatures (>130 °C) and afford moderate yields due to competing decomposition of the substrate and product. The need for high temperature is largely due to slow reaction rates resulting from the low concentration of the active fluorinating reagent [anhydrous tetrabutylammonium fluoride (Bu4NF)] under these conditions. To address this issue, we developed several strategies for generating high concentration solutions of anhydrous tetraalkylammonium fluoride in situ by combining fluorine-containing electrophiles (e.g., hexafluorobenzene, acyl fluorides, sulfonyl fluorides) with tetraalkylammonium nucleophiles (R4NCN or R4NOR). These systems enable SNAr fluorination under unusually mild conditions, affording nearly quantitative yield with chloropicolinate substrates at room temperature. However, the high cost of the electrophiles and the generation of large quantities of byproducts in the R4NF-forming step render this approach unsuitable for process scale applications. As an alternative, we next explored anhydrous tetramethylammonium fluoride (Me4NF) for these transformations. This highly reactive fluoride source can be synthesized directly from inexpensive KF and Me4NCl and then dried by heating under vacuum. Unlike Bu4NF, it is not susceptible to Hofmann elimination. As such, anhydrous Me4NF is stable and isolable, as well as highly effective for the room temperature SNAr fluorination of chloropicolinates and other electron deficient substrates. The studies with anhydrous R4NF drew our attention to another challenge associated with traditional SNAr fluorination reactions: their limitation to substrates bearing resonance electron-withdrawing groups. We hypothesized that this challenge could be addressed by circumven...

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

“…Most of the reactions that employ TMAF as a fluorinating agent for the formation of C(sp 2 )-F bonds are nucleophilic aromatic substitutions (S N Ar) [37]. Physical organic chemistry defines S N Ar reactions as the substitution of a leaving group with a nucleophile on a (hetero)aromatic system [103] and establishes two major categories according to their mechanism: Reactions proceeding via (i) a stepwise addition-elimination mechanism, which is largely the most common type-especially amongst reported TMAF-mediated S N Ar reactions-and (ii) stepwise elimination-addition S N Ar reactions.…”

“…Based on the fluorinating source and reaction mechanism, C-F bond-forming reactions can be categorized into three groups: (i) Nucleophilic [36,37], (ii) electrophilic [38][39][40], and (iii) thermally or photo-induced radical fluorinations [41][42][43][44]. Nucleophilic fluorination reactions are the only class exclusively involving the action of fluoride anions alone or as part of ionic pairs in solution.…”

Revisiting the Balz–Schiemann Reaction of Aryldiazonium Tetrafluoroborate in Different Solvents under Catalyst- and Additive-Free Conditions

“… 2 − 4 , 7 − 11 Over the past few decades, numerous C aryl –F bond formation methods have been developed for the preparation of aromatic fluorides, which mainly include the Balz–Schiemann reaction, nucleophilic aromatic substitution (S N Ar, e.g., the Halex reaction), electrophilic C aryl –H fluorination, and transition-metal-catalyzed fluorination. 7 − 12 Among these approaches, the Balz–Schiemann reaction, first described by Balz and Schiemann in 1927, has been confirmed as an excellent method for the installation of fluorine into the aromatic systems. 13 − 16 …”

“…The importance of the Balz–Schiemann reaction has been borne out in its wide application in the preparation of both electron-rich and -poor (hetero)aryl fluorides that are inaccessible by other methods. 12 − 16 The traditional procedures of this method involve two steps: (1) the preparation and isolation of dry diazonium tetrafluoroborates from arylamines, and (2) the thermal decomposition of these salts into aromatic fluorides, nitrogen, and boron trifluoride. 13 − 16 The BF 4 – ion behaves as a nucleophilic fluoride source in the reaction, and a S N 1 mechanism via intermediacy of an aryl cation is generally accepted.…”

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

“…This finding not only revolutionized the understanding of the mechanistic aspects of these classical reactions but also suggested that, using SNAr chemistry, electron-rich arenes might be converted into a much wider range of products than previously anticipated. [7][8][9][10][11][12][13][14][15] Fluorinated arenes, on the other hand, have recently gained prominence in the areas of materials science and pharmaceutical chemistry owing to their distinct chemical and physiological properties, e.g., enhanced metabolic stability and improved lipophilicity. [16][17][18][19][20][21][22] However, there is no known natural source for fluoroarenes which means that these compounds must be prepared synthetically.…”