Electrophilic fluorination reagents application

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... 

The recent interest in electrophilic fluorination of phosphonates reflects the importance of a-fluorophosphonates as isosteres of biologically important phosphates. However, the use of electrophilic fluorination methods is increasing with the availability of safe and easy to handle fluorine sources. Several reviews of the synthesis and applications of electrophilic fluorination reagents are now available. Here only the most important of these reagents and their use in the electrophilic fluorination of phosphonates are presented. 

Although the majority of radiopharmaceuticals labeled with fluorine-18 have been prepared using nucleophilic fluorination reactions, in a few instances the application of electrophilic fluorination reactions has proved quite suitable. The most significant limitation of electrophilic 18F-fluorinations is the relatively low specific activities (less than lOCi/mmol) commonly obtained for final products. This is a result of the fact that electrophilic 18F-fluorination reagents (perchloryl fluoride, acetyl hypofluorite, xenon difluoride, A-fluoro-zV-alkylsulfonamides, diethylaminosulfur trifluoride) are prepared in low specific activity from 18F-labeled fluorine gas, which in itself produced in a carrier-added fashion. A second drawback of electrophilic fluorination is that the maximum radiochemical yield obtainable is 50%, as only one of the two fluorine atoms in fluorine gas can end up in the product (or, for preparation of electrophilic reagents such as acetyl [18F]hypofluorite, the maximum yield of preparing the reagent from [18F]F2 is 50%). 

The ease of preparation and generality of fluorination make the [N-F] class of reagents an excellent choice for enantioselective electrophilic fluorination. Advantageously, enantioselective electrophilic fluorination was also achieved with silyl enol ethers and oxindoles as substrates using a catalytic amount of bis-cinchona alkaloids and NFSI in the presence of excess base (Scheme 44.14). Applications of these [N-F] reagents include the enantioselective syntheses of a-fluoro-a-amino acid derivatives (Scheme 44.15), a potent opener of maxi-K channels (BMS-204352, MaxiPost Xi an Unique Electronics Chemical Co., Ltd, Xi an, P.R. China), and 20-deoxy-20-fluorocamptothecin (see section 3). 

ASYMMETRIC FLUORINATION METHODS APPLICATION IN THE STEREOSELECTIVE SYNTHESIS OF FLUORINATED DRUGS Electrophilic fluorination by means of chiral [N-F] reagents... 

Ritter et ah, reported on the electrophilic fluorination of atyl stannanes mediated hy silver(i). The reaction was demonstrated to he general with respect to substrate scope and practical because it is performed using commercially available reagents. However, the major drawback for pharmaceutical applications is the use of toxic stannanes and the difficulties often encountered in removing tin residues after the reaction. The reaction conditions and scope are shown in Scheme 15.63. 

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