Electrophilic fluorination reagents

More pertinent to the interests of fluoro-organic chemists, a number of compounds bearing a single N—F bond have become useful electrophilic fluorination reagents, i.e., behaving as effective sources of F+. The structures of some of them are given below, along with the chemical shifts for the N—F fluorine substituent. 

Methylene-l,3-benzoxazin-2-ones 194 were found to be susceptible to addition to the exocyclic double bond. On heating under reflux in ethanol, oxazinones 194 were transformed to the 4-ethoxy derivatives 195. Treatment of 194 with l-chloromethyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane bis(tetrafluoroborate) (F-TEDA-BF4), an electrophilic fluorinating reagent, in the presence of methanol, led to the 4-fluoromethyl-4-methoxy-substituted compounds 196 (Scheme 34) <2003T8163>. 

One of the most active areas of research in fluorine chemistry over the last ten years has been the development of the N-F electrophilic fluorinating reagents. These compounds fall into two categories, namely, neutral molecules and salts, and the reader is referred to recent reviews and papers which describe in detail their preparation and chemistry [7,18,197,203-211]. 

Table 7. N-F Electrophilic Fluorinating Reagents Main Structural Types...

The bridgehead-amine-derived electrophilic fluorinating reagents l-alkyl-4-fluoro-l,4-di-azoniabicyclo[2.2.2]octane ditriflate 5 a or bis(tetrafluoroborates) 5b and 6 can be prepared from l-alkyl-4-aza-l-azoniabicyclo[2.2.2]octane salts and elemental fluorine. For example, treatment of l-methyl-4-aza-l-azoniabicyclo[2.2.2]octane triflate (4a) and lithium triflate in acetonitrile at — 35CC with neat fluorine over three hours gives l-fluoro-4-methyl-l,4-dia-zoniabicyclo[2.2.2]octane ditriflate (5a).81 The reagents 5b, 6, 7, and 8 can be synthesized in a similar manner.76 83... 

Data for two alkyl iodo difluorides and one example of a fluoroiodane electrophilic fluorination reagent are also provided. 

Although a number of electrophilic fluorinating reagents are known, most are toxic, unstable, and difficult to handle. These new, stable N-fluoropyridinium salts are readily obtained in 60-80% yield by reaction of a pyridine with F2/N2(l/9) in CH3CN in the presence of sodium triflate. 

The need for a variety of organofluorine molecules has encountered difficulties with oxygenated substitutes such as carboxylic esters due to their poor nucleophilicity towards electrophilic fluorinating reagents. This has led several groups to explore the conversion of the thiocarbonyl group into the CF2 moiety. It was successful with thioamides [174], dithioesters [175-177] and thionoesters [178, 179], providing new routes to difluoro-sulfides, amines, ethers and alkenes. 

Lal89a has discussed the application of a new family of N—F -type electrophilic-fluorination reagents consisting of l-alkyl-4-fluoro-l,4-diazabicyclo[2.2.2]octane salts (37) whose preparation, patented by Banks89b, utilizes the reaction of elemental fluorine... 

H. Mechanistic Studies of Fluorination with Electrophilic Fluorinating Reagents... 

Several 3-ai"yl-2-fluorobenzo[/ ]thiophenes have been prepared by fluorination of the 2-lithio derivatives using the electrophilic fluorinating reagent AT-fluorobenzenesulfonimide (Equation 110) <2005SL247>. The yields are fair to excellent. 

The selective substitution of the hydrogen a to a carbonyl function by fluorine has been extensively investigated using a range of N-F electrophilic fluorinating reagents these include 1-fluoropyridinium salts, ° l-(chloromethyl)-4-fluoro-l,4-diazoniabicyclo[2.2.2]octane tetra-fluoroborate and other salts, l-fluoro-4-hydroxy-l,4-diazoniabicyclo[2.2.2]octanebis(tetra-fluoroborate) (NFTh) and A -fluorobis(trifluoromethyl)sulfonaniidc (see Vol. ElOa, p 438 ff). ... 

Many electrophilic fluorinating reagents have been used as a source of positive fluo-For the specific case of fluorination of enamines, the most commonly used reagents... 

The use of solid l-fluoropyridin-2(l//)-one (9) as an electrophilic fluorinating reagent for enamines requires no special safety devices. ... 

The reaction of diazo compounds with an electrophilic fluorinating reagent, tri-fluoromethyl hypofluorite. has also been studied (Tabic 8, entries 9 13). ° The reactions are carried out at — 70 C using trichlorofluoromethane as solvent and mixtures of g /n-difluoro compounds and fluoro(trifluoromethoxy) derivatives are obtained. Although conversion is generally complete, the yields of isolated products are low, due to their difficult separation. In some cases (entries 9, 11, and 12), ketones and epoxides arc formed as byproducts. Consequently, this method is not a useful alternative for the preparation ofgcw-difluoro compounds. 

The driving force of these fluorinations is the weakness of the C — X (X = B. Si, Sn) bond, that facilitates ipso substitution of these functional groups by a fluorine atom in reactions with electrophilic fluorinating reagents and, in some cases, with elemental fluorine. 

One of the most convenient synthetic routes for the preparation of vinyl fluorides 2 is by treatment of the corresponding vinyltin compounds 1 with electrophilic fluorinating reagents. This procedure is also used for the preparation of aryl fluorides, since it is well-established that fluorination with electrophilic reagents is facilitated by ipso substitution of a suitable, usually weakly bonded, metal function. In the case of aryl fluorides, the reaction is also carried out using elemental fluorine as the fluorinating agent. ... 

Xenon difluoride (XeF ) is the electrophilic fluorinating reagent whose reactions with vinyltin compounds have been studied most exhaustively. " A series of vinyl fluorides prepared according to this procedure is listed in Table 1. 

Table 4. Synthesis of Aryl Fluorides by Reaction of Aryltrialkyltin Derivatives with Electrophilic Fluorinating Reagents and with Elemental Fluorine...

Trifluoromethyl hypofluorite, CF3OF, the first organic hypofluorite, reacts as if the O-F bond is homolyzed to the trifluoromethoxy radical and a fluorine radical in many reactions, but it has been used effectively as a selective electrophilic fluorination reagent in organic chemistry. It has limited selectivity as a fluorination reagent in inorganic chemistry bnt it can be oxidatively added to numerous compounds. 

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