Catalytic asymmetric nucleophilic fluorination using BF3·Et2O as fluorine source and activating reagent

Abstract

Fluorination using chiral catalytic methods could result in a direct access to asymmetric fluorine chemistry. However, challenges in catalytic asymmetric fluorinations, especially the longstanding stereochemical challenges existed in BF3·Et2O-based fluorinations, have not yet been addressed. Here we report the catalytic asymmetric nucleophilic fluorination using BF3·Et2O as the fluorine reagent in the presence of chiral iodine catalyst. Various chiral fluorinated oxazine products were obtained with good to excellent enantioselectivities (up to >99% ee) and diastereoselectivities (up to >20:1 dr). Control experiments (the desired fluoro-oxazines could not be obtained when Py·HF or Et3N·3HF were employed as the fluorine source) indicated that BF3·Et2O acted not only as a fluorine reagent but also as the activating reagent for activation of iodosylbenzene.

Strategies for Nucleophilic C(sp3)–(Radio)Fluorination

“…While high-energy and strained substrates have afforded access to α-fluorocarbonyls, β-fluoroalcohols, and β-fluoroamines, most substrates leveraged in this type of approach require at least one-step syntheses from abundant, commercial feedstocks. Therefore, there is significant interest in directly engaging the native alkene functionalityan abundant chemical feedstockto access similar fluorinated products. , …”

“…Therefore, there is significant interest in directly engaging the native alkene functionality�an abundant chemical feedstock�to access similar fluorinated products. 72,73 However, without the thermodynamic driving forces associated with gaseous byproducts or ring strain release, the functionalization of alkenes requires alternate strategies, one being the generation of transient reactive intermediates in situ. For example, the addition of HF across an alkene generates a carbocation electrophile that undergoes nucleophilic attack to provide the Markovnikov functionalized product.…”

β-Boron Effect Enables Regioselective and Stereospecific Electrophilic Addition to Alkenes

“…In practice, however, the regioselectivity of electrophilic additions is not always easy to control . Typically, site-selectivity is determined by the Markovnikov rule, − but it can be overrun by conjugative effects − or intramolecular nucleophilic participation. , The introduction of the silyl substituent provides a way to control regioselectivity. The well-known β-silicon effect, or σ­(C–Si)-π hyperconjugation, makes the alkenyl carbon distal to the silyl group more nucleophilic, resulting in a selective outcome (Scheme A).…”

Catalytic Synthesis of 5-Fluoro-2-oxazolines: Using BF3·Et2O as the Fluorine Source and Activating Reagent

“… 17 Among them, aminofluorinations could result in fluorinated N -compounds, including useful N -heterocycles ( Scheme 1 b). 18 In view of operational and environmental advantages associated with hypervalent iodine reagent applied in fluorination reactions, 15 , 19 we recently reported hypervalent iodine-catalyzed fluorinations using BF 3 ·Et 2 O as s fluorine source. Various fluorinated six-membered and seven-membered N,O -heterocycles were synthesized through the metal-free strategy.…”

“…As a versatile, cheap, and easily handled Lewis acid, BF 3 ·Et 2 O could also act as a fluorine source in various fluorination reactions . Among them, aminofluorinations could result in fluorinated N -compounds, including useful N -heterocycles (Scheme b) . In view of operational and environmental advantages associated with hypervalent iodine reagent applied in fluorination reactions, , we recently reported hypervalent iodine-catalyzed fluorinations using BF 3 ·Et 2 O as s fluorine source.…”