Advancements in Aminofluorination of Alkenes and Alkynes: Convenient Access to β‐Fluoroamines

Abstract

Direct aminofluorination of alkenes enables the convenient synthesis of β‐fluorinated amine compounds, which are important and valuable skeletons in medicinal chemistry. In recent years this research field has received much attention and significant advancements have been made by different approaches. In this review, recently disclosed methodologies for the production of β‐fluorinated amines, based on electrophilic and metal‐catalyzed processes, are summarized and discussed. Finally, the outlook and perspectives for aminofluorination are also discussed.

Fluorination and Fluoroalkylation Reactions Mediated by Hypervalent Iodine Reagents

“…Numerous fluorination methods have been developed to meet the requirements in the fields of pharmaceutical, agrochemical, and material sciences. [9] Fluorine substituents in medicines often aim for increasing stability, modulating physicochemical properties (e. g., polarity, lipophilicity, pKa value, hydrogen bonding), and/or regulating their molecular conformations. Nowadays, the commonly used direct fluorination approaches include the Balz-Schiemann reaction, deoxyfluorination, nucleophilic substitution, radial or electrophilic addition, CÀ H bond fluorination, electrochemical fluorination and so on.…”

“…This transformation is significant as it applied to O-unprotected phenols and did not require the synthesis of complex precursors or the use of organometallic reagents. [11b] Additionally, hypervalent-iodine(III)-mediated aromatic fluorination of 3-phenylpropyl ethers (9) with an activated iodosylbenzene monomer/18-crown-6 complex (10) in the presence of Et 2 O • BF 3 and water led to para-selective monofluorination of aryl rings and afforded regioselectively 3-(4-fluorophenyl)propyl ethers (11) in good yields, wherein neighboring alkoxy groups played an essential role (Scheme 2). [12] Positively charged iodine(III) of complex 10 selectively attacks the para position of the aromatic ring of 3phenylpropyl ether and the subsequent nucleophilic attack by the intramolecular methoxy group produces a spiro-1,4-cyclohexadiene (12-I).…”

Kitamura Electrophilic Fluorination Using HF as a Source of Fluorine

“…The most commonly used synthetic approach for preparation of 3-fluoropyrrolidines is based on fluorine substitution for hydroxy group in 3-hydroxylpyrrolidines [167][168][169][170][171]. Another approach, based on aminofluorination of alkenes [172][173][174][175][176], is more practical allowing both ring construction and introduction of a fluorine atom in one convenient synthetic sequence. It was found that the aminofluorination version of this approach can be successfully realized using the Kitamura fluorination protocol.…”

Aminofluorination: transition-metal-free N–F bond insertion into diazocarbonyl compounds

“…N -Fluorobenzenesulfonimide (NFSI) is inexpensive and shelf stable, and is often employed as a mild electrophilic fluorinating or aminating reagent. 8 , 9 Recently, Liu 10 and Zhang 11 demonstrated that NFSI could serve as both an amino and fluorine source for the transition-metal-catalysed aminofluorination of alkenes ( Scheme 2a ). Inspired by these seminal works, we envisioned that NFSI might be an ideal candidate for the transition-metal catalysed N–F bond insertion into D/A carbenes ( Scheme 2b ).…”