Nucleophile assisting leaving groups: a strategy for aliphatic 18F-fluorination.
A series of arylsulfonate nucleophile assisting leaving groups (NALGs) were prepared in which the metal chelating unit is attached to the aryl ring via an ether linker. These NALGs exhibited significant rate enhancements in halogenation reactions using metal halides. Studies with a NALG containing a macrocyclic ether unit suggest that rate enhancements of these nucleophilic halogenation reactions are facilitated by stabilization of charge in the transition state rather than through strong precomplexation with metal cation. In several cases, a primary substrate containing one of the new leaving groups rivaled or surpassed the reactivity of triflates when exposed to nucleophile but was otherwise highly stable and isolable. These and previously disclosed chelating leaving groups were used in (18)F-fluorination reactions using no-carrier-added [18F]fluoride ion (t(1/2) = 109.7 min, beta+ = 97%) in CH3CN. Under microwave irradiation and without the assistance of a cryptand, such as K2.2.2, primary substrates with select NALGs led to a substantial improvement (2-3-fold) in radiofluorination yields over traditional leaving groups.
Lu
Shuiyu
S
Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1003, USA. shuiyu.lu@mail.nih.gov
Lepore
Salvatore D
SD
Li
Song Ye
SY
Mondal
Deboprosad
D
Cohn
Pamela C
PC
Bhunia
Anjan K
AK
Pike
Victor W
VW
D001190:Arylsulfonates / Q000737:chemistry*; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006845:Hydrocarbons, Fluorinated / Q000138:chemical synthesis* / Q000737:chemistry; D007553:Isotope Labeling; D015394:Molecular Structure
D001190:Arylsulfonates; D005462:Fluorine Radioisotopes; D006845:Hydrocarbons, Fluorinated