BF3 Fluorination for Preparing Alkyl Fluorides
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Balz-Schiemann Reaction Chuanfa Ni, Bo Xing and Jinbo Hu Key Laboratory of Organofluorine Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Chinese Academy of Sciences, Shanghai, China
nucleophilic fluorination process that takes advantage of the thermal decomposition of arenediazonium tetrafluoroborates under harsh conditions to produce the corresponding aromatic cation, a quite reactive and short-lived intermediate, to be trapped by the fluoride anion in the reaction system [9].
Introduction
Development of One-Pot Methods for Deaminative Fluorination of Anilines
Aryl fluorides are important structural motifs in pharmaceuticals [1–3], and nearly 20% of 200 best-selling drugs in 2018 contain at least one (hetero)aryl fluoride motif [4]. The past decade has witnessed significant progress in the development of aromatic C-F bond formation, especially via transition metal-mediated or catalyzed processes [5]. However, among all the available methods, Balz-Schiemann reaction (Scheme 1) is one of the most widely used methods for large-scale industrial production of aryl fluorides due to ready availability of the starting materials [6]. Balz-Schiemann reaction was first reported in 1927 by Balz and Schiemann, which exposes arenediazonium tetrafluoroborates to high temperatures to obtain aromatic fluoride compounds [7]. The arenediazonium tetrafluoroborates are usually prepared from anilines, NaNO2, and an inorganic acid in water solution [7, 8]. The fluorodediazoniation of arenediazonium salts is a
The risk on spontaneous and/or violent decomposition of arenediazonium tetrafluorobarates is a major safety concern of Balz-Schiemann reaction. To avoid the isolation and drying of arenediazonium tetrafluoroborates, other diazotization reagents such as NOBF4 [10] and the combination of tBuONO/BF3Et2O [11] have been used for diazoniation in organic systems, and thus anilines can be transformed into aryl fluorides in one pot. Continuous flow processing can further improve the safety of handling arenediazonium tetrafluorobarates [12]. Recently, Buchwald et al. developed a one-pot procedure for deaminative fluorination of anilines by performing the diazotization with tBuONO/BF3Et2O in a flow reactor and the subsequent continuous fluorodediazotization in a stirred batch reactor at 80–130 C (Scheme 2) [13]. The utilization of LiBF4 as an additive could remarkably improve the yield of the aryl fluorides, which also works
© Springer Nature Singapore Pte Ltd. 2020 J. Hu, T. Umemoto (eds.), Fluorination, Synthetic Organofluorine Chemistry 1, https://doi.org/10.1007/978-981-10-3896-9
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Balz-Schiemann Reaction N2BF4
F
heating
R
+ BF3
R
+ N2
or irradiation
Balz-Schiemann Reaction, Scheme 1 Balz-Schiemann reaction
Balz-Schiemann Reaction, Scheme 2 One-pot deaminative fluorination of anilines in continuous flow through the Balz– Schiemann reaction
Ar NH2
CF3CO2H (1 equiv) LiBF4 (3 equiv) tBuONO (1.2 equiv) Flow Reactor
1.8 M LiBF4 in nBuOAc 80−130 oC
A
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